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Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulatory landscape
Abstract
Liposomes were the first nanoscale drug to be approved for clinical use in 1995. Since then, the technology has grown considerably, and pioneering recent work in liposome-based delivery systems has brought about remarkable developments with significant clinical implications. This includes long-circulating liposomes, stimuli-responsive liposomes, nebulized liposomes, elastic liposomes for topical, oral and transdermal delivery and covalent lipid-drug complexes for improved drug plasma membrane crossing and targeting to specific organelles. While the regulatory bodies’ opinion on liposomes is well-documented, current guidance that address new delivery systems are not. This review describes, in depth, the current state-of-the-art of these new liposomal delivery systems and provides a critical overview of the current regulatory landscape surrounding commercialization efforts of higher-level complexity systems, the expected requirements and the hurdles faced by companies seeking to bring novel liposome-based systems for clinical use to market.
... The specificity test was to guarantee that CAP was reliably determined, eliminating the possibility of false-positive results due to encapsulation of CAP in liposomes and constituents of the matrix used in the test or due to the decomposition-derived elements, as shown in Figure 1, chromatograms of CAP standard, and control blank sample, of PBS, the retention time was 3.22 and 2.76 min of CAP and PBS, respectively. The mean ± SD particle size, PDI, zeta potential and EE of all formulations are given in Table 1 and are within the range of nanoliposomes optimum formulation [28,29], where the minimum recorded data of particle size, PDI, zeta potential and %EE was 94.57, 0.05, −17.50 and 13.54%, respectively, and maximum recorded data of particle size, PDI, zeta potential and EE were 149.00, 0.19, −11.50, and 32.10%, respectively. ...
... The TEM study reveals that CAP-loaded nanoliposomes F2 has been done and data The mean ± SD particle size, PDI, zeta potential and EE of all formulations are given in Table 1 and are within the range of nanoliposomes optimum formulation [28,29], where the minimum recorded data of particle size, PDI, zeta potential and %EE was 94.57, 0.05, −17.50 and 13.54%, respectively, and maximum recorded data of particle size, PDI, zeta potential and EE were 149.00, 0.19, −11.50, and 32.10%, respectively. ...
... Effect of Capsaicin Amount on Particle Size, PDI, Zeta Potential, %EE and %DL The mean ± SD particle size, PDI, and zeta potential of all formulations are given in Table 2. All data are within the range of nanoliposomes optimum formulation [28,29]. ...
Abstract: Background: Medicinal plants have proven their value as a source of molecules with therapeutic potential, and recent studies have shown that capsaicin has profound anticancer effects in several types of human cancers. However, its clinical use is handicapped due to its poor pharmacokinetics. This study aims to enhance capsaicin's pharmacokinetic properties by loading the molecule into nanoliposomes model and testing its anticancer activity. Methods: Nanoliposomes were prepared using the thin-film method, and characteristics were examined followed by qualitative and quantitative analyses of encapsulation efficiency and drug loading using HPLC at different lipid/capsaicin ratios. Cell viability assay (MTT) was used to determine IC 50. Results: Capsaicin-loaded nanoliposomes showed optimum characteristics of morphology, particle size, zeta potential, and stability. In vitro anticancer activity of capsaicin and capsaicin-loaded nanoliposomes were compared against MCF7, MDA-MB-231, K562, PANC1, and A375 cell lines. Capsaicin-loaded nanoliposomes showed significant improvement in anticancer activity against cancers cell lines studied (p < 0.001), with increased selectivity against cancer cells compared to capsaicin. Conclusion: The encapsulated capsaicin nanoliposomes produced an improvement in pharmacokinetics properties, enhancing the anticancer activity and selectivity compared with capsaicin. This model seems to offer a potential for developing capsaicin formulations for the prevention and treatment of cancer.
Citation: Al-Samydai, A.; Alshaer, W.; Al-Dujaili, E.A.S.; Azzam, H.; Aburjai, T. Preparation, Characterization, and Anticancer Effects of Capsaicin-Loaded Nanoliposomes. Nutrients 2021, 13, 3995. https://doi.org/10.3390/ nu13113995
... (Dai et al., 2017) Preparation and optimization of curcumin-loaded PLA nanofibers. the target site (Zylberberg and Matosevic, 2016). Madecassoside is an herbal skin-care ingredient that can be derived from Centella asiatica. ...
... In addition, transfersomes have high elasticity properties due to the incorporation of elasticity-imparting substances on the outer surface. The high elasticity of the vesicles improves the transport of herbal drugs across the skin as well as increases the rate of absorption in the progress of wound healing (Zylberberg and Matosevic, 2016). ...
... Ethanol in ethosomes interacts with the lipid molecules of hydrophilic head regions of the bilayer and hence improves the membrane fluidity and permeability. Due to this interaction, herbal drugs can be easily penetrated and released into the skin layers to provide therapeutic actions (Zylberberg and Matosevic, 2016). For example, ethosomal formulation of curcumin could be formulated as an effective dermal delivery to provide enhanced wound healing and antibacterial activities. ...
Management of chronic wound has an immense impact on social and economic conditions in the world. Healthcare costs, aging population, physical trauma, and comorbidities of diabetes and obesity seem to be the major factors of this increasing incidence of chronic wounds. Conditions of chronic wound could not restore functional epidermis; thus, delaying the closure of the wound opening in an expected manner. Failures in restoration of skin integrity delay healing due to changes in skin pathology, such as chronic ulceration or nonhealing. The role of different traditional medicines has been explored for use in the healing of cutaneous wounds, where several phytochemicals, such as flavonoids, alkaloids, phenolic acids, tannins are known to provide potential wound healing properties. However, the delivery of plant-based therapeutics could be improved by the novel platform of nanotechnology. Thus, the objectives of novel delivery strategies of principal bioactive from plant sources are to accelerate the wound healing process, avoid wound complications and enhance patient compliance. Therefore, the opportunities of nanotechnology-based drug delivery of natural wound healing therapeutics have been included in the present discussion with special emphasis on nanofibers, vesicular structures, nanoparticles, nanoemulsion, and nanogels.
... The mean±SD particle size, PDI, zeta potential and EE of the all formulations are given in Table 7and are within the range of nanoliposomes optimum formulation (Zylberberg et al., 2016;Danaei et al., 2018), where the minimum recorded data of particle size, PDI, zeta potential and EE% was 94.57, 0.05, -17.50 and 13.54% ...
... The mean±SD particle size, PDI, and zeta potential of the all formulations are given in Table 9,all data are within the range of nanoliposomes optimum formulation (Zylberberg et al., 2016;Danaei et al., 2018). The results showed, that the average size, PDI and Zeta potential of nanolipasmes for the five formulas (F2,F4,F5,F6, and F7) were not significant differences with P value 0.328, 0.522 and 0.488; respectively, which mean that CAP amount had no impact on particle size, PDI and Zeta potential. ...
... The mean±SD particle size, PDI, and zeta potential of formula F2 during stability study period were given in Table 11, all data are within the range of nanoliposomes optimum formulation (Zylberberg et al., 2016;Danaei et al., 2018), where the Minimum recorded data of particle size, PDI, and zeta potential was 98.01, 0.09, and-17.5 respectively, and maximum recorded data of particle size, PDI, and zeta potential was 179.30, 0.37, and -6.68 respectively. ...
Cancer is the second leading cause of death globally. Cancer resistance become a global crisis, as there is no magic treatment till now.
Medicinal plants have proven, historically, their value as a source of molecules with therapeutic potential, scientific and research interest is drawing its attention towards naturally-derived compounds in cancer therapy as they are considered to have less toxic side effects compared to current treatments such as chemotherapy, radiotherapy and chemically derived drugs.
Recent studies have shown that Capsaicin has profound anticancer effects in several types of human cancers, while Capsaicin's clinical use is handicapped due to its pharmacokinetics.
This study aim to optimized methods of isolation and purification of Capsaicin from Capsicum annuum growing in Jordan then enhances Capsaicin's pharmacokinetic properties by loaded in nanoliposomes model, then anticancer and anti-inflammatory activity test.
Methods of extraction have been optimized using different solvents polarity, qualitative and quantitative analysis of Capsaicin was made using thin-layer chromatography (TLC). High-Performance Liquid Chromatography (HPLC), Capsaicin identification was made by 1H and 13C NMR. Moreover, to optimized the pharmacokinetic properties of Capsaicin, it was loaded into nanocarriers (nano-Liposomes).
Nanoliposomes were prepared using a thin-film method. The nanoliposomes characteristics were investigated by observing morphology, analysis of particle size, zeta potential, and stability. Additionally, qualitative and quantitative analyses of encapsulation efficiency and drug loading were performed using HPLC at different lipid ratio/Capsaicin amounts.
In vitro anticancer activity of Capsicum annuum crude extract, Capsaicin and Capsaicin loaded nanoliposomes were assessed against MCF7, MDA-MB-231, K562, PANC1, and A375 cancers cell lines, where Cell viability (MTT) assay was used to determine IC50. Moreover, anti-inflammatory of Capsaicin loaded nanoliposomes against MDA-MB-231 cancer cells was investigated. The inflammatory cytokines were quantified using Cytometric Beads Array (CBA) Human Inflammatory Cytokines Kit (Biosciences, USA).
Our results showed that this study's extraction method of Capsaicin from Capsicum annuum was fast, simple, low cost, and reproducible. Moreover, our results showed the significant impact of solvents polarity on Capsaicin yield and purity of crude extract.
Capsaicin loaded nanoliposomes showed optimum characteristics of morphology, particle size, zeta potential, and stability. Furthermore, Capsaicin loaded nanoliposomes showed significant improvement in anticancer activity against, (MCF7, MDA-MB-231, K562, PANC1, and A375) cancers cell lines, and increase the selectivity of Capsaicin loaded nanoliposomes against cancer cells compared to Capsaicin.
Additionally, Anti-inflammatory activity of Capsaicin Loaded-nano liposomes showed a noticeable reduction in the production of IL-6 and IL-8 in comparison with untreated cell; this novel formula could reduce MDA-MB-231 tumor cell density and cell migration As there is a notable relationship between MDA-MB-231 tumor cell density and cell migration, and IL-6 and IL-8 production.
In conclusion, Capsaicin's isolation and purification from Capsicum annuum growing in Jordan optimized, the encapsulated Capsaicin in nanoliposomes showed significant improvement in pharmacokinetics properties and enhancement the anticancer activity and selectivity comparing with Capsaicin. This model could open a door for developing Capsaicin as the prevention and treatment of cancer.
... The specificity test was to guarantee that CAP was reliably determined, eliminating the possibility of false-positive results due to encapsulation of CAP in liposomes and constituents of the matrix used in the test or due to the decomposition-derived elements, as shown in Figure 1, chromatograms of CAP standard, and control blank sample, of PBS, the retention time was 3.22 and 2.76 min of CAP and PBS, respectively. The mean ± SD particle size, PDI, zeta potential and EE of all formulations are given in Table 1 and are within the range of nanoliposomes optimum formulation [28,29], where the minimum recorded data of particle size, PDI, zeta potential and %EE was 94.57, 0.05, −17.50 and 13.54%, respectively, and maximum recorded data of particle size, PDI, zeta potential and EE were 149.00, 0.19, −11.50, and 32.10%, respectively. ...
... The TEM study reveals that CAP-loaded nanoliposomes F2 has been done and data The mean ± SD particle size, PDI, zeta potential and EE of all formulations are given in Table 1 and are within the range of nanoliposomes optimum formulation [28,29], where the minimum recorded data of particle size, PDI, zeta potential and %EE was 94.57, 0.05, −17.50 and 13.54%, respectively, and maximum recorded data of particle size, PDI, zeta potential and EE were 149.00, 0.19, −11.50, and 32.10%, respectively. ...
... Effect of Capsaicin Amount on Particle Size, PDI, Zeta Potential, %EE and %DL The mean ± SD particle size, PDI, and zeta potential of all formulations are given in Table 2. All data are within the range of nanoliposomes optimum formulation [28,29]. ...
Background: Medicinal plants have proven their value as a source of molecules with
therapeutic potential, and recent studies have shown that capsaicin has profound anticancer effects
in several types of human cancers. However, its clinical use is handicapped due to its poor pharmacokinetics. This study aims to enhance capsaicin’s pharmacokinetic properties by loading the
molecule into nanoliposomes model and testing its anticancer activity. Methods: Nanoliposomes
were prepared using the thin-film method, and characteristics were examined followed by qualitative
and quantitative analyses of encapsulation efficiency and drug loading using HPLC at different
lipid/capsaicin ratios. Cell viability assay (MTT) was used to determine IC50. Results: Capsaicinloaded nanoliposomes showed optimum characteristics of morphology, particle size, zeta potential,
and stability. In vitro anticancer activity of capsaicin and capsaicin-loaded nanoliposomes were
compared against MCF7, MDA-MB-231, K562, PANC1, and A375 cell lines. Capsaicin-loaded nanoliposomes showed significant improvement in anticancer activity against cancers cell lines studied
(p < 0.001), with increased selectivity against cancer cells compared to capsaicin. Conclusion: The
encapsulated capsaicin nanoliposomes produced an improvement in pharmacokinetics properties,
enhancing the anticancer activity and selectivity compared with capsaicin. This model seems to offer
a potential for developing capsaicin formulations for the prevention and treatment of cancer.
