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Albumin-stabilized epirubicin nanocarriers of core–shell type based on poly(butyl cyanoacrylate) and poly(styrene-co-maleic acid)
... Besides, bioanalytical methods are also important to characterize the pharmacokinetics of drugs loaded in nanosystems through their quantification in biological matrices. For this purpose, a wide number of analytical methods are available for quantitative and qualitative analyses of EPI, including spectroscopy, [7][8][9] fluorimetry, [10,11] and high-performance liquid chromatography. [12,13] In addition to accuracy, sensitivity, reproducibility, simplicity, and cost reduction evaluated by the analyst for developing a new method, another parameter that should be considered is the environmental impact of the method used. ...
... In addition, UV-Vis spectroscopy shows low sensitivity to molecules with very similar structures (e.g., EPI and doxorubicin), being required techniques with higher specificity to differentiate these molecules.. [57] Angelova and Yordanov (2015) and Yordanov et al. (2012) developed poly(butyl cyanoacrylate)-based nanocarriers containing EPI for cancer treatment and used UV-Vis detection as an analytical method to determine EPI entrapment efficiency and drug-releasing profile. [7,58] Yordanov and coworkers performed EPI determination with samples in PBS (pH 7.4) at 480 nm in a quartz cuvette using a double-beam UV-Vis spectrophotometer (Evolution 300, Thermo Scientific) after centrifugation at 14,000 rpm for 60 minutes. Angelova and coworkers used quartz cuvettes and a double-beam UV-Vis spectrophotometer (Shimadzu UV-190) against a calibration curve, with a detection wavelength of 482 nm. ...
Epirubicin (EPI) is a chemotherapeutic agent belonging to the anthracycline drug class indicated for treating several tumors. It acts by suppressing the DNA and RNA synthesis by intercalating between their base pair. However, several side effects are associated with this therapy, including cardiotoxicity and myelosuppression. Therefore, EPI delivery in nanosystems has been an interesting strategy to overcome these limitations and improve the safety and efficacy of EPI. Thus, analytical methods have been used to understand and characterize these nanosystems, including spectrophotometric, spectrofluorimetric, and chromatography. Spectrophotometric and spectrofluorimetric methods have been used to quantify EPI in less complex matrices due to their efficiency, low cost, and green chemistry character. By contrast, high-performance liquid chromatography is a suitable method for detecting EPI in more complex matrices (e.g., plasm and urine) owing to its high sensitivity. This review summarizes physicochemical and pharmacokinetic properties of EPI, its application in drug delivery nanosystems, and the analytical methods employed in its quantification in different matrices, including blood, plasm, urine, and drug delivery nanosystems.
... Albumin can form nanospheres upon desolvation from aqueous solutions and such nanospheres have been used to encapsulate various small molecule drugs [27] and gold nanoparticles [28]. Surface modification with serum albumin has been known to increase stability of organic [29,30] and inorganic [31,32] nanocolloids. Previous studies have also demonstrated that rapid phagocytosis of nanoparticles by macrophages can be diminished by their association with serum albumin [33]. ...
... The -potential of FeO(OH)/albumin nanoparticles expectedly decreased (in absolute value) from −44 ± 1 mV in distilled water to −12 ± 1 mV in 1 × PBS. This value was similar to that of albuminstabilized PSMA/PBCA particles (-11 ± 1 mV) measured at similar conditions in our previous experiments [29]. Probably, mechanisms other than only electrostatic repulsion are involved in stabilization of these dispersions, which are otherwise expected to be quite unstable based on the relatively low absolute value of -potential (<25 mV). ...
... PBCA-MB have been surface functionalized with antibodies and peptides using several strategies including non-covalent and covalent coupling methodologies [11]. Non-covalent coupling strategies are based on simple incorporation of a targeting ligand into the MB shell, such as physical absorption [12], electrostatic interaction [13] and the streptavidin-biotin technology [14,15]. However, these methodologies have their own drawbacks. ...
Molecular ultrasound imaging with actively targeted microbubbles (MB) proved promising in preclinical studies but its clinical translation is limited. To achieve this, it is essential that the actively targeted MB can be produced with high batch-to-batch reproducibility with a controllable and defined number of binding ligands on the surface. In this regard, poly (n-butyl cyanoacrylate) (PBCA)-based polymeric MB have been used for US molecular imaging, however, ligand coupling was mostly done via hydrolysis and carbodiimide chemistry, which is a multi-step procedure with poor reproducibility and low MB yield. Herein, we developed a single-step coupling procedure resulting in high MB yields with minimal batch-to-batch variation. Actively targeted PBCA-MB were generated using an aminolysis protocol, wherein amine-containing cRGD was added to the MB using lithium methoxide as a catalyst. We confirmed the successful conjugation of cRGD on the MB surface, while preserving their structure and acoustic signal. Compared to the conventional hydrolysis protocol, aminolysis resulted in higher MB yields and better reproducibility of coupling efficiency. Optical imaging revealed that under flow conditions, cRGD- and rhodamine-labelled MB, generated by aminolysis, specifically bind to tumor necrosis factor-alpha (TNF-α) activated endothelial cells in vitro. Furthermore, US molecular imaging demonstrated a markedly higher binding of the cRGD-MB than of control MB in TNF-α activated mouse aortas and 4T1 tumors in mice. Thus, using the aminolysis based conjugation approach, important refinements on the production of cRGD-MB could be achieved that will facilitate the production of clinical-scale formulations with excellent binding and ultrasound imaging performance.
Graphical Abstract
... These microbots are biocompatible and comparatively safe. NCs that were a size of 200-300 nm were obtained ( Figure 1A); this size is ideal for transfections in tumor therapy since they can extravasate to the tumor area [16]. Zeta potential of +16 mV was obtained (Figure 1B), and a positive potential represents an advantage in targeted delivery therapies and transfection efficiency since the cell membrane is negatively charged, so cationic NCs can have a strong electrostatic interaction with the cell, which results in rapid endocytosis and allows for efficient transfection [17]. ...
