Development of functional polymeirc micelles responding to intracellular microenvironments for cancer chemotherapy

开发响应细胞内微环境的功能性聚合物胶束用于癌症化疗

基本信息

批准号：
17200031
负责人：
KATAOKA Kazunori
金额：
$ 30.2万
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 (A)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

Polymeric micelles, the self-assemblies of block copolymers, are a promising nanocarrier system for drug delivery. Indeed, several formulations have been studied in clinical trials. Polymeric micelles are characterized by a size of several tens nm and unique core-shell structure, where the drug-loaded core is surrounded by biocompatible poly(ethylene glycol) (PEG) chains. These characteristics of polymeric micelles allow their longevity in the bloodstream and effective tumor accumulation after their systemic administration. In this project, we have prepared pH-sensitive polymeric micelles, in which adriamycin (ADR) is attached to the side chain of the core-forming segment of the block copolymers via an acid-labile hydrazone bond. The system showed appreciable drug release under intracellular low pH conditions, while exhibiting no drug release under physiological pH conditions. We applied such pH-sensitive polymeric micelles for the treatment of pancreatic cancers, which are known to be intractable due to hypovascularity and thick fibrosis. As a result, pH-sensitive polymeric micelles showed significant antitumor efficacy against subcutaneous pancreatic cancers in mice. Meanwhile, the pH-sensitive micelles were modified with a folate molecule to construct the polymeric micelles with the tumor-targetability. A large number of cancer cells are known to overexpress folate-binding proteins (FBP). The folate-conjugated micelles were more efficiently taken up by the FBP-overexpressing cancer cells, achieving remarkable antitumor effect at much lower ADR concentrations than the non-targeted micelles. These results indicate that the use of the folate-conjugated micelles may lower the effective doses over free ADR, improving the safety of the clinical chemotherapy. Thus, functional pH-sensitive polymeric micelles developed in this study are expected to improve the safety and efficacy of the treatments against intractable malignant tumors.

聚合物胶束是块共聚物的自组件，是一种有前途的纳米载体系统。实际上，在临床试验中已经研究了几种配方。聚合物胶束的特征是几十nm的大小和独特的核壳结构，其中载有药物的芯被生物相同的聚（乙二醇）（PEG）链包围。聚合胶束的这些特征使其在全身给药后的血液中寿命和有效的肿瘤积累。在这个项目中，我们制备了对pH敏感的聚合物胶束，其中adrimycin（ADR）通过酸 - 轻型果实粘合剂键连接到块共聚物的核心形成段的侧链。该系统在细胞内低pH条件下显示出明显的药物释放，同时在生理pH条件下没有释放药物。我们将这种pH敏感的聚合物胶束应用于胰腺癌的治疗，由于低血管性和较厚的纤维化，已知这很棘手。结果，pH敏感的聚合物胶束在小鼠中对皮下胰腺癌显示出明显的抗肿瘤功效。同时，用叶酸分子对pH敏感的胶束进行修饰，以构建具有肿瘤靶向性的聚合物胶束。已知大量癌细胞过表达叶酸结合蛋白（FBP）。叶酸偶联的胶束比过表达FBP的癌细胞更有效地吸收了与非靶向胶束相比，ADR浓度低得多的抗肿瘤效应。这些结果表明，使用叶酸偶联的胶束可能会降低有效剂量，而不是自由ADR，从而提高了临床化学疗法的安全性。因此，在这项研究中开发的功能性pH敏感聚合物胶束有望提高治疗对棘手的恶性肿瘤的安全性和功效。

项目成果

期刊论文数量（114）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Iron hydroxide nanoparticles coated with poly (ethylene glycol)-poly (aspartic acid) block copolymer as novel magnetic resonance agents for in vivo cancer imaging

聚（乙二醇）-聚（天冬氨酸）嵌段共聚物包覆的氢氧化铁纳米颗粒作为用于体内癌症成像的新型磁共振剂

DOI：
发表时间：
2007
期刊：
Colloids Surf., B Biointerfaces 56
影响因子：
0
作者：
M. Kumagai;Y. Imai;T. NAkamura;Y. Yamasaki;M. Sekino;S. Ueno;K. Hanaoka;K. Kikuchi;T. Nagano;E. Kaneko;K. Shimokado;K. Kataoka
通讯作者：
K. Kataoka

Preparation and characterzation of polyion complex micelles with a novel thermosrnsitive poly (2-isopropyl-2-oxazoline) shell via the complexation of oppositely charged block ionomers

通过相反电荷嵌段离聚物的络合制备和表征具有新型热敏聚（2-异丙基-2-恶唑啉）壳的聚离子复合胶束