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本研究通过p H敏感的腙键共价连接疏水性化疗药物多柔比星(doxorubicin,DOX)和亲水性抗肿瘤转移的低分子量肝素(low molecular weight heparin,LH)合成了低分子量肝素-多柔比星胶束(LH-DOX),并物理包载光热剂吲哚菁绿(indocyanine green,ICG),以透析法制备了具有p H敏感的载吲哚菁绿的低分子量肝素-多柔比星聚合物胶束(LH-DOX/ICG)。该胶束粒径为(148.7±2.1)nm,在电镜下呈形态规则的球形,粒径均一,并具有良好的稳定性和生物相容性。体外释放结果显示,DOX的释放具有p H敏感性,ICG有一定的缓释效果。ICG包载于胶束后与游离ICG具有相似的光热效应。一方面,划痕愈合实验显示,在激光照射下LH-DOX/ICG胶束具有良好的抗肿瘤转移能力;另一方面,细胞凋亡及细胞毒性实验表明,在激光照射下该胶束诱导黑色素瘤B16F10细胞凋亡的能力和对细胞毒性作用明显增加。因此,LH-DOX/ICG胶束具有良好的前景,用于光疗-化疗联合治疗黑色素瘤。
In this study, a low molecular weight heparin-covalent bond was synthesized by the covalent attachment of p H-sensitive hydrazone bond to the hydrophobic chemotherapeutic drug doxorubicin (DOX) and hydrophilic anti-tumor metastatic low molecular weight heparin (LH) (LH-DOX), and photoluminescence agent indocyanine green (ICG) was physically loaded. The low molecular weight heparin-loaded indocyanine green-sensitive heparin- Doxorubicin polymer micelles (LH-DOX / ICG). The size of the micelles was (148.7 ± 2.1) nm. The shape of the micelles was spherical under electron microscopy. The size of the micelles was uniform with good stability and biocompatibility. In vitro release results show that the release of DOX has p H sensitivity, ICG has a sustained release effect. The ICG encapsulated in micelles has similar photothermal effects as free ICG. On the one hand, scratch healing experiments showed that LH-DOX / ICG micelles had good anti-metastatic ability under laser irradiation; on the other hand, apoptosis and cytotoxicity experiments showed that the micelles induced melanin Tumor B16F10 cell apoptosis and cytotoxicity increased significantly. Therefore, LH-DOX / ICG micelles have good prospects for phototherapy - chemotherapy combined treatment of melanoma.