Department of Chemistry and #Department of Oceanography , Faculty of Science, Alexandria University , Alexandria 21321 , Egypt.
Department of Pharmacology and Toxicology , Faculty of Pharmacy, Damanhour University , Damanhour 22516 , Egypt.
Bioconjug Chem. 2018 Sep 19;29(9):3026-3041. doi: 10.1021/acs.bioconjchem.8b00428. Epub 2018 Aug 27.
In this study, promising approaches of dual-targeted micelles and drug-polymer conjugation were combined to enable injection of poorly soluble anticancer drugs together with site-specific drug release. Ursodeoxycholic acid (UDCA) as a hepatoprotective agent was grafted to maltodextrin (MD) via carbodiimide coupling to develop amphiphilic maltodextrin-ursodeoxycholic acid (MDCA)-based micelles. Sulfasalazine (SSZ), as a novel anticancer agent, was conjugated via a tumor-cleavable ester bond to MD backbone to obtain tumor-specific release, whereas resveratrol (RSV) was physically entrapped within the hydrophobic micellar core. For maximal tumor-targeting, both folic acid (FA) and lactobionic acid (LA) were coupled to the surface of micelles to obtain dual-targeted micelles. The decrease of critical micelle concentration (CMC) from 0.012 to 0.006 mg/mL declares the significance of a dual hydrophobicized core of micelles by both UDCA and SSZ. The dual-targeted micelles showed a great hemocompatibility, as well as enhanced cytotoxicity and internalization into HepG-2 liver cancer cells via binding to overexpressed folate and asialoglycoprotein receptors. In vivo, the micelles demonstrated superior antitumor effects revealed as reduction in the liver/body weight ratio, inhibition of angiogenesis, and enhanced apoptosis. Overall, combined strategies of dual active targeted micelles with bioresponsive drug conjugation could be utilized as a promising approach for tumor-targeted drug delivery.
在这项研究中，结合了双靶向胶束和药物-聚合物偶联的有前途的方法，使具有较差水溶性的抗癌药物能够与定点药物释放一起注射。熊去氧胆酸（UDCA）作为一种保肝剂，通过碳二亚胺偶联接枝到麦芽糊精（MD）上，以开发两亲性麦芽糊精-熊去氧胆酸（MDCA）基胶束。柳氮磺胺吡啶（SSZ）作为一种新型抗癌药物，通过肿瘤可裂解的酯键与 MD 主链偶联，以获得肿瘤特异性释放，而白藜芦醇（RSV）则物理包埋在疏水性胶束核内。为了最大限度地实现肿瘤靶向，叶酸（FA）和乳糖酸（LA）都被偶联到胶束表面，以获得双靶向胶束。临界胶束浓度（CMC）从 0.012 降至 0.006mg/mL，表明胶束双疏水性核（UDCA 和 SSZ）的重要性。双靶向胶束具有良好的血液相容性，并且通过与过表达的叶酸和唾液酸化糖蛋白受体结合，增强了对 HepG-2 肝癌细胞的细胞毒性和内化作用。在体内，胶束表现出优异的抗肿瘤效果，表现为肝/体重比降低、血管生成抑制和细胞凋亡增强。总的来说，双活性靶向胶束与生物响应性药物偶联的联合策略可用于肿瘤靶向药物递送。