In cancer, the use of microbots based on anaerobic bacteria as specific transporters targeting tumor tissues has been explored since most solid tumors exhibit hypoxic regions. The aim of this study was to develop and characterize magnetic microbots based on Bifidobacteria and iron oxide fluorescent magnetic nanoparticles complexed with chitosan and a hypoxia inducible plasmid. In addition, the efficiency of the microbots for gene delivery to solid tumors was evaluated in an in vivo model by florescence and luminescence. To elaborate microbots, iron oxide fluorescent magnetic nanoparticles complexed with chitosan and a hypoxia-inducible plasmid called nanocomplex (NCs) with a size of 302 nm and a ζ potential of +16 mV were obtained and loaded onto Bifidobacteria membranes. Microbots with a diameter between 1–2 µm were characterized by atomic force microscopy (AFM) and scanning electron microscopy (SEM). Microbots were injected intravenously through the tail vein to tumor-bearing mice, and then a magnet was placed to focus them to the tumor area. Forty-eight hours after injection, the biodistribution was determined by florescence and luminescence. The greatest luminescence and fluorescence emitted were found in tumor tissue compared with the normal organs. We created a vector that can be directed by a magnet and deliver genes whose expression is regulated by hypoxic microenvironment of tumor.
... Generally, the adsorption of the protein onto the particles' surfaces yields an albumin-mediated steric stabilization. Additionally, albumin coating diminishes phagocytosis of nanocarriers by macrophages and increases their colloidal stability and circulation lifetime in albumin-containing media [15,16]. In the context of tuning the monodispersity as well as the maximization of the coverage and of an irreversible adsorption, knowledge of the protein behavior under various pHs and ionic strengths is essential for robust protocol development. ...
The protein Human Serum Albumin (HSA) is known to undergo conformational transitions towards partially unfolded forms triggered by acidification below pH 4.5. The extent of Fatty Acids (FA) binding has been thought to have an impact on the conformational equilibrium between the native and acid forms and to be a possible explanation for the observation of more than one band in early electrophoretic migration experiments at pH 4. We compared the acid-induced unfolding processes of commercial FA-free HSA, commercial "fatted" HSA and FA-HSA complexes, prepared at FA:HSA molar ratios between 1 and 6 by simple mixing and equilibration. We used a method for continuous acidification based on the hydrolysis of glucono-δ-lactone from pH 7 to pH 2.5, and followed the average protein changes by the blue shift of the intrinsic fluorescence emission and by performing a small angle X-ray scattering analysis on selected samples. The method also allowed for continuous monitoring of the increase of turbidity and laser light scattering of the protein samples related to the release of the insoluble ligands with acidification. Our results showed that the presence of FA interacting with albumin, an aspect often neglected in biophysical studies, affects the conformational response of the protein to acidification, and slightly shifts the loss of the native shape from pH 4.2 to pH 3.6. This effect increased with the FA:HSA molar ratio so that with three molar equivalents a saturation was reached, in agreement with the number of high-affinity binding sites reported for the FA. These findings confirm that a non-uniform level of ligand binding in an albumin sample can be an explanation for the early-observed conformational heterogeneity at pH 4.
... The non-reactive methods are conducted in two stages [21]: the first, which consists in the elaboration of a polymer solution with defined concentration; and the second, which consists in the application of a precipitation process, such as: solvent evaporation [3,[22][23][24], solvent displacement [25][26][27][28][29][30], salting out [31][32][33], solvent diffusion [34][35][36] and supercritical technology [37][38][39]. ...
The present study aims to present a system for the production of nano particles of poly (methyl methacrylate) (PMMA) and polycaprolactone (PCL) based on the atomization of polymer solution in anti-solvent medium. In this system, polymer solutions are prepared and atomized in the form of a spray. The droplets generated from atomization come into contact with anti-solvent liquid that causes the precipitation and formation of the polymeric nanoparticles. In this study, experiments using the proposed system were performed under different operating conditions and the particles obtained were analyzed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results demonstrated nano and microparticles with a size distribution ranging from 50 to 3000 nm. The morphology and the particle size distribution (PSD) was modified by simple changes in the synthesis as the nature of the polymer, the type of solvent, the atomization pressure and the temperature of the anti-solvent liquid.
... Colloidal stabilizers could affect the zeta potential as well owing to their adsorption on the surface of nanospheres. The lower zeta potential of PBCA nanoparticles was observed after coating with amphiphilic polyanionic poly (styreneco-maleic acid) (PSMA) [42]. P188 is a triblock copolymer of poly(propylene oxide) (PPO) block and poly(ethylene oxide) (PEO) blocks (PEO-PPO-PEO). ...
The article describes the preparation, physicochemical characterization, drug release, and in vivo behavior of 10-hydroxycamptothecin-loaded poly (n-butyl cyanoacrylate) nanospheres (HCPT-PBCA-NSs). HCPT-PBCA-NSs were successfully prepared via emulsion polymerization of n-butyl cyanoacrylate (BCA) monomer in acidic medium with the aid of two colloidal stabilizers (Poloxamer 188 and Dextran 70). The influence of pH, the time of polymerization, and the dosage of the drug on particle size and encapsulation efficiency (EE) were studied. HCPT-PBCA-NSs were of spherical shape and uniformly dispersed with a particle size of 135.7 nm, and zeta potential of -18.18 mV. EE, drug loading (DL), and yield of HCPT-PBCA-NSs were 51.52%, 0.63%, and 88.25%, respectively. FTIR, 1H NMR, and DSC showed complete polymerization of BCA monomer and HCPT existed in the form of molecular or amorphous in NSs. In vitro release of the drug from HCPT-PBCA-NSs exhibited sustained-release behavior with an initial burst release and about 60% of HCPT was released from the formulation within 24 h of dialysis. The pharmacokinetic study in healthy rats after oral administration showed that encapsulation of HCPT into PBCA-NSs increased the Cmax about 3.84 times and increased AUC0-t about 5.40 times compared with that of HCPT suspension. It was concluded that PBCA-NSs could be a promising drug carrier to load HCPT for oral drug delivery if efforts are made in the future to improve its poor drug loading capacity.
... In past decades, surface-enhanced Raman scattering (SERS), has proved to be a versatile interfacial spectroscopic tool for analyzing pollutants and biological samples, due to its enormous enhancements occurring on noble metal nanostructures [2][3][4]. On the other hand, the nanostructure materials can act as efficient quenching platforms of fluorophores [5][6][7][8][9][10]. ...
