聚乙二醇-b-聚(D,L-丙交酯-co-碳酸丙二酯)的胶束化及其药物控释研究

通过开环共聚合成了由D,L-丙交酯、碳酸丙二酯和聚乙二醇构成的两亲性嵌段共聚物(PETLA),研究了PETLA胶束化及药物控释行为.嵌段共聚物和胶束通过核磁共振(1H-NMR)、荧光分光光度计、凝胶渗透色谱(GPC)、动态光散射(DLS)、透射电镜(TEM)和紫外光谱(UV)表征.实验结果发现临界胶束浓度随共聚物疏水链段长度增加而减小,胶束直径随疏水链段长度增加而增大.透射电镜照片表明载药胶束MT1直径为30~40nm,呈规则球形.体外释药表明9-NC以可控方式释放,突释后药物释放速率接近零级恒速.

MICELLIZATION AND DRUG CONTROLLED RELEASE OF AMPHIPHILIC METHOXY POLY(ETHYLENE GLYCOL)-b-POLY(D,L-LACTIDE-co-TRIMETHYLENE CARBONATE)

Amphiphilic block copolymers (PETLA) composed of D,L-lactide,trimethylene carbonate (TMC) and methoxy poly(ethylene glycol) (mPEG) were synthesized with ringopening copolymerization.Initiation of D,L-LA and TMC copolymerization wtih mPEG provided to manipulate the molecular weight of the hydrophobic block. Copolymer characterization with ¹H-NMR and gel permeation chromatograph (GPC) illustrated the final copolymer compositions were agreed with the theoretical values in feeding doses. Studies on micellization and drug controlled release behaviors of copolymer PETLA were performed with fluorescence spectroscopy, GPC, dynamic light scattering (DLS), transmission electron microscope (TEM), and ultraviolet spectroscopy (UV). Micelles of MT1 to MT4 were prepared from PETLA1 to PETLA4 respectively. Fluorescence technique with pyrene as hydrophobic probe was used to study the formation of core-shell type micelles. As a result, the critical micelle concentration (CMC) of PETLA was decreased from 5×10^-3 g/L (PETLA1) to 2.5 × 10^-4 g/L (PETLA4) with the increase of chain length in hydrophobic block while keeping constant corona-forming block. GPC characterization was used to describe the aggregation behavior of copolymers in selective solvent, by which the molecular weight of micelles was determined,and it was increased obviously from MT1 (277500 Dalton) to MT3 (644800 Dalton). Consistent to GPC results, DLS tests indicated the micellar diameters from MT1 to MT3 were increased from 30 nm to 60 nm. This would be related to the following reasons: the length of the hydrophobic block determined the space each chain required in the core, and the block copolymer with high hydrophobic length needed more core space to form larger micelles. TEM photograph illustrated that micelles MT1 had typical core-shell structure and regularly spherical morphology with the diameter of 30~40 nm after negative staining by phosphotungstic acid. Taking 9-nitro-20(s)-camptothecin (9-NC) as model drug, release profiles in vitro shown that the release behavior of 9-NC from micelles was in controlled manner and nearly in zero order after the initial burst release. The release rate decreased from MT1 to MT4, this was because the micelles composed of high hydrophobic composition could form large hydrophobic core and could encapsulate more drags through strong hydrophobic interactions, and the incorporated drug would take relatively long time to overcome the hydrophobic interaction then diffuse across the polymer matrix to the medium. Based on the results given above, micelles with hydrophobic part composed of D,L-lactide and TMC were not only help to control the release behavior of hydrophobic drug, but also help to alleviate local inflammation response which was elicited by acid production biodegraded from poly(D,L-lactide). In conclusion, novel copolymer micelles could open new opportunities for the delivery of poorly soluble anticancer drugs.