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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17200031/
• 关键词: drug delivery; polymeric micelles; cancer chemotherapy; chemotherapeutic agents; environment sensitivity; cancer targeted therapy; nanotechnology; がん; 化学療法; 制がん剤; ブロック共重合体; DDS; pH応答性; ポリエチレングリコール; 抗がん剤; 細胞内環境応答性; アドリアマイシン; 放出制御

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.

聚合物胶束是嵌段共聚物的自组装，是一种很有前途的纳米载药系统。事实上，有几种配方已经在临床试验中进行了研究。聚合物胶束具有几十纳米的尺寸和独特的核壳结构，其中载药核心被生物相容的聚乙二醇链包围。聚合物胶束的这些特性允许它们在血液中持续存在，并在全身给药后有效地积累肿瘤。在这个项目中，我们制备了pH敏感的聚合物胶束，在胶束中，阿霉素(ADR)通过一个不稳定酸化的肼基键连接到嵌段共聚物的成核链段的侧链上。该体系在细胞内低pH条件下有明显的药物释放，而在生理pH条件下没有药物释放。我们将这种对pH敏感的聚合物胶束应用于胰腺癌的治疗，众所周知，胰腺癌由于血管稀少和厚厚的纤维化而难以治愈。结果表明，pH敏感的聚合物胶束对小鼠皮下胰腺癌具有显著的抗肿瘤作用。同时，用叶酸分子修饰pH敏感胶束，构建具有肿瘤靶向性的聚合物胶束。已知大量的癌细胞过度表达叶酸结合蛋白(FBP)。过量表达FBP的癌细胞能更有效地摄取叶酸结合的胶束，在比非靶向胶束低得多的ADR浓度下达到显著的抗肿瘤效果。这些结果表明，使用叶酸偶联胶束可以降低有效剂量，而不是游离ADR，提高了临床化疗的安全性。因此，本研究开发的功能性pH敏感型聚合物胶束有望提高治疗难治性恶性肿瘤的安全性和有效性。

项目成果

Supramolecular nanocarrier of anionic dendrimer porphyrins with cationic block copolymers modified with polyethylene glycol to enhance intracellular photodynamic efficacy

• DOI: 10.1002/anie.200461603
• 发表时间: 2005-01-01
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Jang, WD;Nishiyama, N;Kataoka, K
• 通讯作者: Kataoka, K

Iron hydroxide nanoparticles coated with poly (ethylene glycol)-poly (asparticacid) block copolymer as novel magnetic resonance contrast agents for in vivo cancer imagmg.

涂有聚（乙二醇）-聚（天冬氨酸）嵌段共聚物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造影剂。

• 发表时间: 2007
• 期刊: Colloids Surf., B Biointerfaces 56
• 作者: M. Kumagai;K. Kataoka et al.
• 通讯作者: K. Kataoka et al.

Self-organized nanodevices of smart block copolymers as nanocarriers for gene and drug delivery 〜 Challenge to intracellular nanomedicine 〜

智能嵌段共聚物的自组织纳米器件作为基因和药物输送的纳米载体〜细胞内纳米医学的挑战〜

• 发表时间: 2006
• 作者: H.Uchino;Kataoka et al.;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka
• 通讯作者: K. Kataoka

Clemson award for basic research presentation : smart polymeric micelles as nanocarrier for gene and drug delivery

克莱姆森基础研究报告奖：智能聚合物胶束作为基因和药物输送的纳米载体

• 发表时间: 2005
• 作者: H.Uchino;Kataoka et al.;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka;K. Kataoka
• 通讯作者: K. Kataoka

Supramolecular assemblies for the cytoplasmic delivery of antisense oligodeoxynucleotide: polyion complex (PIC) micelles based on poly (ethyleneglycol)-SS-oligodeoxynucleotide conjugate.

用于反义寡脱氧核苷酸细胞质递送的超分子组装体：基于聚（乙二醇）-SS-寡脱氧核苷酸缀合物的聚离子复合物（PIC）胶束。

• 发表时间: 2007
• 期刊: Biomacromolecules 6
• 作者: M. Oishi;K. Kataoka et al.
• 通讯作者: K. Kataoka et al.