A rapid and mild coating strategy was applied on the millimeter scale calcium alginate capsules (Ca‐SA caps) by in situ interfacial polymerization of ethyl cyanoacrylate (ECA). The generated poly(ethyl cyanoacrylate) (PECA) coating was initiated by trace water in the surface of the Ca‐SA caps. The effects of ECA content, reaction time, and type of aromatic solvent on the morphology and control‐release property of the resulting PECA‐coated Ca‐SA caps (Ca‐SA caps@PECA) were investigated. The results demonstrated a white PECA layer successfully coated on the surface of Ca‐SA caps. Notably, the Ca‐SA caps@PECA remained consistently pleasing spherical shape as prepared in methylbenzene and ethylbenzene. When the ECA was 6 mL, the thickness of PECA layer of the Ca‐SA caps@PECA was 43.52 μm. Compared with the Ca‐SA caps, the weight retention ratio of water in the Ca‐SA caps@PECA increased by 254.61%, indicating the effective delay of water diffusion from core of the Ca‐SA caps@PECA. Moreover, the PECA coating improved the stability of the Ca‐SA caps@PECA, which achieved release‐controlling of dye at different pH. This method provides solution for surface modification of fragile hydrogel capsules to effectively control the releasing of liquid core, which is highly valuable in the field of food, cosmetic, and medical delivery.
Cancer affects millions of people worldwide, and it is projected that there will be 1,958,310 new cancer cases and 609,820 cancer fatalities in the United States in 2023. Epirubicin (EPI) is a prospective anticancer chemotherapeutic agent that has demonstrated efficacy against a variety of malignancies, including breast, ovarian, gastric, lung, and pancreatic cancers, as well as non-Hodgkin lymphomas and acute leukemia, which account for approximately 25% of all cancer cases. Utilizing nanotechnology, novel drug delivery systems (DDS) have been developed to enhance the therapeutic efficacy of EPI and resolve its limitations. This article examines various nanocarriers used for EPI delivery and co-delivery, with dimensions ranging from 1.5 to 876 nm, encapsulation efficiencies between 3.9% and 99.6%, zeta potentials between −31 and + 31 mV, and drug release profiles ranging from 10% to 100% over 40 min to two weeks. Functionalized with targeted ligands such as antibodies, aptamers, folic acid, or transferrin, the nanocarriers can respond to pH, temperature, magnetic fields, or enzymes. In addition, the article discusses the advantages and disadvantages of various nanocarrier types and co-delivery strategies, as well as future prospects and difficulties. This exhaustive analysis provides the most recent data on multiple nanocarriers for EPI delivery and co-delivery, focusing on their design principles, modes of action, and therapeutic effects.
The encapsulation of active pharmaceutical ingredients (APIs) within drug delivery systems such as polymeric nanoparticles (PNPs) vastly improves the therapeutic efficiency of the incorporated APIs. PNPs synthesised using amphiphilic block copolymers are efficient drug delivery systems as the hydrophobic block facilitates the encapsulation of lipophilic components and the hydrophilic block constitutes the hairy corona of the PNP that stabilizes the nanocarriers against aggregation in solution. Poly(styrene‐alt‐maleic acid) (SMA) is an attractive polymer for the hydrophilic corona of PLA based nanoparticles as it allows for post polymerization functionalization and aids in the prevention of NP aggregation. The synthesis of a novel PLA‐b‐SMA block copolymer, via sequential ring opening polymerization (ROP) and reversible addition‐fragmentation chain transfer (RAFT) polymerization, is presented. PLA macro‐CTAs, synthesised via ROP, could be chain extended via RAFT copolymerization of styrene and maleic anhydride to yield PLA‐b‐SMAnh and via RAFT polymerization of N‐vinylpyrrolidone to yield PLA‐b‐PVP block copolymers. Controlled hydrolysis of the anhydride moieties converts PLA‐b‐SMAnh into PLA‐b‐SMA. Monodisperse PLA‐b‐SMA and PLA‐b‐PVP nanoparticles (NPs) ranging in diameter between 60 and 220 nm were prepared. The lipophilic fluorescent dye DiI was encapsulated within the NPs successfully and these fluorescent NPs were used in a preliminary cell uptake study. This article is protected by copyright. All rights reserved
pH-responsive nanocarrier systems exhibit diverse applications due to their relevance to biological systems where, discrete pH differences are displayed between tissues and cellular compartments. Changes in the physicochemical properties of responsive nanocarriers due to variations in pH, can cause release of their cargos in a targeted and controllable manner offering spatiotemporal control. In this study, bovine serum albumin-poly(2-(diisopropylamino)ethyl methacrylate) (BSA-poly(DPA)) biohybrid nanoparticles were synthesized via controlled radical polymerization and found to be stable in neutral pH (7.4) while, at lower pHs (4–5.5) they were shown to disassemble and release their payload. In vitro tests demonstrated low cytotoxicity and energy-, dose- and time-depended internalization. BSA-poly(DPA) nanocarriers loaded with the metachromatic dye acridine orange, were successfully delivered in HeLa cells where, a pH-triggered release of their cargo into lysosomes was evidenced paving the way for applications related with the treatment of lysosomal diseases.
Anthracyclines (ANT), belong to a group of antineoplastic drugs, are commonly used as chemotherapeutic agents in the treatment of various cancers. During the past decade, the number of cancer patients receiving ANT–based chemotherapy drugs has significantly increased. Generally, ANT are very cytotoxic agents and are known to be accompanied by several unpleasant adverse effects. Therefore, the development of a reliable, accurate and sensitive analytical method is necessary and important to analyze ANT in human biomonitoring. The objective of this review is to provide a summary of various analytical methods (spectroscopic, liquid chromatographic and electroanalytical) that have been reported during the last four decades for the analysis of the five most commonly used ANT, daunorubicin (DNR), doxorubicin (DOX), epirubicin (EPI), idarubicin (IDA), valrubicin (VAL) and their metabolites, alone or in combination with other drugs, in various matrices such as biological matrices, environmental samples and pharmaceutical formulations.
In this paper, 10-hydroxycamptothecin (HCPT)-loaded poly (n-butyl cyanoacrylate) nanoparticles (HCPT-PBCA-NPs) co-modified with polysorbate 80, soybean phospholipids, and polyethylene glycol (100) monostearate were successfully prepared via miniemulsion polymerization, and were characterized for particle size, morphology, zeta potential, encapsulation efficiency (EE) and drug loading capacity (DL). The chemical structure of HCPT-PBCA-NPs and the state of HCPT in the PBCA-NPs were investigated by DSC, FTIR and (1)H NMR. Additionally, drug release, cytotoxicity, cellular uptake capacity, cellular uptake mechanism, and in vivo behavior of NPs were investigated as well. The particles were 92.7nm in size with a high EE of 94.24%. FTIR, (1)H NMR, and DSC demonstrated complete polymerization of BCA monomers and the drug was in a molecular or amorphous form inside the NPs. In vitro release of the drug from HCPT-PBCA-NPs exhibited sustained-release and less than 60% of HCPT was released from the NPs within 24h of dialysis. Cellular uptake study displayed that Caco-2 cell uptake of NPs was governed by active endocytosis, clathrin- and caveolin-mediated process, and increased with the increase of the NPs concentration and the time. The pharmacokinetic study in rats showed that encapsulation of HCPT into PBCA-NPs increased the Cmax and AUC0-t about 6.52 and 7.56 times, respectively, in comparison with the HCPT suspension. It was concluded that HCPT loaded PBCA-NPs prepared by miniemulsion polymerization could be promising in oral drug delivery.
