Linolenic acid-modified methoxy poly (ethylene glycol)-oligochitosan conjugate micelles for encapsulation of amphotericin B.

Introduction of linolenic acid (LNA) and methoxy poly (ethylene glycol) (MPEG) to the backbone of oligochitosan (CS) afforded LNA-modified MPEG-CS conjugate (MPEG-CS-LNA). Amphotericin B-loaded MPEG-CS-LNA micelles (AmB-M) were prepared via dialysis method with 82.27 ± 1.96% of drug encapsulation efficiency and 10.52 ± 0.22% of drug loading capacity. The AmB-M enhanced AmB's water-solubility to 1.64 mg/mL, being 1640-folds higher than native AmB. The AmB-M obviously reduced hemolytic effect and renal toxicity of AmB when compared to marketed AmB injection (AmB-I). Its antifungal activity against Candida albicans was equivalent to AmB-I although AmB's release from AmB-M was significantly retarded. According to fluorescence microscopy test, the unchanged activity should be attributed to enhanced fungal cellular uptake of AmB-M caused by combined inducement of LNA and CS. The pharmacokinetic studies demonstrated that AmB-M also improved the pharmacokinetic parameters of AmB with AmB-I as control. Conclusively, developed LNA-modified MPEG-CS micellar system could be a viable alternative to the current toxic commercial AmB-I as a highly efficacious drug delivery system.

Oligochitosan-pluronic 127 conjugate for delivery of honokiol.

Honokiol-loaded micelles were prepared by emulsion-solvent evaporation procedure when oligochitosan-pluronic conjugate (CS-F127) as carrier. Differential scanning calorimetry (DSC) indicated that honokiol existed in amorphous form when it was encapsulated into the micelles with 87.54 ± 1.52% of encapsulation efficiency (EE) and 12.51 ± 0.22% of drug loading (DL) capacity. The water-solubility was increased to 1.46 mg/mL, being >27-folds higher than pure honokiol. The in vitro release study demonstrated a slow and sustained ± release of honokiol from the drug-loaded micelles with pure honokiol as control. The in vitro antifungal and cellular uptake tests indicated that the drug-loaded micelles showed the same activity as pure honokiol against Candida albicans due to its good cellular uptake although it slowly released honokiol. The pharmacokinetic test results showed that the honokiol-loaded micelles increased area under curves and mean retention time of honokiol with low clearance rate and apparent distribution volume when compared with pure honokiol, showing its ability to improve honokiol's pharmacokinetic properties. The honokiol-loaded micelles also showed good bio-security to normal cells and main organs of mice. In conclusion, the CS-F127 conjugate should be a potential carrier for honokiol or other antifungal agents in the treatment of fungal infections.

Recent Progress of Nano-drug Delivery System for Liver Cancer Treatment.

Liver cancer is one of serious diseases which threaten human life and health. Studies on the treatment of liver cancer have attracted widespread attention. Application of nano-drug delivery system (NDDS) can not only improve selective drug delivery to liver tissue and improve the bioavailability of drug, but also can reduce the side effects of drugs when it is specially modified in the respects of structure modification or specific target molecules decoration. This review will address the latest development of liver-targeted drug delivery system.

Y-shaped methoxy poly (ethylene glycol)-block-poly (epsilon-caprolactone)-based micelles for skin delivery of ketoconazole: in vitro study and in vivo evaluation.

Ketoconazole is a hydrophobic broad-spectrum antifungal agent for skin infection therapy. In order to develop topical formulation of ketoconazole for improving its selective skin deposition and water-solubility, ketoconazole-loaded Y-shaped monomethoxy poly(ethylene glycol)-block-poly(ɛ-caprolactone) micelles were prepared through thin-film hydration method with high entrapment efficiency (96.1±0.76%) and small particle (about 58.66nm). The drug-loaded micelles showed comparative in vitro antimicrobial activity with KET cream. In ex in vivo skin deposition and permeation study, ketoconazole-loaded micelles provided skin accumulation higher than marketed ketoconazole cream without obvious permeation in the whole period. Fluorescence microscopy study and histopathological study demonstrated the copolymeric micelles' penetrating into skin in depth due to its capability of weakening the barrier function of stratum corneum. In vivo skin deposition parameters further confirmed high skin deposition of drug-loaded micelles (AUC(0-t)=396.16µg·h/cm2) over marketed ketoconazole cream (AUC(0-t)=250.03µg·h/cm2). Meanwhile, in vivo pharmacokinetic parameters proved that ketoconazole-loaded micelles reduced ketoconazole's distribution in blood in comparison with the cream (AUC(0-t)=93,028.00µg·h/L vs AUC(0-t)=151,714.00µg·h/L), meaning lower possibility of its systemic unwanted effects in the skin fungal infection treatment. The results suggested that the copolymeric micelles can be adopted for specific delivering ketoconazole into skin for fungal infection cure.