... A polyethylene glycol (PEG) is predominantly employed as a non-toxic, non-ionic, biocompatible molecule for PEG modification, so-called PEGylation [66]. PEGylation protects liposomes from immune-mediated clearance and confers higher stability, which leads to prolonged circulation of the PEGylated liposomes in the organism [70]. A coating of the liposomes with glycoproteins, oligosaccharides, and polysaccharides was also studied with the aim to prevent the liposomal blood clearance [71]. ...
... A polyethylene glycol (PEG) is predominantly employed as a nontoxic, non-ionic, biocompatible molecule for PEG modification, so-called PEGylation [66]. PEGylation protects liposomes from immune-mediated clearance and confers higher stability, which leads to prolonged circulation of the PEGylated liposomes in the organism [70]. A coating of the liposomes with glycoproteins, oligosaccharides, and polysaccharides was also studied with the aim to prevent the liposomal blood clearance [71]. ...
Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) 131I-tositumomab and 90Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody–drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of “old” cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies.
... The entrapment of both hydrophilic and hydrophobic drugs, the controllability of liposome size and their feasibility for modification are also of high importance (Akbarzadeh et al., 2013;Daraee et al., 2016). Concerning the transdermal administration, the most important advantage of these formulations is their similarity to the lipid composition of stratum corneum (SC) which allows them to penetrate deeper in the epidermis for an improved drug absorption and increased final efficacy (De Leeuw et al., 2009;Zylberberg and Matosevic, 2016). ...
... They are composed of phospholipids and surfactants (sodium cholate, sodium deoxycholate, Span-60, Span-65, Span-80, Tween-20, Tween-60, Tween-80 or dipotassium glycyrrhizinate) (Karande and Mitragotri, 2009). These surfactants act as edge activators, by squeezing through the channels of SC, possessing a high radius of curvature and thus disrupt the lipid organization in the SC (Zylberberg and Matosevic, 2016). The method of preparation, as well as the type and amount of surfactants, affect the properties of transferosomes. ...
Transdermal administration has gained much attention due to their remarkable advantages such as patient compliance, drug escape from first-pass elimination, favorable pharmacokinetic profile and prolonged release properties. However, the major limitation of these systems is the limited skin penetration of the stratum corneum, the skin’s most important barrier, which protects the body from the insertion of substances from the environment. Transdermal drug delivery systems are aiming to the disruption of the stratum corneum in order for the active pharmaceutical ingredients to enter successfully the circulation. Therefore, nanoparticles are holding a great promise because they can act as effective penetration enhancers due to their small size and other physicochemical properties that will be analyzed thoroughly in this report. Apart from the investigation of the physicochemical parameters, a comparison between the different types of nanoparticles will be performed. The complexity of skin anatomy and the unclear mechanisms of penetration should be taken into consideration to reach some realistic conclusions regarding the way that the described parameters affect the skin permeability. To the best of the authors knowledge, this is among the few reports on the literature describing the technology of transdermal delivery systems and how this technology affects the biological activity.
... The role of drug transporters raised much interest in the pharmaceutical [1], medical [2], and engineering fields [3], especially to improve drug bioavailability and efficacy for target cells [4]. Drug Carriers (DC) have always been considered as transporters of molecules, improving and preserving their properties during administration [5][6][7][8]. ...
Carriers are protective transporters of drugs to target cells, facilitating therapy under each points of view, such as fast healing, reducing infective phenomena, and curing illnesses while avoiding side effects. Over the last 60 years, several scientists have studied drug carrier properties, trying to adapt them to the release environment. Drug/Carrier interaction phenomena have been deeply studied, and the release kinetics have been modeled according to the occurring phenomena involved in the system. It is not easy to define models’ advantages and disadvantages, since each of them may fit in a specific situation, considering material interactions, diffusion and erosion phenomena, and, no less important, the behavior of receiving medium. This work represents a critical review on main mathematical models concerning their dependency on physical, chemical, empirical, or semi-empirical variables. A quantitative representation of release profiles has been shown for the most representative models. A final critical comment on the applicability of these models has been presented at the end. A mathematical approach to this topic may help students and researchers approach the wide panorama of models that exist in literature and have been optimized over time. This models list could be of practical inspiration for the development of researchers’ own new models or for the application of proper modifications, with the introduction of new variable dependency.
... Many attempts have been made to solve the above problems by designing multidrug nanoscale delivery Graphical Abstract systems, such as those incorporating nanosized transition metals, liposomes, polymers, and exosomes [20][21][22]. Photothermal therapy using nanoparticles to transduce near-infrared laser radiation into local heat to kill tumor cells has the advantages of minimal invasiveness, high efficiency, few adverse reactions and effective tumor metastasis inhibition [23,24]. Exosomes, as nanoscale membrane particles secreted by cells, can carry a substantial number of drugs and achieve efficient cancer theranostics through surface modification [25,26]. ...
Exosomes are nanoscale monolayer membrane vesicles that are actively endogenously secreted by mammalian cells. Currently, multifunctional exosomes with tumor-targeted imaging and therapeutic potential have aroused widespread interest in cancer research. Herein, we developed a multifunctional HEK-293T exosome-based targeted delivery platform by engineering HEK-293T cells to express a well-characterized exosomal membrane protein (Lamp2b) fused to the αv integrin-specific iRGD peptide and tyrosine fragments. This platform was loaded with doxorubicin (Dox) and labeled with radioiodine-131 ( ¹³¹ I) using the chloramine-T method. iRGD exosomes showed highly efficient targeting and Dox delivery to integrin αvβ3-positive anaplastic thyroid carcinoma (ATC) cells as demonstrated by confocal imaging and flow cytometry in vitro and an excellent tumor-targeting capacity confirmed by single-photon emission computed tomography-computed tomography after labeling with ¹³¹ I in vivo. In addition, intravenous injection of this vehicle delivered Dox and ¹³¹ I specifically to tumor tissues, leading to significant tumor growth inhibition in an 8505C xenograft mouse model, while showing biosafety and no side effects. These as-developed multifunctional exosomes (denoted as Dox@iRGD-Exos- ¹³¹ I) provide novel insight into the current treatment of ATC and hold great potential for improving therapeutic efficacy against a wide range of integrin αvβ3-overexpressing tumors.
Graphical Abstract
... Examples of manufacturing process parameters which have been shown to influence liposome stability and drug encapsulation and release kinetics in large-scale production techniques are shear force, pressure, pH, temperature, lyophilization, as well as sterilization parameters [103], especially in the case of sterile filtration, where components can interact with the filtering membrane or matrix, which can in turn compromise the integrity and structure of the liposomes [104]. While the preparation, characterization and clinical applicability of liposomes have been described in detail elsewhere [91,[105][106][107] a brief description of conventional and large-scale production methods for liposomes is given below, alongside with a short discussion over the existent production methods for TMZ-loaded lipid nanovehicles. ...
Glioblastoma (GBM) is a lethal brain cancer with a very difficult therapeutic approach and ultimately frustrating results. Currently, therapeutic success is mainly limited by the high degree of genetic and phenotypic heterogeneity, the blood brain barrier (BBB), as well as increased drug resistance. Temozolomide (TMZ), a monofunctional alkylating agent, is the first line chemotherapeutic drug for GBM treatment. Yet, the therapeutic efficacy of TMZ suffers from its inability to cross the BBB and very short half-life (~2 h), which requires high doses of this drug for a proper therapeutic effect. Encapsulation in a (nano)carrier is a promising strategy to effectively improve the therapeutic effect of TMZ against GBM. Although research on liposomes as carriers for therapeutic agents is still at an early stage, their integration in GBM treatment has a great potential to advance understanding and treating this disease. In this review, we provide a critical discussion on the preparation methods and physico-chemical properties of liposomes, with a particular emphasis on TMZ-liposomal formulations targeting GBM developed within the last decade. Furthermore, an overview on liposome-based formulations applied to translational oncology and clinical trials formulations in GBM treatment is provided. We emphasize that despite many years of intense research, more careful investigations are still needed to solve the main issues related to the manufacture of reproducible liposomal TMZ formulations for guaranteed translation to the market.
... Liposomes can entrap lipophilic drugs within the lipid membrane, hydrophilic agents in their internal aqueous compartment, or amphiphilic ones at the water-lipid interface [125]. These carriers are biodegradable, biocompatible, and non-immunogenic [126]. Since liposomes mimic natural membranes, their use in topical applications is generally favorable [127]. ...
La cystéamine, un aminothiol synthétisé par les cellules du corps humain, possède plusieurs activités biologiques notamment un effet radioprotectif et anticancéreux. Elle est connue pour son utilisation dans le traitement de la cystinose, des maladies de Parkinson et de Huntington. Cette molécule a aussi un effet dépigmentant et existe sous différentes formes comme le chlorhydrate de cystéamine. Malgré ses nombreux effets bénéfiques, la cystéamine est hygroscopique, présente des propriétés organoleptiques et un profil pharmacocinétique défavorables. C’est une molécule instable en solution car elle s’oxyde pour former la cystamine. Pour surmonter ces limites, nous avons choisi de développer des formulations de liposomes encapsulant respectivement les deux formes de la molécule (cystéamine et chlorhydrate de cystéamine) dans le but de l’appliquer sur la peau en tant qu’agent dépigmentant. Les suspensions liposomales ont été caractérisées par la distribution en taille des liposomes et le taux d’encapsulation des deux formes de cystéamine pour différentes compositions. Le dosage simultané de la cystéamine et la cystamine par la méthode de chromatographie par paires d’ions a été mis au point. La stabilité de la cystéamine et du chlorhydrate de cystéamine dans les suspensions liposomiales a été ensuite étudiée pour différentes conditions de stockage. Nous avons aussi eu recours à la lyophilisation des suspensions liposomiales pour augmenter la stabilité des formulations au cours de stockage. La caractérisation de la forme lyophilisée après stockage a été évaluée. Les liposomes blancs et encapsulant la cystéamine et le chlorhydrate de cystéamine étaient de taille nanométriques et monodisperses. Des faible taux d’encapsulation ont été obtenus en raison du caractère hydrophile des deux formes de la molécule. La stabilité des deux formes de la cystéamine a augmenté après encapsulation et d’autant plus après lyophilisation des échantillons. Le test de cytotoxicité par MTT, le dosage de la mélanine, l’activité de la tyrosinase ainsi que la pénétration cutanée par cellule de Franz ont été appliqués pour le chlorhydrate de cystéamine libre et encapsulé. Ces tests ont montré que les formulations choisies ne présentaient pas de cytotoxicité vis-à-vis de la lignée cellulaire de mélanome de souris B16. Le chlorhydrate de cystéamine et la cystamine ont inhibé la production de la mélanine et la tyrosinase. L’encapsulation du chlorhydrate de cystéamine a diminué légèrement l’effet de cette inhibition mais a augmenté la pénétration de la molécule dans la peau et sa rétention au niveau de l’épiderme. Toutefois, la cystamine n’a pas pénétré et n’a pas été détectée dans aucun compartiment de la peau
... Additionally, a similar chemical composition also forms the basis for the development and stability of most synthetically formulated nanoparticles, such as liposomes (Siontorou et al., 2017;C. Yang et al., 2018;Zylberberg and Matosevic, 2016). However, PDNPs have been investigated to be devoid of any cholesterol. ...
Background: The advent of nanomaterials has brought about a paradigm shift in the diagnosis, treatment, and prevention of various chronic diseases and cancer is no exception. While these nanoparticles are highly effective, they come with their own set of perils and caveats. These concerns form the basis for numerous scientific investigations for the development of nanomedicines. This article aims to review various Plant-derived edible Nanoparticles (PDNPs) for the management of symptoms associated with various tumors and cancers.
Methods: To provide context and evidence, the relevant publications were identified on Google Scholar, PubMed, and Science-Direct using keywords such as plant-derived nanovesicles, plant-derived nanoparticles, cancer, tumors, and nanotechnology. Results: On several grounds, the Plant-derived edible Nanoparticles (PDNPs) have demonstrated great potential against various tumors and cancers, owing to their exceptional properties. These properties include their safety profile, high stability, low immunogenicity, easy and rapid internalization by mammalian cells, and mass- production capacity. These PDNPs were also studied to present potent anti- inflammatory, anti-proliferative, regenerative, and immune modulatory properties, and are stable in the gastrointestinal tract upon oral administration.
Conclusions: This article aims to critically review various PDNPs that have been studied over the years and to demonstrate their promising role in managing and alleviating the symptoms associated with cancers. However, more conclusive evidence is recommended from various preclinical and clinical studies to corroborate their safety, efficacy, and toxicity profiles in various patient cohorts, before establishing it as a novel drug delivery modality.