Self-healing hydrogels are attractive for a variety of applications including wound dressings and coatings. This paper describes the facile preparation and characterization of an autonomous self-healing hydrogel system comprising surfactant-free hydrophobic associations. The hydrogel comprised a copolymer of benzyl methacrylate (B), octadecyl methacrylate (O), and methacrylic acid (MA). The hydrogels were prepared via a controlled dehydration procedure to achieve the formation of strong intermolecular hydrophobic associations of the octadecyl groups above a critical polymer concentration. Fractured hydrogels healed within 30 min without any external intervention. Increasing hydrogel polymer content from 31 wt % to 39 wt % resulted in a threefold increase in the shear modulus and 50% reduction of the relaxation time. Addition of 4 mM NaCl to a hydrogel of 31 wt % polymer content resulted in 2.5 times longer relaxation time and 24% decrease in shear modulus. The hydrogels swelled up water by up to four times its weight, which corroborates the robustness of the hydrophobic association crosslinks. The bulk properties of the hydrogels are discussed in terms of the hydrophobic associations of the O-groups and the electrostatic interaction of the MA-groups in the polymer chains. (C) 2017 Wiley Periodicals, Inc.
Objective: Drug loading into nanocarriers is used to facilitate drug delivery to target cells and organs. We have previously reported a change in cellular localization of epirubicin after loading to poly(butyl cyanoacrylate) (PBCA) nanoparticles. We aimed to further investigate the altered cellular localization and cellular responses to the described drug formulation.
Materials and methods: HeLa cells were treated with epirubicin-loaded PBCA nanoparticles prepared by the pre-polymerization method. A systematic study was performed to evaluate the formulation cytotoxicity. Cellular localization and uptake of the formulation as well as cellular response to the treatment were evaluated.
Results: Our studies revealed decreased cytotoxicity of the nanoparticle-formulated epirubicin compared to the free drug as well as a noticeable change in the drug’s intracellular localization. Epirubicin-loaded nanoparticles were internalized via endocytosis, accumulated inside endosomal vesicles and induced a two-fold stronger pro-apoptotic signal when compared to the free drug. The level of the tumor suppressor protein p53 in HeLa cells increased significantly upon treatment with free epirubicin, but remained relatively unchanged when cells were treated with equivalent dose of nanoparticle-loaded drug, suggesting a possible shift from p53-dependent DNA/RNA intercalation-based induction of cytotoxicity by free epirubicin to a caspase 3-induced cell death by the epirubicin-loaded PBCA formulation.
First prepared in 1979, the colloidal nanoparticles based on
biocompatible and bioerosive poly(alkyl cyanoacrylate) materials are
still under investigation and hold promise for the development of novel
formulations for targeted drug delivery. Different types of poly(alkyl
cyanoacrylate) nanoparticles have been developed during the last 33
years, such as nanospheres, nanocapsules, hybrid magnetic-polymer
nanoparticles, long-circulating nanoparticles, as well as nanoparticles
functionalized with targeting ligands. A great variety of bioactive
compounds have been loaded on poly(alkyl cyanoacrylate)
nanoparticles, such as cytostatics, antibiotics, antiviral agents, anti-fungal
drugs, non-steroidal anti-inflammatory drugs, bioactive proteins,
nucleotides, etc. Therefore, this review cannot be and is not intended to
be a complete review of all the research that has been done in this area,
but just to bring together the basic concepts and ideas related to the
preparation and applications of poly(alkyl cyanoacrylate) nanoparticles
as drug carriers, emphasizing on the most important findings and
discussing the future perspectives.
Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).
Nanoparticles developed from poly(alkyl cyanoacrylate) (PACA) biodegradable polymers have opened new and exciting perspectives in the field of drug delivery due to their nearly ideal characteristics as drug carriers in connection with biomedical applications. Thanks to the direct implication of organic chemistry, polymer science and physicochemistry, multiple PACA nanoparticles with different features can be obtained: nanospheres and nanocapsules (either oil- or water-containing) as well as long-circulating and ligand-decorated nanoparticles. This review aims at emphasizing the synthetic standpoint of all these nanoparticles by describing the important aspects of alkyl cyanoacrylate chemistry as well as the experimental procedures and the different techniques involved for the preparation of the corresponding colloidal devices.
Classically, drug-loaded poly(alkylcyanoacrylate) colloidal carriers are prepared by the drug entrapment during emulsion polymerization.
However, a number of chemically sensitive drugs are unstable in the conditions of polymerization or can be irreversibly inactivated
by the highly reactive monomer. Furthermore, the particle size distribution and the molecular weight of formed polymer depend
strongly on the polymerization conditions. Here, we investigate the nanoprecipitation approach for the preparation of pure
and drug-load poly(butylcyanoacrylate) nanoparticles. This method allows the successful entrapment of lipophilic and chemically
labile drugs by avoiding the contact with highly reactive monomers. The anticancer agent chlorambucil is chosen as the model
drug for the incorporation and release studies. Pure and drug-loaded nanoparticles are successfully prepared using various
stabilizers (Polysorbate 80, Pluronic F68, Dextran 40). The nanoparticles coated with Polysorbate 80 are of highest interest
since they could overcome the blood–brain barrier and the multidrug resistance in cancer cells. Such nanoparticles can be
easily prepared by the nanoprecipitation approach reported here.
KeywordsPoly(butylcyanoacrylate)-Nanoparticles-Nanoprecipitation-Chlorambucil-Pluronic F68-Polysorbate 80-Dextran 40
For nanocarrier-based targeted delivery systems, preventing phagocytosis for prolong circulation half life is a crucial task. PEGylated poly(n-butylcyano acrylate) (PBCA) NP has proven a promising approach for drug delivery, but an easy and reliable method of PEGylation of PBCA has faced a major bottleneck.
PEGylated PBCA NPs containing docetaxel (DTX) by modified anionic polymerization reaction in aqueous acidic media containing amine functional PEG were made as an single step PEGylation method. In vitro colloidal stability studies using salt aggregation method and antiopsonization property of prepared NPs using mouse macrophage cell line RAW264 were performed. In vitro performance of anticancer activity of prepared formulations was checked on MCF7 cell line. NPs were radiolabeled with 99mTc and intravenously administered to study blood clearance and biodistribution in mice model.
