嵌段共聚物在药学中的应用

嵌段共聚物属于两亲类共聚物 ,在水中能自发生成多分子聚集的胶束 ,这些胶束主要以疏水的嵌段为内核 ,亲水嵌段环绕在外构成外壳 ,这种胶束可以有效地增溶油溶性药物。嵌段共聚物无毒、无刺激、无免疫原性 ,胶束尺寸和病毒相仿 ,其大小适合在体内传输。此文综述了嵌段共聚物胶束在药用载体、药物输送、分离和释放等方面的应用。     

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.     

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。     

胶束给药系统及其进展(下)

3嵌段共聚物胶束给药系统3．1两亲性嵌段共聚物聚合物可分为均聚物(homopolymer,由同一种单体组成)和共聚物(copolymer)两大类,均聚物不是两亲性结构,故不能形成胶束。共聚物又分为嵌     

维甲酸/聚乙二醇-聚乳酸二嵌段共聚物胶束的制备及其体外性质

目的:制备甲氧基聚乙二醇-聚乳酸[methoxyl poly(ethylene glycol)-poly(lactic acid),mPEG-PLA]二嵌段共聚物及其载全反式维甲酸(all-trans-retinoic acid,ATRA)的胶束,验证共聚物的结构,并考察胶束的形态、粒径、载药量、包封率、体外释放特性及其溶血性质。方法:采用辛酸亚锡催化的开环聚合法制备不同嵌段比例的mPEG-PLA二嵌段共聚物,用核磁共振氢谱(1HNMR)和傅利叶红外光谱(FTIR)验证其结构,凝胶渗透色谱(GPC)考察其相对分子质量及分布。用透析法、丙酮溶剂蒸发法及丙酮挥发透析法制备空白及载ATRA胶束。透射电子显微镜(TEM)观察胶束的形态,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载药量和包封率,并研究其体外释放性质及溶血性质。结果:制备了5种不同嵌段比例的mPEG-PLA共聚物,TEM结果显示ATRA胶束呈类球形。胶束的粒径及载药量受制备方法、药物/嵌段共聚物比例以及嵌段共聚物性质的影响,通过筛选得到丙酮挥发透析法及嵌段共聚物/药物的比例为5∶2为最适制备条件,得到胶束的平均粒径在267.5~431.8 nm内,并随着嵌段共聚物疏水部分的增大而增加;胶束的载药量在11.23%~20.01%内,包封率为31.79%~56.57%,也具有随疏水嵌段增大而增加的趋势。载药胶束在PBS-乙醇(9∶1)的释放液中48 h体外累积释药率为61.6%~94.1%,载药胶束与50%血浆混合后药物释放趋于零级,药物的释放随聚合物相对分子质量的减小和载药量的减小而增加。100~150mg.L-1的载药胶束无溶血现象,而5 mg.L-1的ATRA溶液即出现溶血。结论:通过研究嵌段比例对mPEG-PLA嵌段共聚物载ATRA胶束一系列体外性质的影响,为选择最适的嵌段共聚物比例提供了依据。载药量,体外释放及溶血性质结果显示mPEG-PLA嵌段共聚物载ATRA胶束具有明显的增溶,缓释作用,并能够减少药物的毒副作用。     

mPEG-PLA的合成及吡喹酮聚合物胶束的制备

目的 合成聚乙二醇单甲醚-聚乳酸(mPEG-PLA)嵌段共聚物,制备吡喹酮mPEG-PLA嵌段共聚物胶束,提高吡喹酮在水中的溶解度.方法 采用开环聚合反应合成mPEG-PLA嵌段共聚物,并通过IR、1H-HMR确证其结构;采用溶剂蒸发法制备共聚物胶束,分别用扫描电镜观察其形态,激光散射法测定其粒径,HPLC法测定其载药量、包封率及饱和溶解度.结果 制备了3种不同嵌段组成的共聚物胶束,扫描电镜下观察为近球形;共聚物胶束的粒径和载药量受有机溶剂种类和用量、共聚物嵌段比例等因素的影响;通过筛选得到有机溶剂为丙酮,油水比为1:4,共聚物嵌段组成为mPEG2000-PLA5000为最适条件;得到胶束的平均粒径为(34.5±5.1) nm,载药量为(19.6±1.8)％,包封率为(74.2±1.6)％.结论 mPEG-PIA聚合物胶束可作为疏水性药物吡喹酮的载体,具有较高的载药性能,能一定程度提高吡喹酮在水中的溶解度.     

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.     

