Engineered intelligent micelle for tumor pH targeting

用于肿瘤 pH 靶向的工程智能胶束

• 批准号: 7009634
• 负责人: You Han Bae
• 金额: $ 26.93万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-05 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009634
• 关键词: acid base balance; athymic mouse; biomaterial development /preparation; biotechnology; doxorubicin; drug delivery systems; laboratory mouse; micelles; multidrug resistance; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; pharmacokinetics; polymers

DESCRIPTION (provided by applicant): The primary function of this application is to engineer functional polymeric micelles which target solid tumors in acidic extracellular fluid and utilize acidic endosome to treat sensitive and multidrug resistant (MDR) tumors. It is estimated that more than 80% of measured tumor extracellular pH (pile) are below 7.2. For intracellular pH of tumor cells, parenteral drug sensitive cells are characterized to have rather acidic, diffuse cytosolic pH profile; however MDR cells develop more acidic organelles (recycling endosome, lysosome and trans-Golgi network) than cytosol and necleoplasmic pH. Our preliminary results demonstrate that the polymeric micelles composed of poly(L-histidine)/PEG and PLLA/PEG enhanced the release rate of a loaded model anticancer drug (doxorubicin (DOX) in this study) by physical destabilization of the micelle core at pile, resulting in higher cytotoxicity at lower pH. In addition, the micelles, conjugated with folate and destabilized at pH 6.8, showed great efficacy for sensitive and MDR cells after folate receptor-mediated endocytosis. Therefore it is hypothesized that triggered release of DOX from the intelligent polymeric micelles at tumor pile is a more effective modality in cancer chemotherapy, proving higher local concentration at tumor sites (targeted high-dose chemotherapy), while a minimal release during circulation occurs. The micelle destabilization may help further accumulation of the micelles by reducing the physical barriers in the interstitial space. Another hypothesis is that after receptor-mediated endocytosis, simultaneous triggered release in early endosomes (approximately pH 6) and endosomal disruption will provide high concentrations of the drug in cytosol and nucleus. This will be effective not only for sensitive and but for MDR cells where the drug diffusivity the plasma membrane is compromised and the pumping activities of Pgp and MRP. This approach will be especially useful for weakly basic drugs of which partitioning between cytosol and subcellular organelles is greatly influenced by pH gradient (sequestration). The goals of this research are 1) to design biodegradable polymers sensitive to tumor acidity and to engineer polymeric micelles with or without targeting moiety that can truly recognize tumor pile or endosomal pH for triggered release, while keeping a minimal release rate during circulation and 2) to assess the proposed hypotheses for improved chemotherapy.

描述（由申请人提供）： 该应用的主要功能是设计功能性聚合物胶束，其靶向酸性细胞外液中的实体瘤，并利用酸性内体治疗敏感和多药耐药（MDR）肿瘤。据估计，超过 80% 的测量肿瘤细胞外 pH 值（堆）低于 7.2。对于肿瘤细胞的细胞内 pH 值，肠胃外药物敏感细胞的特点是具有相当酸性、弥散的胞质 pH 谱；然而，MDR 细胞会产生比细胞质和核质 pH 值更多的酸性细胞器（循环内体、溶酶体和跨高尔基体网络）。 我们的初步结果表明，由聚（L-组氨酸）/PEG 和 PLLA/PEG 组成的聚合物胶束通过胶束核心的物理去稳定性提高了负载模型抗癌药物（本研究中的阿霉素（DOX））的释放速率，导致在较低pH值下具有较高的细胞毒性。此外，与叶酸结合并在 pH 6.8 下不稳定的胶束在叶酸受体介导的内吞作用后对敏感细胞和 MDR 细胞显示出巨大的功效。因此，推测肿瘤堆处的智能聚合物胶束触发 DOX 的释放是癌症化疗中更有效的方式，证明肿瘤部位的局部浓度较高（靶向高剂量化疗），而循环过程中的释放量极小。胶束不稳定可能通过减少间隙空间中的物理屏障来帮助胶束进一步积累。另一个假设是，在受体介导的内吞作用之后，早期内涵体（pH 值约为 6）中同时触发的释放和内涵体破坏将在细胞质和细胞核中提供高浓度的药物。这不仅对敏感细胞有效，而且对 MDR 细胞也有效，因为在这些细胞中，质膜的药物扩散性以及 Pgp 和 MRP 的泵送活性受到损害。这种方法对于弱碱性药物特别有用，其中细胞质和亚细胞细胞器之间的分配受 pH 梯度（隔离）的影响很大。 这项研究的目标是 1) 设计对肿瘤酸度敏感的可生物降解聚合物，并设计具有或不具有靶向部分的聚合物胶束，能够真正识别肿瘤堆或内体 pH 值以触发释放，同时在循环过程中保持最小释放率；2)评估所提出的改进化疗的假设。