In vitro characterization of pH-sensitive azithromycin-loaded methoxy poly (ethylene glycol)-block-poly (aspartic acid-graft-imidazole) micelles.

In order to improve azithromycin's antibacterial activity in acidic medium, monomethoxy poly (ethylene glycol)-block-poly (aspartic acid-graft-imidazole) copolymer was synthesized through allylation, free radical addition, ring-opening polymerization and amidation reactions with methoxy poly (ethylene glycol) as raw material. Drug loading capacity and encapsulation efficiency of azithromycin-loaded micelles prepared via thin film hydration method were 11.58±0.86% and 96.06±1.93%, respectively. The drug-loaded micelles showed pH-dependent property in the respects of particle size, zeta potential at the range of pH 5.5-7.8. It could control drug in vitro release and demonstrate higher release rate at pH 6.0 than that at pH 7.4. In vitro antibacterial experiment indicated that the activity of azithromycin-loaded micelles against S. aureus was superior to free azithromycin in medium at both pH 6.0 and pH 7.4. Using fluorescein as substitute with pH-dependent fluorescence decrease property, laser confocal fluorescence microscopy analysis confirmed that cellular uptake of micelles was improved due to protonation of copolymer's imidazole groups at pH 6.0. The enhanced cellular uptake and release of drug caused its activity enhancement in acidic medium when compared with free drug. The micellar drug delivery system should be potential application in the field of bacterial infection treatment.

Enhanced effect in combination of curcumin- and ketoconazole-loaded methoxy poly (ethylene glycol)-poly (ε-caprolactone) micelles.

In order to enhance water-solubility and realize controlled release while keeping synergistic effects of ketoconazole and curcumin, drug-loaded methoxy poly (ethylene glycol)-b-poly (ε-caprolactone) micelles were prepared through thin membrane hydration method. Transmission electric microscopy and dynamitic light scattering characterization revealed the formation of ketoconazole- and curcumin-loaded micelles with an average size of 44.70nm and 39.56nm, respectively. The drug-loaded micelles endowed the two drugs' slow controlled release with water-solubility enhanced to 85 and 82000 folds higher than the corresponding raw drugs, respectively. In vitro antifungal activity test, chequerboard test and inhibition zone test indicated that efficacy of ketoconazole-loaded micelles was improved by introduction of curcumin-loaded micelles with a low fractional inhibitory concentration index (0.073). Biofilm formation inhibition assay also demonstrated that participation of curcumin-loaded micelles obviously strengthened the inhibition of fungal biofilms formation induced by ketoconazole-loaded micelles. The high synergistic activity of combinations is encouraging and the MPEG-PCL micelle is a potential drug delivery system for the combination of ketoconazole and curcumin.

Y-shaped Folic Acid-Conjugated PEG-PCL Copolymeric Micelles for Delivery of Curcumin.

BACKGROUND: Curcumin is a natural hydrophobic product showing anticancer activity. Many studies show its potential use in the field of cancer treatment due to its safety and efficiency. However, its application is limited due to its low water-solubility and poor selective delivery to cancer. OBJECTIVE: A Y-shaped folic acid-modified poly (ethylene glycol)-b-poly (ε-caprolactone)2 copolymer was prepared to improve curcumin solubility and realize its selective delivery to cancer. METHOD AND RESULTS: The copolymer was synthesized through selective acylation reaction of folic acid with α- monoamino poly(ethylene glycol)-b-poly(ε-caprolactone)2. Curcumin was encapsulated into the copolymeric micelles with 93.71% of encapsulation efficiency and 11.94 % of loading capacity. The results from confocal microscopy and cellular uptake tests showed that folic acid-modified copolymeric micelles could improve cellular uptake of curcumin in Hela and HepG2 cells compared with folic acid-unmodified micelles. In vitro cytotoxicity assay showed that folic acid-modified micelles improved anticancer activity against Hela and HepG2 cells in comparison to folic acidunmodified micelles. Meanwhile, both drug-loaded micelles demonstrated higher activity against Hela cell lines than HepG2. CONCLUSION: The research results suggested that the folic acid-modified Y-shaped copolymeric micelles should be used to enhance hydrophobic anticancer drugs' solubility and their specific delivery to folic acid receptors-overexpressed cancer.

