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

开发用于药物靶向的新型 pH 响应性嵌段共聚物胶束

• 批准号: 12558102
• 负责人: HARADA Atsushi
• 金额: $ 2.88万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12558102/
• 关键词: polymeric micelle; pH responsive; block copolyme; hydrazone; adriamycin; targeting; poly(ethylene glycol); azomethine bond; 制ガン剤

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

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

项目成果

Y.Kakizawa, A.Harada, K.Kataoka: "Glutatione-Sensitive Stabilization of Block Copolymer Micells Composed of Antisense DNA and Thiolated Poly(ethylene glycol)-block-poly(L-lysine)"Biomacromolecules. 2(2). 491-497 (2001)

Y.Kakizawa、A.Harada、K.Kataoka：“由反义 DNA 和硫醇化聚（乙二醇）-嵌段-聚（L-赖氨酸）组成的嵌段共聚物胶束的谷胱甘肽敏感性稳定”生物大分子。

Y. Akiyama, A. Harada, Y. Nagasaki, K. Kataoka.: "Synthesis of poly(ethylene glycol)-block-poly(ethyleneimine) possessing an acetal group at the PEG end"Macromolecules. 33(16). (2000)

Y. Akiyama、A. Harada、Y. Nagasaki、K. Kataoka.：“在 PEG 末端具有缩醛基团的聚（乙二醇）-嵌段-聚（乙撑亚胺）的合成”大分子。

Y. Nagasaki, K. Yasugi, Y. Yamamoto, A. Harada, K. Kataoka: "Sugar-Installed Block Copolymer Micelles : Their Preparation and Specific Interaction with Lectin Molecules"Biomacromolecules. 2(4). 1067-1070 (2001)

Y. Nagasaki、K. Yasugi、Y. Yamamoto、A. Harada、K. Kataoka：“糖安装的嵌段共聚物胶束：它们的制备及其与凝集素分子的特异性相互作用”生物大分子。

Y.Yamamoto, K.Yasuigi, A.Harada, Y.Nagasaki, K.Kataoka: "Temperature-related change in the properties relevant to drug delivery of poly(ethylene glycol)-poly(D,L-lactide) block copolymer micelles in aqueous milieu"Journal of Controlled Release. 82(2-3). 3

Y.Yamamoto、K.Yasuigi、A.Harada、Y.Nagasaki、K.Kataoka：“与聚（乙二醇）-聚（D，L-丙交酯）嵌段共聚物胶束的药物输送相关的特性与温度相关的变化

A.Harada, K.Kataoka: "Pronounced Activity of Enzymes through the Incorporation into the Core of Polyion Complex Micelles Made from Charged Block Copolymers"J. Controlled Release. 72(1-3). 85-91 (2001)

A.Harada、K.Kataoka：“通过掺入由带电嵌段共聚物制成的聚离子复合胶束的核心，酶具有明显的活性”J。