聚乙二醇-聚乳酸嵌段共聚物及其微粒给药系统的研究进展

 综述可生物降解嵌段共聚物聚乙二醇-聚乳酸（PEG-PLA）及其微粒给药系统在药剂学中的研究与应用。该嵌段共聚物微球能提高蛋白、多肽的稳定性,有利于难溶性药物释放。纳米粒可降低网状内皮吞噬系统的识别与吞噬,改变药物体内分布及清除率,连接识别配体后脑靶向作用显著,具有温敏性和pH敏感性,增加难溶性药物溶解度,且生物相容性良好。PEG-PLA嵌段共聚物微粒给药系统将有广阔的发展和应用前景。     

pH及温度敏感型生物可降解嵌段共聚物的研究进展

pH及温度敏感型生物可降解嵌段共聚物是指生物可降解材料与pH敏感单体聚合或其本身按照一定序列聚合而成的一种高分子材料，对环境的pH及温度变化产生应答。本文结合近年的研究报道，阐述了各种pH及温度敏感型生物可降解嵌段共聚物的作用机制和应用特点。目前，对pH及温度敏感型生物可降解嵌段共聚物的研究备受关注，其能较好的控制药物释放速度，并具有良好的生物相容性，在智能给药系统研究领域有着广阔的应用前景。     

可植入温敏水凝胶的合成及性质研究

目的:合成满足植入给药载体要求的温度敏感型PLGA-PEG-PLGA嵌段共聚物,并对其结构和性质进行研究.方法:采用开环聚合法,以不同比例的丙交酯、乙交酯和PEG为原料,异辛酸亚锡为催化剂,合成PLGA-PEG-PLGA嵌段共聚物.通过考察不同嵌段共聚物的相变温度和黏度,筛选确定符合植入给药载体要求的合成条件和投料比例.结果:合成的凝胶材料,经FTIR和1H-NMR检测,材料符合PLGA-PEGPLGA嵌段共聚物特征.经筛选,按丙交酯-乙交酯-PEG 1500(6:1:3)的质量比投料,0.1%(W/W)催化剂用量,在真空条件下140℃反应12 h,可以得到满足植入给药要求的栽体材料.结论:采用开环聚合法,可以合成温敏型PIGA-PFGA嵌段共聚物,其相变温度可过改变丙交酯、乙交酯投料比例和PEG的相对分子质量在一定范围内调节.实验合成的共聚物在质量分教为20%时.相变温度35℃,黏度与55%甘油水溶液相当,形成的凝胶具备一定的刚性,材料无有机溶剂残留,符合植入蛤药载体的要求.     

Self-assembled filomicelles prepared from polylactide-poly(ethylene glycol) diblock copolymers for sustained delivery of cycloprotoberberine derivatives

Polylactide-poly(ethylene glycol) (PLA-PEG) block copolymers were synthesized by ring opening polymerization of l-lactide using a monomethoxy PEG (mPEG) as macroinitiator and zinc lactate as catalyst. The resulting diblock copolymers were characterized by ¹H NMR and GPC. Polymeric micelles were prepared by self-assembly of copolymers in distilled water using co-solvent evaporation or membrane hydration methods. The resulting micelles are worm-like in shape as shown by TEM measurements. A hydrophobic anticancer drug, cycloprotoberberine derivative A35, was successfully loaded in PLA-PEG filomicelles with high encapsulation efficiency (above 88%). Berberine (BBR) was studied for comparison. In both methods, PLA-PEG filomicelles were prepared with a theoretical loading of 5%, 10% and 20%. Physical stability studies indicated that BBR/A35-loaded filomicelles were more stable when stored at 4?°C than at 25?°C. Compared with BBR-loaded filomicelles, A35-loaded filomicelles exhibited higher antitumor activity. Importantly, the in vitro cytotoxicity and stability of A35-loaded filomicelles evidenced the potential of drug-loaded filomicelles in the development of drug delivery systems.     

