Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India.
Biomater Sci. 2021 Mar 10;9(5):1779-1794. doi: 10.1039/d0bm01033b.
Angiogenesis driven tumor initiation and progression calls for a targeted therapy. Moreover, combined chemotherapy supplements the therapy to act on the cause of concern. In this study, we aimed to develop a targeted crystalsomes approach to delineate tumor cells against normal cells. Self-assembled crystalline monodispersed nanosized polyethylene-polyethylene glycol (PE-PEG)-based hollow crystalsomes were modified with pluronylated putrescine (Put-PF) and loaded with doxorubicin (Dox), synergistically in combination with oleanolic acid (OA) to target the glypican-1 (gp-1) receptor on tumor cells. The developed crystalsomes (Put-D + O@NCs) showed increased intracellular accumulation of Dox and OA in a synergistic combination inside the MDA-MB-231 cell lines. The developed crystalsomes marked an enhanced depolarization of the mitochondrial membrane potential and cell cycle arrest leading to apoptosis. Furthermore, the proposed therapy has a greater anti-angiogenesis activity with vascular endothelial growth factor (VEGF) dependent modulation in the proliferation, invasion, migration and tube formation of human endothelial umbilical vein cells (HUVECs) in vitro and in vivo in a BALB/c mouse model. Interestingly, the perseverance of the tumor boundary, inhibiting the expression and activity of the matrix metalloproteinase (MMPs) (>5.2-fold) with suppressed degradation of the extracellular matrix paves the way for significant inhibition of metastases. However, an intravenously administered Put-D + O@NCs showed an improved pharmacokinetic profile and exquisite inhibition of the 4T1 induced tumor with a significantly lower toxicity. In a nutshell, these findings highlight the important role of Put in the gp-1 receptor for specific targeting and synergistic delivery of Dox and OA through crystalsomes as a potential approach for the treatment of metastatic breast cancer using combined chemotherapy.
血管生成驱动的肿瘤起始和进展需要靶向治疗。此外，联合化疗补充治疗以针对关注的原因。在这项研究中，我们旨在开发一种靶向晶体方法来区分肿瘤细胞与正常细胞。自组装结晶单分散纳米尺寸的聚乙烯-聚乙二醇（PE-PEG）基空心晶体被多聚化腐胺（Put-PF）修饰，并加载多柔比星（Dox），与齐墩果酸（OA）协同作用，以靶向肿瘤细胞上的糖蛋白-1（gp-1）受体。所开发的晶体（Put-D + O@NCs）显示出在 MDA-MB-231 细胞系中协同组合内 Dox 和 OA 的细胞内积累增加。所开发的晶体标记了线粒体膜电位的增强去极化和细胞周期停滞导致细胞凋亡。此外，所提出的治疗具有更大的抗血管生成活性，并且在体外和体内的 BALB/c 小鼠模型中，血管内皮生长因子（VEGF）依赖性调节对人脐静脉内皮细胞（HUVEC）的增殖、侵袭、迁移和管形成有影响。有趣的是，肿瘤边界的维持，抑制基质金属蛋白酶（MMPs）的表达和活性（> 5.2 倍），同时抑制细胞外基质的降解，为显著抑制转移铺平了道路。然而，静脉内给予的 Put-D + O@NCs 显示出改善的药代动力学特征，并通过晶体协同递送至多柔比星和 OA，对 4T1 诱导的肿瘤具有显著的抑制作用，且毒性显著降低。简而言之，这些发现强调了 Put 在 gp-1 受体中的重要作用，用于通过晶体进行特异性靶向和协同递药，作为使用联合化疗治疗转移性乳腺癌的潜在方法。
