Journal of Drug Delivery Science and Technology

Online ISSN: 1773-2247
Publications
Article
Upon activation, T cells of various subsets are the most important mediators in cell-mediated immune responses. Activated T cells play an important role in immune system related diseases such as chronic inflammatory diseases, viral infections, autoimmune disease, transplant rejection, Crohn disease, diabetes, and many more. Therefore, efforts have been made to both visualize and treat activated T cells specifically. This review summarizes imaging approaches and selective therapeutics for activated T cells and gives an outlook on how tracking and treating can be combined into theragnositc agents for activated T cells.
 
Article
Despite the wide variety of highly potent anti-HIV drugs that have been developed and made available in clinical practice over the years, eradication of HIV infection has not been achieved. Currently, HIV infection and AIDS are thought to be chronically treatable. HIV attacks host immune cells namely macrophages and CD4(+)T-cells and sequesters itself into sanctuary and reservoir sites such as the lymphoid tissues, testes, and brain. Initial drug delivery efforts with prodrugs and drug conjugates focused on improving the physicochemical (i.e. solubility), biopharmaceutic (i.e. absorption, metabolism), and pharmacokinetic (i.e. blood concentrations) properties of the parent drugs. Eradicating HIV, however, will require advanced drug delivery approaches in order to access and maintain effective drug concentrations for prolonged periods of time in sanctuary sites. The current review discusses prodrug/conjugate efforts, clinical successes and describes drug delivery challenges and approaches for eradicating HIV infection.
 
Article
Facilitation of protein transport across biomimetic polymers and carriers used in drug delivery is a subject of major importance in the field of oral delivery. Quantitative immunofluorescence of epithelial tight junctions can be a valuable tool in the evaluation of paracellular permeation enhancement and macromolecular drug absorption. The tight junctional space is composed of transmembrane protein networks that provide both mechanical support and a transport barrier. Both of these may be affected by drug delivery agents that enhance paracytosis. Imaging is the only tool that can tease apart these processes. A confocal microscopy imaging method was developed to determine the effect of microparticulate poly(methacrylic acid) grafted poly(ethylene glycol) (P(MAA-g-EG)) hydrogel drug carriers on the integrity of claudin-1 and E-cadherin networks in Caco-2 monolayers. Z-stack projection images showed the lateral disruption of tight junctions in the presence of drug carriers. Tight junction image fraction measurements showed more significant differences between membranes exposed to microparticles and a control group. Mechanical disruption was much more pronounced in the presence of P(MAA-g-EG) microparticles as compared to the effect of EDTA.
 
Article
Tools to selectively and reversibly control gene expression are useful to study and model cellular functions. When optimized, these cellular switches can turn a protein's function "on" and "off" based on cues designated by the researcher. These cues include small molecules, drugs, hormones, and even temperature variations. Here we review three distinct areas in gene expression that are commonly targeted when designing cellular switches. Transcriptional switches target gene expression at the level of mRNA polymerization, with examples including the tetracycline gene induction system as well as nuclear receptors. Translational switches target the process of turning the mRNA signal into protein, with examples including riboswitches and RNA interference. Post-translational switches control how proteins interact with one another to attenuate or relay signals. Examples of post-translational modification include dimerization and intein splicing. In general, the delay times between switch and effect decreases from transcription to translation to post-translation; furthermore, the fastest switches may offer the most elegant opportunities to influence and study cell behavior. We discuss the pros and cons of these strategies, which directly influence their usefulness to study and implement drug targeting at the tissue and cellular level.
 
Article
Chemotherapy is one of the primary treatment mechanisms for treating cancer. Current chemotherapy is systemically delivered and causes significant side effects; therefore the development of new chemotherapeutic agents or enhancing the effectiveness of current chemotherapeutic could prove vital to patients and cancer care. The purpose of this research was to develop a new conjugate composed of doxorubicin (chemotherapeutic) and inulin (polysaccharide chain) and evaluate its potential as a new therapeutic agent for cancer treatment. The synergistic effect of inulin conjugated to doxorubicin has allowed the same cytotoxic response to be maintained or improved at lower doses as compared to doxorubicin. Supporting results include cytotoxicity profiles, calf thymus DNA binding studies, confocal microscopy, and transport studies.
 
Article
A pharmacokinetic model is proposed to describe the glucoregulatory process. The model describes the dynamics of glucose, amino acids, and fatty acids, as well as both the hormonal actions and dynamics of insulin, glucagon, epinephrine, and glucagon-like peptide-one. The model was developed assuming that the dynamics of each species occurrs in only one compartment. Several forms of the metabolic absorption and elimination rates, along with possibilities for increasing the complexity of each compartmental model are discussed. Once properly identified and validated, the novel model has the potential to be more descriptive than other models describing glucose dynamics in the body.
 
Article
Principal components analysis (PCA) and multivariate regression analysis have been employed to study the relationship between a series of calculated physicochemical properties of terpenes (solubility parameter, calculated logKoct, molecular mass, molecular volume, calculated surface tension, scaled H-bonding donor and acceptor values, non-carbonyl carbons per molecule) to the permeation enhancing activity of each terpene for propranolol HCl across newborn pig skin. With PCA, a smaller number of new variables (five principal components) were used as predictors in regression analysis in order to predict the enhancing activity of terpenes on the permeation of the model drug propranolol HCl. A fairly high coefficient of determination (R2 = 0.87) suggested that the resultant regression equation was able to adequately predict trends in the enhancing activity of the terpenes. PCA results suggested the importance of a combination of the physicochemical properties on the enhancing activities of the terpenes. A suitable balance between these terpene properties is required to lead to a considerable enhancement of propranolol HCl penetration.
 