Defining the drug incorporation properties of PLA-PEG nanoparticles

The drug incorporation and physicochemical properties of PLA-PEG micellar like nanoparticles were examined in this study using a model water soluble drug, procaine hydrochloride. Procaine hydrochloride was incorporated into nanoparticles made from a series of PLA-PEG copolymers with a fixed PEG block (5 kDa) and a varying PLA segment (3-110 kDa). The diameter of the PLA-nanoparticles increased from 27.7 to 174.6 nm, with an increase in the PLA molecular weight. However, drug incorporation efficiency remained similar throughout the series. Incorporation of drug into the smaller PLA-PEG nanoparticles made from 3:5, 15:5 and 30:5 copolymers did not influence the particle size, while an increase was observed for the larger systems comprising 75:5 and 110:5 copolymers. An increase in drug content for PLA-PEG 30:5 nanoparticles was achieved by increasing the theoretical loading (quantity of initially present drug). The size of these nanoparticles remained unchanged with the increasing drug content, supporting the proposed micellar type structure of the PLA-PEG 30:5 nanoparticles. The morphology of these systems remained unchanged both at low and high theoretical drug loadings. Formulation variables, such as an increase in the aqueous phase pH, replacement with the base form of the drug and inclusion of lauric acid in the formulation did not improve the incorporation efficiency of drug into PLA-PEG 30:5 nanoparticles. While poly(aspartic acid) as a complexation agent did not improve the drug incorporation efficiency of procaine hydrochloride, it did so for another water soluble drug diminazene aceturate. This may be attributed to a stronger interaction of diminazene aceturate with poly(aspartic acid) relative to procaine hydrochloride, as confirmed by thermodynamic analysis of isothermal titration calorimetric data. The drug incorporation and physicochemical characterisation data obtained in this study may be relevant in optimising the drug incorporation and delivery properties of these potential drug targeting carriers.     

Biodistribution of Long-Circulating PEG-Grafted Nanocapsules in Mice: Effects of PEG Chain Length and Density

Purpose: To study the pharmacokinetics and biodistribution of novel polyethyleneglycol (PEG) surface-modified poly(rac-lactide) (PLA) nanocapsules (NCs) and to investigate the influence of PEG chain length and content. Methods: The biodistribution and plasma clearance in mice of different NC formulations were studied with [³H]-PLA. PLA-PEG copolymers were used in NC preparations at different chain lengths (5 kDa and 20 kDa) and PEG contents (10% and 30% w/w of total polymer). In vitro and in vivo stability were also checked. Results: Limited [³H]-PLA degradation was observed after incubation in mouse plasma for 1 h, probably because of to the large surface area and thin polymer wall. After injection into mice, NCs prepared with PLA-PEG copolymers showed an altered distribution compared to poloxamer-coated PLA NCs. An increased concentration in plasma was also observed for PLA-PEG NCs, even after 24 h. A dramatic difference in the pharmacokinetic parameters of PLA-PEG 45-20 30% NCs compared to poloxamer-coated NCs indicates that covalent attachment, longer PEG chain lengths, and higher densities are necessary to produce an increased half-life of NCs in vivo. Conclusions: Covalently attached PEG on the surface of NCs substantially can reduce their clearance from the blood compartment and alter their biodistribution.     

Effect of poly(ethylene glycol)-block-polylactide nanoparticles on hepatic cells of mouse: low cytotoxicity, but efflux of the nanoparticles by ATP-binding cassette transporters.

The objective of this paper is to study the effects of poly(ethylene glycol)-block-polylactide (PLA-PEG) nanoparticles on hepatic cells of mouse. Blank PLA-PEG nanoparticles have been successfully prepared and MTT assay suggested that the nanoparticles with HepG2 cell co-culture model did not cause significant changes in membrane integrity in controlled concentration range (0.001-0.1 mg/ml). Immunohistochemical analysis demonstrated that large dose of PLA-PEG nanoparticles injection (42.04 mg/kg, i.v.) did not induce hepatic cell apoptosis. From biochemical assay experiments, although the levels of SOD decreased and those of MDA, NOS increased after treatment with large dose of PLA-PEG nanoparticles injection (42.04 mg/kg, i.v.), they were all not significant (p>0.05). Then Kunming mice were treated with large dose of PLA-PEG nanoparticles (42.04 mg/kg, i.v.) and after 4 days total RNA was isolated to elucidate patterns of gene expression using a mouse cDNA-microarray (SuperArray). Treatment with nanoparticles resulted in over-expression of a lot of ATP-binding cassette (ABC) transporters, especially two ABC transporters (ABCA8 and ABCC5/MRP5), and down-regulation of GSTP1, in comparison with the control. ABCA8 could extrude low molecular weight polymers after PLA-PEG nanoparticles hydrolysis outside the cells. We also discovered that ABCC5 expressed multidrug resistance protein 5 (MRP5) to pump out conjugate (GS-X) of PLA-PEG nanoparticles with GSH. The results were confirmed by RT-PCR. Results of in vitro accumulation and efflux experiments indicated that about 51-52% (51.5% and 52.0%) intracellular PLA-PEG nanoparticles was expulsed after mouse primary hepatocytes reached a saturation uptake of nanoparticles during the concentration range of 750-1000 microg/ml. The results suggested that ABC transporters (especially ABCA8) pump out the polymers after hydrolysis from mouse hepatic cells and large dose of PLA-PEG nanoparticles make mouse hepatic cells gain drug resistance to PLA-PEG nanoparticles.     