... The lipid bilayer vesicle resembles the lipid bilayer and offers a large capacity for intravesicular drug loading. 11,12 Different types of liposomes have been developed, ranging from conventional liposomes, hydrophilic polymer coated liposomes to ligand-targeted liposomes. 13,14 Deoxycholic acid (DCA) is a secondary bile acid, which can bind to a Gcoupled protein receptor, TGR5 (or GP-BAR1, or M-BAR) located on CCA cells. ...
Cholangiocarcinoma (CCA), a bile duct cancer, is a significant health problem in Thailand. The major obstacle in CCA treatment is having no effective therapeutic regimen, particularly for late-stage disease. The potent effects of curcumin on CCA have previously been documented, but the application of curcumin has been limited by its solubility and stability. Therefore, this study used liposomes, a well-known drug delivery vehicle, to transport curcumin for enhancing its efficacy. Deoxycholic acid (DCA), a secondary bile acid that has its receptors located on bile duct cells, was selected for the preparation of liposome-mediated curcumin delivery by the thin-film hydration method. The efficacy of DCA-formulated curcumin-containing liposomes (dLip/Cur) on two CCA cells, KKU-213A and KKU-213B, were compared with curcumin-containing liposomes (Lip/Cur) and curcumin alone by determinations of cell proliferation and apoptosis. The results demonstrate that IC50s of dLip/Cur in CCA cell lines were lower than those of other regimens. The growth inhibitory effect of dLip/Cur was partly due to the promotion of caspase-dependent apoptosis. Altogether, the usefulness of DCA-formulated liposomes as an anti-cancer delivery system for CCA treatment is suggested herein. It might be useful as a novel vehicle for CCA treatment in the future.
... Besides mimicking important aspects of cellular membrane permeability, 20 GUVs are also potential drug carriers. 21 Controlling the permeability of GUVs membrane by physical non-invasive methods, such as an ultrasound pulse prompted by the pulsed irradiation of piezophotonic materials, may allow the non-invasive unloading of hydrophilic macromolecules from the GUVs aqueous pool, with important implications in drug delivery. Recently, efficient release of FITC-dextran from GUVs core was promoted by ultrasound pulses without damaging the phospholipid bilayer. ...
... Liposomes are considered to be one of the most studied nanoparticles [49]. Liposomes are vesicular systems composed of one or more phospholipid bilayer surrounding an inner aqueous space [50]. ...
Liver cancer is considered one of the deadliest diseases with one of the highest disease burdens worldwide. Among the different types of liver cancer, hepatocellular carcinoma is considered to be the most common type. Multiple conventional approaches are being used in treating hepatocellular carcinoma. Focusing on drug treatment, regular agents in conventional forms fail to achieve the intended clinical outcomes. In order to improve the treatment outcomes, utilizing nanoparticles—specifically lipid based nanoparticles—are considered to be one of the most promising approaches being set in motion. Multiple forms of lipid based nanoparticles exist including liposomes, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, phytosomes, lipid coated nanoparticles, and nanoassemblies. Multiple approaches are used to enhance the tumor uptake as well tumor specificity such as intratumoral injection, passive targeting, active targeting, and stimuli responsive nanoparticles. In this review, the effect of utilizing lipidic nanoparticles is being discussed as well as the different tumor uptake enhancement techniques used.
Graphical Abstract
... Liposomes are the first nano-scale platforms that were approved for clinical applications. They consist of a phospholipid bilayer membrane and an aqueous core that can carry both hydrophilic and hydrophobic drugs [100]. As a result of the use of natural phospholipids in the preparation of liposomes, they are pharmacologically inactive and have minimal toxicity, thus are biocompatible [101]. ...
Gastric cancer (GC) results from deregulated cell growth in the stomach. Despite significant efforts and recent advancements in the treatment of gastric cancer, it remains a life-threatening disease. This is in part due to the chemotherapy failure resulting from multi-drug resistance (MDR) in the associated Gastric cancer cells (GCC). These cells can acquire MDR through different mechanisms. Perhaps the most important mechanism would be the increased drug efflux by ATP-binding cassette (ABC) transporters, which reduces the intracellular concentration of the chemotherapy drugs. Recently, nanoparticle-based drug delivery systems (nano-DDS) have been emerged to reverse MDR by altering the mechanisms through which the drugs may function. Nano-DDSs are also highly regarded because of their potential to enhance the pharmacological profile of chemotherapy drugs, improving drug solubility, and decrease their adverse effects. This review summarizes known factors that are involved in the MDR of GCC. Additionally, we will describe the application of nano-DDSs to reverse MDR in GCC.
... Decades of research have resulted in a variety of liposomal formulations for use in both therapeutic [1][2][3] and theranostic [4][5][6] applications. Advances in synthesis procedure and membrane functionalization have led to targeting and stealth capabilities, which can increase bioavailability at disease sites several fold with minimal side effects, compared to systemically administered drugs [7,8]. These improvements have in turn led to the FDA approval and commercial use of several liposomal drugs, including Doxil ® for cancer [9], Abelcet ® for fungal infections [10], and DepoDur ® for pain management [11], and more recent Moderna/Pfizer vaccines for Covid-19 [12]. ...
The wide-scale use of liposomal delivery systems is challenged by difficulties in obtaining potent liposomal suspensions. Passive and active loading strategies have been proposed to formulate drug encapsulated liposomes but are limited by low efficiencies (passive) or high drug specificities (active). Here, we present an efficient and universal loading strategy for synthesizing therapeutic liposomes. Integrating a thermal equilibration technique with our unique liposome synthesis approach, co-loaded targeting nanovesicles can be engineered in a scalable manner with potencies 200-fold higher than typical passive encapsulation techniques. We demonstrate this capability through simultaneous co-loading of hydrophilic and hydrophobic small molecules and targeted delivery of liposomal Doxorubicin to metastatic breast cancer cell line MDA-MB-231. Molecular dynamic simulations are used to explain interactions between Doxorubicin and liposome membrane during thermal equilibration. By addressing the existing challenges, we have developed an unparalleled approach that will facilitate the formulation of novel theranostic and pharmaceutical strategies.
... Liposomes are of interest to both the biophysics and pharmaceutical science communities, as model membrane systems [1] and as delivery systems for pharmaceuticals [2]. Liposomes can be made in a variety of sizes of differing compositions and more recently asymmetric liposomes, which more closely resemble biological systems, were also characterized [3]. ...
Small-angle scattering (SAS) is a technique commonly used in the soft matter sciences to characterize the structure of molecules self-assembling in solution. As such, it is suitable to study preparations of homogeneous liposomes to extract simple structural parameters such as radius and lipid bilayer thickness in solution. Here, we describe the preparation of liposomes for small-angle neutron scattering via extrusion and present the simplest way the resulting data can be modeled.
... Indeed, the treated MPs with a lower cholesterol content were found to lack the ability to increase the endosomal pH (Fig. 4e). Liposomes are synthesized nanoparticles that are mainly composed of cholesterol [39]. However, we found that liposomes did not increase the endosomal pH of macrophages ( Supplementary Fig. 2g). ...
Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.
... This type includes liposome-based, polymer-based, and dendrimer NPs. 9 Liposome-based NPs were the first nanomedicine to be approved for clinical use. 10 Polymer-based NPs are considerably more specific for drug delivery on resistant cancer cells than liposome-based NPs. 11 Various polymerbased NPs have been used in breast cancer therapy, including lipid combinations (eg, cholesterol) to form lipo-polymeric NPs. 12 Polyethyleneimine (PEI) is a cationic polymer containing repeating units of primary amino groups and ethylene (CH 2 CH 2 ). ...
Cancer has become one of the leading causes of morbidity and mortality worldwide. This disease is classified broadly by tissue, organ, and system; different cancer types and subtypes require different treatments. Drug bioavailability, selectivity, and high dosage, as well as extended treatment, are significantly associated with the development of resistance - a complex problem in cancer therapy. It is expected that the combination of anticancer drugs and drug delivery systems, using polymers to increase the access of such agents to their site of action, will improve the efficacy of therapy. Polyethyleneimine (PEI) is a polymer used as a co-delivery system for anticancer drugs and gene therapy. PEI is also useful for other purposes, such as transfection and bio-adsorbent agents. In co-delivery, PEI can promote drug internalization. However, PEI with a high molecular weight is linked to higher cytotoxicity, thus requiring further evaluation of clinical safety. This review focuses on the utilization of PEI as a co-delivery system for anticancer therapy, as well as its potential to overcome resistance, particularly in the treatment of specific subtypes (eg, breast cancer). In conclusion, PEI has promising applications and is improvable for the development of anticancer drugs.
... Liposomes are artificial lipid vesicles that can be used for the controlled release of drugs. Control of lamellarity (i.e. the number of lipid bilayers in liposomes), bilayer curvature, and surface modification allow for manipulation of liposomes characteristics [96]. Liposomes can be stimulated for drug release via endogenous entities, such as pH, redox potential, enzymatic activity, or via external stimuli, such as light and heat [97]. ...
Achieving a novel drug delivery system needs site-specificity along with dosage control. Many physical, chemical, mechanical, and biological signals are used for developing these systems, out of which light has been used predominantly in the past decade. Light responsive drug delivery systems have tremendous potential, and their exploration is crucial in developing a precise and controlled delivery system. Spatio-temporal and intensity control of light allows better manipulation of drug delivery vehicles than mechanical, chemical, and biological signals. The use of ultraviolet (UV) and near-infrared (NIR) light has helped in upgrading therapeutic functionalities, while the use of up-conversion nanoparticles (UCNPs) has delivered an extension into theranostic tools. Biomaterials incorporated with photosensitizers can readily respond to changes in light and are vital in achieving clinical success via translational research. Further, the inclusion of biological macromolecules for the transportation of drugs, genes, and proteins has seen a broader application of light-controlled systems. The key objective of this review paper is to summarize the evolution of light-activated targeted drug delivery systems and the importance of biomaterials in developing one.
... However, to achieve this goal, the carrier itself should be non-toxic, chemically stable under the in vivo and in vitro conditions, easily excreted from the body, and recognized selectively by target cells [2,17,18]. Drug carriers may be macrocyclic compounds, such as cyclodextrins, calixarenes, or cucurbiturils as well as liposomes [19][20][21][22][23][24][25]. The crown ethers and azacrown ethers as well as their derivatives also may play this role -they bind both metal ions and neutral molecules, and their wide range of applications have been described in detail in the article of Gokel et al. [26]. ...
The formation of a carrier-drug complex may enhance the biodistribution of the drug and, consequently, improve its therapeutic effect. Since the biodistribution of the tied drug strongly depends on the properties of the carrier molecule, it is advisable to determine its structural features and other physicochemical parameters. Therefore, in this work, the properties of the new potential drug carrier 1,10-N,N’-bis-(β-D\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\small{\text{D}}$$\end{document}-ureidocellobiosyl)-4,7,13-trioxa-1,10-diazacyclopentadecane (L2) were investigated using different quantum chemical methods. The most stable structures obtained from the B3LYP-GD2/6-31G(d,p) calculations have a very compact geometry due to the formation of intramolecular hydrogen bonds between the cellobiose fragments. The Mulliken charge distribution shows that L2 is strongly polar, so it is expected to bind efficiently polar molecules. The complexation ability of the host towards the polar drug paracetamol (PAR) in a stoichiometry 1:1 was investigated for various host-drug structures using the same density functional. The formation of L2:PAR is very profitable: for the most stable configuration, the complexation energy is −18.5 kcal/mol. In all structures, paracetamol is externally attached to the host, interacting mainly with the cellobiose units. The NMR chemical shifts obtained from the quantum calculations for L2 and its complex L2:PAR, are analyzed and compared with the available experimental data.
... Thus, long-circulating liposomes, also known as stealth liposomes, were developed. The liposome shell is coated with hydrophilic polymers like polyethylene glycol (PEG), resulting in decreased blood protein adsorption and prolonged circulation time (Zylberberg and Matosevic, 2016). It was reported that the dose of the PEGmodified liposomes containing antigen is an essential factor for controlling the response of mucosal and systemic immune systems in an oral vaccine. ...
Vaccinations are one of the most successful initiatives of the new era in the public health sector. Different types of vaccines are available nowadays depending on the antigen used and the methods of delivery and administration. Conventional vaccines are produced from dead, attenuated, or inactivated pathogens. The antigen activates the body’s immune system to recognize the foreign body as a threat and kill the virus in question. Antigen proteins can be administered directly, naturally, to strengthen the immune response along with the adjuvant. However, safety and efficacy remain the two main issues in conventional vaccine production. Therefore, new vaccine formulations have been introduced to target the antigen at the worksite, reduce toxicity, increase the bioavailability of active compounds, and prolong release time, thus improving therapeutic efficacy and safety. Loading the antigen into different delivery platforms such as lipid vesicles, nanoparticles, microparticles, microemulsions, virus-like particles, embedding complex agents, and cyclodextrins is a promising current vaccine strategy. The current review focused on the most recent research on vaccine delivery systems and briefly described the design and development of the COVID-19 vaccine uploaded to these carriers. This paper also discusses the current situation and future scenarios in the field of vaccine production.
... High elasticity, permeability, distribution, flexibility, steric stability, and low aggregation [245] Niosomes Non-ionic surfactant Ease of production, low production cost, high chemical stability and storage [246] Cubosomes Lipid cubic phase and coated by apolymer-based outer coating ...