These formulations very effectively prevented phagocytosis and found excellent carrier for drug delivery purpose. In vivo studies display long circulation half life of PBCA-PEG20 NP in comparison to other formulations tested.
The PEGylated PBCA formulation can work as a novel tool for drug delivery which can prevent RES uptake and prolong circulation half life.
The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors related to their anatomical and pathophysiological differences from normal tissues. For example, angiogenesis leads to high vascular density in solid tumors, large gaps exist between endothelial cells in tumor blood vessels, and tumor tissues show selective extravasation and retention of macromolecular drugs. This EPR effect served as a basis for development of macromolecular anticancer therapy. We demonstrated methods to enhance this effect artificially in clinical settings. Of great importance was increasing systolic blood pressure via slow angiotensin II infusion. Another strategy involved utilization of NO-releasing agents such as topical nitroglycerin, which releases nitrite. Nitrite is converted to NO more selectively in the tumor tissues, which leads to a significantly increased EPR effect and enhanced antitumor drug effects as well. This review discusses molecular mechanisms of factors related to the EPR effect, the unique anatomy of tumor vessels, limitations and techniques to avoid such limitations, augmenting tumor drug delivery, and experimental and clinical findings.
Nanocarriers offer unique possibilities to overcome cellular barriers in order to improve the delivery of various drugs and drug candidates, including the promising therapeutic biomacromolecules (i.e., nucleic acids, proteins). There are various mechanisms of nanocarrier cell internalization that are dramatically influenced by nanoparticles' physicochemical properties. Depending on the cellular uptake and intracellular trafficking, different pharmacological applications may be considered. This review will discuss these opportunities, starting with the phagocytosis pathway, which, being increasingly well characterized and understood, has allowed several successes in the treatment of certain cancers and infectious diseases. On the other hand, the non-phagocytic pathways encompass various complicated mechanisms, such as clathrin-mediated endocytosis, caveolae-mediated endocytosis and macropinocytosis, which are more challenging to control for pharmaceutical drug delivery applications. Nevertheless, various strategies are being actively investigated in order to tailor nanocarriers able to deliver anticancer agents, nucleic acids, proteins and peptides for therapeutic applications by these non-phagocytic routes.
Doxorubicin is a commonly used chemotherapy limited by cardiotoxicity. Pirarubicin, derived from doxorubicin, selectively targets tumors when encapsulated in styrene maleic acid (SMA), forming the macromolecular SMA pirarubicin. Selective targeting is achieved because of the enhanced permeability and retention (EPR) effect. SMA-pirarubicin inhibits the growth of colorectal liver metastases, but tumor destruction is incomplete. The role played by the tumor microcirculation is uncertain. This study investigates the pattern of microcirculatory changes following SMA-pirarubicin treatment.
Liver metastases were induced in CBA mice using a murine-derived colon cancer line. SMA-pirarubicin (100 mg/kg total dose) was administered intravenously in 3 separate doses. Twenty-four hours after chemotherapy, the tumor microvasculature was examined using CD34 immunohistochemistry and scanning electron microscopy. Tumor perfusion and permeability were assessed using confocal in vivo microscopy and the Evans blue method.
SMA-pirarubicin reduced the microvascular index by 40%. Vascular occlusion and necrosis were extensive following treatment. Viable cells were arranged around tumor vessels. Tumor permeability was also increased.
SMA-pirarubicin damages tumor cells and the tumor microvasculature and enhances tumor vessel permeability. However, tumor necrosis is incomplete, and the growth of residual cells is sustained by a microvascular network. Combined therapy with a vascular targeting agent may affect residual cells, allowing more extensive destruction of tumors.
We have studied the interaction of macromolecular anticancer agent SMANCS, a conjugate of partially half-butyl-esterified styrene-co-maleic acid polymer[butyl-SMA]- and neocarzinostatin (NCS), with various serum proteins by the fluorescence polarization method. Comparatively strong binding of FITC-labeled SMANCS (F-SMANCS) to human serum albumin (HSA) and weak binding to fibrinogen were observed, while other serum proteins did not exhibit any appreciable binding profile. From Scatchard polt analysis, the asso ciation constant of binding for F-SMANCS to HSA at 37 °C, pH 7.4 was calculated to be 2.19 × 106 M-1 and the number of moles of F-SMANCS bound to 1 mol of HSA was 3.2 Binding of F-NCS to HSA was not observed. The F-SMANCS bound to HSA was effectively displaced by butyl-SMA, but not by NCS. This evidence supports that SMANCS binds to HSA through butyl-SMA, not through NCS portion. A role of the alkyl ester groups of SMA derivatives to HSA binding was investigated by competitive inhibition using butyl-SMA, ethyl-SMA, H-SMA and short chain butyl-SMA. The degree of competitive in hibition was stronger in the following order: butyl-(n = 6) > ethyl (n = 6) = short butyl-(n = 4) > H-SMA. The number of carbons introduced by esterification and the hydrophobicity of SMA derivatives both positively in fluence the binding affinity to HSA. The binding site for SMANCS on HSA was investigated. From the competitive inhibition of known standard drugs (war farin, diazepam and digitoxin) and endogenous substance (bilirubin) in the albumin binding. The binding site on HSA appears to be in the close vicinity to the warfarin or diazepam binding site, and might partially overlap with the bilirubin binding site. These data support that the prolonged plasma half-life of SMANCS in vivo reported previously can be attributed to this albumin binding.
In this review, I have discussed various issues of the cancer drug targeting primarily related to the EPR (enhanced permeability and retention) effect, which utilized nanomedicine or macromolecular drugs. The content goes back to the development of the first polymer-protein conjugate anticancer agent SMANCS and development of the arterial infusion in Lipiodol formulation into the tumor feeding artery (hepatic artery for hepatoma). The brief account on the EPR effect and its definition, factors involved, heterogeneity, and various methods of augmentation of the EPR effect, which showed remarkably improved clinical outcomes are also discussed. Various obstacles involved in drug developments and commercialization are also discussed through my personal experience and recollections.
