两亲性嵌段共聚物胶束的研究进展

综述了两亲性嵌段共聚物胶束的形成机理、组成、结构、理化性质、制备方法、影响因素、药学方面的应用等进展.     

冬凌草甲素嵌段共聚物胶束的制备

目的 制备冬凌草甲素单甲醚聚乙二醇-聚乳酸两亲性嵌段共聚物胶束,改善冬凌草甲素的水溶性. 方法以单甲醚聚乙二醇-聚乳酸作为载体,采用丙酮溶剂挥发法和透析法制备不同药物/共聚物投料比的冬凌草甲素嵌段共聚物胶束. 考察胶束相关性质. 以载药量为评价标准,得出最佳投料比. 结果 电镜结果 显示,胶束呈球形或类球形,载药量和包封率受制备方法和投料比的影响. 透析法得到的胶束粒径较小,分散均匀度好,但载药量和包封率偏低. 丙酮溶剂挥发法在药物共聚物的质量比例12.8：25.2时得到的胶束平均粒径为35.675 nm,载药量为22.1%,包封率为65.61%,粒径分布较窄,有利于纳米分散体系的稳定,且对冬凌草甲素有一定的增溶作用. 结论 聚乙二醇-聚乳酸嵌段共聚物胶束能够作为难溶性抗癌药物冬凌草甲素的良好纳米级载体.     

嵌段共聚物胶束作为药物载体的研究进展

嵌段共聚物胶束通过物理和化学方法将难溶性药物和基因治疗药物增溶,可实现主动或被动靶向给药.综述了嵌段共聚物胶束的特点、载体的制备方法、载药能力、药物的释放和研究实例.     

嵌段共聚物在给药系统中的应用

嵌段共聚物作为一类重要的高分子材料在药学中应用广泛。本文结合近几年的研究报道，对嵌段共聚物在给药系统中作为水凝胶、微球、纳米球等的应用以及部分嵌段共聚物的生物降解性和生物相容性作出简要综述。     

阿霉素共聚物胶束的制备及体外性质研究

目的制备阿霉素共聚物胶束并研究其体外性质。方法采用开环聚合法合成聚乙二醇单甲醚-聚乳酸羟基乙酸（mPEG—PLGA）嵌段共聚物;用透析法、溶剂蒸发法制备空白及载阿霉素胶束;动态光散射仪（DLS）测定其粒径分布;采用紫外分光光度法测定胶束的包封率和载药量。通过体外释药实验研究了载阿霉素胶束的释药特性。结果采用透析法制备载阿霉素胶束大小均匀,平均粒径为（91．1±15．8）nm;药物胶束的包封率为85．2％,载药量为10．4％;与市售阿霉素注射剂相比,载阿霉素胶束具有良好的缓释性能。结论共聚物胶束可作为疏水性药物阿霉素的载体。     

Physical Entrapment of Adriamycin in AB Block Copolymer Micelles

The entrapment of Adriamycin (ADR) in micelles composed of AB block copolymers (poly(ethylene oxide-co--benzyl L-aspartate) (PEO-PBLA)) was investigated. The loading process involved transfer of ADR and PEO-PBLA into an aqueous milieu from dimethyl-formamide (DMF) through a dialysis procedure. Evidence for the physical entrapment of ADR in the polymeric micelles was derived from fluorescence spectroscopy and gel permeation chromatography (GPC). The total fluorescence intensity of ADR was low, suggesting that the drug was self-associated in the micelles. In addition, quenching experiments, using a water-soluble quencher (iodide (I^–)), showed that the fluorescence of ADR present in micellar solutions was largely unaffected by I^–, whereas the fluorescence of free ADR was readily quenched. From Stern-Volmer plots, quenching constants (K_SV) of 2.2 and 17 M^–l were determined for ADR in micellar solutions and free ADR, respectively. As a result of the entrapment of ADR in the micelles, ADR binds only slightly serum albumin as evidenced by GPC. In contrast, ADR readily binds serum albumin in aqueous solutions. The findings suggest that ADR is stably entrapped in PEO-PBLA micelles. ADR entrapment in polymeric micelles is expected to affect markedly the pharmacokinetics of ADR.     

Disposition of Drugs in Block Copolymer Micelle Delivery Systems

Since their discovery in the early 1980s, polymeric micelles have been the subject of several studies as delivery systems that can potentially improve the therapeutic performance and modify the toxicity profile of encapsulated drugs by changing their pharmacokinetic characteristics. The efforts in this area have led in recent years to the advancement of several polymeric micellar formulations to clinical trials, some of which have shown promise in changing the biodistribution of the incorporated drug after intravenous administration as a means of tumour-targeted drug delivery. Recently, the possible benefit of polymeric micellar delivery in enhancing the absorption and bioavailability of incorporated drugs from alternative routes of drug administration has attracted interest. This article provides an overview of the effect of polymeric micellar delivery on absorption, distribution, metabolism and excretion of incorporated therapeutic agents. It also aims to assess the current information on the performance of polymeric micellar delivery systems in modifying the pharmacokinetics/pharmacodynamics of the incorporated drugs in clinical trials, and to re-examine the important structural factors required for successful design of polymeric micellar delivery systems capable of inducing favourable changes in the pharmacokinetics of the encapsulated drug.     