Free radicals are generated as byproducts of normal metabolic processes as well as due to exposure to several environmental pollutants. They are highly reactive species, causing cellular damage and are associated with a plethora of oxidative stress-related diseases and disorders. Antioxidants can control autoxidation by interfering with free radical propagation or inhibiting free radical formation, reducing oxidative stress, improving immune function, and increasing health longevity. Antioxidant functionalized metal nanoparticles, transition metal oxides, and nanocomposites have been identified as potent nanoantioxidants. They can be formulated in monometallic, bimetallic, and multi-metallic combinations via chemical and green synthesis techniques. The intrinsic antioxidant properties of nanomaterials are dependent on their tunable configuration, physico-chemical properties, crystallinity, surface charge, particle size, surface-to-volume ratio, and surface coating. Nanoantioxidants have several advantages over conventional antioxidants, involving increased bioavailability, controlled release, and targeted delivery to the site of action. This review emphasizes the most pioneering types of nanoantioxidants such as nanoceria, silica nanoparticles, polydopamine nanoparticles, and nanocomposite-, polysaccharide-, and protein-based nanoantioxidants. This review overviews the antioxidant potential of biologically synthesized nanomaterials, which have emerged as significant alternatives due to their biocompatibility and high stability. The promising nanoencapsulation nanosystems such as solid lipid nanoparticles, nanostructured lipid carriers, and liposome nanoparticles are highlighted. The advantages, limitations, and future insights of nanoantioxidant applications are discussed.
... Liposomes are made up of an exterior lipid layer and a core that contains either hydrophobic or hydrophilic medications; they were the first nano-scale drugs to be licensed for clinical use [64]. Liposomes can be modified to perform a variety of tasks by altering the lipid layer structure; for instance, the lipid layer can be altered to mimic the biophysical properties of living cells [65], which can improve the efficiency of targeted drug delivery [66]. ...
Presently, nanocarriers (NCs) have gained huge attention for their structural ability, good biocompatibility, and biodegradability. The development of effective NCs with stimuli-responsive properties has acquired a huge interest among scientists. When developing drug delivery NCs, the fundamental goal is to tackle the delivery-related problems associated with standard chemotherapy and to carry medicines to the intended sites of action while avoiding undesirable side effects. These nanocarriers were able of delivering drugs to tumors through regulating their pH, temperature, enzyme responsiveness. With the use of nanocarriers, chemotherapeutic drugs could be supplied to tumors more accurately that can equally encapsulate and deliver them. Material carriers for chemotherapeutic medicines are discussed in this review keeping in viewpoint of the structural properties and targeting methods that make these carriers more therapeutically effective, in addition to metabolic pathways triggered by drug-loaded NCs. Largely, the development of NCs countering to endogenous and exogenous stimuli in tumor regions and understanding of mechanisms would encourage the progress for tumor therapy and precision diagnosis in future.
Graphical Abstract
... Organic NPs, like liposomes, polylactic-co-glycolic acid (PLGA) NPs, and extracellular vesicles (EVs), are known to have high drug delivery efficiency and low toxicity (36). Liposomes were the first nanomedicine approved for clinical use (37), and their application in breast cancer has been gaining popularity (38,39). Liposome has an outer lipid layer that can be modified to mimic the biophysical properties of the host cells, and a core carrying its cargo, usually chemotherapeutic agents (40,41). ...
Breast cancer remains the most common malignancy among women worldwide. Although the implementation of mammography has dramatically increased the early detection rate, conventional treatments like chemotherapy, radiation therapy, and surgery, have significantly improved the prognosis for breast cancer patients. However, about a third of treated breast cancer patients are known to suffer from disease recurrences and progression to metastasis. Immunotherapy has recently gained traction due to its ability to establish long-term immune surveillance, and response for the prevention of disease recurrence and extension of patient survival. Current research findings have revealed that gold nanoparticles can enhance the safety and efficacy of cancer immunotherapy, through their unique intrinsic properties of good biocompatibility, durability, convenient surface modification, as well as enhanced permeability and retention effect. Gold nanoparticles are also able to induce innate immune responses through the process of immunogenic cell death, which can lead to the establishment of lasting adaptive immunity. As such gold nanoparticles are considered as good candidates for next generation immunotherapeutic strategies. This mini review gives an overview of gold nanoparticles and their potential applications in breast cancer immunotherapeutic strategies.
... TNF-α small interfering RNA Short half-life, deprived extravasation from blood vessels to target cells, low cellular uptake PEGylated solid-lipid nanoparticles Encapsulation efficiency more than 90%, precise targeting to inflamed sites in a mouse model, declined bone loss, [30] The foremost hindrance in designing a drug transporter is the burst release of the payload before reaching the targeted site [31]. Undoubtedly, these lipid-based delivery systems have many advantages; still, the biggest challenge is the successful loading of drugs without wasting any fraction and keeping them intact [32]. The right selection of the type of drug carrier with the best fit composition can keep the entrapped drug molecule stable for more than 6 months, which otherwise may deteriorate in 30 days when available in solution form [33]. ...
Bone metastasis has been considered the fatal phase of cancers, which remains incurable and to be a challenge due to the non-availability of the ideal treatment strategy. Unlike bone cancer, bone metastasis involves the spreading of the tumor cells to the bones from different origins. Bone metastasis generally originates from breast and prostate cancers. The possibility of bone metastasis is highly attributable to its physiological milieu susceptible to tumor growth. The treatment of bone-related diseases has multiple complications, including bone breakage, reduced quality of life, spinal cord or nerve compression, and pain. However, anticancer active agents have failed to maintain desired therapeutic concentrations at the target site; hence, uptake of the drug takes place at a non-target site responsible for the toxicity at the cellular level. Interestingly, lipid-based drug delivery systems have become the center of interest for researchers, thanks to their biocompatible and bio-mimetic nature. These systems possess a great potential to improve precise bone targeting without affecting healthy tissues. The lipid nano-sized systems are not only limited to delivering active agents but also genes/peptide sequences/siRNA, bisphosphonates, etc. Additionally, lipid coating of inorganic nanomaterials such as calcium phosphate is an effective approach against uncontrollable rapid precipitation resulting in reduced colloidal stability and dispersity. This review summarizes the numerous aspects, including development, design, possible applications, challenges, and future perspective of lipid nano-transporters, namely liposomes, exosomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and lipid nanoparticulate gels to treat bone metastasis and induce bone regeneration. Additionally, the economic suitability of these systems has been discussed and different alternatives have been discussed. All in all, through this review we will try to understand how far nanomedicine is from clinical and industrial applications in bone metastasis.
... This means that liposomes have better drug distribution and lower systemic toxicity (Park, 2002). These properties make them the most versatile nanocarriers (Bamrungsap et al., 2012;Majzoub and Ewert, 2016;Zylberberg and Matosevic, 2016). Nanoparticles are usually composed of phospholipids and can form unilamellar and multilamellar liposome structures, allowing the transport and delivery of lipophilic, hydrophilic, and hydrophobic drugs and can expand their use by capturing lipophilic and hydrophilic compounds in the same system (Sarfraz et al., 2018). ...
The placenta plays a significant role during pregnancy. Placental dysfunction contributes to major obstetric complications, such as fetal growth restriction and preeclampsia. Currently, there is no effective treatment for placental dysfunction in the perinatal period, and prophylaxis is often delivered too late, at which point the disease manifestation cannot be prevented. However, with recent integration of nanoscience and medicine to perform elaborate experiments on the human placenta, it is expected that novel and efficient nanotherapies will be developed to resolve the challenge of managing placental dysfunction. The advent of nanomedicine has enabled the safe and targeted delivery of drugs using nanoparticles. These smart nanoparticles can load the necessary therapeutic substances that specifically target the placenta, such as drugs, targeting molecules, and ligands. Packaging multifunctional molecules into specific delivery systems with high targeting ability, diagnosis, and treatment has emerged as a novel theragnostic (both therapeutic and diagnostic) approach. In this review, the authors discuss recent advances in nanotechnology for placental dysfunction treatment. In particular, the authors highlight potential candidate nanoparticle-loaded molecules that target the placenta to improve utero-placental blood flow, and reduce reactive oxygen species and oxidative stress. The authors intend to provide basic insight and understanding of placental dysfunction, potential delivery targets, and recent research on placenta-targeted nanoparticle delivery systems for the potential treatment of placental dysfunction. The authors hope that this review will sensitize the reader for continued exploration of novel nanomedicines.
... The FDA has currently authorized liposome-based systems. (Sercombe et al., 2015, Zylberberg andMatosevic, 2016). ...
Nanomedicine and nano drug delivery systems are pretty new but swiftly evolving sciences that use na-noscale materials as diagnostic tools for the controlled delivery of therapeutic agents to specific sites. Nanotechnology offers many benefits in the treatment of chronic human diseases by providing accurate medicines to specific target areas. Recently, nanomedicines (chemotherapeutic agents, biological agents, immunotherapeutic agents, etc.) have found many important uses in the treatment of various diseases. This chapter summarizes the latest developments in nanomedicine and nanotechnology-based drug delivery systems and describes the discovery and use of nanomaterials to improve the efficacy of new and old drugs (such as natural products) and diagnosis by disease marker molecule. It also discusses the potential and challenges of nanomedicines in delivering medicines from synthetic/natural sources for their clinical applications. Moreover, this chapter also includes the trends and prospects in nanomedicine.
Oral delivery of drugs and biologics has challenged the development of hybrid delivery devices that combine nanoparticles and polymeric systems. Such combination allows to merge the technological advantages of the two formulations and to improve their pharmaceutical performance which is usually limited by multifaceted biological challenges. The aim of the present work was the development of hybrid polymeric-lipid systems based on nanoemulsions (NEs) loaded into a chitosan sponges and supersaturable self-microemulsifying drug delivery systems (S-SMEDDS). Both systems were designed for improving intestinal residence time following oral administration and to increase local or systemic drug absorption. In the first part of this thesis, mucopenetrating NEs have been designed and optimized by mean of an experimental design. Stable NEs showing a droplet size of 100 nm and a neutral surface charge were obtained. NEs were efficiently dried using spray-drying and freeze-drying overcoming major challenges related with the production of dry powders from oil based systems. Then, an original structural characterization of NEs, with an in-depth focus on the NE shell crystalline and fluid nature was performed via X-ray diffraction, differential scanning calorimetry (DSC) and a novel polarity-sensitive fluorophore. NEs proved to be non-toxic on Caco-2 cells at concentration higher than 1 mg/mL, while a time- and concentration-dependent inhibition of cell viability was observed on HCT 116 cells being the threshold of toxicity at 313 µg·mL1 after 24 h. The NEs mucopenetrating potential was confirmed by the absence of surface affinity and thermodynamic interactions with mucins, together with the rapid diffusion in a preformed mucins network. The natural polymer chitosan was used as mucoadhesive macrosystem to load mucopenetrating NEs and prepare nanocomposite sponges by freeze-drying. The sponge matrix allowed to sustainably release NEs in simulated biorelevant fluids (FaSSIF-V2) showing 28% release in 2 h followed by a plateau at 50% until 72 h. Moreover, in vivo intestinal residence time was enhanced for sponges compared to NE alone when orally administered to mice. As a second part of this work, SMEDDS intended for the solubility and bioavailability enhancement of a hydrophobic anticancer model benzoimidazole drug were formulated and optimized. The hydroxypropyl cellulose (HPC) polymer was added as precipitation inhibitor to create supersaturable SMEDDS (S-SMEDDS). S-SMEDDS improved drug loading and system stability in simulated intestinal fluids compared to SMEDDS. Systems enhanced epithelial permeability in intestinal Caco-2 cell monolayers via a transient and reversible opening of tight junctions. Moreover, plasmatic drug concentrations in mice after oral gavage indicated that S-SMEDDS provided sustained drug absorption up to 24 h, 4.5-fold higher AUC and slower elimination rate compared to free drug dispersion in HPC, thanks to their ability in maintaining the drug in a supersaturated state over time. Overall, this thesis provided an extensive investigation on hybrid formulation strategies aimed at overcoming the biological hurdles for intestinal delivery. The combination of nanosystems with additional delivery approaches proved to be a winning strategy for a complete control over oral administration in view of both local and systemic treatment
Mesoporous organosilica as drug delivery carriers capable of achieving improved cargo release, enhanced biodegradation, and direct imaging with prolonged circulation time and tracking cargo distribution is highly in demand for biomedical applications. Herein, we report a ditelluride-bridged mesoporous organosilica nanoparticle (DTeMSN)/polyethylene glycol-curcumin (PEG-CCM) nanocomposite through coassembly with oxidative/redox and self-fluorescent response. Tellurium is introduced into the silica framework for the first time as a drug delivery vehicle. In this case, the DTeMSNs as an inner core enable disassembly under oxidative and redox conditions via the cleavage of ditelluride bond, facilitating the drug release of doxorubicin (DOX) in a matrix degradation controlled manner. Through the systematical comparison of diselenide-bridged MSNs and DTeMSNs, DTeMSNs exhibit remarkable advantages in loading capacity, drug release, and degradation behavior, thereby significantly affecting the cytotoxicity and antitumor efficacy. The self-fluorescent response of PEG-CCM shell coated on the surface of DTeMSNs can real-timely track the cellular uptake, DOX release, and biodistribution owing to the intrinsic and stable fluorescence of CCM. Moreover, PEG-CCM could prolong circulation time, provide preferable drug accumulation in tumors, and increase antitumor efficacy of DOX-loaded DTeMSNs. Our findings are likely to enrich the family of organosilica that served as fluorescence-guided drug delivery carriers.
