Rational Design of Anticancer Drug Resistance Nanoparticles

[4082 . 82]耐药是癌症治疗中的一大难题。耐药形式通过减缓药物摄取、通过p -糖蛋白（P-gp）泵将药物排出细胞和生物转化等机制有效降低细胞药物浓度。因此，常规剂量治疗效果低，毒性大，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存在药物在血液中过早爆裂释放的问题，但在癌症组织中药物释放缓慢和细胞摄取缓慢。再加上耐药，这些问题导致肿瘤细胞内药物浓度低，治疗效果低。该项目的目标是设计、合成、表征并在体外和体内评估能够克服癌症耐药的纳米颗粒，以实现有效的化疗。假设是，癌细胞细胞质内大量药物的快速释放会压倒P-gp泵和其他形式的耐药性，从而使细胞药物浓度高于细胞杀伤阈值。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渗漏特性使纳米颗粒优先被困在癌症组织中，利用基于静电相互作用的吸附细胞摄取来有效地内化纳米颗粒，并利用溶酶体pH值来触发药物的快速释放。这项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。所获得的结果可能为与癌症的战争提供一种有效的新的癌症治疗策略。关于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.