Intraperitoneal Administration of a Tumor-Associated Antigen SART3, CD40L, and GM-CSF Gene-Loaded Polyplex Micelle Elicits a Vaccine Effect in Mouse Tumor Models

Abstract

Polyplex micelles have demonstrated biocompatibility and achieve efficient gene transfection in vivo. Here, we investigated a polyplex micelle encapsulating genes encoding the tumor-associated antigen squamous cell carcinoma antigen recognized by T cells-3 (SART3), adjuvant CD40L, and granulocyte macrophage colony-stimulating factor (GM-CSF) as a DNA vaccine platform in mouse tumor models with different types of major histocompatibility antigen complex (MHC). Intraperitoneally administrated polyplex micelles were predominantly found in the lymph nodes, spleen, and liver. Compared with mock controls, the triple gene vaccine significantly prolonged the survival of mice harboring peritoneal dissemination of CT26 colorectal cancer cells, of which long-term surviving mice showed complete rejection when re-challenged with CT26 tumors. Moreover, the DNA vaccine inhibited the growth and metastasis of subcutaneous CT26 and Lewis lung tumors in BALB/c and C57BL/6 mice, respectively, which represent different MHC haplotypes. The DNA vaccine highly stimulated both cytotoxic T lymphocyte and natural killer cell activities, and increased the infiltration of CD11c+ DCs and CD4+/CD8a+ T cells into tumors. Depletion of CD4+ or CD8a+ T cells by neutralizing antibodies deteriorated the anti-tumor efficacy of the DNA vaccine. In conclusion, a SART3/CD40L+GM-CSF gene-loaded polyplex micelle can be applied as a novel vaccine platform to elicit tumor rejection immunity regardless of the recipient MHC haplotype.

Applications of polymer-based nanoparticles in vaccine field

“…The acquired compounds can stimulate higher levels of OVAspecific antibodies and CD8+ T cells in mice and significantly inhibit tumor increase following attack with the OVA expressing EG7 tumor cells [78]. The carrier system based on a mixture of a homopolymer of a DNA polymer with a cationic polyaspartamide P[Asp(DET)] and block copolymer PEG-b-P [Asp(DET)] are presentated [79]. Optimization of homopolymers and block copolymers for DNA complexes, against non-specific eliminate stability and cells transfection efficient.…”

Structural Basis of the Recruitment of Ubiquitin-specific Protease USP15 by Spliceosome Recycling Factor SART3

“…SART3 plays multiple roles in mRNA splicing, viral and host gene transcription, as well as stem cell survival, proliferation, and differentiation. It is also a potential antigen for cancer immunotherapy (7)(8)(9). The biological functions of SART3 have been summarized in a recent comprehensive review (10).…”

Polymeric Micelles in Cancer Immunotherapy

“…The SART3 micelles significantly improved the survival rates of mice bearing CT26 tumors, while delivering naked SART3 genes failed to elicit such therapeutic responses. The elevated activities of CTL and NK cells of splenocytes, as well as the increased infiltration of DCs and CD8a + T cells into tumor tissue, were also observed with the administration of SART3 micelles [ 91 , 92 ]. Polymeric micelles were also used for gene delivery to enhance the efficacy of tumor antigens.…”

“…Li et al and Ni et al reported that polymeric micelles made from PCL-PEI/PCL-PEG and PEG-PLA could increase antigen/adjuvant uptake by DCs and prolong their retention in the lymph nodes [ 139 , 140 ]. Besides, Cui et al, Furugaki et al, and Coumes et al reported that antigens and adjuvants co-delivered via polymeric micelles successfully inhibited tumor growth and metastasis in mice as well as prolonged tumor-bearing mice survival, compared to free antigen–adjuvant combinations [ 91 , 92 , 141 , 142 ]. The improved pharmacological responses are also supported by the observations of increased CD11c + DCs and CD4 + /CD8a + T cells infiltration into tumors, stronger CTL activities, and higher CD4 + IFN-ɣ (Th1) response [ 92 , 139 , 143 ].…”