Introduction: Liposomes, as nanocarriers, have developed advanced systems for transporting biological molecules, such as vaccine adjuvants, anti-cancer drugs, antifungals, and painkillers. In this study, liposomal vancomycin was prepared and its antimicrobial effect on methicillin-resistant Staphylococcus aureus (MRSA), as one of the most important nosocomial infections, was investigated.
Materials and Methods: Liposomes were prepared using hydration and dehydration methods. Their surface morphology was measured using a scanning electron microscope (SEM), medium size of DLS (Dynamic Light Scattering), zeta potential, liposome stability, and drug loading rate. Antimicrobial effects and minimum inhibitory concentration (MIC) were performed using disc diffusion and microdilution methods, respectively, and the results were compared with the original form of the drug.
Results: Liposomal vancomycin was performed in several syntheses with DSPC:DCP: Cholesterol ratio, which showed the best result with a ratio of 7:2:1. Its size was reported with 154 nm in DLS and 100 nm in SEM. The drug loading rate was 61.6% and liposome stability was 30 days. The mean diameter of non-growth halos in the samples was 19.44 mm in free form and 22.7 mm in liposomal form. The MIC of free form was 1.2 mg/ml and liposomal form was 4.27 mg/ml.
Conclusion: The results indicated that the liposomal vancomycin form was stable for up to 30 days and its antimicrobial effects showed better results than the free vancomycin form against the MRSAs isolated from the hospital.
Liposomes are one of the most studied and most promising nanocarriers to date, representing a biocompatible, safe, and efficient delivery system for both hydrophilic and lipophilic compounds.
This work aimed to evaluate the efficacy in encapsulating an aqueous extract of Lisosan G (LG), a Triticum aestivum whole grains fermented powder with strong antioxidant activity, into Eudragit-liposomes designed for oral delivery.
The total phenolics and the antioxidant activity of LG extract and LG extract encapsulated in Eudragit-liposomes were evaluated by the Folin-Ciocalteu, DPPH, and FRAP colorimetric assays. Finally, the biological activity of both LG formulations was assessed as human erythrocytes protection from oxidative stress through the cellular antioxidant activity (CAA) assay.
Our results demonstrate that the encapsulation into Eudragit-liposomes preserved the phenolics content of LG extract and retained its antioxidant properties both in vitro and ex vivo. Furthermore, LG Eudragit-liposomes exhibited increased ferric reducing capacity and protection of human erythrocytes from oxidative insult, probably due to the antioxidant properties of liposome constituents.
Therefore, the encapsulation into Eudragit-liposomes represents an excellent strategy to prevent possible reduction and loss of activity of LG bioactive compounds, and to deliver them via oral administration.
Skin hyperpigmentation is caused by an excessive production of melanin. Cysteamine, an aminothiol compound physiologically synthetized in human body cells, is known as depigmenting agent. The aim of this study was to evaluate the depigmenting activity and skin penetration of liposome formulations encapsulating cysteamine hydrochloride. First, cysteamine hydrochloride-loaded liposomes were prepared and characterized for their size, polydispersity index, zeta potential and the encapsulation efficiency of the active molecule. The stability of cysteamine hydrochloride in the prepared liposome formulations in suspension and freeze-dried forms was then assessed. The in vitro cytotoxicity of cysteamine and cysteamine-loaded liposome suspensions (either original or freeze-dried) was evaluated in B16 murine melanoma cells. The measurement of melanin and tyrosinase activities was assessed after cells treatment with free and encapsulated cysteamine. The antioxidant activity of the free and encapsulated cysteamine was evaluated by the measurement of ROS formation in treated cells. The ex vivo human skin penetration study was also performed using Franz diffusion cell. The stability of cysteamine hydrochloride was improved after encapsulation in liposomal suspension. In addition, for the liposome re-suspended after freeze-drying, a significant increase of vesicle stability was observed. The free and the encapsulated cysteamine in suspension (either original or freeze-dried) did not show any cytotoxic effect, inhibited the melanin synthesis as well as the tyrosinase activity. An antioxidant activity was observed for the free and the encapsulated cysteamine hydrochloride. The encapsulation enhanced the skin penetration of cysteamine hydrochloride. The penetration of this molecule was better for the re-suspended freeze-dried form than the original liposomal suspension where the drug was found retained in the epidermis layer of the skin.
Nanomaterials-based hybrid nano therapy is gaining attraction as a promising way to treat intracellular bacterial infections. Gold-based nanomaterials have been widely used for biomedical applications such as photothermal therapy (PTT). This thesis discusses the development of a combination therapeutic approach that kills intracellular bacteria in conjunction with photothermal and antibiotic therapy using gold nanorod (GNR) based nano-assembly. This NIR laser-activated nano-assembly delivers antibiotics to the site of infection and offers PTT. The synergistic application of both therapies increases the efficacy of treatment. The protected delivery of antibiotics and their release in the proximity of the bacterial surface decreases off-target toxicity and drug dosage. The core of the nano-assembly is composed of GNRs coated with a mesoporous silica shell (MS). The MS shell serves as a carrier for the anti-tuberculosis drug bedaquiline. The core-shell nanoparticle is encapsulated within a thermo-sensitive liposome (TSL). The TSL layer is further conjugated to the mycobacteria-targeting peptide NZX. NZX mediates the adhesion of the final nano-assembly onto the mycobacterial surface. Upon NIR laser irradiation GNRs convert the photon energy of the laser to localized heat, which melts the TSL, triggering the release of bedaquiline. The antibacterial activity of the final nano-assembly against Mycobacterium smegmatis (Msmeg) was 20 folds more efficacious than the free drug equivalent. Mtb can alter immune defense mechanisms exerted by the host macrophage. Hence, host-targeted nano-assemblies (HTNs) were fabricated by conjugating host targeting ligands (β-Glucan) onto the nano-assembly. The binding of β-Glucan conjugated HTNs to the dectin-1 receptor present on macrophages increases the free radical production and cellular uptake of HTNs. An NIR laser triggers the photothermally induced structural disruption of the nano-assembly, releasing the drug at the targeted sites. The released bedaquiline within the macrophage promotes phagosome acidification and phagolysosome formation, effectively killing 99% of intracellular bacteria. Similar nano-assemblies were developed for dual-targeted drug delivery against lung carcinoma and proved to be 20 fold more effective than the anticancer drug alone. Finally, a simple and rapid diagnostic test was developed for detecting mycobacteria within a minute using lectin conjugated multi-core silica-coated magnetic nanoparticles.
Nucleic acid-based therapy shows excellent potential in the treatment of various diseases, which are strenuous to cure. However, the rapid degradation of naked therapeutic genes by nuclease enzyme reduces its transfection efficiency. Wide varieties of viral and nonviral vectors have been developed to upgrade the efficiency and stability of gene delivery. Among nonviral vectors, cationic liposome-DNA complexes gained widespread clinical appreciation. It can safely and effectively deliver genetic materials, including DNA, siRNA, miRNA, and oligonucleotides to the target site. Low immunogenicity, ease of preparation and the apparent safety of cationic liposomes demonstrate their tremendous role in delivering the nucleic acids for therapeutic purposes. Cationic liposomes exhibited a great advantage with their biodegradable nature along with high biocompatibility and low cytotoxicity. This chapter highlights various nucleic acid-based cationic liposomes as a potential bionanomaterial and its recent progress in the application of therapeutic nucleic acid delivery.
Cancer is one of the biggest causes of mortality in the world. The advances in cancer research have taken us to distance in understanding the disease, which helps develop therapeutic strategies. Surgery and chemotherapy are the two main chosen routes of combat for cancer. These chemotherapeutic agents are good at targeting cancer, but many lack the specificity to make the distinction between healthy cells. Also, the toxicity of these chemotherapeutic agents is very high. This gap makes it quintessential to either look for better and safe agents or makes it possible for existing agents to meet these needs. Nanotechnology has the potential to deal with these unmet needs. Nanotechnology has been a hot topic recently due to its applications, one of these being nanomedicine. Studies have proven that cancer nanomedicine has a scope of being revolutionary. With the help of nanoparticles, we can make drugs specific for the cancer tissue; it can also help in increasing the bioavailability of the drug. A nanoparticle can be modified as such that it can carry the drug load that is required and delivers it to the specific target. In this review article, we have discussed the advances in nanomedicine and the current clinical status of various nanomedicines. We have extensively explored various strategies used to develop cancer nanomedicine while also discussing their mechanism of action.
The simulated liposome models provide events in molecular biological science and cellular biology. These models may help to understand the cell membrane mechanisms, biological cell interactions, and drug delivery systems. In addition, the liposomes model may resolve specific issues such as membrane transports, ion channels, drug penetration in the membrane, vesicle formation, membrane fusion, and membrane protein function mechanism. One of the approaches to investigate the lipid membranes and the mechanism of their formation is by molecular dynamics (MD) simulations. In this study, we used the coarse-grained MD simulation approach and designed a liposome model system. To simulate the liposome model, we used phospholipids that are present in the structure of natural cell membranes (1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)). Simulation conditions such as temperature, ions, water, lipid concentration were performed based on experimental conditions. Our results showed a liposome model (ellipse vesicle structure) during the 2100 ns was formed. Moreover, the analysis confirmed that the stretched and ellipse structure is the best structure that could be formed. The eukaryotic and even the bacterial cells have elliptical and flexible structures. Usually, an elliptical structure is more stable than other assembled structures. The results indicated the assembly of the lipids is directed through short-range interactions (electrostatic interactions and, van der Waals interactions). Total energy (Van der Waals and electrostatic interaction energy) confirmed the designed elliptical liposome structure has suitable stability at the end of the simulation process. Our findings confirmed that phospholipids DOPC and DOPE have a good tendency to form bilayer membranes (liposomal structure) based on their geometric shapes and chemical-physical properties. Finally, we expected the simulated liposomal structure as a simple model to be useful in understanding the function and structure of biological cell membranes. Furthermore, it is useful to design optimal, suitable, and biocompatible liposomes as potential drug carriers.
In bone regenerative strategies, the controlled release of growth factors is one of the main aspects for successful tissue regeneration. Recent trends in the drug delivery field increased the interest in the development of biodegradable systems able to protect and transport active agents. In the present study, we designed degradable poly(lactic-co-glycolic)acid (PLGA) nanocarriers suitable for the release of Transforming Growth Factor-beta 1 (TGF-β1), a key molecule in the management of bone cells behaviour. Spherical TGF-β1-containing PLGA (PLGA_TGF-β1) nanoparticles (ca.250 nm) exhibiting high encapsulation efficiency (ca.64%) were successfully synthesized. The TGF-β1 nanocarriers were subsequently combined with type I collagen for the fabrication of nanostructured 3D printed scaffolds able to mimic the TGF-β1 presence in the human bone extracellular matrix (ECM). The homogeneous hybrid formulation underwent a comprehensive rheological characterisation in view of 3D printing. The 3D printed collagen-based scaffolds (10 mm × 10 mm × 1 mm) successfully mimicked the TGF-β1 presence in human bone ECM as assessed by immunohistochemical TGF-β1 staining, covering ca.3.4% of the whole scaffold area. Moreover, the collagenous matrix was able to reduce the initial burst release observed in the first 24 h from about 38% for the PLGA_TGF-β1 alone to 14.5%, proving that the nanocarriers incorporation into collagen allows achieving sustained release kinetics.
The eggplant glycoalkaloids solasonine and solamargine are efficient biomacromolecules against skin diseases but are water-insoluble which results in inefficient treatment due to inadequate transdermal delivery. To address this problem, several liposomal formulations were prepared and evaluated for parameters including lecithin type, hydration temperature, and pH. The optimal formula with high physical and chemical stability included the lecithin Phospholipon 80H hydrated with 10 mM NaCl (pH 5.5). Solasonine - solamargine loaded liposomes were tested for their physical and chemical stability and drug leakage over a three-month period. Furthermore, the drug release profile of the loaded liposomes was evaluated with different release media. The glycoalkaloids and their liposomal formulations were assessed for their biological activity in culture using HaCaT and SCC-25 cell lines. This work resulted in a biologically effective liposomal formulation that was stable (size <220 nm, PDI <0.25, encapsulation efficiency >80%) for at least three months.
