Enhanced Tumor Targeting and Antitumor Efficacy via Hydroxycamptothecin-Encapsulated Folate-Modified N-Succinyl-N′-Octyl Chitosan Micelles

10-Hydroxycamptothecin (HCPT) is an effective anticancer drug against various types of solid tumors. But the antitumor efficacy of HCPT is far from satisfactory because of its poor physicochemical properties, short circulating half-life, low stability, and nonspecific toxicity to normal tissues. Therefore, a targeted delivery strategy for HCPT to pathological sites is eagerly needed to overcome these limitations. The folate-modified N-succinyl-N′-octyl chitosan (folate-SOC) micelle was chosen in this study and served as the targeted delivery system for HCPT to improve the antitumor efficacy. The water-insoluble anticancer drug HCPT was encapsulated into the folate-SOC micelles by the dialysis method. The near- spherical HCPT-loaded folate-SOC (HCPT/folate-SOC) micelles were formed in aqueous media with diameter of about 100-200 nm. The HCPT/folate-SOC micelles displayed a good stability, reasonable drug-loading content (about 10%), and sustained release behavior for the water- insoluble HCPT. Compared with free HCPT, HCPT/folate-SOC micelles exhibited a significant enhancement of cellular uptake, higher cytotoxicity against folate receptor positive tumor cell (Bel-7402), excellent tumor-targeting capability and substantially better antitumor efficacy on the nude mice bearing Bel-7402 xenografts. These results demonstrate the potential of folate- SOC micelles as long-term stable and effective drug delivery systems in cancer therapy.     

PEGylated chitosan-based polymer micelle as an intracellular delivery carrier for anti-tumor targeting therapy

Stearic acid-grafted chitosan oligosaccharide (CSO-SA) micelles presented a potential candidate for intracellular drug delivery carrier due to its special spatial structure. In this article, CSO-SA was further modified by polyethylene glycol (PEG). The physicochemical properties of PEGylated CSO-SA (PEG-CSO-SA) micelles were characterized. After PEGylation, the critical micelle concentration (CMC) of PEG-CSO-SA had no significant change; the micelle size increased; and the zeta potential decreased. The cellular uptake of CSO-SA micelles before and after PEGylation in macrophage RAW264.7, immortalized rat liver cells BRL-3A and human liver tumor cells HepG2 was studied. About 58.4 ± 0.63% of CSO-SA micelles were uptaked by RAW264.7 in 24 h, however, only 17.7 ± 0.94% of PEG-CSO-SA micelles were internalized into RAW264.7 after the CSO-SA was modified with PEG in five molar times. Meanwhile, there were no changes in the uptake after PEGylation of CSO-SA in BRL-3A and HepG2. Using mitomycin C as a model drug, the in vitro anti-tumor activities of the drug loaded in the micelles were investigated. The 50% cellular growth inhibition (IC₅₀) of the drug decreased from 1.97 ± 0.2 to 0.13 ± 0.02 μg/mL after mitomycin C was loaded into CSO-SA micelles, and the IC₅₀ value of the drug had no obvious change when the CSO-SA was modified by PEG.     

Stabilized polymeric micelles by electrostatic interactions for drug delivery system

Methoxy poly(ethylene glycol)-block-oligo(l-aspartic acid)-block-poly(-caprolactone) with four aspartic acid groups was synthesized with a molecular weight and M_w/M_n of 8930 and 1.22. Polymeric micelles were formed by dialysis and stabilized by electrostatic interactions between the carboxylic acid groups and calcium cations. The critical micelle concentration of mPEG–Asp–PCL was determined to be 0.078 mg/mL. At 0.02 mg/mL, the dissociation of micelles without ionic stabilization formed an opaque, phase-separated solution, while the stabilized micelles under the same conditions showed structural stability through ionic stabilization. The paclitaxel-loading and efficiency were 8.7% and 47.6%, respectively, and the drug loading increased the mean diameter from 73.0 nm to 87 nm, which was increased further to 96 nm after ionic fixation. Rapid releases of approximately 65% of the encapsulated paclitaxel from a non-stabilized micelle and 45% from a stabilized micelle were observed in the first 24 h at pH 7.4 in a PBS solution containing 0.1 wt% Tween 80. The stabilized micelles then showed a sustained, slow release pattern over a couple of weeks, while the profile from the non-stabilized micelles reached a plateau at approximately 75% after 50 h. The enhanced micelle stability independent of concentration through ionic stabilization opens a way for preparing long circulating delivery systems encapsulating water-insoluble drugs.     

