Jang Eunji, Lim Eun-Kyung, Choi Yuna, Kim Eunjung, Kim Hyun-Ouk, Kim Dong-Joo, Suh Jin-Suck, Huh Yong-Min, Haam Seungjoo
Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul 120-749, Republic of Korea.
J Mater Chem B. 2013 Nov 7;1(41):5686-5693. doi: 10.1039/c3tb20906g. Epub 2013 Sep 18.
Molecular targeted delivery of therapeutic agents and their stimuli-responsive release are some of the major issues for modern medical administration, particularly in cancer chemotherapy. In this study, we developed a π-hyaluronan nanocarrier (πHNC) for CD44-targeted and pH-boosted delivery of an aromatic anticancer drug to cancer cells. Amphiphilic π-hyaluronan (pyrenyl hyaluronan, πHA) was synthesized using EDC chemistry, and self-assembled to form πHNC, the structure of which was obviously micellar but was convincingly effective to function; (i) a π-rich pyrenyl core of πHNC, a loading aromatic drug (doxorubicin, DOX) by π-stacking attraction, showed a rapid release profile under low pH conditions which is a notable characteristic of the cancer microenvironment as well as the endolysosomal state after uptake into the target cell and (ii) the hydrophilic hyaluronan shell of πHNC acted as a ligand for CD44 resulting in the localization of πHNC into the target cell by CD44-mediated endocytosis, without cytotoxicity. With its targeted and stimulated delivery of aromatic drugs to the target cells, DOX-loaded πHNC (πHNC/DOX) provided effectual therapeutic activity in both in vitro and in vivo models of CD44-positive human gastric cancer, which is suitable as a facile and efficient drug delivery platform.
治疗剂的分子靶向递送及其刺激响应释放是现代医学给药的一些主要问题，尤其是在癌症化疗中。在本研究中，我们开发了一种用于将芳香族抗癌药物靶向递送至癌细胞并在pH值升高时释放的π-透明质酸纳米载体（πHNC）。使用EDC化学合成两亲性π-透明质酸（芘基透明质酸，πHA），并自组装形成πHNC，其结构明显呈胶束状，但功能上令人信服地有效；（i）πHNC富含π的芘基核心通过π-堆积吸引力负载芳香族药物（阿霉素，DOX），在低pH条件下显示出快速释放特征，这是癌症微环境以及被靶细胞摄取后的内溶酶体状态的一个显著特征，以及（ii）πHNC的亲水性透明质酸外壳作为CD44的配体，通过CD44介导的内吞作用使πHNC定位于靶细胞，且无细胞毒性。通过将芳香族药物靶向递送至靶细胞并进行刺激释放，负载DOX的πHNC（πHNC/DOX）在CD44阳性人胃癌的体外和体内模型中均提供了有效的治疗活性，适合作为一种简便高效的药物递送平台。