Article
This review describes the application of customized surface modifications using biomimetic polymers to attempt to reduce unspecific protein adsorption to the materials or promote specific cell adhesion to implants or tissue engineering scaffolds. Various polymers that are suited to suppress almost all unspecific protein interactions and underlying mechanisms of cell adhesion are presented and discussed. Suitable modifications to the inert polymers that can later favor the adhesion of specific cell types are also described. These modifications involve utilizing the binding characteristics of peptide sequences to promote specific cell attachment, and techniques to incorporate these sequences into the polymers are explained. Finally, it is shown that biomimetic surface modification techniques are also of tremendous importance for drug delivery with nanoparticles, and the opportunities and limits associated with these approaches are demonstrated.
 
Article
The aim of the present study was to compare different regularly used transfection agents, i.e.poly(L-lysine) (PLL), branched poly(ethyleneimine) (BPEI), linear PEI (LPEI), poly(2-(dimethylamino)ethyl methacrylate)(pDMAEMA) and 1,2-dioleyl-3-trimethylammonium-propane (DOTAP), regarding their in vivo transfection behavior after intravenous administration. An attempt was made to study whether the in vitro behavior of these transfectants is relevant for the in vivo situation in terms of their transfection efficiency and serum aggregation properties. In vivo, at an N/P ratio of 5, transfection mediated by the various cationic transfectants mainly occurred in the lungs. The order of decreasing lung transfection was: DOTAP > LPEI > pDMAEMA > BPEI > PLL. Similar rankings were found in in vitro experiments regarding the extent of serum-induced aggregation, suggesting that in vitro studies are certainly relevant for the in vivo situation. As a whole, the in vitro data suggest that the induction of aggregates in the circulation is a major mechanistic factor underlying the phenomenon of dominant lung transfection.
 
-The amount of pilocarpine hydrochloride release (µg) from microporous PCL matrices.  
-Cumulative release of pilocarpine hydrochloride (%) from microporous PCL matrices.  
Article
Microporous polycaprolactone (PCL) matrices loaded with hydrophobic steroidal drugs or a hydrophilic drug - pilocarpine hydrochloride - were produced by precipitation casting using solutions of PCL in acetone. The efficiency of steroid incorporation in the final matrix (progesterone (56 %) testosterone (46 %) dexamethasone (80 %)) depended on the nature of the drug initially co-dissolved in the PCL solution. Approximately 90 % w/w of the initial load of progesterone, 85 % testosterone and 50 % dexamethasone was released from the matrices in PBS at 37°C over 8 days. Pilocarpine hydrochloride (PH)-loaded PCL matrices, prepared by dispersion of powder in PCL solution, released 70-90 % of the PH content over 12 days in PBS. Application of the Higuchi model revealed that the kinetics of steroid and PH release were consistent with a Fickian diffusion mechanism with corresponding diffusion coefficients of 5.8 × 10-9 (progesterone), 3.9 × 10 -9 (testosterone), 7.1 × 10-10 (dexamethasone) and 22 × 10-8 cm2/s (pilocarpine hydrochloride). The formulation techniques described are expected to be useful for production of implantable, insertable and topical devices for sustained delivery of a range of bioactive molecules of interest in drug delivery and tissue engineering.
 
Article
Although numerous drugs are used to treat HIV infection with increasing efficacy, the patient's brain is often infected by the virus and acts as a sanctuary where drugs cannot penetrate due to their low passage through the blood brain barrier. Therefore, the design of new medicine able to reach the brain is extemely challenging. An approach based on prodrug synthesis and encapsulation into PEGylated nanocarriers was proposed and applied to didanosine, a nucleosidic analogue used to treat HIV-1 associated dementia. In this study, appropriate formulations of PEGylated liposomes were designed to incorporate two glycerolipidic prodrugs of didanosine. Preparation methods based on Bangham's or emulsion/evaporation techniques formulations exhibited particle size under 300 nm with high incorporation of prodrugs as shown by light scattering, optical microscopy experiments and differential scanning calorimetry. Finally the uptake of fluorescently labeled PEGylated formulations by rat brain immortalized endothelial cells modeling the BBB was evidence by confocal laser scanning microscopy. All the results suggest that the encapsulation of didanosine prodrugs into PEGylated liposomes is a promising approach in the goal increasing didanosine concentration in the brain and treating HIV-1-associated dementia.
 
-Top: plastic mould with removable plastic bottom used to prepare polymeric films by a casting-solvent evaporation technique. Bottom: polymeric films (A: alginate-based film; B: agar-based film; C: alginate-chitosan based film).  
-Plastic pocket (6.5 x 6.5 cm, mesh aperture approximately 4 mm) used to suspend films in the dissolution medium.  
-Release profiles of polyphenols from polymeric films. Each point represents the mean of six experiments.  
-Swelling index of the prepared polymeric films in phosphate buffer at different contact times.  
-Inhibitory zone of discs obtained from alginate-based films against Staphylococcus aureus.  
Article
Propolis is a natural resinous substance, with a high polyphenol content, produced by honeybees and characterized by antimicrobial, anti-inflammatory and antioxidant properties, which make it useful for different therapeutic applications, especially in the stomatological field in the treatment of mild buccal diseases. The aim of this study was to prepare some polymeric film formulations for local delivery of propolis into the oral cavity. For this purpose, a commercial propolis fluid extract and three extracts (dry, ethanolic, glyceric) obtained from raw propolis were previously characterized with regard to their polyphenolic fraction composition and their antimicrobial properties against Candida albicans, Escherichia coli and Staphylococcus aureus strains. Commercial fluid extract, judged the most suitable in terms of polyphenol content and antimicrobial activity, was then incorporated into alginate, alginate-chitosan and agar films, prepared using a casting-solvent evaporation technique, which were finally evaluated in terms of thickness, total polyphenol content, in vitro polyphenol release profiles, swelling behaviour and antimicrobial properties. Our results demonstrate that polymeric films can be proposed as new propolis vehicles in the treatment of dental and buccal diseases.
 