In vitro controlled release of clove essential oil in self-assembly of amphiphilic polyethylene glycol-block-polycaprolactone

In this study, a micellar delivery system with an amphiphilic diblock copolymer of poly (ethylene glycol) and poly (?-caprolactone) was synthesised and used to incorporate hydrophobic clove essential oil (CEO). To determine an optimal delivery system, the effects of the copolymer’s hydrophobic block length and the CEO-loading content on the encapsulation of CEO were investigated. Percentages of entrapment efficiency (%EE), CEO loading (%CEO), and in vitro release profiles were determined. The size, size distribution, zeta potential, and morphology of the obtained micelles were determined by DLS, FE-SEM, and TEM. The %EE, %CEO, and in vitro release profiles of CEO incorporated in micelles were analysed by HPLC. The study revealed a sustained release profile of CEO from CEO-loaded micelles. The results indicate the successful formulation of CEO-loaded PEG-b-PCL micelle nanoparticles. It is suggested that this micelle system has considerably potential applications in the sustained release of CEO in intravascular drug delivery.     

Doxorubicin-Loaded Polymeric Micelles Based on Amphiphilic Polyphosphazenes with Poly( N -isopropylacrylamide-co- N , N -dimethylacrylamide) and Ethyl Glycinate as Side Groups: Synthesis, Preparation and In Vitro Evaluation

Purpose  To construct novel Doxorubicin-loaded polymeric micelles based on polyphosphazenes containing N-isopropylacrylamide copolymers and evaluate their various properties as well as in vitro anticancer effect. Methods  These amphiphilic graft polyphosphazenes PNDGP were synthesized via thermal ring-opening polymerization and subsequent two-step substitution reaction of hydrophilic and hydrophobic side groups. Micellization behavior in an aqueous phase was confirmed by fluorescence technique, DLS and TEM. Doxorubicin (DOX) was physically loaded into micelles by dialysis or O/W emulsion method. CLSM and MTT test were applied to observe intracellular drug distribution and determine cytotoxicity of drug-loaded micelles on Hela and HepG2 cells lines, respectively. Results  A series of PNDGPs with controlled substitution ratios were obtained. Poly(NIPAm-co-DMAA) can act as hydrophilic segments in micellular system since its LCST was over 37°C when PNIPAm was copolymerized with DMAA. The CMC value was decreased with the increase of Glyet content. In addition, more hydrophobic group content introduced into the polymer would facilitate DOX encapsulation into the micelle. DOX-loaded micelle could achieve comparative cytotoxicity as free drug via endocytosis and succedent drug release into cytoplasm of cancer cells. Conclusions  The results suggest that these polymers might be used as potential carriers of hydrophobic anti-tumor drug for cancer therapy.     

A Photo-Activated Targeting Chemotherapy Using Glutathione Sensitive Camptothecin-Loaded Polymeric Micelles

Purpose  A novel photo-activated targeted chemotherapy was developed by photochemical internalization (PCI) of glutathione-sensitive polymeric micelles incorporating camptothecin (CPT) prepared from thiolated CPT (CPT-DP) and thiolated poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-P(Glu-DP)) Methods  PEG-b-P(Glu-DP) and CPT-DP were synthesized and characterized by ¹H-NMR and gel permeation chromatography, and then mixed to prepare CPT-loaded polymeric micelles (CPT/m). The CPT release from the micelle was studied by reverse phase liquid chromatography. The PCI-activated cytotoxicity of CPT/m against HeLa cells was studied in combination with a non-toxic concentration of dendrimer phthalocyanine-loaded micelles (DPc/m) as the photosensitizer. Results  The diameter of CPT/m was 96 nm and the drug loading was 20% (w/w). CPT was slowly released under the conditions reproducing the extracellular or endosomal environments. However, under the reductive conditions mimicking the cytosol, CPT was rapidly released achieving approximately 90% of the drug release after 24 h. The cytotoxicity of CPT/m was drastically increased on photoirradiation, whereas the CPT/m were not cytotoxic without PCI. Conclusions  The CPT/m released the drug responding to reductive conditions. The PCI-induced endosomal escape exposed CPT/m to the cytosol triggering the drug release. Thus, CPT/m in combination with DPc/m will behave as smart nanocarriers activated only at photoirradiated tissues. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

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.     