Block Copolymer Micelles for the Encapsulation and Delivery of Amphotericin B

Purpose. To assess the effect of fatty acid substitution of a micelle-forming poly(ethylene oxide)-block-poly(N-hexyl stearate-L-aspartamide) (PEO-b-PHSA) on the encapsulation, hemolytic properties and antifungal activity of amphotericin B (AmB). Methods. PEO-b-PHSA with three levels of stearic acid substitution were synthesized and used to encapsulate AmB by a solvent evaporation method. Size exclusion chromatography and UV spectroscopy were used to confirm and measure levels of encapsulated AmB. The hemolytic activity of encapsulated AmB toward human red blood cells and its minimum inhibitory concentration against Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans were obtained and compared to AmB alone. Results. An increase in the level of stearic acid substitution on PEO-b-PHSA improved the encapsulation of AmB while reducing its hemolytic activity. PEO-b-PHSA micelles having 50% and 70% stearic acid substitution (mol fatty acid: mol reacted and unreacted hydroxyls) were completely non-hemolytic at 22 g/ml. At 11% stearic acid substitution, AmB caused 50% hemolysis at 1 g/ml. AmB in PEO-b-PHSA micelles was as effective as AmB alone against pathogenic fungi. Conclusions. PEO-b-PHSA micelles with a high level of stearic acid side chain substitution can effectively solubilize AmB, reduce its hemolytic activity yet retain its potent antifungal effects.     

Block Copolymer Micelles for Controlled Delivery of Glycolytic Enzyme Inhibitors

Purpose  

To develop block copolymer micelles as an aqueous dosage form for a potent glycolytic enzyme inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO).     

pH-Sensitive Multi-PEGylated Block Copolymer as a Bioresponsive pDNA Delivery Vector

Purpose  

A reversibly-PEGylated diblock copolymer, poly(aspartate-hydrazide-poly(ethylene glycol))-block-poly(aspartate-diaminoethane) (p[Asp(Hyd-PEG)]-b-p[Asp(DET)]) was reported here for enhanced gene transfection and colloidal stability. The diblock copolymer possessed a unique architecture based on a poly(aspartamide) backbone. The first block, p[Asp(Hyd)], was used for multi-PEG conjugations, and the second block, p[Asp(DET)], was used for DNA condensation and endosomal escape.     

Determination of the Surface Tension of Block Copolymer Micelles by Phagocytosis

Purpose. This work was carried out to determine the surface tension of block copolymer micelles of ¹⁴C labelled ABA poly (oxyethylene-bi-isoprene-b-oxyethylene) which have a long circulating half life in animals. Methods. The method used was that of phagocytosis. The percentage of micelles phagocytosed by human mononuclear cells was determined in solutions of different surface tension. Results. The values obtained were 72 mN/m which may be predicted for a particle with a long circulating half life in animals. The method also gave an estimate of the surface tension for the mononuclear cells. Conclusions. This technique has the advantage of determining the surface tension of highly hydrated small particles including stable micelles in an environment similar to that in which they normally exist.     

Block Copolymer Cross-Linked Nanoassemblies Improve Particle Stability and Biocompatibility of Superparamagnetic Iron Oxide Nanoparticles

Purpose

To develop cross-linked nanoassemblies (CNAs) as carriers for superparamagnetic iron oxide nanoparticles (IONPs).

Methods

Ferric and ferrous ions were co-precipitated inside core-shell type nanoparticles prepared by cross-linking poly(ethylene glycol)-poly(aspartate) block copolymers to prepare CNAs entrapping Fe₃O₄ IONPs (CNA-IONPs). Particle stability and biocompatibility of CNA-IONPs were characterized in comparison to citrate-coated Fe₃O₄ IONPs (Citrate-IONPs).

Results

CNA-IONPs, approximately 30 nm in diameter, showed no precipitation in water, PBS, or a cell culture medium after 3 or 30 h, at 22, 37, and 43°C, and 1, 2.5, and 5 mg/mL, whereas Citrate-IONPs agglomerated rapidly (> 400 nm) in all aqueous media tested. No cytotoxicity was observed in a mouse brain endothelial-derived cell line (bEnd.3) exposed to CNA-IONPs up to 10 mg/mL for 30 h. Citrate-IONPs (> 0.05 mg/mL) reduced cell viability after 3 h. CNA-IONPs retained the superparamagnetic properties of entrapped IONPs, enhancing T2-weighted magnetic resonance images (MRI) at 0.02 mg/mL, and generating heat at a mild hyperthermic level (40?~?42°C) with an alternating magnetic field (AMF).

