Micelles based on polyvinyl alcohol substituted with oleic acid for targeting of lipophilic drugs

Polymeric micelles based on polyvinyl alcohol substituted with oleic acid were used as vehicles for progesterone and folic acid. The ability of this amphiphilic polymer to entrap lipophilic drugs and to generate stable micelles in aqueous neutral medium makes it a good candidate for drug delivery. The release of the loaded drugs in acidic environments represents another important property of these systems. Size of micelles, their stability, and their drug-loading capacity were evaluated, as well as the in vitro controlled-release profiles at pH 7.4 and 5.5.     

Non-ionic micellar affinity capillary electrophoresis for analysis of interactions between micelles and drugs

Micellar affinity capillary electrophoresis (MACE) was introduced to evaluate the affinity of various kinds of drugs as benzoic acid, salicylic acid, trinitrophenol, p-hydroxybenzoic acid and o-acetylsalicylic acid. Non-ionic micelles as Brij 35 (polyethylenglycol dodecylether), Tagat (polyoxyethylene (20) glycerol monooleate) and Tween 20 (polyoxyethylen sorbitan monolaurate) were used as a pseudostationary phase in capillary electrophoresis. For polyvinyl alcohol (PVA) coated capillary was used in this examinations. The drugs had negative electrophoretic mobilities at a pH value of pH 7.2. The negatively charged drugs migrated toward the anode and were related by their interaction with the micelles. The difference in the mobility of the drugs owing to the presence of the micelles reflected the interaction between these drugs and the micelles. Equations were derived to calculate the capacity factor k' from the migration times in the presence of micelles t' and in the absence of micelles t, the partition coefficients Pwm and the Gibbs free energy. The drugs show different interaction and affinity with the micelles in the systems. Strong interaction was observed between benzoic acid and the micelles. Furthermore, a linear relationship (R = 0.999) was obtained between deltaG(o) and ln Pwm in the micellar solubilization of drugs. These results show that deltaG(o) can give us information on the affinity and on the partition behaviour of the drugs in these systems.     

Efficient entrapment of poorly water-soluble pharmaceuticals in hybrid nanoparticles

Polymeric micelles consisting of amphiphilic block copolymers have emerged as a promising carrier of various drugs, but unfortunately show a limited potential for encapsulating (solubilizing) such drugs. In this study, hybrid nanoparticles consisting of monomethoxypolyethyleneglycol-polylactide block copolymer (PEG-PLA) and oleic acid calcium salt were prepared to enhance the solubilization of poorly water-soluble drugs. Micelles made of a mixture of sodium oleate and PEG-PLA at various ratios were used as the template for preparation of the nanoparticles. These mixed micelles could efficiently solubilize poorly water-soluble drugs in aqueous media, when compared with polymeric micelles made of PEG-PLA alone. Addition of calcium to the mixed micelles induced the formation of oleic acid calcium salt, resulting in hybrid nanoparticles. These hybrid nanoparticles had a high colloidal stability, neutral zeta potential, and high drug entrapment efficiency. Drugs entrapped in nanoparticles made at a high PEG-PLA ratio were protected from enzymatic degradation in serum, while drugs entrapped in the mixed micelles were not, indicating that the hybrid nanoparticles show good drug retention. These results suggested that such hybrid nanoparticles may be used to expand the availability of poorly water-soluble drugs for various therapeutic applications.     

去氧胆酸修饰的聚合物胶束的构建及其跨膜转运的研究

口服给药是患者顺应性最好的给药方式,而小肠上皮是口服药物吸收的主要屏障.为了克服小肠上皮屏障口服递送难溶性药物,本研究设计合成了小肠胆酸转运体的底物脱氧胆酸偶联的聚(2-乙基-2-噁唑啉)-聚(D,L-乳酸)(DA-PEOz-PLA),并基于小肠胆酸特殊的转运途径构建了由DA-PEOz-PLA和mPEG-PLA组成的聚...     