Novel self-assembling PEG-p-(CL-co-TMC) polymeric micelles as safe and effective delivery system for Paclitaxel

Paclitaxel (PTX) is an effective anti-cancer drug currently used to treat a wide variety of cancers. Unfortunately, nonaqueous vehicle containing Cremophor^® EL is associated with serious clinical side effects. This work aimed to evaluate the ability of polymeric micelles to (i) solubilize PTX without Cremophor^® EL and to be used as a (ii) safe and (iii) effective delivery system for PTX. Hence, we developed novel self-assembling poly(ethyleneglycol)₇₅₀-block-poly(ε-caprolactone-co-trimethylenecarbonate) (PEG-p-(CL-co-TMC)) polymeric micelles which form micelles spontaneously in aqueous solution. The solubility of PTX increased up to three orders of magnitude. The PTX-loaded micelles showed a slow release of PTX with no burst effect. The HeLa cells viability assessed by the MTT test was lower for PTX-loaded micelles than for Taxol^® (IC₅₀ 10.6 vs. 17.6 μg/ml). When solubilized in micelles, PTX induced apoptosis comparable with Taxol^®. The maximum tolerated doses (MTD) of PTX-loaded micelles and Taxol^® in mice were 80 mg/kg and 13.5 mg/kg, respectively, after intraperitoneal administration; and 45 mg/kg and 13.5 mg/kg, respectively, after intravenous administration. Similar anti-tumor efficacy of PTX-loaded micelles and Taxol^® was observed at the dose of 13.5 mg/kg on TLT-tumor-bearing mice, while the body weight loss was only observed in Taxol^® group. However, as higher dose was tolerated (80 mg/kg – IP), a higher growth delay was induced with PTX-loaded micelles. These results demonstrated that PTX-loaded self-assembling micelles present a similar anti-tumor efficacy as Taxol^®, but significantly reduced the toxicity allowing the increase in the dose for better therapeutic response.     

Spray-dried casein-based micelles as a vehicle for solubilization and controlled delivery of flutamide: Formulation,characterization, and in vivo pharmacokinetics

Novel casein (CAS)-based micelles loaded with the poorly soluble anti-cancer drug, flutamide (FLT), were successfully developed in a powdered form via spray-drying technique. Genipin (GNP) was used to crosslink CAS micelles as demonstrated by color variation of the micelles. Drug solubilization was enhanced by incorporation within the hydrophobic micellar core which was confirmed by solubility study and UV spectra. Spherical core–shell micelles were obtained with a particle size below 100 nm and zeta potential around −30 mV. At low drug loading, FLT was totally incorporated within micellar core as revealed by thermal analysis. However, at higher loading, excess non-incorporated drug at micelle surface caused a significant reduction in the surface charge density. Turbidity measurements demonstrated the high physical stability of micelles for 2 weeks dependent on GNP-crosslinking degree. In a dry powdered form, the micelles were stable for 6 months with no significant changes in drug content or particle size. A sustained drug release from CAS micelles up to 5 days was observed. After i.v. administration into rats, CAS micelles exhibited a prolonged plasma circulation of FLT compared to drug solution. Furthermore, a more prolonged drug systemic circulation was observed for GNP-crosslinked micelles. Overall, this study reports the application of spray-dried natural protein-based micelles for i.v. delivery of hydrophobic anti-cancer drugs such as FLT.     

Self-Assembled Hydrophobic Honokiol Loaded MPEG-PCL Diblock Copolymer Micelles

Purpose  Honokiol showed potential application in cancer treatment, but its poor water solubility restricts its clinical application greatly. So, we designed a self-assembled monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelle to load honokiol to overcome its poor water solubility. Methods  We synthesized MPEG-PCL diblock copolymer that could self-assemble into monodisperse micelles at the particle size of ca.18 nm in water. Honokiol was loaded into MPEG-PCL micelle by direct dissolution method assisted by ultrasound, without any surfactants, organic solvents, and vigorous stirring. Results  The blank MPEG-PCL micelles (100 mg/mL) did not induce any hemolysis in vitro and showed very low toxicity ex vivo and in vivo. Honokiol could be molecularly incorporated into MPEG-PCL micelles at the drug loading of about 20% by direct dissolution method assisted by ultrasound. After loaded into MPEG-PCL micelles, honokiol maintained its molecular structure and anticancer activity in vitro. Honokiol could be sustained released from MPEG-PCL micelles in vitro. The honokiol loaded MPEG-PCL micelles could be lyophilized without any adjuvant. Conclusion  The prepared honokiol formulation based on self-assembled MPEG-PCL micelle was stable, safe, effective, easy to produce and scale up, and showed potential clinical application. This work was financially supported by National Natural Science Foundation of China (NSFC20704027), National 863 project (2007AA021902, 2007AA021804 and 2006AA03Z356), Specialized Research Fund for the Doctoral Program of Higher Education (200806100065) and Chinese Key Basic Research Program (2004CB518807).     

