Rational Design of Anticancer Drug Resistance Nanoparticles

耐药性是癌症治疗中的一个主要问题。耐药形式通过诸如减慢药物摄取、通过P-糖蛋白（P-gp）泵将药物排出细胞以及生物转化等机制有效地降低细胞药物浓度。因此，常规剂量具有低的治疗功效，毒性很大并引起各种副作用。纳米颗粒是理想的药物载体，因为它们的亚细胞大小，稳定性和逃避网状内皮系统的能力。 然而，目前开发的用于癌症治疗的纳米颗粒通常具有在血流中过早药物爆发释放的问题，但在癌症组织中缓慢药物释放和缓慢细胞摄取。再加上耐药性，这些问题导致癌细胞中的药物浓度低，治疗效果低。该项目的目标是设计，合成，表征和体外和体内评估纳米颗粒，可以克服癌症耐药性，有效的化疗。 该假说认为，大量药物在癌细胞胞质内的快速释放将压倒P-gp泵和其他形式的耐药性，从而建立高于细胞杀伤阈值的细胞药物浓度。为了验证这一假设，研究人员将使用不会过早释放药物的纳米颗粒作为药物载体，利用癌症毛细血管的泄漏性质使纳米颗粒优先捕获在癌症组织中，使用基于静电相互作用的吸附细胞吸收来有效细胞内化纳米颗粒并使用溶酶体pH值触发药物的快速释放。这种多学科的研究工作结合了聚合物合成和表征，纳米科学，生物医学工程，热力学和自组装的元素。 这些结果可能为癌症的治疗提供一种新的有效策略。 有关聚合物和纳米粒子的生物医学应用的选定主题将为各种课程开发。

0401982ShenDrug resistance is a major problem in the treatment of cancer. Forms of resistance effectively reduce the cell drug concentration by mechanisms such as slowing drug uptake, ejecting drugs out of the cells by P-glycoprotein (P-gp) pumps, and bio-transforming. Thus, conventional dosages have low therapeutic efficacy, are very toxic and cause various side effects. Nanoparticles are ideal drug carriers because of their subcellular sizes, stability, and ability to evade the reticulo-endothelial systems. However, currently developed nanoparticles for cancer treatment generally have issues of premature drug burst release in the blood stream, but slow drug release and slow cellular uptake in cancer tissues. Coupled with drug resistance, these issues cause low drug concentration in the cancer cells and low therapeutic efficacy. The goal of this project is to design, synthesize, characterize and in vitro and in vivo evaluate nanoparticles that can overcome cancer drug resistance for effective chemotherapy. The hypothesis is that a fast release of a large amount of drugs inside the cancer cell cytoplasm would overwhelm P-gp pumps and other forms of drug resistance and thus build up a cell drug concentration higher than the cell killing threshold. To test this hypothesis, the investigators will use nanoparticles with no premature drug release as the drug-carrier, exploit the leaky nature of cancer capillary to have the nanoparticles preferentially trapped in cancer tissues, use electrostatic-interaction based adsorptive cellular uptake for efficient cell-internalization of the nanoparticles and use the lysosomal pH to trigger the rapid release of the drugs. This multidisciplinary research effort combines the elements of polymer synthesis and characterization, nanoscience, biomedical engineering, thermodynamics, and self-assembly. Results obtained may provide an effective new cancer therapeutic strategy for the war with cancer. Selected topics on biomedical applications of polymers and nanoparticles would be developed for a variety of courses.