Engineered intelligent micelle for tumor pH targeting

描述（由申请人提供）： 本申请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%的测量的肿瘤细胞外pH（pile）低于7.2。对于肿瘤细胞的细胞内pH，胃肠外药物敏感细胞的特征是具有相当酸性的、弥漫性的胞质pH特征;然而，MDR细胞比胞质和胞浆pH形成更多酸性细胞器（再循环核内体、溶酶体和反式高尔基体网络）。 我们的初步研究结果表明，由聚（L-组氨酸）/PEG和PLLA/PEG增强了负载模型抗癌药物的释放速率（在本研究中为阿霉素（DOX）），导致在较低pH下更高的细胞毒性。此外，与叶酸缀合并在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细胞显示出极大的功效。因此，假设DOX从肿瘤堆处的智能聚合物胶束的触发释放是癌症化疗中更有效的模式，证明了肿瘤部位处的更高局部浓度（靶向高剂量化疗），而在循环期间发生最小释放。胶束去稳定化可以通过减少间隙空间中的物理屏障来帮助胶束的进一步积累。另一种假设是，在受体介导的内吞作用后，早期内体（约pH 6）中的同时触发释放和内体破坏将在胞质溶胶和细胞核中提供高浓度的药物。这将不仅对敏感细胞有效，而且对MDR细胞有效，其中药物扩散性、质膜以及Pgp和MRP的泵送活性受到损害。这种方法将是特别有用的弱碱性药物的细胞质和亚细胞器之间的分区是极大地影响pH梯度（螯合）。 本研究的目标是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，其可以真正识别肿瘤堆或内体pH以触发释放，同时在循环期间保持最小释放速率，以及2）评估改进化疗的拟议假设。

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.