Wang Zhen, Ma Guanglong, Zhang Juan, Lin Weifeng, Ji Fangqin, Bernards Matthew T, Chen Shengfu
State Key Laboratory of Chemical Engineering, Department of Chemical and Biological Engineering, Zhejiang University , Hangzhou, Zhejiang 310027, P. R. China.
Langmuir. 2014 Apr 8;30(13):3764-74. doi: 10.1021/la5000765. Epub 2014 Mar 26.
Polymer-drug conjugates are commonly used as nano drug vehicles (NDVs) to delivery anticancer drugs. Zwitterionic polymers are ideal candidates to conjugate drugs because they show higher resistance to nonspecific protein adsorption in complex media than that of nonionic water-soluble polymers, such as poly(ethylene glycol). However, the charge balance characteristics of zwitterionic polymers used as NDVs will be broken from the inclusion of additional charged groups brought by conjugated drugs or functional groups, leading to the loss of resistance to protein adsorption. Consequently, the nonspecific protein adsorption on drug carriers will cause fast clearance from the blood system, an immune response, or even severe systemic toxicity. To overcome this drawback, a model zwitterionic polymer, poly(carboxybetaine methacrylate) (pCBMA), was modified by the introduction of a negatively charged component, to neutralize the positive charge provided by the model drug, doxorubicin (DOX). A DOX-conjugated NDV which possesses excellent resistance to nonspecific protein adsorption was achieved by the formation of a strongly hydrated pCBMA shell with a slightly negative surface charge. This kind of DOX-conjugated NDV exhibited reduced cytotoxicity and prolonged circulation time, and it accelerated DOX release under mild acid conditions. In tumor-bearing mouse studies a 55% tumor-inhibition rate was achieved without causing any body weight loss. These results indicate the importance of charge tuning in zwitterionic polymer-based NDVs.
聚合物-药物偶联物通常用作纳米药物载体（NDV）来递送抗癌药物。两性离子聚合物是偶联药物的理想候选者，因为与非离子水溶性聚合物（如聚乙二醇）相比，它们在复杂介质中对非特异性蛋白质吸附表现出更高的抗性。然而，用作NDV的两性离子聚合物的电荷平衡特性会因偶联药物或官能团带来的额外带电基团的加入而被打破，导致对蛋白质吸附抗性的丧失。因此，药物载体上的非特异性蛋白质吸附会导致从血液系统中快速清除、免疫反应甚至严重的全身毒性。为了克服这一缺点，通过引入带负电荷的组分对模型两性离子聚合物聚（甲基丙烯酸羧酸甜菜碱）（pCBMA）进行修饰，以中和模型药物阿霉素（DOX）提供的正电荷。通过形成具有轻微负表面电荷的强水合pCBMA壳层，获得了对非特异性蛋白质吸附具有优异抗性的DOX偶联NDV。这种DOX偶联NDV表现出降低的细胞毒性和延长的循环时间，并且在温和酸性条件下加速了DOX释放。在荷瘤小鼠研究中，实现了55%的肿瘤抑制率，且未引起任何体重减轻。这些结果表明了在基于两性离子聚合物的NDV中进行电荷调节的重要性。