Multi-drug delivery to tumor cells via micellar nanocarriers

The aim of this study was to develop micellar nanocarriers for concomitant delivery of paclitaxel and 17-allylamino-17-demethoxygeldanamycin (17-AAG) for cancer therapy. Paclitaxel and 17-AAG were simultaneously loaded into polymeric micelles by a solvent evaporation method. Two candidate nanocarrier constructs, polyethylene glycol-poly(D, L-lactic acid) (PEG-PLA) micelles and PEG-distearoylphosphatidylethanolamine/tocopheryl polyethylene glycol 1000 (PEG-DSPE/TPGS) mixed micelles, were assessed for the release kinetics of the loaded drugs. Compared to PEG-PLA micelles, entrapment of paclitaxel and 17-AAG into PEG-DSPE/TPGS mixed micelles resulted in significantly prolonged release half-lives. The simultaneous incorporation of paclitaxel and 17-AAG into PEG-DSPE/TPGS mixed micelles was confirmed by (1)H NMR analysis. Paclitaxel/17-AAG-loaded PEG-DSPE/TPGS mixed micelles were as effective in blocking the proliferation of human ovarian cancer SKOV-3 cells as the combined free drugs. PEG-DSPE/TPGS mixed micelles may provide a novel and advantageous delivery approach for paclitaxel/17-AAG combination therapy.     

Block copolymer micelles as long-circulating drug vehicles

The development of block copolymer micelles as long-circulating drug vehicles is described. As well, a recent fundamental study of block copolymer micelles, where much insight into their structures and properties has been realized, is briefly summarized in order to shed light on their properties in vivo. There is emphasis on block copolymer micelles having poly(ethylene oxide) as the hydrophilic block and poly(l-amino acid) as the hydrophobic block, with some discussion on the properties of poly(ethylene oxide). Comparisons are drawn with other drug vehicles and with micelles formed from low molecular weight surfactants. Micelle-forming, block copolymer-drug conjugates are described. Hydrophobic drugs, such as doxorubicin, distribute into block copolymer micelles, and details of several examples are given. Finally, the paper presents studies that evidence the long circulation times of block copolymer micelles. Like long-circulating liposomes, block copolymers that form micelles accumulate passively at solid tumors and thus have great potential for anti-cancer drug delivery.     

Choleresis and hepatic transport mechanisms

Summary To investigate binding of drugs to biliary micelles as a possible factor in the hepatic transport process, interaction of two uncharged compounds, ³H-ouabain and ³H-K-strophanthoside with biliary micelles was studied by ultracentrifugation of bile. The various bile acids normally present in rat bile were predominantly associated with cholesterol containing micelles, but not to the same extent. The tendency of the bile salts to be associated with mixed micelles was the greatest for conjugated chenodeoxycholate, somewhat lower for conjugated deoxycholate and the least for conjugated cholate. The sedimentation patterns of the water-soluble cardiac glycosides, added in vitro, indicated binding to mixed biliary micelles as well as non-cholesterol containing micelles. Also mannitol, a drug used to estimate canalicular bile flow, was found to be associated with both categories of biliary micelles.In spite of the binding of cardiac glycosides to the micelles, administration of taurocholate, which promotes formation of biliary micelles, did not stimulate biliary output of both glycosides. Also administration of the choleretics dehydrocholate and ethacrynic acid failed to enhance biliary output of the glycosides.These results indicate, that binding of drugs to biliary micelles diminishes the free concentration of drugs in bile and confirms earlier studies with organic anions that binding to biliary micelles is not a pertinent factor in the rate of biliary excretion.     

Evaluation of the Interaction and Drug Release from α,β-Polyaspartamide Derivatives to a Biomembrane Model

This Article reports on a comparative study on the ability of various polymers, containing hydrophilic and/or hydrophobic groups, to interact with a biomembrane model using the differential scanning calorimetry (DSC) technique. Multilamellar vesicles of mixed dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidic acid (DMPA) were chosen as a model of cell membranes. The investigated samples were a water soluble polymer, the α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) and its derivatives partially functionalized with polyethylene glycol (PEG₂₀₀₀) to obtain PHEA-PEG₂₀₀₀, with hexadecylamine (C₁₆) to obtain PHEA-C₁₆, and with both compounds to obtain PHEA-PEG₂₀₀₀-C₁₆. These polymers are potential candidates to prepare drug delivery systems. In particular, some samples give rise to polymeric micelles able to entrap hydrophobic drugs in an aqueous medium. The migration of drug molecules from these micelles to DMPC/DMPA vesicles also has been evaluated by DSC analysis, by using ketoprofen as a model drug.     