Article
The purpose of this study was to evaluate the effect of cyclosporine (CyA)-cyclodextrin (CD) complex incorporated within PLGA inicrospheres on microsphere characteristics, with particular emphasis on drug release kinetics. For this purpose, microspheres encapsulated with CyA and those loaded by CyA-CD complex were prepared by solvent evaporation and multiple emulsification solvent evaporation methods, respectively. Morphology, size, encapsulation efficiency and drug release pattern from microspheres were evaluated. Also, physicochemical properties of drug inside microspheres were characterized by differential scanning calorimetry (DSC) and infrared spectroscopy (IR) studies. Scanning electron microscopy (SEM) studies showed that microspheres encapsulated with CyA had islands on the microsphere surface but the islands were not seen on the surface of microspheres loaded by complex. Size range varied from 1 to 25 mu m for CyA encapsulated microspheres and 1 to 50 mu m for complex loaded microspheres. The release of CyA was biphasic with an initial more rapid release phase followed by a slower phase but drug release was twice as fast for complex loaded microspheres. IR studies did not indicate any chemical interaction between the components of microspheres and DSC thermograms revealed that CyA was present either in its amorphous state in microspheres or the presence of CyA as an inclusion complex within microspheres loaded by complex. In conclusion, using CyA as an inclusion complex with CD within microspheres can affect microsphere characteristics and drug release and it is possible to modify microsphere properties like drug release by incorporating CDs as complexing agents.
 
Article
Cyclodextrins are cyclic oligosaccharides that are able to form water-soluble complexes with many lipophilic drugs. Thus, through cyclodextrin complexation it is possible to formulate lipophilic water-insoluble drugs as aqueous eye drop solutions. The ocular barrier to topical drug delivery into the eye consists of the aqueous tear film and lipophilic epithelium, and most drugs permeate this barrier via passive diffusion. Cyclodextrins enhance permeation of lipophilic drugs through the aqueous tear film to the epithelial surface increasing drug availability immediately to the membrane surface. However, since hydrophilic cyclodextrins and cyclodextrin complexes do not readily permeate lipophilic membranes, excess amounts of cyclodextrin will hamper drug penetration into the eye. Cyclodextrins frequently reduce drug delivery of hydrophilic drugs.
 
Article
Nanosuspension has been widely used to improve the bioavailability of poorly soluble drugs. ZL-004, a promising small molecular compound with the function of raising counts of white blood cells, was developed to nanosuspensions to solve the low solubility and bioavailability by the precipitation method. The effects of the important factors (THF/Water ratio, Tween-80, PEG 400) on the particle size were investigated by a central composite design. After freeze drying, with 6% sucrose as protective agent, a 399 ± 20 nm nanosuspension (NS-A) and a 208 ± 14 nm nanosuspension (NS-B) were obtained with good appearances, rapid redispersity, and stable particle sizes. The morphology and crystal forms were evaluated by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). In vitro release test proved that the solubility and dissolution rate were improved by reducing the particle size. In vivo pharmacokinetic study and tissue distribution study in rats showed that particle size affected the pharmacokinetic behavior significantly by different accumulation in reticuloendothelial system (RES). NS-A with a larger particle size was captured and accumulated more in RES, achieving higher t1/2 and MRT; NS-B with a smaller particle size was captured and accumulated less in RES, achieving higher AUC and Cmax.
 
Article
The incidence and prevalence of spinal cord injury (SCI) as a high disabling injury have enc ouraged the researchers to find some therapeutic strategies. The spinal cord is highly sensitive to oxidative stress and maintaining homeostasis is essential for redox status in neurons. Therefore, in this study. On the other hand, the application of drugs can induce some unwanted effects on the viability of neurons. Therefore, in this study, 1,2-benzisoxazole-3-methanesulfonamide (zonisamide) as a second-generation antiepileptic drug was formulated by micelles and characterized by TEM and DLS techniques. Afterwards the protective effects of 1,2-benzisoxazole-3-methanesulfonamide-loaded micelles against stimulated oxidative stress and cytotoxicity were assessed by MTT, ROS, staining and enzyme activity assays. It was shown that the fabricated 1,2-benzisoxazole-3-methanesulfonamide-loaded micelles with a size of about 60-90 nm have a good colloidal stability and show a sustained drug release at physiological pH. Furthermore, it was determined that the neuroprotective effects of 1,2-benzisoxazole-3-methanesulfonamide-loaded micelles against cytotoxicity, ROS production, morphological changes, caspase-3 activation triggered by H2O2 was more pronounced than non-formulated drug. In conclusion, this study may provide useful information regarding the advancement of therapeutic approach for treatment of SCI.
 
Article
Benzodiazepines form a class of drugs that are used to treat wide variety of conditions such as anxiety, seizures, and insomnia. In general, benzodiazepines are lipophilic and poorly soluble in water at physiologic pH, and when solubilized undergo hydrolytic degradation. Thus, marketed products containing solubilized benzodiazepines most often consist of organic solvents or aqueous solutions containing relatively high concentrations of organic cosolvents and surfactants. There is however one exception. Midazolam injection is essentially pure aqueous solution of midazolam, unbuffered at pH of about 3 and shelf-life of over 2 years at room temperature. While most benzodiazepines form an unstable protonated ring-open form at acidic pH, the ring-open form of midazolam is both relatively stable and water-soluble. Still, for more concentrated midazolam solutions, such as nasal spray, organic solvents have been used. Benzodiazepines can be solubilized through formation of water-soluble cyclodextrin complexes but in spite of numerous successful clinical studies in humans, as well as in vivo studies in animals, no benzodiazepine/cyclodextrin formulations have reached the market. Here the chemistry of 1,4-benzodiazepines, their unusual degradation pathways and solubility in water is reviewed.
 
