Development of novel pH-responsive block copolymer micelles for drug targeting

本研究制备了酸可切割腙连接剂功能化的pH响应聚合物胶束，并对其进行了表征。该胶束药物载体由两亲性嵌段共聚物聚乙二醇-聚天冬氨酸肼-阿霉素[PEG-p(Asp-Hyd-ADR)]组成，在不同的pH条件下均表现出良好的pH响应性。通过动态光散射（DLS）测试，证实胶束的直径为几十nm。抗癌药物。adramycin （ADR）通过ADR的C13羰基与PEG-PBLA嵌段共聚物的p（Asp）段上的肼基之间的酸不稳定的席夫碱键结合到聚合物主链上。一种名为希夫碱键的拖带结合连接体被设计成在细胞溶酶体腔室中水解裂解，在那里，局部pH值（pH 4.5-5.5）比生理条件（pH 7.4）低一个数列，因此希夫碱键可以最有效地裂解。采用反相高效液相色谱（HPLC）对胶束的pH响应特性进行了表征。在相应溶酶体区室的较低pH条件下（pH 4.5 ~ 5.5）， ADR在10小时内成功从胶束中释放出来，并在pH 7.4下保持稳定80小时。在pH 7.4下长时间不释放药物反映了最小的全身泄漏的可能性，并且由于药物在实体瘤的优先释放，酸性条件下药物的快速释放从位点特异性给药的角度来看可能是一个优势。通过静态光散射（SLS）测量，可以通过相对光散射强度的降低来识别胶束的分解。胶束被认为是由于失去胶束动力而解离成自由聚合物链，随着药物的释放，胶束核心发生疏水相互作用。这种新功能的pH反应性聚合物胶束的重要数据表明，作为一种药物载体，它不仅可以通过改善不良反应的细胞内定位来减少死亡副作用，还可以避免癌症化疗中的多重耐药（MDR）问题。少

The pH responsive polymeric micelles functionalized with acid-cleavable hydrazone linkers were prepared and characterized in this study. This micellar drug carrier from amphiphilic block copolymer polyethylene glycol)-poly(aspartate hydrazide adriamycin) [PEG-p(Asp-Hyd-ADR)] showed a good pH responsive drug release profile in various pH conditions. The size of micelles was confirmed to be tens of nm in diameter by dynamic light scattering (DLS) measurement.The anticancer drug. Adiramycin(ADR), was bound to the polymer backbone through an acid-labile Schiff base linkage between me carbonyl at the C13 of ADR and the hydrazide group attached to the p(Asp) segment of PEG-PBLA block copolymer. A drag binding linker, Schiff base linkage, was designed to be hydrolytically cleaved in the lysosomal compartment of the cell, where local pH is one order of magnitude lower (pH 4.5-5.5) than physiological condition (pH 7.4) so the Schiff base bond can be cleaved most efficiently.The pH responsive pr … More operty of the micelles was characterized by reversed-phase high performance liquid chromatography (HPLC). In lowered pH conditions (pH 4.5〜5.5) corresponding lysosomal compartments, ADR was successfully released from the micelles within 10h while it remained stable at pH 7.4 over 80hr. No drug release at pH 7.4 for a long period reflects the possibility of minimal systemic leakage and the rapid drug release in acidic conditions could be an advantage from the standpoint of site-specific drug delivery due to the preferential drug release at the solid tumor.Disintegration of the micelles was recognized monitoring the decrease of relative light scattering intensity by static light scattering (SLS) measurement. The micelles were considered to dissociate into free polymer chains by losing the driving force of micellization, hydrophobic interaction in the micellar core as drugs released.A significant figure of this neo-functional pH responsive polymeric micelle indicated the promising solution as a drug carrier not only to reduce die side-effects by improving the intracellular localization of ADR but also to circumvent the multi-drug resistant (MDR) problems in cancer chemotherapy. Less