The surface charges on biodegradable albumin nanoparticles were introduced by covalent coupling different primary amines to examine their influence on phagocytosis by macrophages under in vitro conditions. Albumin particles with a zeta potential close to zero showed a reduced phagocytic uptake in comparison with charged particles, especially nanoparticles with a positive zeta potential. The phagocytic uptake in the present study was examined using an established cell culture model based on primary mouse peritoneal macrophages and a human hematopoietic monocytic cell line (U-937) treated with phorbol-12-myristic-13-acetate to induce cell differentiation. The influence of opsonins on in vitro phagocytosis experiments was characterized using carriers pre-treated with human serum. In the presence of human serum the phagocytic activity of U-937 cells was found to be similar to primary mouse macrophages without serum. In contrast to peritoneal macrophages, U-937 cells showed no phagocytic activity in the absence of serum. In particular, only the C3b- complement deposition on the particle surface seems to promote the phagocytic process. The in vivo distribution of albumin carriers in rats was investigated using magnetic resonance imaging (MRI). No differences in blood circulation times and organ accumulation between different nanoparticle preparations with positive, neutral and negative surface charges could be observed in rats, suggesting that the in vivo fate of albumin nanoparticles is significantly influenced by factors not reflected in the in vitro cell culture models.
Proteins bind the surfaces of nanoparticles, and biological materials in general, immediately upon introduction of the materials into a physiological environment. The further biological response of the body is influenced by the nanoparticle–protein complex. The nanoparticle's composition and surface chemistry dictate the extent and specificity of protein binding. Protein binding is one of the key elements that affects biodistribution of the nanoparticles throughout the body. Here we review recent research on nanoparticle physicochemical properties important for protein binding, techniques for isolation and identification of nanoparticle-bound proteins, and how these proteins can influence particle biodistribution and biocompatibility. Understanding the nanoparticle–protein complex is necessary for control and manipulation of protein binding, and allows for improved engineering of nanoparticles with favorable bioavailability and biodistribution.
Unlabelled:
Recent technological advances in nanomedicine and nanotechnology in parallel with knowledge accumulated from the clinical translation of disease- and drug-related genomic data have created fertile ground for personalized medicine to emerge as the new direction in diagnosis and drug therapy. To this end, the development of sophisticated nano-based systems for targeted drug delivery, along with the advent of pharmacogenomics, moves the drug-prescription process toward pharmacotyping, e.g., the individualized adjustment of drug selection and dosage. However, the clinical validity and utility of pharmacogenomic testing must be demonstrated by cost-effectiveness analysis and establishment of clinical-practice reimbursement codes. Within this framework, and to achieve major benefits for all patients worldwide, a multidisciplinary scientific and technological infrastructure has to be organized in the healthcare system to address better the issues affecting regulatory environment, clinical pharmacology guidelines, education, bioethics and genomics data dissemination.
From the clinical editor:
Individualized pharmacotyping, patient and disease-specific delivery of drugs, combining nanotechnology and pharmagenomics-based approaches would result in much more specific and efficient treatment of a variety of illnesses. While this clearly is one of the main cornerstones of individualized medicine; the cost effective integration of this complex technology is far from trivial, as discussed in details in this opinion paper.
Enhanced permeability and retention (EPR) effect is the physiology-based principal mechanism of tumor accumulation of large molecules and small particles. This specific issue of Advanced Drug Delivery Reviews is summing up multiple data on the EPR effect-based drug design and clinical outcome. In this commentary, the role of the EPR effect in the intratumoral delivery of protein and peptide drugs, macromolecular drugs and drug-loaded long-circulating pharmaceutical nanocarriers is briefly discussed together with some additional opportunities for drug delivery arising from the initial EPR effect-mediated accumulation of drug-containing macromolecular systems in tumors.
Nanoparticles developed from poly(alkyl cyanoacrylate) (PACA) biodegradable polymers have opened new and exciting perspectives in the field of drug delivery due to their nearly ideal characteristics as drug carriers in connection with biomedical applications. Thanks to the direct implication of organic chemistry, polymer science and physicochemistry, multiple PACA nanoparticles with different features can be obtained: nanospheres and nanocapsules (either oil‐ or water‐containing) as well as long‐circulating and ligand‐decorated nanoparticles. This review aims at emphasizing the synthetic standpoint of all these nanoparticles by describing the important aspects of alkyl cyanoacrylate chemistry as well as the experimental procedures and the different techniques involved for the preparation of the corresponding colloidal devices. Copyright © 2008 John Wiley & Sons, Inc.
This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies
This review considers some of the obstacles to successful drug targeting and delivery of therapeutic agents to desired target sites in the body, in the context of the sometimes overblown claims made for nanoparticle and nanosystem based delivery. It covers aspects of issues surrounding the instability of particles in vivo through flocculation and aggregation, their complex flow and adhesion patterns in the capillary network, particle jamming and bridging, the heterogeneity of access of drugs to some sites such as tumours even in their free molecular state, the diffusion of free drug and nanoparticles in tumour tissue and in single cells. There are the fundamental laws of physics and materials, especially in relation to diffusion, adsorption, adhesion and hydrodynamics, which apply and these cannot be denied in our attempts to target carriers to anatomically distant targets, tumours being the archetypal target experiencing most of the barriers which prevent quantitative carrier and hence drug uptake. The paper closes with a discussion of some of the unmet challenges which must be addressed before quantitative delivery and targeting is achieved in many disease states. It is clear that if progress is to be made an International System for testing nanoparticulate delivery systems should be established. In this way data from different laboratories will be comparable. The International protocol should cover both in vitro and in vivo testing.
This review highlights the properties of nanoparticles used in targeted drug delivery, including delivery to cells as well as organelle targets, some of the known pharmacokinetic properties of nanoparticles, and their typical modifications to allow for therapeutic delivery. Nanoparticles exploit biological pathways to achieve payload delivery to cellular and intracellular targets, including transport past the blood-brain barrier. As illustrative examples of their utility, the evaluation of targeted nanoparticles in the treatment of cancers and diseases of the central nervous system, such as glioblastoma multiforme, neurovascular disorders, and neurodegenerative diseases, is discussed.
The in vitro protein-rejecting properties of PEG-coated polyalkylcyanoacrylate (PACA) nanoparticles were for the first time visualized after freeze-fracture of the nanoparticles pre-incubated with fibrinogen as a model blood protein. The reduced protein association to the nanoparticles was evidenced also by two-dimensional PAGE after incubation of the nanoparticles with human plasma. In vivo experiments showed the 'stealth' long-circulating properties of the PEGylated nanoparticles after intravenous administration to mice. Thus, the images obtained after nanoparticle-protein incubation were predictive of the behavior observed in vivo. In conclusion, freeze-fracture analysis represents a novel and original qualitative approach to investigate the interactions between proteins and particulate systems.
