Molecular-Targeted Immunotherapeutic Strategy for Melanoma via Dual-Targeting Nanoparticles Delivering Small Interfering RNA to Tumor-Associated Macrophages

• Published in: ACS nano 2017-09, Vol.11 (9), p.9536-9549
• Main Authors: Qian, Yuan, Qiao, Sha, Dai, Yanfeng, Xu, Guoqiang, Dai, Bolei, Lu, Lisen, Yu, Xiang, Luo, Qingming, Zhang, Zhihong
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Cytokines - immunology; Drug Delivery Systems; Female; Immunotherapy - methods; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Melanoma - genetics; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Mice, Inbred C57BL; Nanoparticles - chemistry; Peptides - chemistry; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - immunology; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; RNA, Small Interfering - therapeutic use; RNAi Therapeutics - methods; Tumor Microenvironment
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.7b05465

Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancer immunotherapy. Targeted delivery of therapeutic drugs to the tumor-promoting M2-like TAMs is challenging. Here, we developed M2-like TAM dual-targeting nanoparticles (M2NPs), whose structure and function were controlled by α-peptide (a scavenger receptor B type 1 (SR-B1) targeting peptide) linked with M2pep (an M2 macrophage binding peptide). By loading anti-colony stimulating factor-1 receptor (anti-CSF-1R) small interfering RNA (siRNA) on the M2NPs, we developed a molecular-targeted immunotherapeutic approach to specifically block the survival signal of M2-like TAMs and deplete them from melanoma tumors. We confirmed the validity of SR-B1 for M2-like TAM targeting and demonstrated the synergistic effect of the two targeting units (α-peptide and M2pep) in the fusion peptide (α-M2pep). After being administered to tumor-bearing mice, M2NPs had higher affinity to M2-like TAMs than to tissue-resident macrophages in liver, spleen, and lung. Compared with control treatment groups, M2NP-based siRNA delivery resulted in a dramatic elimination of M2-like TAMs (52%), decreased tumor size (87%), and prolonged survival. Additionally, this molecular-targeted strategy inhibited immunosuppressive IL-10 and TGF-β production and increased immunostimulatory cytokines (IL-12 and IFN-γ) expression and CD8+ T cell infiltration (2.9-fold) in the tumor microenvironment. Moreover, the siRNA-carrying M2NPs down-regulated expression of the exhaustion markers (PD-1 and Tim-3) on the infiltrating CD8+ T cells and stimulated their IFN-γ secretion (6.2-fold), indicating the restoration of T cell immune function. Thus, the dual-targeting property of M2NPs combined with RNA interference provides a potential strategy of molecular-targeted cancer immunotherapy for clinical application.