Abstract
The present study investigated a pulmonary delivery system of plasmid DNA (pDNA) and its application to melanoma DNA vaccines. pCMV-Luc, pEGFP-C1, and pZsGreen were used as a model pDNA to evaluate transfection efficacy after inhalation in mice. Naked pDNA and a ternary complex, consisting of pDNA, dendrigraft poly-l-lysine (DGL), and γ-polyglutamic acid (γ-PGA), both showed strong gene expression in the lungs after inhalation. The transgene expression was detected in alveolar macrophage-rich sites by observation using multi-color deep imaging. On the basis of these results, we used pUb-M, which expresses melanoma-related antigens (ubiquitinated murine melanoma gp100 and tyrosinase-related protein 2 (TRP2) peptide epitopes), as DNA vaccine for melanoma. The inhalation of naked pUb-M and its ternary complex significantly inhibited the metastasis of B16-F10 cells, a melanoma cell line, in mice. The levels of the inflammatory cytokines, such as TNF-α, IFN-γ, and IL-6, which enhance Th1 responses, were higher with the pUb-M ternary complex than with naked pUb-M and pEGFP-C1 ternary complex as control. In conclusion, we clarified that the inhalation of naked pDNA as well as its ternary complex are a useful technique for cancer vaccination.
Highlights
Melanoma is one of the deadliest forms of skin cancer and its incidence is expected to increase over the two decades
The ternary complex showed a stronger vaccine effect than naked plasmid DNA (pDNA), suggesting that the ternary complex can be efficiently taken up by alveolar macrophages than naked pDNA. These results strongly suggest that pulmonary administration is a suitable route for the application of DNA vaccines for naked pDNA, and the ternary complex
To assess immune induction effects after the pulmonary administration of the DNA vaccine, we examined the suppression of lung metastasis by melanoma using pUb-M as a model antigen. pEGFP-C1 complex appears to slightly inhibit lung metastasis of B16-F10, not significantly (Figure 4c)
Summary
Melanoma is one of the deadliest forms of skin cancer and its incidence is expected to increase over the two decades. Lung metastases frequently occur and the prognosis of patients with metastatic melanoma is extremely poor [1,2,3,4]. Despite significant advances in melanoma research, effective treatments have not yet been developed for advanced melanoma [5,6]. Cancer vaccines have potential in the prevention and treatment of melanoma through its various surface antigens. Traditional protein-based vaccines have been limited by the weak induction of cell-mediated immune responses [9]. Inactivated and subunit vaccines are often impotent, stimulating suboptimal immune responses that are incapable of achieving therapeutic effects against cancer [10].
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