Article
Emphysema is a type of chronic obstructive pulmonary disease (COPD) usually leading to difficulty breathing. It is highly in need of effective interventions to prevent airspace damage and stretch. Herein, we studied the protective effect of 1,8-cineole (CIN) on porcine pancreatic elastase (PPE)-induced emphysema in mice via quantitative pulmonary administration. To overcome the volatility, instability and poor water solubility of CIN that limits its pharmacological activities in vivo, a hyaluronic acid (HA)-coated liposome was prepared to encapsulate CIN (Lipo/[email protected]), which facilitated the delivery of CIN to lung tissue and improved its therapeutic effect for emphysema. A MicrosprayerⓇ aerosolizer was used to deliver free CIN and its liposomal preparations every other day for four weeks and evaluate the therapeutic effects on emphysema in mice. The results clearly showed that CIN significantly reduced the level of inflammation and oxidative stress, resulting in less lung cell apoptosis. Compared with the free CIN and Lipo/CIN, Lipo/[email protected] exhibited superior protective effects on mice to prevent the PPE-induced emphysema. Furthermore, the therapeutic mechanisms were verified to be mainly mediated by Nrf2/NQO1 and NF-κB/IκBα pathways. In conclusion, quantitative pulmonary administration of CIN could alleviate the progression of emphysema and the therapeutic effects were further improved by the HA-coated liposome carrier.
 
Article
In this study, a new formulation of miRNA-loaded cationic liposomes (CLs) was prepared for bone marrow cells. CLs and miRNA-loaded cationic liposomes (CL/miR-101) were prepared and their characteristics were assessed using Dynamic light scattering (DLS) technique. MTT assay was used for bone marrow cell lines (KG-1 and HBMF-SPH cell lines) to evaluate cytotoxicity of CLs and CL/miR-101. The results have shown that the size and charge of the prepared CLs with new formulation were 84.5 nm and 20.1 mV and for CL/miR-101 were 126.6 nm and 4.31 mV. MTT assay results have demonstrated that different concentrations of CLs had no obvious cytotoxicity in both KG-1 and HBMF-SPH cells. The cytotoxicity of CL/miR-101 was approximately 12% more than the bare miRNA-101 in KG-1 cells and comparatively less significant amount of cytotoxicity was seen in HBMF-SPH cells. In this study, a new formulation of cationic liposome was successfully designed to deliver miRNA into bone marrow cells effectively. The suitable size and charge of CLs made them capable to form efficient CL/miR-101 complex, which was stable and penetrated significantly into the cells. CL/miR-101 complex proved to be cytotoxic for cancer cells and hence can be considered as a novel gene therapy system.
 
Article
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the editor as one of the named authors (Liang Zhang) has plagiarized part of a paper that had already appeared in Nanomaterials 2018, 8(2), 126 (https://doi.org/10.3390/nano8020126). One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. The editor would like to add that there are indications that this manuscript was submitted by Liang Zhang without the knowledge of the other named authors, Yue Zhang, Yan Du, Jing Wang, Lijun Chi. If the submission happened without their knowledge, then they are not at fault for this retraction.
 
Article
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Significant similarities were noticed post-publication between this article, submitted on 27 April 2021 and an article that was submitted to Pharmaceutical Development and Technology on 10 June 2021 https://doi.org/10.1080/10837450.2021.1999471 by an apparently unrelated research group. Moreover, the authors did not respond to the journal request to comment on these similarities and to provide the raw data. Although this article was published earlier than the article from Pharmaceutical Development and Technology, the Editor-in-Chief decided to retract this article given the concerns on the reliability of the data. One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and genuine. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.
 
Article
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Significant similarities were noticed post-publication between this article and the article previously published by Chenfei Tian, Lu Zeng, Le Tang, Jingni Yu and Mei Ren in AAPS PharmSciTech 22 (2021) 212 https://doi.org/10.1208/s12249-021-02096-6. Moreover, the authors did not respond to the journal request to comment on these similarities and to provide the raw data, and the Editor-in-Chief decided to retract the article. One of the conditions of submission of a paper for publication is that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents an abuse of the scientific publishing system.
 
Article
Background Docetaxel (DTX) has been used to treat numerous types of cancers. Its poor solubility, serious side effects, and multi-drug resistance (MDR) limits its use in cancer treatment. As mixed micelles (MMs) can be developed easily to improve the pharmacokinetics and dynamics of DTX, the current study was aimed to develop DTX-loaded MMs and investigate their anticancer effects alone and in combination with Verapamil (VPM) to repurpose in ovarian cancer. Methods The DTX interaction with the lipophilic core of TPGS with Pluronic® F108 (PF108) MMs (DTP MMs) was studied using in silico study. The critical micelle concentration (CMC) of TPGS, PF108, and their molar ratios were determined using Iodine spectroscopic method. A solvent evaporation method was used to prepare the DTP MMs, and were optimized using 3² full factorial design. The inhibitory effect of drug and co-polymers on p-glycoprotein (P-gp) and β-tubulin were investigated with help of in silico studies. DTP MMs were characterized for % entrapment efficiency (%EE), mean particle size (MPS), zeta potential, surface morphology using TEM, in vitro drug release, % haemolysis against human blood, and cytotoxicity against SKOV-3 cells using MTT assay. Result The in silico studies confirmed the good DTX interaction with lipophilic cavity of MMs. The CMC value of TPGS, PF108 and their molar ratios (MMs) were found to 0.01 mM, 0.032 mM, and 0.025 mM respectively. Out of 9 formulations, formulation K3 was optimized based on %EE (73.93 ± 2.4%), % drug loading capacity (%DLC) (2.06 ± 0.08%) and MPS (233 ± 3 nm, PDI with 0.439 ± 0.26). The developed DTP MMs showed a sustained release behaviour, reduced hemolytic behaviour, and lower in vitro cytotoxicity when compared to plain DTX. TEM images showed that the self-assembled MMs are well distributed as spherical-shaped particles. The IR, DSC, and PXRD studies indicate no chemical interaction between drug and excipients. The molecular docking study reveals the P-gp inhibitory effect of VPM and TPGS; whereas, DTX and TPGS have shown potential binding affinity towards β-tubulin. The presence of VPM at lowest concentration showed significantly improved SKOV-3 cell growth inhibition; whereas, the higher VPM concentration does not result in increased cell death as compared to plain DTX and K3 MMs. Conclusion The developed DTP MM is a promising approach for improved ovarian cancer treatment. Further, VPM could be repurposed along with DTP MMs against ovarian cancer. As VPM improves the anticancer effect of DTX at lowest concentration, it can be successfully being used in clinical cancer treatment with its minimum inherent pharmacological activities. However, further studies are needed to optimize VPM clinical dose for cancer treatment with DTX or other drugs. The P-gp inhibitory effect of VPM and TPGS, and tubulin inhibitory effect of TPGS are further needs to be proved quantitatively using other techniques in order to use them against resistant and non-resistant cancer types.
 
