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

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• 作者：Meirong Huo^a ; ^b ; Yan Zhao^a ; ^c ; Andrew Benson Satterlee^a ; ^d ; Yuhua Wang^a ; Ying Xu^a ; ^e ; Leaf Huang^a ; ^{leafh@unc.edu}
• 关键词：LCP ; lipid calcium phosphate ; NP ; nanoparticles ; Trp2 ; tyrosinase-related protein 2 (Trp2) ; TME ; tumor microenvironment ; PM ; polymeric micelle ; PLGA-PEG-MBA ; anisamide modified poly-lactic-glycolic-acid-poly(ethylene glycol) (PLGA-PEG-MBA) ; SUNb-PM ; sunitinib base-loaded polymeric micelles ; SUNos ; sunitinib malmate oral suspension ; TKI ; tyrosine kinase inhibitor ; VEGF ; vascular endothelial growth factor ; CTL ; cytotoxic T lymphocyte ; DPTAP ; 1 ; 2-dioleoyl-3-trimethylammonium-propane chloride salt
• 刊名：Journal of Controlled Release
• 出版年：2017
• 出版时间：10 January 2017
• 年：2017
• 卷：245
• 期：Complete
• 页码：81-94
• 全文大小：3179 K
• 卷排序：245

文摘

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.