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体，是一种很有前途的药物纳米载体系统。事实上，已经在临床试验中研究了几种制剂。聚合物胶束的特征在于几十nm的尺寸和独特的核-壳结构，其中载药核被生物相容性聚（乙二醇）（PEG）链包围。聚合物胶束的这些特性允许它们在血流中的寿命和在它们的全身施用后的有效肿瘤积累。在本项目中，我们制备了pH敏感的聚合物胶束，其中阿霉素（ADR）通过酸不稳定的腙键连接到嵌段共聚物的成核链段的侧链上。该系统在细胞内低pH条件下显示出明显的药物释放，而在生理pH条件下不显示药物释放。我们应用这种pH敏感的聚合物胶束治疗胰腺癌，这是已知的是由于血管和厚纤维化是难治的。结果表明，pH敏感的聚合物胶束对小鼠皮下胰腺癌显示出显著的抗肿瘤功效。同时，将叶酸分子修饰到pH敏感胶束上，构建了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）。叶酸缀合的胶束更有效地被FBP过表达的癌细胞吸收，在比非靶向胶束低得多的ADR浓度下实现显著的抗肿瘤效果。这些结果表明，叶酸偶联胶束的使用可能会降低有效剂量超过游离ADR，提高临床化疗的安全性。因此，本研究中开发的功能性pH敏感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

PEG-based block catiomers possessing DNA anchoring and endosomal escaping functions to form polyplex micelles with improved stability and high transfection efficacy

• DOI: 10.1016/j.jconrel.2007.06.020
• 发表时间: 2007-10-08
• 期刊: JOURNAL OF CONTROLLED RELEASE
• 影响因子: 10.8
• 作者: Miyata, Kanjiro;Fukushima, Shigeto;Kataoka, Kazunori
• 通讯作者: Kataoka, Kazunori

Bone regeneration by regulated in vivo gene transfer using Biocompatible polyplex nanomicelles

• DOI: 10.1038/sj.mt.6300218
• 发表时间: 2007-09-01
• 期刊: MOLECULAR THERAPY
• 影响因子: 12.4
• 作者: Itaka, Keiji;Ohba, Shinsuke;Kataoka, Kazunori
• 通讯作者: Kataoka, Kazunori

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