title: Tumor-targeted delivery of sunitinib base enhances vaccine therapy for advanced melanoma by remodeling the tumor microenvironment.
abstract: 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-PMnot 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-PMmay 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.
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Meirong
authors.initials: M
authors.lastname: Huo
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Department of Pharmaceutics, School of Pharmacy, China Medical University, Shenyang 110122, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; UNC and NCSU Joint Department of Biomedical Engineering, Chapel Hill, NC 27599, United States.
authors.forename: Andrew Benson
authors.initials: AB
authors.lastname: Satterlee
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang 212013, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States. Electronic address: leafh@unc.edu.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D002130:Calcium Phosphates / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D005260:Female; D016233:Immunotherapy, Active; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D008823:Micelles; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077210:Sunitinib; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002130:Calcium Phosphates; D019496:Cancer Vaccines; C423449:CpG ODN 1826; D016207:Cytokines; D007211:Indoles; D008565:Membrane Proteins; D008823:Micelles; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D011108:Polymers; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C500290:peptide SVYDFFVWL; C020243:calcium phosphate; D051057:Proto-Oncogene Proteins c-akt; D000077210:Sunitinib
keywords: Advanced melanoma; Peptide vaccine; Polymeric micelles; Sunitinib base; Tumor microenvironment