Self-assembled polyion complex micelles for sustained release of hydrophilic drug

Graft copolymer polyethylenimine-graft-poly(N-vinylpyrrolidone) (PEI-g-PVP) was prepared by coupling mono carboxyl-terminated PVP (PVP-COOH) with PEI using N,N'-dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS) as coupling agents. In aqueous medium, PVP-g-PEI can self-assemble into stable polyion complex micelles with an oppositely charged block copolymer, poly(N-vinylpyrrolidone)-block-poly(2-acrylamido-2-methyl-1-propanesulphonic acid) (PVP-b-PAMPS). Transmission electron microscopy images showed that these micelles were regularly spherical in shape. The micelle size determined by size analysis was around 142 nm. To estimate their feasibility as vehicles for drugs, the model drug folic acid (FA) was incorporated into the cores of the micelles via electrostatic interactions. In vitro release test of FA showed that the drug-release rates are dependent on the pH value of the release media. Based on these results, we can conclude that the polyion complex micelles prepared from the PEI-g-PVP/PVP-b-PAMPS copolymers have great potential as drug delivery nanocarriers.     

PEG–lipid micelles as drug carriers: physiochemical attributes,formulation principles and biological implication

PEG–lipid micelles, primarily conjugates of polyethylene glycol (PEG) and distearyl phosphatidylethanolamine (DSPE) or PEG–DSPE, have emerged as promising drug-delivery carriers to address the shortcomings associated with new molecular entities with suboptimal biopharmaceutical attributes. The flexibility in PEG–DSPE design coupled with the simplicity of physical drug entrapment have distinguished PEG–lipid micelles as versatile and effective drug carriers for cancer therapy. They were shown to overcome several limitations of poorly soluble drugs such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Therefore, considerable efforts have been made to exploit the full potential of these delivery systems; to entrap poorly soluble drugs and target pathological sites both passively through the enhanced permeability and retention (EPR) effect and actively by linking the terminal PEG groups with targeting ligands, which were shown to increase delivery efficiency and tissue specificity. This article reviews the current state of PEG–lipid micelles as delivery carriers for poorly soluble drugs, their biological implications and recent developments in exploring their active targeting potential. In addition, this review sheds light on the physical properties of PEG–lipid micelles and their relevance to the inherent advantages and applications of PEG–lipid micelles for drug delivery.     

Analytical methods for the determination of folic acid in a polymeric micellar carrier

Amphiphilic copolymers have been the object of growing scientific interest due to their ability to form polymeric micelles in aqueous environments entrapping lipophilic drugs in their inner core. In this study, polyvinylalcohol substituted with oleic acid was employed as an amphiphilic micellar carrier for folic acid (FA), a model drug similar for its chemical-physical characteristics to methotrexate. In order to investigate the stability of the polymeric micelles, the drug incorporation and the kinetic aspects of drug release from these systems, selective analytical methods are required. The development of three analytical methods suitable for selectively identifying and reliably determining FA contained in the micelles and in the delivery systems is reported. UV derivative (first and second order) spectrophotometry was first applied to the aqueous solution of the FA containing micelles obtained at pH 9.0 and provided a characteristic spectral profiling with sharp peaks, related to the analyte, whose amplitude was used for quantitative application. A second approach involved a solid phase extraction (strong anion exchanger), which provided an effective clean up of the FA micelles solution, allowing accurate analysis to be performed also by a conventional spectrophotometric method. A RP-HPLC method, selectively supplying the FA separation from the micelles' components, was then used as a reference method to determine the accuracy of the spectrophotometric methods. These methods were applied to various micelle composition and to the delivery system study.     