Pharmacokinetics and biodistribution of polymeric micelles of paclitaxel with pluronic P105/poly(caprolactone) copolymers

A novel polymeric micellar formulation of paclitaxel (PTX) with Pluronic/poly(caprolactone) (P105/ PCL50) has been developed with the purpose of improving in vitro release and in vivo circulating time of PTX in comparison to the current Taxol injection. This study was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of the PTX-loaded, biodegradable, polymeric, P105/PCL50 micelle system. The drug-loaded micelles were prepared by dialysis using the hydrophobic drug, PTX, and the nonionic surfactant Pluronic P105 modified with a low molecular weight PCL. The results of dynamic light scattering (DLS) experiment indicated that the PTX-loaded micelles had a mean size of approximately 150 nm with narrow size distribution (polydispersity index < 0.3). The in vitro release study showed that the release of PTX from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic assessment in rats, in which t1/2 beta and AUC of the PTX micelle formulation were 4.0 and 2.2-fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX micelle formulation not only decreased drug uptake by the liver, but also prolonged drug retention in the blood, and increased the distribution of drug in kidney, spleen, ovaries and uterus. These results suggested that the P105/ PCL50 polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i.v. administration of PTX.     

Novel Redox-Responsive Amphiphilic Copolymer Micelles for Drug Delivery: Synthesis and Characterization

A novel redox-responsive amphiphilic polymer was synthesized with bioreductive trimethyl-locked quinone propionic acid for a potential triggered drug delivery application. The aim of this study was to synthesize and characterize the redox-responsive amphiphilic block copolymer micelles containing pendant bioreductive quinone propionic acid (QPA) switches. The redox-responsive hydrophobic block (polyQPA), synthesized from QPA-serinol and adipoyl chloride, was end-capped with methoxy poly(ethylene glycol) of molecular weight 750 (mPEG₇₅₀) to achieve a redox-responsive amphiphilic block copolymer, polyQPA-mPEG₇₅₀. PolyQPA-mPEG₇₅₀ was able to self-assemble as micelles to show a critical micelle concentration (CMC) of 0.039% w/v (0.39 mg/ml, 0.107 mM) determined by a dye solubilization method using 1,6-diphenyl-1,3,5-hexatriene (DPH) in phosphate-buffered saline (PBS). The mean diameter of polymeric micelles was found to be 27.50 nm (PI = 0.064) by dynamic light scattering. Furthermore, redox-triggered destabilization of the polymeric micelles was confirmed by ¹H-NMR spectroscopy and particle size measurements in a simulated redox state. PolyQPA-mPEG₇₅₀ underwent triggered reduction to shed pendant redox-responsive QPA groups and its polymeric micelles were swollen to be dissembled in the presence of a reducing agent, thereby enabling the release of loaded model drug, paclitaxel. The redox-responsive polyQPA-mPEG₇₅₀ polymer micelles would be useful as a drug delivery system allowing triggered drug release in an altered redox state such as tumor microenvironments with an altered redox potential and/or redox enzyme upregulation.KEY WORDS: amphiphilic polymer, micelle, redox-responsive polymer, targeted drug delivery, trimethyl-locked quinone propionic acid     

Preparation,characterization, and drug release behaviors of drug nimodipine-loaded poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) amphiphilic triblock copolymer micelles

Amphiphilic triblock copolymers, poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) (PCL-PEO-PCL), were synthesized by ring opening polymerization of epsilon-caprolactone initiated with the hydroxyl functional groups of poly(ethylene glycol) at both ends of the chain. The micelles composed of this type of copolymer had such a structure that both ends of the PEO chain were anchored to the micelle. The critical micelle concentration of the block copolymer in distilled water was determined by a fluorescence probe technique using pyrene. As the hydrophobic components of the block copolymer increased, the critical micelle concentration value decreased. To estimate the feasibility as novel drug carriers, the block copolymer micelles were prepared by precipitation of polymer from acetone solution into water. From the observation of transmission electron microscopy, the micelles exhibited a spherical shape. Nimodipine was incorporated into the hydrophobic inner core of micelles as a lipophilic model drug to investigate the drug release behavior. The PEO/PCL ratio of copolymer was a main factor in controlling micelle size, drug-loading content, and drug release behavior. As PCL weight ratio increased, the micelle size and drug-loading content increased, and the drug release rate decreased.     

