Tumor vaccine is a promising therapeutic strategy, which produces long-term anti-tumor immunity by stimulating immune responses accordingly. However, due to inefficient vaccination, the clinical efficacy of such vaccines is limited. Recently, in a research report entitled “Farnesylthiosalicylic acid-derivatized PEI-based nanocomplex for improved tumor vaccination” published in the Cell sub-journal Molecular Therapy Nucleic Acids, the authors developed a new nanocomposite vaccine delivery system. Nano-complex-mediated vaccines can effectively deliver nucleic acids encoding new antigens to lymphoid tissues and antigen-presenting cells.
Polyethyleneimine (PEI) combines with farnesylthiosalicylic acid (FTS) to form micelles. Then it interacts with nucleic acid to form polymer/nucleic acid nanocomposites with controllable structure. Transfection of tumor by FTS-PEI is more effective than that of PEI, other PEI derivatives, or naked DNA. A large number of transfected cells were also observed in draining lymph nodes (LNs). FTS-PEI delivers ovalbumin (OVA, a model antigen) expression plasmid (pOVA) in vivo and significantly inhibits B16 tumors expressing OVA by presenting OVA epitopes and other epitopes through epitope diffusion.
New tumor antigens derived from somatic mutations in tumor tissues provide an attractive target for cancer vaccines, a type of immunotherapy. Vaccines against tumor-specific new antigens have the ability to reduce the potential induction of central and peripheral tolerance. It has been reported that personalized vaccines based on new antigens have shown significant therapeutic potential in preclinical and early clinical studies. However, major challenges remain in the effective and safe delivery of vaccine components to induce an effective and extensive anti-cancer T cell response.
At present, a variety of gene delivery systems have been developed, including viral vectors and non-viral vectors. A variety of non-viral systems have been reported, including peptides, liposomes, and cationic polymers. Synthetic polymers have attracted more and more attention in nucleic acid delivery because of their wide applications, safety, and easy production. Nano-complexes can protect the vaccine from degradation, prolong the retention time, and enhance the targeting of lymphoid organs, so it has been widely studied in vaccine delivery.
The authors developed a delivery system based on polyethyleneimine (PEI), a cationic polymer that has been widely used in non-viral gene delivery, including intratumoral injection. PEI has high charge density and proton sponge effect. The unprotonated secondary amine of PEI absorbs protons when internalized into the nucleus, making more protons brought into the nucleus, which in turn increases the inflow of Cl- ions and water. This can cause the endosome to rupture and then release the endocytosis into the cytoplasm. As a water-soluble molecule, PEI can randomly interact with nucleic acids in aqueous solution.
By anchoring PEI molecules to the surface of specific size nanoparticles (NPs), more effective and controllable interactions with nucleic acids can be achieved. For example, PEI is modified with cholesterol, deoxycholic acid, or lipoic acid to improve the polymer’s ability to protect and transmit genes to cells. The more lipophilic derivatives of PEI are thought to promote interaction with cells. Lipid-derived PEI can also self-assemble to form NPs, providing more controlled interactions with nucleic acids.
In this study, the authors coupled farnesylthiosalicylic acid (FTS) with PEI to obtain amphiphilic FTS-PEI conjugates which self-assembled to form micelles. FTS, which is insoluble in water, acted as a hydrophobic region of polymer micelles, while PEI acted as a cationic hydrophilic region to bind nucleic acids to increase cell uptake. FTS is a nontoxic RAS antagonist, which can inhibit receptor-mediated RAS activation, thus inhibiting the growth of RAS-dependent tumors. FTS-PEI is characterized by transfection efficiency in vitro and in vivo. In addition, ovalbumin (OVA) as a model antigen and tyrosinase associated protein 2 (Trp2) as a new endogenous melanoma antigen were used to test the effectiveness of fts-pei mediated vaccine.