Tumor-Adhesive and pH-Degradable Microgels by Microfluidics and Photo-Cross-Linking for Efficient Antiangiogenesis and Enhanced Cancer Chemotherapy.

Abstract

Tumor angiogenesis with the vascular network formation provides nutrition and oxygen for cancer cells, promoting the proliferation and metastasis of malignant tumors. Bevacizumab (Bev) as an efficient antiangiogenic antibody is able to normalize the tumor vasculature with better blood flow and reduced interstitial fluid pressure, allowing drugs with more uniform distribution and deeper penetration into the tumor; however, it is highly difficult to realize the simultaneous delivery of Bev and anticancer drugs localized at the tumor tissue. Here, we prepared tumor-adhesive and pH-degradable poly(vinyl alcohol) (PVA) microgels for tumor-localized delivery of Bev and docetaxel (DTX), to achieve efficient antiangiogenesis and enhanced cancer chemotherapy. PVA microgels (∼200 μm) decorated with tissue-adhesive dopamine (DA) moieties were fabricated by a combination of high-throughput microfluidics technology and photo-cross-linking chemistry with a considerable coencapsulation efficiency for Bev and DTX. PVA microgels exhibited sustained drug release at the tumoral acidic conditions as the microgel degradation, and DA moieties on the microgels facilitated Bev with long retention at the tumor tissue, highly blocking the vascular endothelial growth factor (VEGF) and inhibiting tumor angiogenesis, as compared to free Bev or no DA-decorated microgels. In addition, the antitumor activity on the 4T1-Luc breast tumor mouse model treated with Bev/DTX-coloaded microgels showed obviously superior tumor growth inhibition than the other treatment groups, in which the combinational therapy efficacy of Bev and DTX mediated by the tumor-adhesive microgels was further confirmed by the immunohistochemistry (IHC) analysis. These PVA microgels with efficient antiangiogenesis and enhanced cancer chemotherapy provide a highly potential platform to treat different malignant tumors as well as the recurrent and metastatic tumors.