This review article describes three aspects of polymeric drugs. The general mechanism of the EPR (enhanced permeability and retention) effect and factors involved in the effect are discussed, in view of the advantages of macromolecular therapeutics for cancer treatment, which are based on the highly selective EPR-related delivery of drug to tumor. Also described are advantages of more general water-soluble polymeric drugs as primary anticancer agents, using SMANCS as an example. Last, SMANCS/Lipiodol is discussed with reference to the type of formulation for arterial injection with most pronounced tumor selective delivery, as well as its advantages, precautions, and side effects from the clinical standpoint.
This review considers the use of poly(alkylcyanoacrylates) (PACAs) as biomedical materials. We first present the different aspects of the polymerization of alkylcyanoacrylate monomers and briefly discuss their applications as skin adhesives, surgical glues and embolitic materials. An extensive review of the developments and applications of PACAs as nanoparticles for the delivery of drugs is then given. The methods of preparation of the nanoparticles are presented and considerations concerning the degradation, in vivo distribution, toxicity and cytotoxicity of the nanoparticles are discussed. The different therapeutic applications are presented according to the route of administration of the nanoparticles and include the most recent developments in the field.
We report a molecular simulation study of doxorubicin interacting within a frame of n-butyl polycyanoacrylate, one of the most commonly encountered polymers in the production of nanoparticles. Emphasis is put on the tetrameric, hexameric and octameric oligomers (PACA's). Log P was calculated for all interacting species. Molecular dynamics along with energy minimization processes (molecular mechanics MM2, semi-empirical quantum mechanics PM3) were employed to probe the conformational behavior of doxorubicin and polyalkylcyanoacrylate both as isolated species and interacting with each other. A docked structure of protonated doxorubicin with two octamers of n-butyl polycyanoacrylate is described. Among the main stability factors of the assembly was the charge-dipole interaction representing a stabilizing contribution of -33 kcal/mol. The mechanism of aggregation and desegregation (doxorubicin release) can be summarized as follows: oligomeric PACA's are lipophilic entities that scavenge amphiphilic doxorubicin already during the polymerization process by extraction of the protonated species from the aqueous environment to the increasingly lipophilic phase of the growing PACA's. The establishment of hydrogen bonds between the ammonium N-H function and the cyano groups is noteworthy. The cohesion in PACA nanoparticle comes therefore from a blend of dipole-charge interaction, H bonds, and hydrophobic forces,
Copolymer of styrene-maleic acid (SMA) was used to construct micelles containing doxorubicin by means of a hydrophobic interaction between the styrene moiety of SMA and doxorubicin (Dox). The micelles obtained (SMA-Dox) showed a high solubility in water and a constant doxorubicin release rate of about 3-4%/day in vitro. The SMA-Dox micelle preparation was less (36-70%) cytotoxic to the SW480 human colon cancer cell line in vitro compared with free doxorubicin. In vivo assay of SMA-Dox in ddY mice bearing S-180 tumor revealed a potent anticancer effect with no remarkable toxicity up to a dose of 100 mg/kg of free doxorubicin equivalent. The drug concentration in tumor after administration of SMA-Dox was 13 times higher than that after the free drug. This result can be attributed to the enhanced permeability and retention (EPR) effect of macromolecular drugs observed in solid tumors. Complete blood counts and cardiac histology showed no serious side effects for intravenous (i.v.) doses of the micellar formulation as high as 100 mg/kg doxorubicin equivalent in mice. These data indicate that i.v. administration of SMA-Dox micellar formulation can enhance the therapeutic effect of doxorubicin while reducing greatly cardiac and bone marrow toxicity, which should allow safe use of high doses of this agent.
The copolymer of styrene-maleic acid (SMA) was used to construct micelles containing pirarubicin (4'-O-tetrahydropyranyladriamycin, or THP) as a new anticancer drug formulation. The procedure for the preparation of the micelles was simple, the component consisting of only SMA and pirarubicin in a noncovalent association, possibly by hydrophobic interaction between the styrene portion of SMA and pirarubicin chromophore. This method ensures more than 80% recovery of pirarubicin by weight, and 60% of drug loading (by weight) was achieved. The micelles obtained (SMA-THP) showed high solubility in water and a constant pirarubicin release rate of about 3-4%/day in vitro. SMA-THP micelles had an average molecular size of about 34 kDa according to gel chromatography; this size is a marked increase from the 627.6 Da of free THP, which suggests the formation of a micellar structure. When albumin was added, the molecular size of the micelles increased to about 94 kDa, which indicates binding to albumin, a unique characteristic of SMA. SMA-THP micelle preparation had a cytotoxic effect (93-101%) on MCF-7 breast cancer cells and SW480 human colon cancer cells in vitro that was comparable to that of free THP. An in vivo assay of SMA-THP at doses of 20 mg/kg in ddY mice bearing S-180 tumor revealed complete tumor eradication in 100% of tested animals. Mice survived for more than 1 year after treatment with micellar drug doses as high as 100 mg/kg pirarubicin equivalent. This marked antitumor activity can be attributed to the enhanced permeability and retention (EPR) effect of macromolecular drugs seen in solid tumors, which enables selective delivery of drugs to tumor and thus much fewer side effects. Complete blood counts, liver function test, and cardiac histology showed no sign of adverse effects for intravenous doses of the micellar preparation. These data thus suggest that intravenous administration of the SMA-THP micellar formulation can enhance the therapeutic effect of pirarubicin more than 50-fold.
The process of opsonization is one of the most important biological barriers to controlled drug delivery. Injectable polymeric nanoparticle carriers have the ability to revolutionize disease treatment via spatially and temporally controlled drug delivery. However, opsonin proteins present in the blood serum quickly bind to conventional non-stealth nanoparticles, allowing macrophages of the mononuclear phagocytic system (MPS) to easily recognize and remove these drug delivery devices before they can perform their designed therapeutic function. To address these limitations, several methods have been developed to mask or camouflage nanoparticles from the MPS. Of these methods, the most preferred is the adsorption or grafting of poly(ethylene glycol) (PEG) to the surface of nanoparticles. Addition of PEG and PEG-containing copolymers to the surface of nanoparticles results in an increase in the blood circulation half-life of the particles by several orders of magnitude. This method creates a hydrophilic protective layer around the nanoparticles that is able to repel the absorption of opsonin proteins via steric repulsion forces, thereby blocking and delaying the first step in the opsonization process.