Methoxy poly (ethylene glycol)-b-poly (δ-valerolactone) copolymeric micelles for improved skin delivery of ketoconazole.

Ketoconazole is a broad spectrum imidazole antifungal drug. For the treatment of superficial fungal infections with ketoconazole, it needs to be permeated to deep skin layers. In order to develop topical formulation of ketoconazole for improving its skin deposition and water-solubility, ketoconazole-loaded methoxy poly (ethylene glycol)-b-poly (δ-valerolactone) micelles were developed through thin-film hydration method. Particle size, drug loading capacity, infrared spectrum and X-ray diffraction of drug-loaded micelles were characterized. The optimal drug formulation was selected for skin delivery and deposition investigation performed by use of mice skin, and its in vitro release and antifungal activity were also investigated. Penetration and distribution in the skin were also visualized using fluorescein-loaded micelles and fluorescence microscopy. The drug-loaded micelles were obtained with encapsulation efficiency of 86.39% and particle diameter of about 12 nm. The micelles made ketoconazole aqueous solubility increase to 86-fold higher than crude one. Ketoconazole-loaded micelles showed no skin permeation of ketoconazole, obviously enhance skin deposition and demonstrated similar antifungal activity as compared with marketed ketoconazole cream. Fluorescein-loaded micelles displayed higher skin deposition than fluorescein water solution. These results demonstrate that the MPEG-PVL micelle is a potential delivery system for ketoconazole in the field of skin delivery.

Development on PEG-modified Poly (Amino Acid) Copolymeric Micelles for Delivery of Anticancer Drug.

BACKGROUND: Polymeric micelles can provide a valid way for cancer treatment with several benefits including high water-solubility of lipophilic drugs, low unwanted effects of cytotoxic drugs by way of reduced systemic exposure and prolonged retention time in the circulatory system. OBJECTIVE: Recently, there is an increasing interest in preparing poly (ethylene glycol)-poly (amino acid) copolymeric micelles as drug delivery carriers due to their multifunctional property, easy decoration and biosafety. The copolymer contains several functional groups, which show stronger interactions with drugs or can be transferred to develop different types of the copolymers showing pH-, reduction-, thermo-sensitive, targeted or double-function properties. In addition, conjugation of drugs with these copolymers also becomes a novel modification method with the aim of higher drug loading capacity and stability. Copolymeric micelles show exciting advantages on improving a drug's water-solubility, release behavior, in vitro activity, targeted delivery pharmacokinetic property and biodistribution. In this review, we will introduce the recent development of poly(ethylene glycol)-modified poly (amino acid) copolymeric micelles as anticancer drug delivery systems containing different stimuli (such as thermo-, pH-, reduction- or special enzyme- condition) functional groups and targeting ligands to improve cellular uptake or biostablility of drug-loaded micelles. CONCLUSION: Poly (ethylene glycol)-poly (amino acid) copolymeric micelles provide an opportunity to realize anticancer drug delivery with environment-responsive and/or targeting property.

Recent Development of Copolymeric Delivery System for Anticancer Agents Based on Cyclodextrin Derivatives.

Core-shell structured aggregates of amphiphilic block copolymer are hopefully drug delivery system because of their ability to encapsulate hydrophobic drugs, and their hydrophilic shell can prolong retention time of drugs in the blood circulation system. Cyclodextrin is a kind of hydrophilic polysaccharide containing multiple hydroxyl groups, providing an inner hole that can load small molecule through host-guest interaction. These hydroxyl groups or their derived functional ones are utilized in conjugation with polymeric chains to form block copolymers. These copolymers can not only encapsulate hydrophobic drugs, but also encapsulate hydrophilic drugs (like DNA, protein, etc) through hydrophobic, host-guest or electrostatic interactions, which strengthen interaction between drugs and materials compared with general copolymers, indicating that formed drug delivery systems are more stable. By introduction of target molecule, they also achieve selective delivery of drugs to specific tissues or organs. So, several researchers are stimulated to carry out many studies for the development of cyclodextrin copolymeric drug delivery systems in recent. In this review, we focus the cyclodextrin copolymers' application in the anticancer agents' delivery.