Drug release from thermo-responsive self-assembled polymeric micelles composed of cholic acid and poly(N-isopropylacrylamide)

Cholic acid, conjugated with amine-terminated poly(N-isopropylacrylamide) (abbreviated as CA/ATPNIPAAm), was synthesized by a N, N'-dicyclohexyl carbodiimide (DCC)-mediated coupling reaction. Self-assembled CA/ATPNIPAAm micelles were prepared by a diafiltration method in aqueous media. The CA/ATPNIPAAm micelles exhibited a lower critical solution temperature (LCST) at 31.5 degrees C. Micelle sizes measured by photon correlation spectroscopy (PCS) were approximately 31.6+/-5.8 nm. The CA/ATPNIPAAm micelles were spherical and their thermal size transition was observed by transmission electron microscope (TEM). A fluorescence probe technique was used for determining the micelle formation behavior of CA/ATPNIPAAm in aqueous solutions using pyrene as a hydrophobic probe. The critical micelle concentration (CMC) was evaluated as 8.9 x 10(-2) g/L. A drug release study was performed using indomethacin (IN) as a hydrophobic model drug. The release kinetics of IN from the CA/ATPNIPAAm micelles revealed a thermo-sensitivity by the unique character of poly(N-isopropylacrylamide) i.e. the release rate was higher at 25 degrees C than at 37 degrees C.     

阿霉素温度/pH双敏型自组装嵌段共聚物胶束的制备

本文用透析法制备了新型温度/pH双敏自组装嵌段共聚物聚组氨酸-聚乳酸羟基乙酸-聚乙二醇-聚乳酸羟基乙酸-聚组氨酸 (OLH-b-PLGA-b-PEG-b-PLGA-b-OLH) 胶束, 采用荧光探针技术测定其不同温度下临界胶束浓度 (CMC); 用透析法测定共聚物胶束的包封率和载药量; 对胶束的粒径、形态和表面电位进行考察, 并对阿霉素胶束的体外释药和pH敏感性进行了研究。CMC介于0.022 4～0.001 7 μg·mL⁻¹, 胶束包封率为92.8%, 载药量为15.7%; 载药胶束粒径为 (61.7 ± 13.4) nm, zeta电位为−9.88 mV; 阿霉素的体外释药速率随pH降低 (pH 7.4～5.0) 而增加。结果表明, 胶束的CMC随温度升高而降低, 体外释药具有明显的pH敏感性, 该载体材料作为抗肿瘤药物的靶向传递系统具有较好的应用前景。     

多西他赛pH敏感嵌段共聚物胶束的制备

本文在合成pH敏感两亲性嵌段共聚物聚(2-乙基-2-噁唑啉)-聚乳酸(PEOz-PDLLA)的基础上，采用薄膜分散法制备多西他赛pH敏感嵌段共聚物胶束，利用芘荧光探针技术测定胶束的临界胶束浓度(CMC)；通过高效液相色谱测定胶束的载药量及包封率；分别利用透射电镜、动态光散射法和zeta电位分析仪对胶束的形态、粒径和表面电位进行了表征；采用透析法考察了载药聚合物胶束的体外释放行为。结果表明，胶束的临界胶束浓度值为1.0×10^-3 g·L^-1；载药量可达15.0%，包封率为91.1%；胶束的粒度分布很窄，平均粒径为28.7nm；胶束粒子为圆球形且分散良好，其表面zeta电位值为(1.19±0.12)mV；在pH 7.4释放介质中，多西他赛胶束具有缓释作用；而在pH 5.0条件下，胶束释药明显加快，体现出PEOz-PDLLA胶束释药行为的pH敏感性。综合上述研究可见，PEOz-PDLLA嵌段共聚物胶束作为疏水性抗肿瘤药物的给药系统具有很好的应用前景。     

Doxorubicin-conjugated PLA-PEG-Folate based polymeric micelle for tumor-targeted delivery: Synthesis and in vitro evaluation

Background

Selective delivery of anticancer agents to target areas in the body is desirable to minimize the side effects while maximizing the therapeutic efficacy. Anthracycline antibiotics such as doxorubicin (DOX) are widely used for treatment of a wide variety of solid tumors.This study evaluated the potential of a polymeric micellar formulation of doxorubicin as a nanocarrier system for targeted therapy of a folate-receptor positive human ovarian cancer cell in line.

