Engineered intelligent micelle for tumor pH targeting

描述(由申请人提供)： 这一应用的主要功能是设计功能性聚合物胶束，在酸性细胞外液中靶向实体肿瘤，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%的测得的肿瘤细胞外pH(PILL)低于7.2。对于肿瘤细胞内的pH，肠外药物敏感细胞具有相当酸性的、弥漫的胞浆pH分布；然而，MDR细胞比胞浆和核浆pH更多地发展酸性细胞器(循环内小体、溶酶体和反高尔基网络)。 我们的初步结果表明，由聚(L-组氨酸)/聚乙二醇和聚乳酸/聚乙二醇组成的聚合物胶束通过胶束核心的物理失稳提高了载药模型抗癌药物(在本研究中为阿霉素)的释放速度，导致在较低pH下具有更高的细胞毒性。此外，与叶酸结合的胶束在pH 6.8时不稳定，在叶酸受体介导的内吞作用后，对敏感细胞和多药耐药细胞显示出很好的效果。因此推测，在肿瘤化疗中，触发从肿瘤堆积的智能聚合物胶束中释放DOX是一种更有效的方式，它证明了肿瘤部位的局部浓度较高(靶向高剂量化疗)，而循环中存在最低限度的释放。胶束的失稳可能通过减少间隙中的物理屏障来帮助胶束进一步积累。另一种假说是，在受体介导的内吞作用后，早期内体(约pH为6)同时触发释放和内体破坏将在胞浆和细胞核中提供高浓度的药物。这不仅对敏感的和多药耐药细胞有效，而且对药物扩散率、质膜和Pgp和MRP的泵送活性受损的MDR细胞有效。这种方法将特别适用于弱碱性药物，其胞浆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，以真正识别触发释放的肿瘤堆积或内膜pH，同时在循环中保持最低释放速率；2)评估所提出的改进化疗的假设。

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.