<i>In situ</i> injection of dual-delivery PEG based MMP-2 sensitive hydrogels for enhanced tumor penetration and chemo-immune combination therapy
Jianqin Yan, Zhuangzhuang Zhang, Xiaohui Zhan, Keqi Chen, Yuji Pu, Yan Liang, Bin He
Abstract
Improving the deep penetration of nanoparticles and realizing the combination of chemotherapy and immunotherapy have become a promising strategy for cancer treatment. Herein, a nuclear-targeted tetrahedral DNA nanostructure (NLS-TDNs, NT) was synthesized to construct matrix metalloproteinase (MMP-2) sensitive hydrogels as delivery vehicles with co-loaded disulfide cross-linked polyethyleneimine (PSP)/nuclear-targeted tetrahedral DNA (NLS-TDNs, NT)/doxorubicin (DOX) nanoparticles (NPs) (PSP/NT/DOX NPs and PNT/DOX NPs) and an immune adjuvant imiquimod (R837) to realize a combination of chemotherapy and immunization for metastatic breast cancer. Due to the membrane-breaking ability of the PNT/DOX NPs, the nanoparticles could effectively achieve deep penetration into tumor tissues, and the in situ generation of tumor-associated antigens by PNT/DOX elicited a strong immune response in the presence of R837, achieving a chemo-immune combination therapy of breast cancer, inducing the maturation of dendritic cells (DCs) and secretion of related cytokines, such as interleukin-6 (IL-6), interleukin-12 (IL-12p70) and tumor necrosis factor (TNF-α) in vitro. The combination significantly promoted the proportions of cytotoxic T cells (CD8+ CTL) and cytotoxic T cells/regulatory T cells (CD8+ CTL/Treg) (5.52% and 11.46%, respectively) and the secretion of cytokines, which cooperatively eradicated primary tumor growth (the tumor growth inhibition (TGI) value was 78.3%) and inhibited the tumor from metastasizing effectively in vivo. Our study provided the basis for activating the antitumor immune system to realize chemo-immunotherapy and tumor metastasis therapy.