Conclusion

Compared to citric acid coating, CNAs with a cross-linked anionic core improved particle stability and biocompatibility of IONPs, which would be beneficial for future MRI and AMF-induced remote hyperthermia applications.     

温度敏感型聚酯/聚乙二醇三嵌段生物可降解共聚物的降解性能及药物释放的影响因素研究进展

温度敏感型生物可降解水凝胶作为一种注射缓释给药系统的新型载体己受到越来越多的关注,聚酯(A嵌段)/聚乙二醇(B嵌段)三嵌段共聚物是目前最常用的温度敏感型聚合物,具有良好的生物相容性和生物降解性.本文综述了聚乙二醇嵌段含量、聚酯嵌段种类、共聚物凝胶水溶液浓度、处方中添加剂、药物与共聚物分子间的作用力、载药量及制剂形状、介质pH及温度等因素对聚酯/聚乙二醇三嵌段共聚物降解速率及药物释放速率的影响,为聚酯/聚乙二醇三嵌段共聚物水凝胶注射剂开发过程中共聚物降解速率和药物释放速率的调节提供有价值的思路与科学依据.     

PEG-poly(amino acid) Block Copolymer Micelles for Tunable Drug Release

Purpose  

To achieve tunable pH-dependent drug release in tumor tissues.     

Brushed Block Copolymer Micelles with pH-Sensitive Pendant Groups for Controlled Drug Delivery

Purpose

To investigate the effects of small aliphatic pendent groups conjugated through an acid-sensitive linker to the core of brushed block copolymer micelles on particle properties.

Methods

The brushed block copolymers were synthesized by conjugating five types of 2-alkanone (2-butanone, 2-hexanone, 2-octanone, 2-decanone, and 2-dodecanone) through an acid-labile hydrazone linker to poly(ethylene glycol)-poly(aspartate hydrazide) block copolymers.

Results

Only block copolymers with 2-hexanone and 2-octanone (PEG-HEX and PEG-OCT) formed micelles with a clinically relevant size (< 50 nm in diameter), low critical micelle concentration (CMC, < 20 μM), and drug entrapment yields (approximately 5 wt.%). Both micelles degraded in aqueous solutions in a pH-dependent manner, while the degradation was accelerated in an acidic condition (pH 5.0) in comparison to pH 7.4. Despite these similar properties, PEG-OCT micelles controlled the entrapment and pH-dependent release of a hydrophobic drug most efficiently, without altering particle size, shape, and stability. The molecular weight of PEG (12 kDa vs 5 kDa) induced no change in pH-controlled drug release rates of PEG-OCT micelles.

Conclusion

Acid-labile small aliphatic pendant groups are useful to control the entrapment and release of a hydrophobic drug physically entrapped in the core of brushed block copolymer micelles.     

Cell-Penetrating Peptide-Modified Block Copolymer Micelles Promote Direct Brain Delivery via Intranasal Administration

Purpose  

In order to develop non-invasive and effective nose-to-brain delivery of drugs, we synthesized Tat analog-modified methoxy poly(ethylene glycol) (MPEG)/poly(ε-caprolactone) (PCL) amphiphilic block copolymers through the ester bond.     

Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensitive Block Copolymer Hydrogels

Purpose

In order to obtain dermal vehicles of ketorolac tromethamine (KT) for the local treatment of inflammation and restrict undesirable side effects of systemic levels hydrogels (HGs) of poloxamer and carbomer were developed.

Methods

KT poloxamer based HG (KT-P407-HG) and KT carbomer based HG (KT-C940-HG) were elaborated and characterized in terms of swelling, degradation, porosity, rheology, stability, in vitro release, ex vivo permeation and distribution skin layers. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed.

Results

HGs were transparent and kept stable after 3 months exhibiting biocompatible near neutral pH values. Rheological patterns fitted to Herschel-Bulkley for KT-C940-HG and Newton for KT-P407-HG due to its low viscosity at 25°C. Rapid release profiles were observed through first order kinetics. Following the surface the highest concentration of KT from C940-HG was found in the epidermis and the stratum corneum for P407-HG. Relevant anti-inflammatory efficacy of KT-P407-HG revealed enough ability to provide sufficient bioavailability KT to reach easily the site of action. The application of developed formulations in volunteers did not induce any visual skin irritation.