Compared to oral and injectable administration, a dermal and transdermal drug delivery system that can deliver therapeutic molecules to desired target sites with noninvasive, low toxicity, and convenient self-application is a unique method with high potential and excellent prospects. However, the poor skin uptake rate of therapeutic agents has always been a principal challenge when effective therapy is the primary concern. During past decades, nanocarriers (NCs) composed of biocompatible lipids, polymers, or inorganic materials have been deemed a potential desirable and safe percutaneous penetration enhancer. With the assistance of nanotechnology, the dermal and transdermal penetrability, as well as the scope of topical therapeutic agents, have been augmented to provide more effective percutaneous treatment and enable the use of previously unsuitable substances (such as insulin, nucleotide, protein, and vaccine) in topical skin administration. This overview provides a detailed description of the classification, composition, examples, and possible mechanisms of NCs applied in dermal and transdermal drug delivery.
Neurodegenerative disorders are pervasive and entrenched widely in society. Numerous barriers have appeared for effective treatment of neurodegenerative disorders. The presence of the blood–brain barrier (BBB), blood-cerebrospinal fluid barrier, efflux system, and enzymatic expression limits the penetration of therapeutics in CNS and thus the therapy of neurodegenerative disorders. Nanomaterial-based drug delivery systems possess attractive characteristics like targeted delivery, high drug loading capacity, controlled release, higher stability, passive targeting biocompatibility, and higher BBB penetrability. This chapter provides knowledge about different neurodegenerative disorders, hurdles for brain targeting, briefing approaches to improve the brain delivery and focuses on some examples of nanomaterial-based drug delivery systems utilized in treatment of neurodegenerative disorders.
Nano-formulations are systems that have taken on great importance due to their size. They can pass through the cracks found in the basement membrane and then reach and internalize the different organs needed. The use of materials that release their content by using different stimuli is also a plus of these compounds. Therefore, this chapter summarized the nanotechnology used to formulate drug delivery systems on a nanometric scale, their different most-frequently-used forms, and their properties and preparation. Also, the different used forms and their properties and preparation are described together with the different applications, biocompatibility, and mechanisms of release and action of these systems.
Achieving synergism, often by combination therapy via codelivery of chemotherapeutic agents, remains the mainstay of treating multidrug-resistance cases in cancer and microbial strains. With a typical core-shell architecture and surface functionalization to ensure facilitated targeting of tissues, nanocarriers are emerging as a promising platform toward gaining such synergism. Co-encapsulation of disparate theranostic agents in nanocarriers-from chemotherapeutic molecules to imaging or photothermal modalities-can not only address the issue of protecting the labile drug payload from a hostile biochemical environment but may also ensure optimized drug release as a mainstay of synergistic effect. However, the fate of co-encapsulated molecules, influenced by temporospatial proximity, remains unpredictable and marred with events with deleterious impact on therapeutic efficacy, including molecular rearrangement, aggregation, and denaturation. Thus, more than just an art of confining multiple therapeutics into a 3D nanoscale space, a co-encapsulated nanocarrier, while aiming for synergism, should strive toward achieving a harmonious cohabitation of the encapsulated molecules that, despite proximity and opportunities for interaction, remain innocuous toward each other and ensure molecular integrity. This account will inspect the current progress in co-encapsulation in nanocarriers and distill out the key points toward accomplishing such synergism through reciprocity.
Innovative developments in drug delivery technologies rely on our ability to tune the properties of supramolecular and macromolecular carriers through the chemical characteristics of individual components or building-blocks. In this regard, oxanorbornane-based synthetic lipids offer great promise as novel drug delivery systems (NDDS). As part of our efforts to develop them as vehicles for anticancer drugs, we have designed and synthesized a new derivative with a fluorescent tag (NBD) on the head group, and investigated its uptake and distribution in A549 cells. Addition of its DMSO solution to aqueous phase followed by extrusion generated solid lipid particles (SLPs), which were characterized by DLS, AFM and TEM techniques. Vesicles of this lipid in a co-assembled state with phosphatidylcholine (PC) and cholesterol were also prepared by thin-film hydration method. DLS data obtained from samples suspended in PBS showed that average size of SLPs is relatively smaller (∼56 nm) than that of vesicles (∼262 nm). The zeta potential of these particles was between −45 to −51 mV, which favor stable formulations. Confocal microscopic analysis of these aggregates after incubation with A549 cells showed that they get distributed predominantly in the cytosolic side. Concentration- and time-dependent flow cytometry analysis revealed that the uptake commences in the initial 5 minutes itself, and almost 90% of cells become NBD-positive in 2 h. There was an increase in uptake at higher concentration, indicative of passive diffusion. At the same time, a reduction in uptake at lower temperature (4 °C) compared to that at 37 °C pointed towards some contribution from active transport as well. Variation in uptake after pre-treatment with endocytosis inhibitors such as chlorpromazine and methyl-β-cyclodextrin suggested involvement of clathrin- and caveolae-mediated endocytic pathways. Cell viability and hemolytic assays further indicated that these nanocarriers have good safety profile.
Liposomes, enclosed phospholipid vesicles with bilayered membrane structures, are effective and widely used encapsulation systems in the pharmaceutical and dietary supplement industries such as nutritional supplements. These encapsulating materials have attracted great attention due to their bioavailability, biodegradability, absence of toxicity, ability to deliver a wide variety of bioactive compounds, increasing ingredients solubility, and enhanced stability against a range of environmental, enzymatic, and chemical stresses. There has been rapid development of liposomes to carry different functional compounds known as supplements needed for a healthy life. In this chapter, the application of liposomes as emerging 236carrier vehicles of supplements such as minerals, vitamins, herbal extracts, essential fatty acids, and antioxidant compounds is discussed in detail.
Nanoscale technologies are crucial for the characterization and fabrication of biomaterials that are useful in targeted drug delivery systems. New materials enable the delivery of therapeutic agents to specific tissues and cells in order to treat a range of diseases.
Bionanotechnology: Next-Generation Therapeutic Tools provides a quick overview of the use of nanomaterials in modern drug delivery and targeted drug therapy systems. The book starts with an overview of nanomaterial toxicity with subsequent chapters detailing their applications in nanomedicine. Concepts such as immunotherapy, cancer theranostics, molecular imaging, aptamers and viral nanoparticles are highlighted in specific chapters. The simplified presentation along with scientific references makes this book ideal for pharmacology and biomedical engineering scholars and life science readers.
Over the last few decades, there has been an impressive progress on developing novel drug delivery systems and targeted therapies through the use of Nanotechnology. In particular, lipid-based nanosystems attracted attention due to their interesting biological properties and potential to improve safety, stability and delivery efficiency of susceptible drugs.
Despite the technological breakthroughs and multiple advantages related to the lipid-based nanosystems, concerns regarding quality, efficacy, and safety have increased along with the widespread of these drug products. The complex and heterogeneous structure that cannot be fully quantitated, characterized, or described by physicochemical analytical methods, as well as, the nonstandard manufacturing process, makes it very hardly to comply with reproducibility requirements and quality standards in their pharmaceutical development.
Therefore, the application of a more holistic approach, such as Quality by Design (QbD), may be an effective way of surpassing technical and quality challenges. QbD is a systematic approach to product development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. In this way, a deeper product and process understanding will be achieved, that will lead to more robust and consistent lipid-based nanosystems.
The present work aims to map and provide a basic understanding concerning the current state of implementation of the QbD approach in the pharmaceutical development of lipid-based nanosystems. The survey methodology applied relied on the thorough analysis of the existing literature and databases regarding lipid-based nanosystems already approved by the regulatory authorities. This analysis discloses the most common material attributes, process parameters, quality attributes, and other variables that are critical for the quality, efficacy, and safety of lipid-based nanosystems. It also includes a brief survey of current trends of risk assessment tools, design of experiments (DoE) methodologies, and characterization techniques applied to the development of these products. This higher level of knowledge will have a definite contribution to facilitate pharmaceutical development and the increase of the number of lipid-based nanosystems reaching the market in the future.
The application of liposomes to assist drug delivery has already had a major impact on many biomedical areas. They have been shown to be beneficial for stabilizing therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo. This enables effective delivery of encapsulated compounds to target sites while minimizing systemic toxicity. Liposomes present as an attractive delivery system due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address different delivery considerations. Despite considerable research in the last 50 years and the plethora of positive results in preclinical studies, the clinical translation of liposome assisted drug delivery platforms has progressed incrementally. In this review, we will discuss the advances in liposome assisted drug delivery, biological challenges that still remain, and current clinical and experimental use of liposomes for biomedical applications. The translational obstacles of liposomal technology will also be presented.
Pegylation of nanoparticles has been widely implemented in the field of drug delivery to prevent macrophage clearance and increase drug accumulation at a target site. However, the shielding effect of polyethylene glycol (PEG) is usually incomplete and transient, due to loss of nanoparticle integrity upon systemic injection. Here, we have synthesized unique PEG-dendron-phospholipid constructs that form super stealth liposomes (SSLs). A β-glutamic acid dendron anchor was used to attach a PEG chain to several distearoyl phosphoethanolamine lipids, thereby differing from conventional stealth liposomes where a PEG chain is attached to a single phospholipid. This composition was shown to increase liposomal stability, prolong the circulation half-life, improve the biodistribution profile and enhance the anticancer potency of a drug payload (doxorubicin hydrochloride).
Copyright © 2014. Published by Elsevier B.V.
To evaluate the safety and efficacy of ketoprofen in Transfersome® gel (IDEA-033) in comparison with a ketoprofen-free vehicle (TDT 064) for the treatment of osteoarthritis (OA) of the knee.
Patients with knee OA (N = 866) were randomly assigned to receive topical IDEA-033 containing 100, 50, or 25 mg ketoprofen, or TDT 064 twice daily for 12 weeks, in a double-blind trial. The primary efficacy endpoint was the change in the Western Ontario and McMaster Universities (WOMAC®) Osteoarthritis Index pain subscale score. The coprimary efficacy endpoints were the WOMAC function subscale score and the patient global assessment of response to therapy. The secondary endpoints included the numeric pain rating for the first 14 days of treatment and the Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) responder rates.
The WOMAC pain scores were reduced by approximately 50% or more in all four groups. The 100 and 50 mg ketoprofen groups, but not the 25 mg group, showed a superior reduction in the WOMAC pain score versus the TDT 064 group (100 mg: -57.4% [P = 0.0383]; 50 mg: -57.1% [P = 0.0204]; and 25 mg: -53.4% [P = 0.3616] versus TDT 064: -49.5%). The superiority of the ketoprofen-containing formulations was not demonstrated for the WOMAC function subscale score, whereas the patient global assessment of 50 mg ketoprofen group, but not the 100 or 25 mg group, was superior to that of the TDT 064 group (P = 0.0283). Responder rates were significantly higher for all the IDEA-033 groups versus the TDT 064 group, but were high in all groups (100 mg: 88.6%; 50 mg: 86.8%; 25 mg: 88.6%; and TDT 064: 77.5%). Dermal reactions were the only relevant drug-related adverse events in all four groups.
The 50 and 100 mg ketoprofen doses of IDEA-033 were only marginally superior to TDT 064 for reducing pain associated with knee OA. The study indicates a high treatment response to the topical ketoprofen-free vehicle TDT 064.
The field of cancer nanomedicine is considered a promising area for improved delivery of bioactive molecules including drugs, pharmaceutical agents and nucleic acids. Among these, drug delivery technology has made discernible progress in recent years and the areas that warrant further focus and consideration towards technological developments have also been recognized. Development of viable methods for on-demand spatial and temporal release of entrapped drugs from the nanocarriers is an arena that is likely to enhance the clinical suitability of drug-loaded nanocarriers. One such approach, which utilizes light as the external stimulus to disrupt and/or destabilize drug-loaded nanoparticles, will be the discussion platform of this article. Although several phototriggerable nanocarriers are currently under development, I will limit this review to the phototriggerable liposomes that have demonstrated promise in the cell culture systems at least (but not the last). The topics covered in this review include (i) a brief summary of various phototriggerable nanocarriers; (ii) an overview of the application of liposomes to deliver payload of photosensitizers and associated technologies; (iii) the design considerations of photoactivable lipid molecules and the chemical considerations and mechanisms of phototriggering of liposomal lipids; (iv) limitations and future directions for in vivo, clinically viable triggered drug delivery approaches and potential novel photoactivation strategies will be discussed.
To describe the preparation of nano emodin transfersome (NET) and investigate its effect on mRNA expression of adipose triglyceride lipase (ATGL) and G0/G1 switch gene 2 (G0S2) in adipose tissue of diet-induced obese rats.
NET was prepared by film-ultrasonic dispersion method. The effects of emodin components at different ratios on encapsulation efficiency were investigated.The NET envelopment rate was determined by ultraviolet spectrophotometry. The particle size and Zeta potential of NET were evaluated by Zetasizer analyzer. Sixty male SD rats were assigned to groups randomly. After 8-week treatment, body weight, wet weight of visceral fat and the percentage of body fat (PBF) were measured. Fasting blood glucose and serum lipid levels were determined. The adipose tissue section was HE stained, and the cellular diameter and quantity of adipocytes were evaluated by light microscopy. The mRNA expression of ATGL and G0S2 from the peri-renal fat tissue was assayed by RT-PCR.