Formulation of drugs in block copolymer micelles: drug loading and release

Block copolymer micelles have become accepted as a viable strategy for drug formulation and delivery. Block copolymer micelles may serve as solubilizers and/or true drug carriers depending on their drug retention properties in vivo. Indeed the formulation of hydrophobic drugs in these micelle systems has been shown to provide up to a 30,000 fold increase in the water solubility of some compounds. In addition, the administration of drugs in copolymer micelles has been shown to reduce their toxicity and improve their therapeutic efficacy. The present review is focused on the drug loading and release properties of block copolymer micelles. Specifically, the properties of the drug, properties of the micelle core and the presence of interactions between the drug and the core-forming block are discussed in terms of their influence on the drug loading and release properties of the micelles. The various methods employed to prepare drug-loaded micelles are reviewed and the in vitro release assays used to predict the in vivo release characteristics of the formulations are discussed. The balance between drug loading and micelle stability is highlighted as a critical factor in the optimization of micelle-based formulations. The in vivo performance of micelles as delivery systems is evaluated by comparing the pharmacokinetics of free drug and drug administered in micelle-based formulations. Overall, the composition-property and property-performance relationships outlined in this review may aid in guiding the rational design of block copolymer micelles for drug delivery. In addition, suggestions for future research in this area are provided as a means to assist in furthering block copolymer micelles as one of the leading advanced drug delivery technologies for the systemic administration of drugs.     

Mechanism for the inducement of the intestinal absorption of poorly absorbed drugs by mixed micelles II. Effect of the incorporation of various lipids on the permeability of liposomal membranes

The mechanism for the enhancement of the intestinal absorption of drugs in the presence of mixed micelles was investigated using liposomal membranes as a biomembrane model. The effect of the incorporation of various lipids on the permeability of drugs through liposomal membranes was studied. Liposomes were prepared from egg phosphatidylcholine. Lipids used were fatty acids, glycerides, oleyl alcohol and methyl oleate, and drugs were phenol red, bromphenol blue, cefazolin, sulfanilic acid and procainamide ethobromide (PAEB). The absorption of these drugs in the large intestine was enhanced by the addition of monoolein—bile salt mixed micelles. The incorporation of monoolein into liposomal membranes markedly increased the release rate of these drugs through the membranes. Unsaturated fatty acids such as oleic acid and linoleic acid markedly enhanced the release rate of PAEB, while saturated fatty acids caused a small increase in the release rate. Diolein, triolein, oleyl alcohol, methyl oleate, oleic acid and linoleic acid had no enhancing effect on the release of phenol red. The effect of the treatment of liposomes with various solutions on the permeability of drugs through the membranes was investigated. Treatment solutions were a lipid—bile salt mixed micellar solution, a lipid-emulsion and a bile salt micellar solution. The treatment with a mixed micellar solution increased the release and the uptake of drugs. Temperature-dependent studies demonstrated that the incorporation of monoolein caused a decrease in the activation energy for the permeation process of phenol red through liposomal membranes from 17.5 to 14.3 kcal/mol.     

Targeted delivery by pH-responsive mPEG-S-PBLG micelles significantly enhances the anti-tumor efficacy of doxorubicin with reduced cardiotoxicity

Stimuli-responsive nanotherapeutics hold great promise in precision oncology. In this study, a facile strategy was used to develop a new class of pH-responsive micelles, which contain methoxy polyethylene glycol (mPEG) and poly(carbobenzoxy-l-glutamic acid, BLG) as amphiphilic copolymer, and β-thiopropionate as acid-labile linkage. The mPEG-S-PBLG copolymer was synthesized through one-step ring-opening polymerization (ROP) and thiol-ene click reaction, and was able to efficiently encapsulate doxorubicin (DOX) to form micelles. The physicochemical characteristics, cellular uptake, tumor targeting, and anti-tumor efficacy of DOX-loaded micelles were investigated. DOX-loaded micelles were stable under physiological conditions and disintegrated under acidic conditions. DOX-loaded micelles can be internalized into cancer cells and release drugs in response to low pH in endosomes/lysosomes, resulting in cell death. Furthermore, the micellar formulation significantly prolonged the blood circulation, reduced the cardiac distribution, and selectively delivered more drugs to tumor tissue. Finally, compared with free DOX, DOX-loaded micelles significantly improved the anti-tumor efficacy and reduced systemic and cardiac toxicity in two different tumor xenograft models. These results suggest that mPEG-S-PBLG micelles have translational potential in the precise delivery of anti-cancer drugs.     