Article
Niosomes composed of non-ionic surfactants (NISs) are novel drug carriers that can deliver both hydrophilic and hydrophobic drugs similarly to liposomes, and have several advantages over liposomes, such as lower cost and higher availability owing to their relative abundance and variety. In this study, polyethylene glycol (PEG)-coated (PEGylated) Span 20 niosome was labeled with indium-111 using a remote-loading method, and its in vivo behavior was compared with that of the liposome. In addition, niosomes based on Span 20, 40, 60, and 80 were compared to evaluate the effects of differences in the lipophilic moiety of NIS. We succeeded in convenient labeling of PEGylated niosomes with high labeling efficiency (>95%) and purity (>95%). The stability of ¹¹¹In-labeled niosomes in the serum was high enough to trace the in vivo behavior. Span 20 niosome exhibited significantly extended retention in blood and high accumulation in the tumor at 48 h post-injection compared to the liposome. Niosomes composed of Span 80 with an unsaturated hydrocarbon chain showed decreased radioactivity in the blood and increased accumulation in the spleen compared with the other niosomes composed of Span 20, 40, and 60 with saturated hydrocarbon chain. Meanwhile, all studied niosomes were highly accumulated in the tumor. These results suggest that the PEGylated niosomes can be useful as tumor-targeting drug carriers.
 
Article
Glioblastoma multiforme (GBM), known as astrocytoma grade IV, is the most common primary malignant brain tumor and one of the most lethal forms of cancer with a median survival rate of approximately 15 months after standard treatment. Currently, the chance of increasing the survival rate is found in therapy with doxorubicin (DOX) delivered to the central nervous system by polymeric carriers. In this study, we synthesized and characterized by NMR spectroscopy, a vehicle for DOX based on glucoheptoamidated poly (amidoamine) dendrimers of third generation (G3gh) and its derivative substituted with 4 residues of DOX attached via succinate linkers (G3gh4DOX). The pH dependent DOX release profile from the well soluble G3gh4DOX indicates a slow release that is significantly higher in an acidic environment due to hydrolytic cleavage of an amide bond between DOX and the succinate linker, not the ester bond between succinate linker and the glucoheptoamide substituent. Biological studies demonstrate efficient grade IV human U-118 MG glioma cells damage by G3gh4DOX conjugates at very low concentrations, with IC50 < 1 μM after 24–72 h of incubation. The conjugate studied was about 2.7–4.5 fold more toxic than DOX alone. G3gh4DOX killed glioma cells through a more desirable apoptosis pathway and inhibited their proliferation with cell cycle-arrest at the G2/M phase. The effect of G3gh4DOX was probably the result of action of the entire conjugate, but not DOX alone. Therefore, G3gh4DOX seems to be a promising candidate for local glioma therapy.
 
Article
Nitroxoline (NIT) is a quinoline antibiotic with anti-cancer effects which prevents cell migration by inhibition of cathepsin B enzyme. Cisplatin (CIS) is normally used for various kinds of malignancies such as metastatic breast cancer. The goal of the present study was increasing cellular toxicity and cell migration inhibition by co-delivery of NIT-CIS using targeted liposomes by anti HER2 nanobody. Liposomes were prepared by solvent injection method using cholesterol, soy lecithin and maleimide-polyethylene glycol 2000 distearoyl phosphatidyl ethanolamine (Mal-PEG-DSPE) and targeted by anti HER2 nanobody. The liposomes were optimized for their particle size, zeta potential, drugs loading and release efficiency. Then their cytotoxicity, migration, cellular uptake and apoptosis induction were tested on TUBO (HER2⁺) and MDA-MB-213 (HER2⁻) cell lines. The in vivo antitumor activity of CIS-NIT loaded in targeted liposomes was compared with free drugs solution and non-targeted liposomes in TUBO cells induced breast cancer in Balb-c mice. Results indicated that the mixture of CIS and NIT significantly increased cytotoxicity. Moreover, targeted liposomes increased cellular toxicity and cellular uptake in TUBO cells, unlike MDA-MB-213 cells. Cell migration studies implied the effect of NIT combinations on lowering the invasiveness of the cells. Targeted liposomes loaded with CIS-NIT had outstanding tumor suppression efficiency compared to control group, non-targeted liposomes and free drugs.
 
Article
The aim of this study was to prepare nitric oxide (NO) releasing nanoparticle/hydrogel with potential uses in topical applications. NO is a signaling molecule in skin. It controls the dermal blood flow, skin defense, and tissue repair. There is an interest for designing topical formulations that release NO/NO donors directly at the desired application site. S-nitrosoglutathione (GSNO), a NO donor, was incorporated into chitosan nanoparticles (CS NPs) (hydrodynamic size of 112.2 ± 2.22 nm). Free GSNO or GSNO-containing CS NPs were incorporated in Pluronic F-127 (PL) hydrogels. The purpose of this study was to combine the advantages of CS NPs (as a drug delivery system with mucoadhesive properties) and a PL hydrogel, which permits a prolonged contact time for the NO donor on the mucosal/skin surfaces. Rheological measurements were performed to determine the sol-gel transition temperature, the rheological parameters, and the viscosity. The polymeric matrices spontaneously released free NO. GSNO diffusion from the polymeric matrices was evaluated using a diffusion system. The results indicate that the incorporation of GSNO-CS NPs into a PL hydrogel may find important dermatological applications due to their mechanical properties and their ability to release therapeutic and sustained amounts of NO at the desired application site.
 