Conclusions

KT-P407-HG was proposed as suitable formulation for anti-inflammatory local treatment without theoretical systemic side effect.

     

Characterization and Antimicrobial Activity of N-Methyl-2-pyrrolidone-loaded Ethylene Oxide-Propylene Oxide Block Copolymer Thermosensitive Gel

The purpose of this study is to investigate the effects of N-methyl-2-pyrrolidone on the thermosensitive properties of aqueous ethylene oxide-propylene oxide block copolymer (Lutrol^® F127) system. Due to the aqueous solubility enhancement and biocompatibility, N-methyl-2-pyrrolidone is an interesting solubilizer for the poorly water soluble drugs to be incorporated in the Lutrol^® F127 system. Effect of N-methyl-2-pyrrolidone on physicochemical properties of Lutrol^® F127 system was investigated using appearance, pH, gelation, gel melting temperature and rheology. The antimicrobial activity of the thermosensitive N-methyl-2-pyrrolidone gel was also tested. Lower N-methyl-2-pyrrolidone amount (≤30%w/w) could shift the sol-gel transition to a lower temperature but the gel-sol transition was shifted to a higher temperature. Higher N-methyl-2-pyrrolidone (≥40%w/w) could shift both sol-gel and gel-sol transitions of the system to a lower temperature. The amount of N-methyl-2-pyrrolidone >60% w/w could reverse the phase of the Lutrol^® F127 system to non-newtonian flow at 4° and Newtonian flow at high temperature. Aqueous Lutrol^® F127 system containing N-methyl-2-pyrrolidone exhibited antimicrobial activities against Staphylococcus aureus, Escherichia coli and Candida albicans with the N-methyl-2-pyrrolidone in a dose-dependent manner.     

Block Copolymer Design for Camptothecin Incorporation into Polymeric Micelles for Passive Tumor Targeting

PURPOSE: Polymeric micelles were designed for targeting of a water-insoluble anticancer agent, camptothecin (CPT). Chemical structures of inner core segment were optimized to achieve high incorporation efficiency and stable CPT-loaded micelles. METHODS: Poly(ethylene glycol)-poly(beta-benzyl L-aspartate) block copolymer (PEG-PBLA) was synthesized. The PBLA chain was modified by alkaline hydrolysis of its benzyl group followed by esterification with benzyl, n-butyl, and lauryl groups. Incorporation of CPT into micelles was carried out by an evaporation method. The stability of drug-loaded micelles was studied by gel-permeation chromatography (GPC), and their in vitro release behaviors were analyzed. RESULTS: CPT was incorporated into polymeric micelles constructed by various block copolymers. Among the esterified groups, block copolymers with high benzyl ester contents showed high CPT loading efficiency and stable CPT-loaded micelles. In chain lengths, 5-27 Bz-69 showed the highest incorporation efficiency. In contrast, 5-52 Bz-67, which had a longer hydrophobic chain, showed low incorporation efficiency. Release of CPT from the micelles was dependent on the benzyl contents and chain lengths. Sustained release was obtained when the benzyl content was high. CONCLUSIONS: CPT was successfully incorporated into polymeric micelles with high efficiency and stability by optimizing chemical structures of the inner core segment.     

Pharmaceutical Differences Between Block Copolymer Self-Assembled and Cross-Linked Nanoassemblies as Carriers for Tunable Drug Release

Purpose

To identify the effects of cross-linkers and drug-binding linkers on physicochemical and biological properties of polymer nanoassembly drug carriers.

Methods

Four types of polymer nanoassemblies were synthesized from poly(ethylene glycol)-poly(aspartate) [PEG-p(Asp)] block copolymers: self-assembled nanoassemblies (SNAs) and cross-linked nanoassemblies (CNAs) to each of which an anticancer drug doxorubicin (DOX) was loaded by either physical entrapment or chemical conjugation (through acid-sensitive hydrazone linkers).

Results

Drug loading in nanoassemblies was 27?~?56% by weight. The particle size of SNA changed after drug and drug-binding linker entrapment (20?~?100 nm), whereas CNAs remained 30?~?40 nm. Drug release rates were fine-tunable by using amide cross-linkers and hydrazone drug-binding linkers in combination. In vitro cytotoxicity assays using a human lung cancer A549 cell line revealed that DOX-loaded nanoassemblies were equally potent as free DOX with a wide range of drug release half-life (t_1/2?=?3.24?~?18.48 h, at pH 5.0), but 5 times less effective when t_1/2?=?44.52 h.

Conclusion

Nanoassemblies that incorporate cross-linkers and drug-binding linkers in combination have pharmaceutical advantages such as uniform particle size, physicochemical stability, fine-tunable drug release rates, and maximum cytotoxicity of entrapped drug payloads.