Novel Drug Delivery Systems Research Center, Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
Department of Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
Anticancer Agents Med Chem. 2019;19(11):1405-1417. doi: 10.2174/1871520619666190415165849.
Mitomycin C (MMC) is an anti-cancer drug used for the treatment of breast cancer with limited therapeutic index, extreme gastric adverse effects and bone marrow suppression. The purpose of the present study was the preparation of a dual-targeted delivery system of MMC for targeting CD44 and LHRH overexpressed receptors of breast cancer.
MMC loaded LHRH targeted chonderosome was prepared by precipitation method and was characterized for their physicochemical properties. Cell cycle arrest and cytotoxicity tests were studied on cell lines of MCF-7, MDA-MB231 and 4T1 (as CD44 and LHRH positive cells) and BT-474 cell line (as CD44 negative receptor cells). The histopathology and antitumor activity of MMC-loaded chonderosomes were compared with free MMC in 4T1 cells inducing breast cancer in Balb-c mice.
MMC loaded LHRH targeted chonderosomes caused 3.3 and 5.5 fold more cytotoxicity on MCF-7 and 4T1 cells than free MMC at concentrations of 100μM and 10μM, respectively. However, on BT-474 cells the difference was insignificant. The cell cycle test showed no change for MMC mechanism of action when it was loaded in chonderosomes compared to free MMC. The antitumor studies showed that MMC loaded LHRH targeted chonderosomes were 6.5 fold more effective in the reduction of tumor volume than free MMC with the most severe necrosis compared to non-targeted chonderosomes in pathological studies on harvested tumors.
The developed MMC loaded LHRH targeted chonderosomes were more effective in tumor growth suppression and may be promising for targeted delivery of MMC in breast cancer.
丝裂霉素 C（MMC）是一种用于治疗乳腺癌的抗癌药物，其治疗指数有限，具有极端的胃部不良反应和骨髓抑制作用。本研究的目的是制备一种 MMC 的双靶向递药系统，用于靶向乳腺癌过表达的 CD44 和 LHRH 受体。
采用沉淀法制备载 LHRH 的 MMC 靶向多囊体，并对其理化性质进行了表征。在 MCF-7、MDA-MB231 和 4T1（作为 CD44 和 LHRH 阳性细胞）细胞系以及 BT-474 细胞系（作为 CD44 阴性受体细胞）上研究了细胞周期阻滞和细胞毒性试验。在 Balb-c 小鼠诱导乳腺癌的 4T1 细胞中，比较了载 MMC 多囊体与游离 MMC 的组织病理学和抗肿瘤活性。
在浓度为 100μM 和 10μM 时，载 LHRH 的 MMC 靶向多囊体对 MCF-7 和 4T1 细胞的细胞毒性分别比游离 MMC 高 3.3 倍和 5.5 倍。然而，在 BT-474 细胞中，差异不显著。细胞周期试验表明，与游离 MMC 相比，载药多囊体对 MMC 作用机制没有变化。抗肿瘤研究表明，与游离 MMC 相比，载 LHRH 靶向多囊体在减少肿瘤体积方面的效果提高了 6.5 倍，在收获肿瘤的病理学研究中，与非靶向多囊体相比，其导致的肿瘤坏死最为严重。
研制的载 LHRH 的 MMC 靶向多囊体在肿瘤生长抑制方面更为有效，可能有望用于乳腺癌中 MMC 的靶向递送。