Article
New polymeric systems are constantly developed for novel biomedical applications. Pluronic F127 (PF127) is a tri-block copolymer with surface-active properties. It comprises a focal hydrophobic (polypropylene oxide) chain and two terminal hydrophilic poly (ethylene oxide) chains. They are attractive for several biomedical applications because of their non-toxicity, biocompatibility, and heat-sensitive sol-gel properties. Nanocarriers are used for the efficient transport of drug molecules and helps in sustained drug delivery. Recently, the development of several PF 127-based hydrogels is gaining attention as an advanced treatment system. The drug-loaded nanocarriers embedded PF-127 hydrogels effectively protect the drug from degradation and increase the residence time at the site of administration. These hybrid systems are compatible with different drug molecules that can be used for different channels of administration and provide controlled release of encapsulated drugs with high therapeutic potential based on the nanomaterial used. This review article explains the strategies and therapeutic applications of temperature-sensitive PF127 hydrogels containing different biocompatible nanocarriers to improve the biopharmaceutical properties of the drugs.
 
Article
This report describes the kinetics of Huntington’s Disease (HD) gene (HTT) lowering in brains of YAC 128 mice. Lowering (or “knock-down”) of HTT mRNA expression was achieved by intranasal administration of specially designed siRNA loaded into chitosan nanoparticles. Kinetic patterns of HTT lowering observed in different brain regions allowed calculation of cumulative lowering effects that result from multiple consecutive administrations. Mathematical modeling generated dosing schedules for approaching a steady knock-down effect and for prediction of magnitude and duration of HTT lowering. Kinetic modeling of HTT lowering with our algorithm will be useful in determining intranasal dosing schedules to produce chronic, therapeutically significant lowering effect of gene expression.
 
Article
The role of two carriers —Gelucire 50/13 and PEG 15000— was evaluated to improve the characteristics of the dissolution of albendazole, an anthelmintic drug with very low solubility and dissolution rate. Solid dispersions were elaborated by using the fusion method. The results from solid-state characterisation techniques (DSC, HSM, FTIR and PXRD) reported immiscibility and absence of interactions in the solid phase. In vitro release studies of binary systems showed a substantial enhancement of dissolution performance when compared with the control, which constitutes an actual alternative to increase the bioavalilability and/or reduce the dosage of the currently marketed formulations.
 
Article
The co-administration of anti-tumor and anti-angiogenesis agents represents a well-established strategy for cancer treatment. However, the clinical use of this “combined therapy” approach showed several limitations probably due to the inability of most angiogenic inhibitors to target tumor vessels. Herein, we evaluated the in vitro angiogenesis effects of N,O-carboxymethyl chitosan (N,O-CMCS) surface modified curcumin (CUR)-loaded solid lipid nanoparticles (SLN) intended for CUR oral administration. For this purpose, SLN formulations based on Gelucire® 50/13 were prepared and characterized for their physicochemical properties. From stability tests such SLN resulted useful to protect CUR from oxidative and hydrolytic degradation for a long period at 4 °C. Moreover, N,O-CMCS-c-CUR SLN (F4) displayed enhanced cytocompatibility with Caco-2 cells. Data from angiogenesis studies showed that the CUR-unloaded and surface unmodified SLN (b-SLN, F1) possess anti-angiogenic activity and, moreover, due to the features of the coating polysaccharide, F4 may constitute an anti-angiogenic delivery platform for CUR oral delivery and such delivery system seems promising in vascular angiogenesis inhibition.
 
Article
Theranostic nanosystems have attracted the attention of many scientists in worldwide due to its ability to accumulate and release selectively, in specific sites, compounds capable to generate images and to treat tumors, allowing simultaneously, the diagnose and treatment of cancer. Radioactive Gadolinium-159, a beta e gamma radiation emitter, has the properties to generate scintigraphic images and simultaneously, to conduct cancer cells to the death through high radiation doses. In this sense, the purpose of this study was to prepare PEG-coated and folate-PEG-coated long-circulating and pH-sensitive liposomes loaded with Gd-159, and to evaluate the feasibility of these systems as theranostic probes in tumor-bearing mice. Liposomes were prepared by loading Gd-159 and Poly-t-Lysine, with a mean diameter of 120 nm in a monodisperse formulation. Scintigraphic images performed in Ehrlich tumor-bearing mice indicated that folate-coated liposome accumulation was more than 3-times higher than liposomes with no coating. Animals also showed higher survival rates when treated with folate-coated liposomes loaded with Gd-159. Therefore, Gd-159-FTSpHL improved the survival of the animals and showed higher tumor uptake, indicating that Gd-159-FfSpHL possesses potential applications as a theranostic probe.
 
Article
In this article, we have reported the exogenous delivery of a newly synthesized biologically relevant fluorophore, namely, (E)-1,5-diphenyl-3-styryl-4,5 -dihydro-1H-pyrazole (DSDP) from a non-ionic Triton X-165 micellar nanocarrier to the biomolecular target DNA, exploiting an external stimulant β-cyclodextrin. Vivid steady state and time resolved spectroscopic studies reveal that in the presence of both the micelle and the ctDNA, the probe remains exclusively within the micellar environment because of the higher binding affinity of the probe with the former. However, upon addition of β-CD, the probe is displaced from the micellar environment to get bound to the DNA grooves. Inclusion complexation property of the stimulant with the hydrophobic chain of the constituents of the micelle is assigned to be responsible for the transfer of the probe from the micellar carrier to the DNA. Non-toxic biocompatible micellar carrier and cyclodextrin of proper dimension may be exploited to execute the present strategy of exogenous activation for effective and targeted delivery of drugs.
 