The appropriate formulation was deoxycholic acid sodium salt vs. phospholipids 1:8, cholesterol vs. phospholipids 1:3, vitamin Evs. phospholipids 1:20, and emodin vs. phospholipid 1:6. Zeta potential was -15.11 mV, and the particle size was 292.2 nm. The mean encapsulation efficiency was (69.35 +/- 0.25)%. Compared with the obese model group, body weight, wet weight of visceral fat, PBF and mRNA expression of G0S2 from peri-renal fat tissue were decreased significantly after NET treatment (all P < 0.05), while high-density lipoprotein cholesterol (HDL-C), the diameter of adipocytes and mRNA expression of ATGL from peri-renal fat tissue were increased significantly (all P < 0.05).
The preparation method is simple and reasonable. NET with negative electricity was small and uniform in particle size, with high encapsulation efficiency and stability. NET could reduce body weight and adipocyte size, and this effect was associated with the up-regulation of ATGL, down-regulation of G0S2 expression in the adipose tissue, and improved insulin sensitivity.
Sustained delivery of analgesic agents at target sites remains a critical issue for effective pain management. The use of nanocarriers has been reported to facilitate effective delivery of these agents to target sites while minimizing systemic toxicity. These include the use of biodegradable liposomal or polymeric carriers. Of these, liposomes present as an attractive delivery system due to their flexible physicochemical properties which allow easy manipulation in order to address different delivery considerations. Their favorable toxicity profiles and ease of large scale production also make their clinical use feasible. In this review, we will discuss the concept of using liposomes as a drug delivery carrier, their in vitro characteristics as well as in vivo behavior. Current advances in the targeted liposomal delivery of analgesic agents and their impacts on the field of pain management will be presented.
The aim of this study was to prepare and investigate the potential use of liposomes in the
transdermal drug delivery of meloxicam (MX). The vesicles containing a constant amount of MX,
phosphatidylcholine (PC), cholesterol (Chol) and cetylpyridinium chloride (CPC) (1:5:1:1
MX/PC/Chol/CPC molar ratio) to obtain liposomes. MX loaded liposomes were investigated for
particle size, zeta potential, entrapment efficiency (%EE) and in vitro skin permeation. The results
indicated that the liposomes were spherical in structure, 77 to 100 nm in size and charged. The %EE
of MX in the vesicles ranged from 55 to 56%. The elastic liposomes consisting of
MX/PC/Chol/CPC provided a significantly higher skin permeation of MX compared to the other
formulations. Fourier Transform Infrared Spectroscopy (FT-IR) and Differential Scanning
Calorimetry (DSC) analysis indicated that the application of liposomes may disrupt the stratum
corneum lipid. Our research suggests that MX loaded elastic liposomes can be potentially used as a
transdermal drug delivery system.
Abstract Liposomes are well known lipid carriers for drug delivery of bioactive molecules encapsulated inside their membrane. Liposomes as skin drug delivery systems were initially promoted primarily for localized effects with minimal systemic delivery. Subsequently, a novel vesicular system, transferosomes was reported for transdermal delivery with efficiency similar to subcutaneous injection. The multiple bilayered organizations of lipids applied in these vesicles structure are somewhat similar to complex nature of stratum corneal intercellular lipids domains. The incorporation of novel agents into these lipid vesicles results in the loss of entrapped markers but it is similar to fluidization of stratum corneum lipids on treatment with a penetration enhancer. This approach generated the utility of penetration enhancers/fluidizing agents in lipids vesicular systems for skin delivery. For the transdermal and topical applications of liposomes, fluidity of bilayer lipid membrane is rate limiting which governs the permeation. This article critically reviews the relevance of using different types of vesicles as a model for skin in permeation enhancement studies. This study has also been designed to encompass all enhancement measurements and analytical tools for characterization of permeability in liposomal vesicular system.
Liposomes are used as a delivery vehicle for drug molecules and imaging agents. The major impetus in their biomedical applications comes from the ability to prolong their circulation half-life after administration. Conventional liposomes are easily recognized by the mononuclear phagocyte system and are rapidly cleared from the blood stream. Modification of the liposomal surface with hydrophilic polymers delays the elimination process by endowing them with stealth properties. In recent times, the development of various materials for surface engineering of liposomes and other nanomaterials has made remarkable progress. Poly(ethylene glycol)-linked phospholipids (PEG-PLs) are the best representatives of such materials. Although PEG-PLs have served the formulation scientists amazingly well, closer scrutiny has uncovered a few shortcomings, especially pertaining to immunogenicity and pharmaceutical characteristics (drug loading, targeting, etc.) of PEG. On the other hand, researchers have also begun questioning the biological behavior of the phospholipid portion in PEG-PLs. Consequently, stealth lipopolymers consisting of non-phospholipids and PEG-alternatives are being developed. These novel lipopolymers offer the potential advantages of structural versatility, reduced complement activation, greater stability, flexible handling and storage procedures and low cost. In this article, we review the materials available as alternatives to PEG and PEG-lipopolymers for effective surface modification of liposomes.
The purpose of this work was to explore the feasibility of ethosomes for improving the antiarthritic efficacy of tetrandrine by topical application. It was found that tetrandrine was a weak base (pK a = 7.06) with pH-dependent partition coefficient. The spherical-shaped ethosomes were prepared by pH gradient loading method. Ex vivo permeation and deposition behavior demonstrated that the drug flux across rat skin and deposition of the drug in rat skin for ethosomes was 2.1- and 1.7-fold higher than that of liposomes, respectively. Confocal laser scanning microscopy confirmed that ethosomes could enhance the topical delivery of the drug in terms of depth and quantity compared with liposomes. The ethosomes were shown to generate substantial enhancement of therapeutic efficacy of tetrandrine on Freund's complete adjuvant-induced arthritis with regard to liposomes. These results indicated that ethosomes would be a promising carrier for topical delivery of tetrandrine into and across the skin.
The current investigation aimed to evaluate the transdermal potential of novel testosterone propionate (TP) ethosomes and liposomes prepared by surfactant modification. The effect of hexadecyl trimethyl ammonium bromide and cremophor EL-35 on the particle size and zeta potential of the prepared vesicles was investigated. The entrapment efficiency and stability, as well as in vitro and in vivo skin permeation, were studied with the various techniques, such as differential scanning calorimetry, confocal laser scanning microscopy, transmission electron microscopy, dynamic light scattering, and so on. The results indicated that the ethosomes were defined as spherical, unilamellar structures with low polydispersity (0.100 ± 0.015) and nanometric size (156.5 ± 3.5 nm). The entrapment efficiency of TP in ethosomal and liposomal carriers was 92.7% ± 3.7% and 64.7% ± 2.1%, respectively. The stability profile of the prepared TP ethosomal system assessed for 120 days revealed very low aggregation and very low growth in vesicular size. TP ethosomes also provided an enhanced transdermal flux of 37.85 ± 2.8 μg/cm(2)/hour and a decreased lag time of 0.18 hours across mouse skin. The skin permeation efficiency of the TP ethosomes as further assessed by confocal laser scanning microscopy revealed enhanced permeation of rhodamine red-loaded formulations to the deeper layers of the skin (260 μm) than that of the liposomal formation (120 μm).
Failure of clinical trials of nonviral vector-mediated gene therapy arises primarily from either an insufficient transgene expression level or immunostimulation concerns caused by the genetic information carrier (e.g., bacteria-generated, double-stranded DNA (dsDNA)). Neither of these issues could be addressed through engineering-sophisticated gene delivery vehicles. Therefore, we propose a systemic delivery of chemically modified messenger RNA (mRNA) as an alternative to plasmid DNA (pDNA) in cancer gene therapy. Modified mRNA evaded recognition by the innate immune system and was less immunostimulating than dsDNA or regular mRNA. Moreover, the cytoplasmic delivery of mRNA circumvented the nuclear envelope, which resulted in a higher gene expression level. When formulated in the nanoparticle formulation liposome-protamine-RNA (LPR), modified mRNA showed increased nuclease tolerance and was more effectively taken up by tumor cells after systemic administration. The use of LPR resulted in a substantial increase of the gene expression level compared with the equivalent pDNA in the human lung cancer NCI-H460 carcinoma. In a therapeutic model, when modified mRNA encoding herpes simplex virus 1-thymidine kinase (HSV1-tk) was systemically delivered to H460 xenograft-bearing nude mice, it was significantly more effective in suppressing tumor growth than pDNA.Molecular Therapy (2012); doi:10.1038/mt.2012.250.
Liposomes, phospholipid vesicles with a bilayered membrane structure, have been widely used as pharmaceutical carriers for drugs and genes, in particular for treatment of cancer. To enhance the efficacy of the liposomal drugs, drug-loaded liposomes are targeted to the tumors by means of passive (enhanced permeability and retention mediated) targeting, based on the longevity of liposomes in blood and its accumulation in pathological sites with compromised vasculature, and active targeting, based on the attachment of specific ligands to the liposomal surface to bind certain antigens on the target cells. Antibody-targeted liposomes loaded with anticancer drugs demonstrate high potential for clinical applications. This review highlights evolution of liposomes for both passive and active targeting and challenges in development of targeted liposomal therapeutics specifically antibody-targeted liposomes.
TDT 067 is a novel, carrier-based dosage form of terbinafine in Transfersome (1.5%) formulated for topical delivery of terbinafine to the nail, nail bed, and surrounding tissue. We examined the effects of TDT 067 and conventional terbinafine on the morphology of dermatophytes. Trichophyton rubrum hyphae were exposed to TDT 067 or terbinafine (15 mg/ml) and examined under white light, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Subungual debris from patients treated with TDT 067 in a clinical trial was also examined. Exposure of T. rubrum hyphae to TDT 067 led to rapid and extensive ultrastructural changes. Hyphal distortion was evident as early as 4 h after exposure to TDT 067. After 24 h, there was complete disruption of hyphal structure with few intact hyphae remaining. Exposure to terbinafine resulted in morphological alterations similar to those seen with TDT 067; however, the effects of TDT 067 were more extensive, whereas a portion of hyphae remained intact after 24 h of exposure to terbinafine. Lipid droplets were observed under TEM following 30 min of exposure to TDT 067, which after 24 h had filled the intracellular space. These effects were confirmed in vivo in subungual debris from patients with onychomycosis who received topical treatment with TDT 067. The Transfersome in TDT 067 may potentiate the action of terbinafine by delivering terbinafine more effectively to its site of action inside the fungus. Our in vivo data confirm that TDT 067 can enter fungus in the nail bed of patients with onychomycosis and exert its antifungal effects.
The physical properties of the lamellar lipid-bilayer component of biological membranes are controlled by a host of thermodynamic forces leading to overall tensionless bilayers with a conspicuous lateral pressure profile and build-in curvature-stress instabilities that may be released locally or globally in terms of morphological changes. In particular, the average molecular shape and the propensity of the different lipid and protein species for forming non-lamellar and curved structures are a source of structural transitions and control of biological function. The effects of different lipids, sterols, and proteins on membrane structure are discussed and it is shown how one can take advantage of the curvature-stress modulations brought about by specific molecular agents, such as fatty acids, lysolipids, and other amphiphilic solutes, to construct intelligent drug-delivery systems that function by enzymatic triggering via curvature.
Practical applications: The simple concept of lipid molecular shape and how it impacts on the structure of lipid aggregates, in particular the curvature and curvature stress in lipid bilayers and liposomes, can be exploited to construct liposome-based drug-delivery systems, e.g., for use as nano-medicine in cancer therapy. Non-lamellar-forming lysolipids and fatty acids, some of which may be designed to be prodrugs, can be created by phospholipase action in diseased tissues thereby providing for targeted drug release and proliferation of molecular entities with conical shape that break down the permeability barrier of the target cells and may hence enhance efficacy.
TB is an infectious disease that is far from being eradicated and controlled. The treatment for TB is associated with noncompliance to therapy because it consists of a long-term treatment with a multidrug combination and is associated with the appearance of several side effects. Liposomal formulations are being developed with first- and second-line antibiotics, and might be an extremely useful alternative to current therapies. This article will thus focus on the role of liposomes as nanodelivery systems for the treatment of TB. Among several advantages, these nanocarriers allow an increase in the bioavailability of antibiotics, which may lead to a reduction in the time of treatment. Results obtained with such nanosystems, although preliminary, are promising and are perspective of the use of inhalation for TB treatment.
Pharmacosomes are amphiphilic lipid vesicular systems containing phospholipid complexes with a potential to improve bioavailability of poorly water soluble as well as poorly lipophilic drugs. To improve the water solubility, bioavailability and minimize the gastrointestinal toxicity of aceclofenac, its pharmacosomes were prepared. Aceclofenac was complexed with phosphatidylcholine (80%) in two different ratios (1:1 and 2:1) using conventional solvent evaporation technique. Pharmacosomes thus prepared were subjected to solubility and drug content evaluation, scanning electron microscopy, differential scanning calorimetry, X ray powder diffraction and in vitro dissolution study. Pharmacosomes of aceclofenac were found to be disc shaped with rough surface in scanning electron microscopy. Drug content was found to be 91.88% (w/w) for aceclofenac phospholipid complex (1:1) and 89.03% (w/w) aceclofenac-phospholipid complex (2:1). Differential scanning calorimetric thermograms and X ray powder diffraction datas confirmed the formation of phospholipid complex. Solubility and dissolution profile of the prepared complex was found to be much better than aceclofenac.