Development and characterization of CyA-loaded poly(lactic acid)-poly(ethylene glycol)PEG micro- and nanoparticles. Comparison with conventional PLA particulate carriers.

Cyclosporin A (CyA) loaded poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) micro- and nanoparticles have been developed using an emulsion-solvent evaporation method. Physico-chemical properties, peptide loading content and in vitro release profiles of these novel CyA carriers were compared with those corresponding to conventional PLA micro- and nanoparticles. Results obtained confirm the previously described disposition of PEG chains on the surface of the PLA-PEG formulations. In addition, they revealed the presence of CyA molecules on the surface of both PLA and PLA-PEG systems. Further determination of the surface chemical composition by electron spectroscopy for chemical analysis (ESCA) allowed us to quantify the amount of CyA in the nanospheres' top layers, this amount being higher for nanoparticles than for microparticles, and higher for the PLA systems than for those based on PLA-PEG. In vitro release experiments revealed that PLA-PEG particles provided a more adequate control of CyA release than conventional PLA micro- and nanoparticles. Physico-chemical characterization of the systems during the release studies showed that the developed PLA and PLA-PEG micro- and nanoparticles were not degraded, which suggest a diffusion-mediated release mechanism. Furthermore, we have hypothesized that the hydrophilic outer shell of PEG provides a stationary layer for the diffusion of CyA.     

PLA-PEG particles as nasal protein carriers: the influence of the particle size

Previous studies have shown that PLA-PEG nanoparticles (NP) are able to enhance the transport of the encapsulated model protein, tetanus toxoid (TT), across the rat nasal mucosa. The aim of this work was to study if the size of PLA-PEG particles affects the nasal transport of the encapsulated protein and, also, the potential contribution of blank nanoparticles to the transport of the free protein. To achieve this purpose, 125I-TT was encapsulated into PLA-PEG particles of different sizes (200 nm, 1.5, 5 and 10 microm) prepared by the water-in-oil-in-water solvent evaporation technique. Firstly, in order to investigate the carrier role of the particles, two series of either conscious or anaesthetized rats were nasally treated with 125I-TT-loaded NP, free 125I-TT, and a physical mixture of blank NP and free 125I-TT. Secondly, the influence of the particle size on the nasal transport of TT encapsulated into PLA-PEG particles was evaluated in conscious rats. The amount of radioactivity recovered in the blood compartment, lymph nodes and other relevant tissues was monitored for up to 24h. Finally, the nasal bioavailability of 125I-TT-loaded PLA-PEG NP was calculated. The results indicated that the use of anaesthesia enhances the transport of 125I-TT and that the physical presence of PLA-PEG NP does not affect the transport of the toxoid. In contrast, when TT was encapsulated into the particles its transport across the nasal mucosa of conscious rats was significantly enhanced. Furthermore, the efficacy of this transport was related to the particle size, reaching the most important transport for the smallest particle size. The intensity of this transport was also illustrated by the high nasal bioavailability of TT encapsulated into nanoparticles (200 nm) (F = 70-80%). These results led us to conclude that PLA-PEG NP can be accepted as nasal protein carriers for nasal administration.     

Stealth PLA-PEG Nanoparticles as Protein Carriers for Nasal Administration

Purpose. The aim of the study was to encapsulate a model protein antigen, tetanus toxoid (TT), within hydrophobic (PLA) and surface hydrophilic (PLA-PEG) nanoparticles and to evaluate the potential of these colloidal carriers for the transport of proteins through the nasal mucosa. Methods. TT-loaded nanoparticles, prepared by a modified water-in-oil-in-water solvent evaporation technique, were characterized in their size, zeta potential and hydrophobicity. Nanoparticles were also assayed in vitro for their ability to deliver active antigen for extended periods of time. Finally, ¹²⁵I-TT-loaded nanoparticles were administered intranasally to rats and the amount of radioactivity recovered in the blood compartment, lymph nodes and other relevant tissues was monitored for up to 48 h. Results. PLA and PLA-PEG nanoparticles had a similar particle size (137-156 nm) and negative surface charge, but differed in their surface hydrophobicity: PLA were more hydrophobic than PLA-PEG nanoparticles. PLA-PEG nanoparticles, especially those containing gelatine as an stabilizer, provided extended delivery of the active protein. The transport of the radiolabeled protein through the rat nasal mucosa was highly affected by the surface properties of the nanoparticles: PLA-PEG nanoparticles led to a much greater penetration of TT into the blood circulation and the lymph nodes than PLA nanoparticles. Furthermore, after administration of ¹²⁵I-TT-loaded PLA-PEG nanoparticles, it was found that a high amount of radioactivity persisted in the blood compartment for at least 48 h. Conclusions. A novel nanoparticulate system has been developed with excellent characteristics for the transport of proteins through the nasal mucosa.     

