Tumor-targeted delivery of sunitinib base enhances vaccine therapy for advanced melanoma by remodeling the tumor microenvironment

• Published in: Journal of controlled release Vol. 245; pp. 81 - 94
• Main Authors: Huo, Meirong, Zhao, Yan, Satterlee, Andrew Benson, Wang, Yuhua, Xu, Ying, Huang, Leaf
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.01.2017
• Subjects: Advanced melanoma; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; apoptosis; blood vessels; calcium phosphates; Calcium Phosphates - administration & dosage; Calcium Phosphates - chemistry; Calcium Phosphates - therapeutic use; Cancer Vaccines - administration & dosage; Cancer Vaccines - therapeutic use; Cell Line, Tumor; Cell Survival - drug effects; collagen; cytokines; Cytokines - immunology; cytotoxicity; enzyme inhibitors; Female; fibroblasts; growth retardation; immune evasion; immune response; immunotherapy; Immunotherapy, Active; Indoles - administration & dosage; Indoles - chemistry; Indoles - therapeutic use; lipids; melanoma; Melanoma - immunology; Melanoma - metabolism; Melanoma - pathology; Melanoma - therapy; Membrane Proteins - administration & dosage; Membrane Proteins - chemistry; Membrane Proteins - therapeutic use; mice; Mice, Inbred C57BL; Micelles; nanoparticles; neoplasm cells; Oligodeoxyribonucleotides - administration & dosage; Oligodeoxyribonucleotides - chemistry; Oligodeoxyribonucleotides - therapeutic use; Peptide Fragments - administration & dosage; Peptide Fragments - chemistry; Peptide Fragments - therapeutic use; Peptide vaccine; Polymeric micelles; Polymers - administration & dosage; Polymers - chemistry; Polymers - therapeutic use; Proto-Oncogene Proteins c-akt - metabolism; Pyrroles - administration & dosage; Pyrroles - chemistry; Pyrroles - therapeutic use; receptor protein-tyrosine kinase; signal transduction; STAT3 Transcription Factor - metabolism; Sunitinib; Sunitinib base; T-lymphocytes; Tumor Burden - drug effects; Tumor microenvironment; Tumor Microenvironment - drug effects; tyrosine; vaccines; NP; Scr; MDSC; ALP; DiI; Trp2; HRP; ALT; Peptide vaccine; Advanced melanoma; PLGA-PEG-MBA; BSA; TUNEL; DPTAP; CMC; BUN; DOPA; Th1; Sunitinib base; SUNb-PM; Th2; AST; Tumor microenvironment; VEGF; RBCs; Treg; SUNos; IR; H&E staining; TME; TKI; DSPE-PEG; LCP; TAF; CTL; PM; TEM; Polymeric micelles
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2016.11.013

Development of an effective treatment against advanced tumors remains a major challenge for cancer immunotherapy. We have previously developed a potent mannose-modified lipid calcium phosphate (LCP) nanoparticle (NP)-based Trp2 vaccine for melanoma therapy, but because this vaccine can induce a potent anti-tumor immune response only during the early stages of melanoma, poor tumor growth inhibition has been observed in more advanced melanoma models, likely due to the development of an immune-suppressive tumor microenvironment (TME). To effectively treat this aggressive tumor, a multi-target receptor tyrosine kinase inhibitor, sunitinib base, was efficiently encapsulated into a targeted polymeric micelle nano-delivery system (SUNb-PM), working in a synergistic manner with vaccine therapy in an advanced mouse melanoma model. SUNb-PM not only increased cytotoxic T-cell infiltration and decreased the number and percentage of MDSCs and Tregs in the TME, but also induced a shift in cytokine expression from Th2 to Th1 type while remodeling the tumor-associated fibroblasts, collagen, and blood vessels in the tumor. Additionally, inhibition of the Stat3 and AKT signaling pathways by SUNb-PM may induce tumor cell apoptosis or decrease tumor immune evasion. Our findings indicated that targeted delivery of a tyrosine kinase inhibitor to tumors can be used in a novel synergistic way to enhance the therapeutic efficacy of existing immune-based therapies for advanced melanoma. [Display omitted]