Abstract
Improving the efficacy of melanoma treatment remains an important global challenge. Here, we combined chemotherapy with protein tyrosine phosphatase nonreceptor type 2(Ptpn2) based immunotherapy in an effort to address this challenge. Short-hairpin RNA (shRNA) targeting Ptpn2 was coencapsulated with doxorubicin (DOX) in the cell membrane of M1 macrophages (M1HD@RPR). The prepared nanoparticles (NPs) were effectively phagocytosed by B16F10 cells and M1 macrophages, but not by M0 macrophages. Hence, NP evasion from the reticuloendothelial system (RES) was improved and NP enrichment in tumor sites increased. M1HD@RPR can directly kill tumor cells and stimulate immunogenic cell death (ICD) by DOX and downregulate Ptpn2. It can promote M1 macrophage polarization and dendritic cell maturation and increase the proportion of CD8+ T cells. M1HD@RPR killed and inhibited the growth of primary melanoma and lung metastatic tumor cells without harming the surrounding tissue. These findings establish M1HD@RPR as a safe multifunctional nanoparticle capable of effectively combining chemotherapy and gene immunotherapies against melanoma.
Highlights
Malignant melanoma is an aggressive tumor that readily develops resistance to treatment [1]
The 1H-NMR results showed that compared with HA, oxidized hyaluronic acid (OHA) had an aldehyde proton peak at 8.3 PPM and a resonant hemiacetal proton peak at 5.0-5.25 ppm, indicating that HA had been successfully oxidized to OHA
FTIR spectra showed that compared with HA, a typical C=O stretching band of the aldehyde group appeared at 1731 cm–1 for OHA, while C(O)-H at 2750 cm–1 coexisted with the C-H absorption peak of HA itself
Summary
Malignant melanoma is an aggressive tumor that readily develops resistance to treatment [1]. Melanoma can be cured by surgical resection and has a long survival rate (SR; 5-year SR > 90%). Once metastasized, the 5year SR drops markedly to about 5% [2, 3]. Chemotherapy, including monotherapy or combination chemotherapy, has become the primary treatment modality for patients with advance stages of cancer and metastasis. With standard regimens of dacarbazine and temozolomide, the median survival time is less than one year [4,5,6,7,8]. New therapeutic approaches for melanoma are urgently required
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