Polylactide-poly(ethylene Glycol) Micellar-like Particles as Potential Drug Carriers: Production,Colloidal Properties and Biological Performance

The micellar-like particle systems produced from poly-D,L-lactide-poly(ethylene glycol) (PLA-PEG) copolymers have been assessed using a range of physicochemical characterisation methods, followed by in vivo studies of their biodistribution after intravenous administration to the rat. The size of the PEG chain was kept constant at 5 or 2 kDa, while the PLA size increased within a series from 2 to 25 kDa. The results obtained reveal, that in an aqueous medium the copolymers assembled into micellar-like structures, with the PLA segments forming the core and the PEG segments the surrounding corona. The size of the PLA segments dominated the process of assembly of the molecules and the characteristics of the resultant micellar-like particles. The PLA-PEG micellar particles were found to be less dynamic than those obtained from conventional surfactants. Particles formed from the lower molecular weight PLA polymers allowed a level of chain mobility while the cores of the micellar particles formed from higher molecular weight PLA appeared to be solid-like in nature. The size of the micellar particles was dependent on the copolymer molecular weight and the z-average diameter increased from 25 to 76 nm as the molecular weight of the PLA moiety increased. This provides an ability to control the particle size by adjusting the molecular weight of the PLA moiety. Following intravenous administration to the rat model, micellar-like particles smaller than approximately 70 nm accumulated in the liver, despite the fact that the PEG corona provided an effective steric stabilization effect. Micellar-like particles with a diameter of more than approximately 70 nm exhibited prolonged systemic circulation and reduced liver uptake, although the steric stabilisation of these particles was shown to be less effective. These findings agree with recent observations from other research groups; that indicate a possibility that very small particulates can pass through the sinusoidal fenestrations in the liver and gain access to the parenchymal cells of the liver.     

Evaluation of In Vivo toxicity of Novel Biosurfactant from Candida parapsilosis loaded in PLA-PEG Polymeric Nanoparticles

The aim of this study was to evaluate the toxicological profile of biosurfactant encapsulated polymeric nanoparticles of Polylactic acid-Polyethylene glycol (PLA-PEG) in mice. Hematological, biochemical and histopathological samples of rodents were evaluated. Mice were selected randomly and divided into 3 treatment groups and one control group. Group I mice served as a control group, Group II were administrated with biosurfactant, Group III were treated with Polymeric nanoparticles of PLA-PEG. Group IV mice were injected with biosurfactant loaded polymeric nanoparticles of PLA-PEG. The formulations were administered intravenously via tail vein with 20 μg/mL dose concentration of biosurfactant. The normal control group was injected with only PBS. Blood samples were collected on 7th, 14th and 21st day and hematological and biochemical assays were performed. After the blood collection, mice were sacrificed for histopathological examination. The results showed that there were no significant difference in hematology parameter between the control and treated group. Some minute, non-significant changes were found in biochemical parameters which were not considered. Histopathological result of selected vital organs revealed that the biosurfactant and/or PLA-PEG polymeric nanoparticles can be considered as safe as no toxicological features were observed in histopathology of tissues. Hence, it can be deliberated that the biosurfactant encapsulated in PLA-PEG copolymeric nanoparticles are non toxic and can provide a safe, suitable platform for biomedical applications in future.     

生物降解聚合物PLGA-PEG-PLGA的合成及表征

目的对生物降解聚合物PLGA-PEG-PLGA进行合成及表征。方法以丙交酯、乙交酯及PEG为原料,用开环聚合法合成生物降解聚合物PLGA-PEG-PLGA,并用DSC、GPC和1H-NMR对其结构进行表征。结果合成的聚合物为嵌段聚合物。由1H-NMR可知聚合物数均相对分子质量为6 400~8 000,重均相对分子质量为7 100~9 200。上述制备的聚合物的水溶液具有反向热敏性质。质量分数为30%的PLGA-PEG-PLGA(3)水溶液的胶凝(由溶胶变为凝胶)温度为33℃,符合人体生理温度。结论提供了一种新的生物降解性药物载体材料。