Article
Recently, it has been reported that type 17 collagen, which is one type of collagen, functions as a cell adhesion molecule of hemidesmosome and maintains stem cells. Furthermore, continuous expression of type 17 collagen in hair follicles is indispensable for stem cell maintenance and is thought to lead to prevention of thinning hair. However, type 17 collagen cannot be supplied via skin penetration because it is a transmembrane protein. Therefore, it is necessary to promote the production of type 17 collagen in epidermal cells. Chlorogenic acid has been discovered as a compound that promotes the production of type 17 collagen, and their effects have been confirmed in vitro experiments. However, to promote the production of type 17 collagen in the stem cells, chlorogenic acid should be exposed to cells at high concentrations. Therefore, in consideration of actual use, it is necessary to develop a drug delivery system that exerts the effect of chlorogenic acid at lower concentrations. We have developed poly (lactide-co-glycolic acid) nanoparticles (PLGA NP) with a mean particle diameter of 200 nm as a drug delivery system carrier and reported that skin permeability and the sustainability of the effect of the encapsulated ingredient could be enhanced. In this paper, we have also developed the PLGA NP encapsulating chlorogenic acid (Cha), which is known to promote the production of type 17 collagen, and evaluated the enhancement effect of type 17 collagen production using normal human epidermal keratinocytes. Cha solution could not promote the production of type 17 collagen due to the degradation in the medium. In contrast, by applying the Cha-enclosed PLGA NP, the mRNA of type 17 collagen and the production amount of the collagen were significantly increased. These results showed that PLGA NP is a potential tool to encourage the development of efficient skin care products.
 
Article
17-Hydroxyprogesterone caproate (HPC) is an approved efficacious drug for reducing the incidence of a preterm birth defect by intramuscular (I.M.) injection. Oral administration of HPC encounters challenges given by slow absorption and low bioavailability. Thus, the objective of this study was to explore the feasibility of delivering HPC through the oral route using niosomes. Niosomes were prepared with different non-ionic surfactants having permeation enhancing properties (NSPEs) in combination with Span 60 and cholesterol to form hybrid niosomes and later screened for the lead formulation by variability studies. All the formulations were characterized in terms of entrapment efficiency, particle size. Results indicated that 1:2:2 M ratio of Brij 76: cholesterol: Span 60 (N2-c) demonstrated optimal characteristics with entrapment efficiency (92.2 ± 1.05%), particle size (62.9 ± 0.65 nm), PDI (0.2 ± 0.003) and zeta potential (−22.2 ± 0.85 mV) and was chosen as the lead formulation. Ex vivo intestinal permeation study showed significantly high permeation of HPC. In vivo pharmacokinetics in rats showed an increase in oral bioavailability (AUC0-t) by niosomes (1.8-fold, 802.4 ± 273.84 h*ng/mL) compared to the oral suspension and better efficacy than intramuscular injection. Overall, results showed hybrid niosomes enhanced the bioavailability of HPC by increasing the intestinal permeation, which may be a better approach to minimize side effects of administration associated with intramuscular injection.
 
Article
Betamethasone-17-valerate (BM-17-V) is a corticosteroid commonly administered in semisolid preparations for cutaneous use. In this study, an ointment and a cream from the German Pharmacopoeia, i.e. wool fat alcohol ointment (WS) and basis cream DAC were loaded separately with BM-17-V. Two conventional penetration enhancers, namely isopropyl alcohol (IPA) and isopropyl myristate (IPM) as sole additives, as well as a mixture of both, IPA-IPM 1:1 (w/w) were also incorporated into the different semisolid formulations and in vitro permeation experiments of BM-17-V were carried out in Franz diffusion cells using excised human stratum corneum (SC). The effect of the additives on the thermal behavior of the SC lipid matrix was evaluated by differential scanning calorimetry (DSC). The saturation concentrations of BM-17-V within the formulations were estimated based on microscopical characterization. BM-17-V is transformed into its hydrolization product, betamethasone (BM), during the permeation experiments by the effect of the SC using the BM-21-V pathway. Furthermore the microstructure of the lipids and protein complexes located at the membrane of the corneocytes was altered by the use of the enhancers. The combination of IPA and IPM resulted in a synergetic enhancement of the BM flux. The BM permeation was augmented by approximately 12 times when a combination of IPA-IPM 1:1 (w/w) was used in wool fat alcohol ointment.
 
Article
The study describes the fabrication of an implantable nanofibrous scaffold loaded with 17AAG as a heat shock protein 90 (Hsp90) inhibitor for possible application in breast cancer therapy. In order to, 17AAG loaded PCL/PEG nanofibers (NFs) were prepared by electrospinning technique and their chemical and physical properties studied by FTIR and FESEM. To assess cytotoxicity of 17AAG loaded PCL/PEG NFs and free 17AAG on T47D cancer cells as in vitro model of breast cancer, MTT assay was performed. The mRNA expression level of Hsp90 and telomerase activity in treated cells with 17AAG loaded PCL/PEG NFs also were investigated using real-time PCR (RT-PCR) and TRAP method, respectively. MTT method indicated which loading of the 17AAG into PCL/PEG NFs increased effectively cytotoxicity against T47D cells. This result was correlated with significant decrease of telomerase activity and mRNA expression level in treated cells with 17AAG loaded PCL/PEG NFs compared to free 17AAG. In conclusion, the results confirmed which 17AAG loaded PCL/PEG NFs are further effective compared with free 17AAG on T47D breast cancer cells through reduction of telomerase activity and Hsp90 mRNA expression level. Therefore, 17AAG loaded NFs might be a superior device to remove of residual breast cancerous cells and prevent locally cancer recurrence.
 
Article
Melittin (MEL) is the major component of bee venom, which has recently emerged as an attractive candidate for cancer chemotherapy. As a polypeptide, rapid degradation of MEL is considered as one of the most critical challenges in therapeutic applications. In this study, atomically precise gold nanoclusters with 6-mercaptohexanoic acid (MHA) as a thiolate ligand, termed as Au25(MHA)18, were synthesized and employed as the delivery vehicles of MEL to human cervical cancer HeLa cells. The characterization including Zeta potential, UV–Vis spectra, X-ray photoelectron spectroscopy (XPS), and transmission electron microscope (TEM), showed that Au25(MHA)18 nanoclusters can load MEL with high efficiency, resulting in formation of MEL-Au25(MHA)18 complexes. The anti-cancer effect of MEL-Au25(MHA)18 complexes on human cervical cancer HeLa cells in vitro were further evaluated by cell proliferation and cytotoxicity assay, flow cytometry assay, and confocal microscopy imaging. It was found that Au25(MHA)18 nanoclusters protected MEL from degradation leading to long-lasting cytotoxicity on HeLa cells, and maintained the good anti-cancer activity of MEL. The anti-cancer activity of MEL-Au25(MHA)18 complexes on HeLa cells can be well explained through the pore formation by MEL on the surface of cell membrane, which ultimately leading to cytolysis. This work demonstrated the feasibility of atomically precise gold nanoclusters as the delivery vehicles of unstable polypeptide such as MEL, achieving improved efficiency in chemotherapy.
 
