Drug/gene co-delivery carriers are a promising strategy for cancer treatment. Thus, herein, T7-conjugated redox-sensitive amphiphilic polyethylene glycol–polyethyleneimine–poly(caprolactone)-SS-poly(caprolactone)–polyethyleneimine–polyethylene glycol (PEG–PEI–PCL-SS-PCL–PEG) (PPPT) is designed to realize the co-delivery of pORF-hTRAIL and DOX efficiently into tumor cells. PPPT is synthesized via the ring opening polymerization (ROP) of ε-caprolactone followed by Michael addition polymerization and atom transfer radical polymerization (ATRP) of the maleic imide group of MAL-PEG-NHS. The PPPT micelles present a spherical or ellipsoidal geometry with a mean diameter of approximately 100–120 nm. Meanwhile, they also exhibit a redox-responsive drug release profile in vitro. The blood compatibility and complement activation tests reveal that the PPPT micelles do not induce blood hemolysis, blood clotting, or complement activation. The T7-modified co-delivery system shows a higher cellular uptake efficiency than the unmodified co-delivery system in human breast cancer MCF-7 cells and is accumulated in tumor more efficiently in vivo. These results suggest that the T7-targeted codelivery system of DOX and pORF-hTRAIL is a combined delivery platform that can significantly improve the treatment of breast cancer.
Yang Sui,Ji Li,Jiqiang Qu,Ting Fang,Hongyan Zhang,Jian Zhang,Zheran Wang,Mingyu Xia,Yinghui Dai,Dongkai Wang
Cancer vaccine contributing to the success of the treatment and prevention of tumors has attracted a huge attention as a strategy for tumor immunotherapy in recent years. A major challenge of cancer vaccine is to target cytosols of dendritic cells (DCs) in the lymph nodes (LNs) to enhance efficiency of antigen cross-presentation, which elicits high levels of cytotoxic T-lymphocytes to destruct tumor cells. Here, we address this issue by conjugating ovalbumin (OVA) to PEG-PCL using disulfide bond (-ss-), and the degradable pH-responsive polymer-PEI-PCL as delivery carrier. In addition, the mol ratio of PEG-PCL to PEI-PCL in the mixed micelles was tailored to deliver the OVA to LNs. Subsequently, CpG ODN 1826 , a TLR-9 agonist, was further introduced into a mixed micelle of 30 nm or less as a unique tumor vaccine. Importantly, the results demonstrated the mixed micelles with 1:1 mol of PCL-PEG and PCL-PEI can effectively migrate to distal LNs where antigen were efficiently captured by DCs, meanwhile, OVA was modified to the surface of mixed micelles via disulfide bonds (-ss-) for promotion efficiency of antigen cross-presentation. More surprisingly, combination of tumor vaccine with anti-PD-1, the therapy of ectopic melanoma (B16-OVA) and lung metastasis melanoma (B16-OVA) is excellent therapeutic effect. Taken together, our works offers a novel strategy for the cytosol delivery of antigens to achieve potent cancer immunotherapy.
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