In this article a method is described to prepare composite colloidal nanoparticles, consisting of a magnetic core (carbonyl iron) and a biodegradable polymeric shell [poly(butylcyanoacrylate) or PBCA]. The method is based on the so-called anionic polymerization procedure, often used in the synthesis of poly(alkylcyanoacrylate) nanospheres designed for drug delivery. Interest of this investigation is based upon the fact that the heterogeneous structure of the particles can confer them both the possibility to respond to external magnetic fields and to be used as drug carriers. In order to investigate to what extent do the particles participate of this mixed properties, we compare in this work the physical characteristics (structure, chemical composition, specific surface area and surface electrical and thermodynamic properties) of the core/shell particles with those of both the nucleus and the coating material. This preliminary study shows that the mixed particles display an intermediate behavior between that of carbonyl iron and PBCA spheres. Electrophoretic mobility measurements as a function of pH and as a function of KNO3 concentration, show a great similarity between the core/shell and pure polymer nanoparticles. Similarly, a surface thermodynamic study performed on the three types of particles demonstrated that the electron-donor component of the surface free energy of the solids is very sensitive to the surface composition. In fact, a measurable decrease of such component is found for core/shell particles as compared to carbonyl iron. We also analyzed the influence of the relative amounts of polymer and carbonyl iron on the characteristics of the composite particles: data on the coating thickness, the amount of polymer bound to the magnetic nuclei, the redispersibility characteristics of the suspensions and the surface electrical and thermodynamic properties, suggest that the optimal synthesis conditions are obtained for a 4/3 initial monomer/carbonyl iron weight ratio.
The historical development of nanoparticles starting with Paul Ehrlich and then first attempts by Ursula Scheffel and colleagues and the extensive work by the group of Professor Peter Speiser at the ETH Zürich in the late 1960s and early 1970s are described from a personal point of view. Special attention is given to the years between 1970 and the early 1980s. Further developments resulting from this work are also followed, and focus is placed on especially interesting improvements such as nanoparticles for the delivery of drugs across the blood-brain barrier (BBB) and PEGylated nanoparticles with a prolonged blood circulation time.
The relationship between the time-dependent change in serum proteins adsorbed on nanoparticles and their disposition to the liver was investigated by employing lecithin-coated polystyrene nanosphere with a size of 50 nm (LNS-50) as a model nanoparticle in rats. The total amount of proteins adsorbed on LNS-50 increased and the qualitative profile of serum proteins adsorbed on LNS-50 changed during the incubation with serum up to 360 min. The liver perfusion study indicated that the hepatic uptake of LNS-50 incubated with serum for 360 min was significantly larger than those of LNS-50 incubated for shorter period. It was suggested that the increase in the hepatic uptake of LNS-50 with the increase in incubation time would be ascribed mainly to the increase in the opsonin-mediated uptake by Kupffer cells. Semi-quantification of major opsonins, complement C3 (C3) and immunoglobulin G (IgG), and in vitro uptake study in primary cultured Kupffer cells demonstrated that the increase in C3 and IgG amounts adsorbed on LNS-50 was directly reflected in the increased disposition of LNS-50 to Kupffer cells. These results indicate that the amounts of opsonins associated on nanoparticles would change over time and this process would be substantially reflected in the alteration of their hepatic disposition characteristics.
The possible combination of specific physicochemical properties operating at unique sites of action within cells and tissues has led to considerable uncertainty surrounding nanomaterial toxic potential. We have investigated the importance of proteins adsorbed onto the surface of two distinct classes of nanomaterials (single-walled carbon nanotubes [SWCNTs]; 10-nm amorphous silica) in guiding nanomaterial uptake or toxicity in the RAW 264.7 macrophage-like model. Albumin was identified as the major fetal bovine or human serum/plasma protein adsorbed onto SWCNTs, while a distinct protein adsorption profile was observed when plasma from the Nagase analbuminemic rat was used. Damaged or structurally altered albumin is rapidly cleared from systemic circulation by scavenger receptors. We observed that SWCNTs inhibited the induction of cyclooxygenase-2 (Cox-2) by lipopolysaccharide (LPS; 1 ng/ml, 6 h) and this anti-inflammatory response was inhibited by fucoidan (scavenger receptor antagonist). Fucoidan also reduced the uptake of fluorescent SWCNTs (Alexa647). Precoating SWCNTs with a nonionic surfactant (Pluronic F127) inhibited albumin adsorption and anti-inflammatory properties. Albumin-coated SWCNTs reduced LPS-mediated Cox-2 induction under serum-free conditions. SWCNTs did not reduce binding of LPS(Alexa488) to RAW 264.7 cells. The profile of proteins adsorbed onto amorphous silica particles (50-1000 nm) was qualitatively different, relative to SWCNTs, and precoating amorphous silica with Pluronic F127 dramatically reduced the adsorption of serum proteins and toxicity. Collectively, these observations suggest an important role for adsorbed proteins in modulating the uptake and toxicity of SWCNTs and nano-sized amorphous silica.
Albumin is playing an increasing role as a drug carrier in the clinical setting. Principally, three drug delivery technologies can be distinguished: coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugation with bioactive proteins and encapsulation of drugs into albumin nanoparticles. The accumulation of albumin in solid tumors forms the rationale for developing albumin-based drug delivery systems for tumor targeting. Clinically, a methotrexate-albumin conjugate, an albumin-binding prodrug of doxorubicin, i.e. the (6-maleimido)caproylhydrazone derivative of doxorubicin (DOXO-EMCH), and an albumin paclitaxel nanoparticle (Abraxane) have been evaluated clinically. Abraxane has been approved for treating metastatic breast cancer. An alternative strategy is to bind a therapeutic peptide or protein covalently or physically to albumin to enhance its stability and half-life. This approach has been applied to peptides with antinociceptive, antidiabetes, antitumor or antiviral activity: Levemir, a myristic acid derivative of insulin that binds to the fatty acid binding sites of circulating albumin, has been approved for the treatment of diabetes. Furthermore, Albuferon, a fusion protein of albumin and interferon, is currently being assessed in phase III clinical trials for the treatment of hepatitis C and could become an alternative to pegylated interferon. This review gives an account of the different drug delivery systems which make use of albumin as a drug carrier with a focus on those systems that have reached an advanced stage of preclinical evaluation or that have entered clinical trials.
Nanocarriers' entry into the cell: relevance to drug delivery
- H Hillaireau
- P Couvreur
H. Hillaireau, P. Couvreur, Nanocarriers' entry into the cell: relevance to drug
delivery, Cell. Mol. Life Sci. 66 (2009) 2873-2896.