Article
Bedaquiline fumarate (BDQN) is approved in year 2012 to treat multidrug resistance tuberculosis (MDR-TB) through accelerated approval pathway by FDA. It belongs to class II of biopharmaceutical classification system (BCS) and shows poor aqueous solubility and dissolution rate which eventually leads to compromised bioavailability. In the present study, BDQN loaded binary solid dispersion (BSD) and ternary solid dispersion (TSD) were prepared with the aid of solvent evaporation technique wherein poloxamer 188 and tocopheryl polyethylene glycol 1000 succinate (TPGS) were used as dispersing matrix. The prepared BSD and TSD were characterized by dynamic light scattering (DLS), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), hot stage microscopy (HSM), powder X-ray diffraction (PXRD), and evaluated for enhancement in saturated solubility, in vitro dissolution performance, and permeability through rat intestine. BSD and TSD showed 5.68-fold and 7.46-fold increment in saturation solubility respectively. In vitro dissolution data showed about 99.98 ± 1.48 % BDQN release from BSD within 15 min (t15 min, %) and, 98.68 ± 1.98 % release from TSD within 30 min (t30 min, %) which were significantly higher than that of BDQN plain drug and their respective physical mixtures at respective time points. However, BSD was unable to sustain the parachute effect of BDQN in dissolution medium and showed decreased concentrations whereas TSD maintained the same throughout experimental period. Permeability of BDQN from BSD and TSD was found to be 1.86-fold and 3.53-fold, respectively, when compared to BDQN plain drug. TSD was found to be stable at accelerated condition for the period of 3 months when evaluated by PXRD, FTIR, DSC and in vitro dissolution. We may conclude from this study that solid dispersions of BDQN can be accepted as promising alternative formulation approach to enhance biopharmaceutical performance of BDQN in terms of solubility, dissolution rate and permeability for treatment of tuberculosis and may benefit the patients with MDR-TB for the emergency treatment with BDQN, which could ultimately lead to increase in bioavailability and reduced cost of final product.
 
Article
Annonaceous acetogenins (ACGs) have extensive antitumor activities. However, the poor solubility limits their clinical application. In this research, ACGs nanosuspensions (ACGs-NSps) were prepared by antisolvent-precipitation method using poloxamer 188 (P188) as stabilizer. The prepared P188-ACGs-NSps had a mean particle size of 115.9 nm, the polydispersity index (PDI) was 0.208. P188-ACGs-NSPs were stable in different physiological media and displayed a sustained drug release behavior until 144 h. Lyophilized P188-ACGs-NSps using 0.5% glucose as lyoprotectant were stable for long-term storage. P188-ACGs-NSps significantly enhanced the cytotoxicity against 4T1 and HeLa cell lines compared with ACGs solution (IC50:1.426 ± 0.308 vs.3.106 ± 0.691, IC50: 0.718 ± 0.1934 vs. 1.521 ± 0.1992). In vivo antitumor study indicated that P188-ACGs-NSps exhibited great antitumor efficacy against 4T1 tumor with an inhibition rate of 63% at a low intravenous injection dose of 0.4 mg/kg. P188-ACGs-NSps seem to be a promising drug delivery system for ACGs to improve their solubility that can be applied in clinic in the future.
 
Article
Block copolymer micelles (BCMs), nano-self-assemblies of amphiphilic copolymers with a hydrophobic core surrounded by a hydrophilic corona, were explored for the simultaneous delivery of a lipophilic chemotherapeutic drug and radiation to tumors. Docetaxel (DTX)-functionalized BCMs were radiolabeled with the β⁻ emitter ¹⁸⁸Re by two different approaches (direct and indirect labelling) affording in both cases ¹⁸⁸Re-Pz-DTX-BCMs with high purity (>98%). The ¹⁸⁸Re-labeled BCMs are stable in PBS pH 7.4 and in cell culture medium, at 37°C. Cell uptake of ¹⁸⁸Re-Pz-DTX-BCMs in MDA-MB-231 metastatic breast cancer cells and MNNG/HOS osteosarcoma cells presented a maximal uptake of ca. 12% at 24 h incubation time. Biodistribution studies in tumor-bearing nude mice (MDA-MB-231 human xenografts) has shown prolonged circulation lifetime in the bloodstream and moderate uptake in the tumor (1.8 ± 0.8% I.A./g at 24h p.i.). The prolonged blood circulation lifetime together with the in vivo stability, suggests that the micelles are potentially useful as drug delivery system to tumors by the EPR effect. As far as we are aware, we describe herein the first example of BCMs, ¹⁸⁸Re-Pz-DTX-BCMs, as versatile nanoplatforms for the simultaneous delivery of beta radiation (¹⁸⁸Re) and the chemotherapeutic drug (DTX) potentially useful for cancer therapy. The expected synergistic effect of such combination in pain therapy and/or cancer progression holds promise when compared to the conventional sequential treatment.
 
Top-cited authors
Prasad Jamkhande
  • Department of Pharmacology, Swami Ramanand Teerth Marathwada University
Mohan G. Kalaskar
  • R. C. Patel Institute of Pharmaceutical Education & Research
Prashant Kesharwani
  • Jamia Hamdard University
Thorsteinn Loftsson
  • University of Iceland
Michael A Repka
  • University of Mississippi