Results

DOX-conjugated targeting and non-targeting micelles prepared by the dialysis method were about 188 and 182 nm in diameter, respectively and their critical micelle concentration was 9.55 μg/ml. The DOX-conjugated micelles exhibited a potent cytotoxicity against SKOV3 human ovarian cancer cells. Moreover, the targeting micelles showed higher cytotoxicity than that of non-targeting ones (IC₅₀ = 4.65 μg/ml vs 13.51 μg/ml).

Conclusion

The prepared micelle is expected to increase the efficacy of DOX against cancer cells and reduce its side effects.     

Creation of an assessment system for measuring the bitterness of azithromycin-containing reverse micelles

We aimed to develop a novel method for assessing the bitterness of azithromycin-containing reverse micelles (AM-containing RMs). Azithromycin-containing reverse micelles were prepared by processing Lipoid E80 and medium chain triglycerides via a freeze-drying method. The bitterness threshold of azithromycin was determined by human taste test, and an equation was derived to correlate the azithromycin concentrations and bitterness scores of standard solutions. Simulated salivary fluids and sampling times were fixed based on the drug release profile of AM-containing RMs, with Zithromax^® (a commercial formulation of azithromycin) used as the control. The drug release concentrations from stimulated salivary fluids were then used to assess the bitterness of AM-containing RMs and Zithromax^®. Afterward, the oral bioavailability of both formulations was evaluated by in vivo experiments in male Wistar rats. The results showed that the bitterness threshold of azithromycin standard solutions was between 25.3 µg/ml and 30.4 µg/ml. Thereafter, we calculated that the bitterness scores and the drug release concentrations of the azithromycin-containing reverse micelle formulation were similar to those of Zithromax^® at each time point after 10 min of dispersal in simulated salivary fluid. In addition, the AUC_0−t after oral administration of AM-containing RMs was 1.75-fold (P < 0.05) higher than that of Zithromax^®. In conclusions, a system for assessing bitterness was developed using an in vitro drug release evaluation method and a human taste test panel. We found that the bitterness of azithromycin was successfully masked by reverse micelles, which also improved the oral bioavailability of azithromycin compared to that of Zithromax^®.     

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.     

A novel micelle of coumarin derivative monoend-functionalized PEG for anti-tumor drug delivery: in vitro and in vivo study

In this paper, a novel micelle for anti-tumor drug delivery was reported. Two 7-carboxymethoxy coumarin molecules were immobilized on the terminal group of a methoxy poly(ethylene glycol) chain via l-lysine as linker. The amphiphilic 7-carboxymethoxy coumarin monoend-functionalized methoxy poly(ethylene glycol) (mPEG-Lys-DCOU) chains were self-assembled micelles. Anti-tumor drug doxorubicin was loaded in the mPEG-Lys-DCOU micelles and the release profile was studied. The cytotoxicity of mPEG-Lys-DCOU was evaluated by NIH 3T3 fibroblasts. The drug-loaded micelles were incubated with HepG2 tumor cells to investigate the in vitro anti-tumor effect. The in vivo inhibition efficacy of drug-loaded micelles was carried out on 4T1 breast cancer animal model. The results showed that both hydrophobic and π-π stacking interactions within mPEG-Lys-DCOU amphiphiles were contributed to the self-assembly. Both blank and drug loaded micelles were monodisperse nanoparticles with the average diameters around 300?nm. The release profile exhibited certain pH dependence. The drug release rate at pH?=?5.5 was much faster than that at pH?=?7.4. mPEG-Lys-DCOU amphiphiles were non-toxic to NIH 3T3 fibroblasts. Both in vitro and in vivo studies demonstrated that the inhibition efficacy of drug-loaded micelles were comparable to that of doxorubicin hydrochloride. mPEG-Lys-DCOU micelles are promising carriers for anti-tumor drug delivery.