Triblock polymeric micelles as carriers for anti-inflammatory drug delivery

Abstract

This study evaluated the properties of poly(ethylene oxide)-b-poly(n-butyl acrylate)-b-poly(acrylic acid) (PEO-PnBA-PAA) polymeric micelles as carriers for anti-inflammatory drugs (prednisolone and budesonide). The micelles comprising a hydrophobic PnBA core and a PEO/PAA corona showed average diameter less than 40?nm. The size of the drug-loaded micelles did not change during eight hours into media that mimic physiological fluids indicating high colloidal stability. The calculation of Flory–Huggins parameter showed greater compatibility between budesonide and micellar core suggesting its location in the micellar core, whereas prednisolone was located also into the interface layer. This observation correlated further with slower release of budesonide, especially in acid medium (pH?=?1.2). The inclusion of budesonide into micelles showed significant protective effect against the cytotoxic damage induced by the co-cultivation of differentiated human EOL-1 and HT-29 cells. This study revealed the capacity of PEO-PnBA-PAA terpolymer as carrier of nanosized micelles suitable for oral delivery of anti-inflammatory drugs.     

Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers

This review describes our recent efforts on the design and preparation of intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) (PEG-PAA) block copolymers. The polymeric micelles feature a spherical sub-100 nm core-shell structure in which anticancer drugs are loaded avoiding undesirable interactions in vivo. Chemical modification of the core-forming block of PEG-PAA with a hydrazone linkage allows the polymeric micelles to release drugs selectively at acidic pH (4-6). Installation of folic acids on the micelle surface improves cancer cell-specific drug delivery efficiency along with pH-controlled drug release. These intelligent micelles appear to be superior over classical micelles that physically incorporate drugs. Studies showed both controlled drug release and targeted delivery features of the micelles reduced toxicity and improved efficacy significantly. Further developments potentiate combination delivery of multiple drugs using mixed micelles. Therefore clinically relevant performance of the polymeric micelles provides a promising approach for more efficient and patient-friendly cancer therapy.     

Poly(ethylene oxide)-block-poly(L-amino acid) micelles for drug delivery

Block copolymer micelles encapsulate water insoluble drugs by chemical and physical means, and they may target therapeutics to their site of action in a passive or active way. In this review, we focus on micelles self-assembled from poly(ethylene oxide)-block-poly(L-amino acid) (PEO-b-PLAA). A common theme in these studies is the chemical modification of the core-forming PLAA block used to adjust and optimize the properties of PEO-b-PLAA micelles for drug delivery. Micelle-forming block copolymer-drug conjugates, micellar nanocontainers and polyion complex micelles have been obtained that mimic functional aspects of biological carriers, namely, lipoproteins and viruses. PEO-b-PLAA micelles may be advantageous in terms of safety, stability, and scale-up.     