A novel mitochondrial-targeted liposomal drug-delivery system was prepared by modification of the liposomal surface with a newly synthesized polymer, rhodamine-123 (Rh123)-PEG-DOPE inserted into the liposomal lipid bilayer. This novel polymer was synthesized by conjugating the mitochondriotropic dye Rh123, with the amphiphilic polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugate. The modified liposomes showed better uptake by cells (HeLa, B16F10) estimated by fluorescence microscopy and FACS analysis. The co-localization study with stained mitochondria as well as with the isolation of mitochondria of the cultured cells after their treatment with Rh123 liposomes showed a high degree of accumulation of the modified liposomes in the mitochondria. We also prepared mitochondrial-targeted and nontargeted paclitaxel (PCL)-loaded liposomes. Mitochondrial-targeted PCL-loaded liposomes demonstrated enhanced cytotoxicity toward cancer cells compared with nontargeted drug-loaded liposomes or free PCL. Thus, Rh123-modified liposomes target mitochondria efficiently and can facilitate the delivery of a therapeutic payload to mitochondria.
Mesenchymal stem cells (MSCs) hold a great promise for application in several therapies due to their unique biological characteristics. In order to harness their full potential in cell-or gene-based therapies it might be advantageous to enhance some of their features through gene delivery strategies. Accordingly, we are interested in developing an efficient and safe methodology to genetically engineer human bone marrow MSC (BM MSC), enhancing their therapeutic efficacy in Regenerative Medicine. The plasmid DNA delivery was optimized using a cationic liposome-based reagent. Transfection efficiencies ranged from approximately 2% to approximately 35%, resulting from using a Lipid/DNA ratio of 1.25 with a transgene expression of 7 days. Importantly, the number of plasmid copies in different cell passages was quantified for the first time and approximately 20,000 plasmid copies/cell were obtained independently of cell passage. As transfected MSC have shown high viabilities (>90%) and recoveries (>52%) while maintaining their multipotency, this might be an advantageous transfection strategy when the goal is to express a therapeutic gene in a safe and transient way.
The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50-60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia.
Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30-75 mg/m(2)), paclitaxel (100-175 mg/m(2)), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy.
Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%-76%) and the four-year overall survival was 75% (95% CI, 58-86%).
Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.
Neomycin sulphate (a hydrophilic drug) is extensively used topically in treatment if various skin infections. The objective of the present research was to investigate the dermal delivery of neomycin sulphate through elastic liposomes for effective treatment of deep skin infections. Elastic liposomes containing neomycin sulphate were prepared using Phospholipon®90 G and Tween 80/Span 80. Elastic liposomal-gel was prepared by incorporating prepared EL in corbopol resins. Extent of skin penetration of NS from EL and its gel was studied. EL was characterized for vesicular shape, size, zeta potential, entrapment efficiency, stability, in vitro skin penetration and in vivo antibacterial study in rats. TEM and Zeta Seizer defined EL as spherical, unilamellar structures with low polydispersity and nanometric size range (145 ± 5.85nm). Drug entrapment efficiency of EL carrier was found to be (34.6% ± 0.15%). EL suspension was found to be stable for 14 d when stored at 2-80C where as its gel was stable for 2 months. CLSM studies revealed that vesicles facilitated the co-penetration of NS to the deeper layers of the rat skin up to 180μm. In vitro penetration studies showed enhanced deposition of NS (25.92% ± 3.48%) in rat skin after 24 hours. Histological findings after deep dermal S. aureus infection in rats indicated that EL were efficient carriers for delivery of NS to bacteria localized within deep skin strata and showed complete eradication of staphylococcal infections within 7 d. The results showed that effective treatment of deep dermal infection is possible with neomycin through elastic liposomes.
Sophisticated drug delivery systems (DDS) are required for delivering drugs, especially macromolecules such as nucleic acids or proteins, to their sites of action. Therefore it is a prerequisite that future DDS are designed to selectively target a tissue. In this review, we focus on systems that actively target the vasculature in tumors or adipose tissues. For targeting tumor vasculatur, a new strategy referred to as dual-targeting is proposed that uses a combination of a receptor specific ligand and a cell penetrating peptide, which can induce the synergistic enhancement of tissue selectivity under in vivo conditions. A novel pH-sensitive cationic lipid was designed to enhance the endosomal release of encapsulated compounds such as siRNA as well as to improve the stability in blood circulation after intravenous administration. A cyclic RGD peptide is used as an active targeting ligand. For targeting adipose vasculature, prohibitin, which is expressed on the surface of adipose endothelial cells, was targeted with KGGRAKD peptides on the surface of PEGylated nanoparticles. Prohibitin targeted nanoparticles (PTNP) encapsulating Cytochrome c (CytC) can selectively target adipose vasculature by optimizing the lengths of the PEG linkers and can deliver CytC to adipose endothelial cells. PTNP can successfully induce anti-obese effects as well as apoptosis by delivering CytC to the cytosol in endothelial cells. Unexpectedly, the EPR (enhanced permeability and retention) effect, which is usually observed in tumor tissue, was also observed in the adipose vasculature, especially in obese mice, where PEGylated nanoparticles can pass through the endothelial barriers in adipose tissue. We believe that these achievements in active targeting will allow a greatly expanded use of DDS for nanomedicines.
Cells move and change shape by dynamically reorganizing their cytoskeleton next to the plasma membrane. In particular, actin assembly generates forces and stresses that deform the cell membrane. Cell-sized liposomes are designed to mimic this function. The activation of actin polymerization at their membrane is able to push the membrane forward, thus reproducing the mechanism of lamellipodium extension at the cell front. Moreover, the cell cortex, a submicrometer-thick actin shell right beneath the cell membrane can be reproduced; it contributes to cell tension with the action of molecular motors. We will describe experimental methods to prepare liposomes that mimic the inside geometry of a cell, and that reproduce actin-based propulsion of the liposome using an outside geometry. Such systems allow to study how actin-related proteins control and affect actin cortex assembly and can produce forces that drive cell shape changes.
Copyright © 2015 Elsevier Inc. All rights reserved.
Background: CPX-351 is a liposomal formulation that co-encapsulates Cyt and Daun enabling delivery of both drugs at a synergistic 5:1 molar ratio. A Phase I study in advanced AML patients demonstrated substantial efficacy with complete remissions (CRs) and acceptable safety. The MTD was 101 units/m2. One unit of CPX-351 contains 1 mg Cyt and 0.44mg of Daun. Here we examine the PK of CPX-351 as a function of dose, inter-patient variability and patient characteristics in order to identify potential PD relationships. Methods: 35 male and female patients with advanced hematologic malignancies were included in the PK portion of this Phase I trial and received 24, 32, 43, 57, 76, 101, or 134 units/m2 of CPX-351 by IV infusion over 90 minutes on Days 1, 3, and 5. Validated LC/MS/MS assays were used for determination of total plasma Cyt and Daun. PK parameters [Cmax, AUC, t1/2, Vss, CL, Cmax/Dose, AUC/Dose] were determined on Days 1 and 5. Results: Mean Cyt and Daun PK parameters are presented in the table below. No significant differences were observed in t1/2, Vss, CL, Cmax/Dose, or AUC/Dose among dose groups on either study day, although some drug accumulation was observed from day 1 to day 5. Cyt and Daun PK parameters were not correlated with patient gender, age or race. Incidence of non-hematologic toxicity increased with dose and systemic exposure. CRs were observed in patients receiving doses of 32-134 units/m2 of CPX-351. The responses at 101 units/m2 and above appear to be more durable. The Cyt:Daun molar ratio remained near 5:1 for up to 48 hours on both study days for all dose levels. Conclusions: Cyt and Daun delivered in CPX-351 exhibited linear single dose and multiple dose PK and low inter-patient variability in plasma concentrations within dose groups. CPX-351 provides predictable, extended systemic exposure of elevated Cyt:Daun concentrations near a 5:1 molar ratio. The 100 unit/m2 dose is undergoing testing in Phase II studies.
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Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1292. doi:10.1158/1538-7445.AM2011-1292
The Silences of the Archives, the Reknown of the Story.
The Martin Guerre affair has been told many times since Jean de Coras and Guillaume Lesueur published their stories in 1561. It is in many ways a perfect intrigue with uncanny resemblance, persuasive deception and a surprizing end when the two Martin stood face to face, memory to memory, before captivated judges and a guilty feeling Bertrande de Rols. The historian wanted to go beyond the known story in order to discover the world of the heroes. This research led to disappointments and surprizes as documents were discovered concerning the environment of Artigat’s inhabitants and bearing directly on the main characters thanks to notarial contracts. Along the way, study of the works of Coras and Lesueur took a new direction. Coming back to the affair a quarter century later did not result in finding new documents (some are perhaps still buried in Spanish archives), but by going back over her tracks, the historian could only be struck by the silences of the archives that refuse to reveal their secrets and, at the same time, by the possible openings they suggest, by the intuition that almost invisible threads link here and there characters and events.
A brain drug delivery system for glioma chemotherapy based on transferrin and cell-penetrating peptide dual-functioned liposome, Tf/TAT-lip, was made and evaluated with doxorubicin (DOX) as a model drug. TAT conjugated liposome (TAT-lip) loaded with doxorubicin (DOX) were prepared by the thin film hydration methods (lip-DOX) and then conjugated with transferrin (Tf) to yield Tf/TAT-lip-DOX which was characterized for their various physicochemical and pharmaceutical properties. Cellular uptakes were explored in both brain capillary endothelial cells (BCECs) of rats and U87 cells. The blood brain barrier model in vitro was established to evaluate the trans-endothelial ability crossing the BBB. The biodistribution of each formulation was further identified. The Tf/TAT-lip-DOX presents the best anti-proliferative activity against U87 cells. The orthotropic glioma model was established for the evaluation of anti-glioma effect. In conclusion, the experimental data in vitro and in vivo indicated that the Tf/TAT-lip was a promising brain drug delivery system due to its high delivery efficiency across the BBB.
This single-arm Phase II trial was designed to assess the safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer.
Patients with a histological diagnosis of epithelial ovarian, fallopian tube or primary peritoneal carcinoma, who were relapse-free at least 6 months after completion of first-line platinum-based chemotherapy, and who had measurable disease and gave consent to participate in this study received infusions of pegylated liposomal doxorubicin (30 mg/m(2)) at 1 mg/min, followed by carboplatin (AUC 5 mg min/ml) over 30 min every 28 days.
Thirty-three of 35 enrolled patients were eligible for efficacy analysis. One patient (3.0%) achieved a complete response, while 16 (48.5%) achieved a partial response, with an overall objective response rate of 51.5% (95% confidence interval, 34.5-68.6%). Among the 22 patients who had evaluable CA125 levels at entry, responses were observed in 18 patients, with a response rate of 81.8% (95% confidence interval, 65.3-98.3%). The median progression-free survival and overall survival rates for all 35 patients were 10.7 months (95% confidence interval, 8.1-13.2 months) and 38.8 months (95% confidence interval, 31.0-46.7 months), respectively. The most frequent Grade 3-4 toxicities, regardless of cause, were neutropenia (82.9%), thrombocytopenia (51.4%), leukopenia (45.7%) and anemia (17.1%).
The safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer were confirmed. Although there were concerns of severe hematological toxicity with this therapy, this potential complication was safely managed through adequate monitoring of bone marrow function.
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The goal of this study was to develop and evaluate the potential use of transfersome vesicles in the transdermal drug delivery of Ibuprofen. It was investigated by encapsulating the drug in various formulations of composed of various ratios of soya phosphatidylcholine, span 80 and tween 80, prepared by lipid film hydration by rotatary evaporation method and evaluated for particle shape, size, zeta potential, entrapment efficiency (%EE),elasticity, stability, and in vitro skin permeation. The vesicles were spherical in structure as confirmed by Scanning Electron Microscopy and TEM, the vesicle size of best formulation for Span 80 and Tween 80 was 962 nm and 2250 nm respectively, and zeta potential (negatively charged) for Span 80 and Tween 80 was found to be -16.1 and -17.5 respectively. The %EE of ibuprofen in the vesicles was 47.8(plus or minus)2.2 and the elasticity of both increases with increase in surfactant conc. and were found to be 34.4(plus or minus)1.4 and 26.5(plus or minus)1.6. Stability studies for Transferosome were carried out for 5 weeks at 450C. In vitro skin permeation studies were carried by human cadaver skin using franz diffusion cell, and drug release after 24 hrs and flux was found 2.5824 and 1.9672 ug/cm2/hr respectively. Fourier Transform Infrared Spectroscopy (FT-IR) and Differential Scanning Calorimetry (DSC) analysis indicated that the application of transfersomes significantly disrupted the stratum corneum lipid. It is evident from this study that transfersomes are a promising prolonged delivery system for Ibuprofen and have reasonably good stability characteristics. This research suggests that ibuprofen loaded transfersomes can be potentially used as a transdermal drug delivery system.