Enhanced Antitumor Activity of Proteasome Inhibitor MG132-loaded Polymeric Micelle Drug Carriers, Analyzed by In Vivo Real-Time Confocal Microangiography

通过体内实时共焦微血管造影分析负载蛋白酶体抑制剂 MG132 的聚合物胶束药物载体的抗肿瘤活性增强

基本信息

批准号：
21791542
负责人：
MATSUMOTO Yoko
金额：
$ 2.75万
依托单位：
The University of Tokyo (2010)Research Institute for Clinical Oncology, Saitama Cancer Center (2009)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

项目摘要

Macromolecular carriers for therapeutic agents are attractive as they can improve the performance of certain drugs by prolonged blood circulation, reduced nonspecific accumulation in normal tissues and preferential tumor accumulation due to the enhanced permeability and retention (EPR) effect. Core-shell type polyion complex (PIC) micelles have received considerable attention as a promising macromolecular carrier system. Antitumor drug-loaded micelles containing platinum and taxane have been reported to have strong target effects with decreased side effects. Proteasomes degrade or process intracellular proteins, some of which represent mediators of cell-cycle progression and apoptosis, such as the cyclins, caspases, BCL2 and nuclear factor ofκB (NF-κB). Proteasome inhibitor (PI) is attracting considerable attention as a new antitumor drug widely effective for various cancers. Bortezomib was the first PI to enter clinical development and was approved by the FDA in 2003 for the treatment … More of relapsed and refractory multiple myeloma. However, this drug has been known to cause strong side effects such as interstitial pneumonia. By applying PIC micelles technology to PI, we might possibly increase the antitumor effect and reduce side effects.We developed a new class of polymeric micelles incorporating PI MG132 through the polymer-drug complex formation between MG132 and poly- (ethylene glycol)-b-poly (benzyl-L-glutamate) block copolymers (MG132/m). To analyze biodistribution of free MG132 and MG132/m, we used a Nikon A1R confocal laser scanning microscope system. Blood circulation and accumulation at the tumor (HeLa-H2BGFP cervical carcinoma) and normal tissue were evaluated by visual image.To evaluate the in vivo antitumor effect of MG132/m, subcutaneous xenograft models were established by transplanting human cervical cells (Hela and CaSki) into severe combined immunodeficient (SCID) mice. The SCID mice were treated with free MG132 or MG132/m intravenously (1 mg/kg/dose) twice a week for 4 weeks.In vivo real-time confocal micro-angiography demonstrated that MG132/m had prolonged blood circulation and effective accumulation into solid tumors. Analysis of tumor size following injection of MG132 or MG132/m indicated that MG132/m had a stronger growth inhibitory effect against cervical cancers.Core-shell type polyion complex micelles could be an outstanding drug delivery system for MG132 and possibly other proteasome inhibitors in the treatment of cervical cancer. Less

热剂的大分子载体具有吸引力，因为它们可以通过长时间的血液循环，正常组织中的非特异性积累以及由于渗透率增强和保留率（EPR）效应而改善某些药物的性能。核壳型Polyion复合物（PIC）胶束已将注意力注重作为有希望的大分子载体系统。据报道，抗肿瘤药物的胶束含有铂，紫杉烷具有强大的靶向作用，副作用改善。蛋白酶体降解或过程内蛋白质，其中一些代表细胞周期进展和凋亡的介体，例如细胞周期蛋白，caspase，caspase，bcl2和κB的核因子（NF-κB）。蛋白酶体抑制剂（PI）吸引人们的注意作为一种对各种癌症广泛有效的新抗肿瘤药物。硼替佐米（Bortezomib）是第一个进入临床发育的PI，并于2003年获得FDA的批准进行治疗……更多的继电器和难治性多发性骨髓瘤。但是，已知该药物会引起强大的副作用，例如间质性肺炎。通过将PIC胶束技术应用于PI，我们可能会增加抗肿瘤效应并降低副作用。我们开发了一种新的聚合物胶束，通过MG132和MG132和Poly-（乙二醇）-B-POLY（苯甲基 - 甲苯甲酸酯）（苯甲基 - 甲基甲酸酯）块状嵌段的聚合物-Drug络合物形成增加了PI MG132。为了分析自由MG132和MG132/M的生物分布，我们使用了Nikon A1R共聚焦激光扫描显微镜系统。通过视觉图像评估了肿瘤（HELA-H2BGFP宫颈癌）和正常组织的血液循环和积累。为了评估MG132/M的体内抗肿瘤效应，通过将人宫颈细胞（Hela和Caski）（Caski和Caski）（hela和Caski）进行严重的组合免疫剂（Scki）（Scki），确定了皮下的异种移植模型。 SCID小鼠用游离MG132或MG132/M静脉内（1 mg/kg/剂量）每周两次治疗4周。注射MG132或MG132/M后肿瘤大小的分析表明，MG132/M对宫颈癌具有更强的生长抑制作用。核壳型Polyion型复合胶束可能是MG132的出色药物递送系统，以及可能是其他蛋白酶体抑制剂，可能是颈癌治疗的其他蛋白酶体抑制剂。较少的

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Enhanced Antitumor Activity of Proteasome Inhibitor MG132-loaded Polymeric Micelle Drug Carriers, Analyzed by In Vivo Real-Time Confocal Microangiography

通过体内实时共聚焦微血管造影分析负载蛋白酶体抑制剂 MG132 的聚合物胶束药物载体的增强抗肿瘤活性

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
Yoko Matsumoto;Yu Matsumoto;Yuichiro Miyamoto;Horacio Cabral;Nobuhiro Nishiyama;Shunsuke Nakagawa;Tetsu Yano;Yuji Taketani;Kazunori Kataoka
通讯作者：
Kazunori Kataoka

高得点演題「高分子ナノミセル内包抗悪性腫瘍薬の組織内取り込みに対する高速蛍光イメージングシステムを用いたin vivoリアルタイム解析」

高分演讲题目：“使用高速荧光成像系统对封装在聚合物纳米胶束中的抗癌药物的组织摄取进行体内实时分析”