Micelles in anticancer drug delivery

In recent years, the development of micelle-based carriers for cancer chemotherapy has been the object of growing scientific interest, both in academia and the pharmaceutical industry. Micelles have attracted attention in drug formulation and targeting, given that they provide a set of unique features. The core/shell structure accounts for their qualities as efficient drug delivery systems. The core provides a reservoir where hydrophobic drugs can be dissolved, and the corona confers hydrophilicity to the overall system. Sequestration of anticancer drugs in the inner core can protect them from premature degradation and allow their accumulation at tumoral sites. Micelles can be subdivided into two different groups according to their molecular weights: low-molecular-weight surfactant micelles and polymeric micelles. Although surfactant micelles such as polyethoxylated castor oil (e.g. Cremophor® EL) are commonly used to solubilize hydrophobic anticancer drugs such as paclitaxel, they have often been associated with serious adverse effects. Polymeric micelles may offer several advantages over surfactant micelles in terms of drug loading, adverse effects, stability, and targeting of tumors. Indeed, polymeric micelles can increase the circulation time of cytostatics and induce substantial changes in their biodistribution, including tumor accumulation via the enhanced permeation and retention effect. In addition, some recent studies have demonstrated that amphiphilic block copolymers (e.g. poloxamers) used for the preparation of polymeric micelles could increase the activity of several cytostatics by reversing multidrug resistance. This review first describes and compares surfactant micelle and polymeric micelle systems, already commercialized or under investigation, used to administer cytostatics. Secondly, their in vitro interactions with neoplastic cells and tissues are discussed in terms of cellular uptake and pharmacologic activity. In particular, the pharmacokinetics and biodistribution of micelles, along with the factors affecting their delivery to tumoral sites, are thoroughly discussed. Finally, in vivo studies reporting the anticancer activity and toxicity of drugs associated with micelles are reviewed.     

Intestinal absorption of drugs. The influence of mixed micelles on on the disappearance kinetics of drugs from the small intestine of the rat.

The solubilization of the hydrophilic drugs paracetamol and theophylline, and the lipophilic drugs dantrolene, griseofulvin and ketoconazole has been determined in mixed micellar aqueous dispersions composed of 10 mM taurocholate + 5 mM oleic acid. The solubilization of dantrolene and paracetamol has also been determined in aqueous (mixed) micellar dispersions of 1 g L-1 lysophosphatidyl-choline (LPC), or taurocholate/LPC. The influence of these (mixed) micelles on the absorption of the model drugs from solution was studied in the rat chronically isolated internal loop. Absorption kinetics of the drugs were evaluated on the basis of the disappearance rate of the drug dissolved in the perfusion medium in this loop. Absorption experiments with taurocholate/oleic acid in the perfusate resulted in a reduction of the disappearance rate for the lipophilic drugs and the hydrophilic drug theophylline. This could partly be ascribed to the decreased fraction of drug free in solution as a result of its micellar solubilization for dantrolene, griseofulvin and ketoconazole, but the decrease in the disappearance rate of theophylline was unexpected. Taurocholate/oleic acid, LPC and taurocholate/LPC micelles had no effect on the disappearance of paracetamol. The disappearance rate of dantrolene in the presence of LPC alone was not altered, in spite of the decreased fraction of the drug free in solution owing to its micellar solubilization. In contrast, taurocholate/LPC micelles caused a reduction in the rate of disappearance of dantrolene, as expected according to the phase-separation model. In-vitro, taurocholate and taurocholate/LPC reduced the molecular cohesion of porcine intestinal mucus, whereas LPC alone did not exhibit an effect on the gel structure of mucus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Self-assembled polyion complex micelles for sustained release of hydrophilic drug

Graft copolymer polyethylenimine–graft–poly(N-vinylpyrrolidone) (PEI-g-PVP) was prepared by coupling mono carboxyl-terminated PVP (PVP–COOH) with PEI using N,N′-dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS) as coupling agents. In aqueous medium, PVP–g–PEI can self-assemble into stable polyion complex micelles with an oppositely charged block copolymer, poly(N-vinylpyrrolidone)–block–poly(2-acrylamido-2-methyl-1-propanesulphonic acid) (PVP-b-PAMPS). Transmission electron microscopy images showed that these micelles were regularly spherical in shape. The micelle size determined by size analysis was around 142?nm. To estimate their feasibility as vehicles for drugs, the model drug folic acid (FA) was incorporated into the cores of the micelles via electrostatic interactions. In vitro release test of FA showed that the drug-release rates are dependent on the pH value of the release media. Based on these results, we can conclude that the polyion complex micelles prepared from the PEI-g-PVP/PVP-b-PAMPS copolymers have great potential as drug delivery nanocarriers.