Adaptable Polymer Micelles for Tumor Targeting

描述(申请人提供)：聚合物胶束已被广泛用于输送难溶于水的药物。尽管它们有很好的性能，但它们还没有完全发展成为靶向递送抗癌药物的载体。这主要是由于对静脉给药时聚合物胶束的体内行为缺乏了解。物理上自组装的聚合物胶束在血液中并不稳定，然而，还没有进行系统的研究。本研究致力于了解聚合物胶束与血液成分之间的相互作用，以开发一种新型的抗癌药物靶向递送的聚合物胶束，用于临床应用。这项研究的长期目标是开发适应性聚合物胶束，这种胶束在血液中稳定，但能被肿瘤部位丰富的酶解离。该项目的假设是，血液中聚合物胶束的稳定性是肿瘤治疗成功的先决条件。只有稳定的聚合物胶束才有机会靶向肿瘤，并在治疗有效的水平上输送抗肿瘤药物。本项目的具体目标是：(1)开发适应性聚合物胶束；(2)检测胶束在血液中的稳定性；(3)阐明胶束与细胞之间的相互作用；(4)表征胶束在体内的去向，并研究载药胶束的抗肿瘤活性。用于肿瘤治疗的两种药物是紫杉醇和吉非替尼，这两种药物具有相似的疏水性。预计这两种药物对的协同作用将产生实质上更好的抗肿瘤效果。通过二硫键或可被肿瘤部位丰富的凝血酶或基质金属蛋白酶2(MMP2)降解的多肽将胶束的疏水核心交联成适应性聚合物胶束。适应性聚合物胶束的血液稳定性和肿瘤靶向性将通过相干反斯托克斯拉曼散射(CARS)、荧光反射成像(FRI)和荧光分子断层扫描(FMT)进行检测。体内外实验的结果将被用来改善适应性聚合物胶束的性能，并重复这样的反馈循环，以产生最佳的聚合物胶束。我们提出的研究的意义在于，它将阐明影响聚合物胶束在血液中的稳定性的因素，以及细胞摄取，以及胶束在体内的命运/行为。该项目的成功完成有望产生可适应的聚合物胶束，有效地将两种药物对定向输送到肿瘤部位。

DESCRIPTION (provided by applicant): Polymer micelles have been used widely for delivery of poorly water-soluble drugs. Despite their promising properties, they have not been fully developed as a vehicle for target delivery of anticancer agents. This is mainly due to the lack of understanding on the in vivo behavior of polymer micelles upon intravenous administration. Physically self-assembled polymer micelles are not expected to be stable in blood, and yet, no systematic studies have been made. This study is focused on understanding the interactions between polymer micelles and blood components for development of a new class of polymer micelles for targeted delivery of anticancer agents for clinical applications. The long-term goal of this research is to develop adaptable polymer micelles that are stable in blood but undergo dissociation by enzymes abundant at the tumor site. The hypothesis in this project is that the stability of polymer micelles in blood is prerequisite for successful tumor therapy. Only the stable polymer micelles have chances to target tumors and deliver anti-tumoral drugs at the therapeutically effective level. Specific Aims of this project are: (1) to develop adaptable polymer micelles; (2) to examine the micelle stability in blood; (3) to elucidate the micelle-cell interactions; and (4) to characterize the in vivo fate of micelles and to study the anti-tumoral activity of drug-loaded micelles. The two drugs to be used for tumor therapy are paclitaxel and gefitinib, which have similar hydrophobicity. The synergistic effect of the two-drug pair is expected, resulting in substantially better anti-tumoral effect. The adaptable polymer micelles will be prepared by crosslinking the hydrophobic core of the micelles through disulfide or peptides that are degradable by thrombin or matrix metalloproteinase 2 (MMP2) which are abundant at the tumor sites. The blood stability and tumor targeting properties of the adaptable polymer micelles will be examined by coherent anti-Stokes Raman scattering (CARS), fluorescence reflectance imaging (FRI), and fluorescence molecular tomography (FMT). The results of in vitro and in vivo experiments will be used to improve the properties of the adaptable polymer micelles, and such feedback cycle will be repeated to produce the optimal polymer micelles. The significance of our proposed research is that it will elucidate the factors affecting the stability of polymer micelles in blood, as well as cellular uptake, and in vivo fate/behavior of the micelles. Successful completion of this project is expected to produce adaptable polymer micelles that are effective for targeted delivery of a two-drug pair to the tumor sites.