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Sequential delivery of VEGF siRNA and paclitaxel for PVN destruction, anti-angiogenesis, and tumor cell apoptosis procedurally via a multi-functional polymer micelle

Yang, Yanfang, Meng, Yingying, Ye, Jun, Xia, Xuejun, Wang, Hongliang, Li, Lin, Dong, Wujun, Jin, Dujia, Liu, Yuling
Journal of controlled release 2018 v.287 pp. 103-120
angiogenesis, apoptosis, blood vessels, coculture, composite polymers, drug therapy, drugs, endocytosis, females, histidine, in vivo studies, metastasis, mice, micelles, models, neoplasm cells, neoplasms, pH, paclitaxel, peptides, small interfering RNA, transmission electron microscopy, vascular endothelial growth factors
Co-delivery of chemotherapy drugs and VEGF siRNA (siVEGF) to control tumor growth has been a research hotspot for improving cancer treatment. Current systems co-deliver siVEGF and chemo drugs into tumor cells simultaneously. Although effective, these systems do not flow to the abnormal blood vessels around tumor cells (vascular niche, PVN), which play an important role in the metastasis and deterioration of the tumor. Thus, we custom-synthesized triblock copolymer poly(ε-caprolactone)-polyethyleneglycol-poly(L-histidine) (PCL-PEG-PHIS) with previously synthesized folate-PEG-PHIS to construct a targeted multifunctional polymer micelle (PTX/siVEGF-CPPs/TMPM) to sequentially deliver siVEGF-CPPs (disulfide bond-linked siVEGF and cell-penetrating peptides) and paclitaxel (PTX). The sequential delivery vesicles showed the anticipated three-layered TEM structure and dual-convertible (surface charge- and particle size-reversible) features in the tumor environment (pH 6.5), which guaranteed the sequential release of siVEGF-CPPs and PTX in the tumor extracellular environment and tumor cells, respectively. To mimic the in vivo tumor environment, a double cell model was employed by co-culturing HUVECs and MCF-7 cells. Improved cell endocytosis efficiency, VEGF gene silence efficacy, and in vitro anti-proliferation activity were achieved. An in vivo study on MCF-7 tumor-bearing female nude mice also indicated that sequential delivery vesicles could lead to significant induction of tumor cell apoptosis, loss of VEGF expression, and destruction of tumor blood vessels (PVN and neovascularization). These sequential delivery vesicles show potential as an effective co-delivery platform for siVEGF and chemo drugs to improve cancer therapy efficacy.