A dual macrophage polarizer conjugate for synergistic melanoma therapy

• Published in: Journal of controlled release 2021-07, Vol.335, p.333-344
• Main Authors: Sallam, Marwa A., Wyatt Shields IV, C., Prakash, Supriya, Kim, Jayoung, Pan, Daniel C., Mitragotri, Samir
• Format: Article
• Language: English
• Subjects: Antitumor; Macrophage; Melanoma; Polarization; Polymer conjugates
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2021.05.033

Tumor associated macrophages (TAMs) play a paradoxical role in the fate of aggressive tumors like melanoma. Immune modulation of TAMs from the tumor-permissive M2 phenotype to antitumoral M1 phenotype is an emerging attractive approach in melanoma therapy. Resiquimod is a TLR7/8 agonist that shifts the polarization of macrophages towards M1 phenotype. Bexarotene (BEX) is a retinoid that induce the expression of phagocytic receptors in macrophages besides its ability to downregulate the M2 polarization. However, the clinical use of both agents is hindered by poor pharmacokinetic properties. Here, for the first time we repurposed BEX based on its immunomodulatory properties and combined it with RES by designing hyaluronic acid (HA) conjugates of both drugs that act synergistically as a dual macrophage polarizer to promote the M1 phenotype and suppress the M2 phenotype. This combination enhanced the macrophage secretion of proinflammatory cytokines (IL-6 and TNF-α), while suppressing the production of tumor promoting cytokine CCL22. It enhanced the macrophage phagocytic ability and showed superior inhibitory effects against B16F10 cells. In vivo studies on a mouse melanoma model confirmed the superiority of the dual conjugate compared to the single HA-drug conjugates in suppressing the tumor growth. Immunoprofiling of the excised tumors revealed a significant increase in the M1/M2 ratio of TAMs in mice treated with the dual conjugate. Our intravenously injectable HA conjugate of RES and BEX provides a promising immunotherapeutic combination strategy for resetting the M1/M2 ratio, supporting the tumoricidal activity of TAMs for effective melanoma treatment. [Display omitted] •Re-education of TAMs from M2 to M1 phenotype is an attractive approach for melanoma.•Resiquimod and bexarotene promote macrophage polarization to antitumoral phenotype.•Clinical translation of both drugs is hindered by poor pharmacokinetics.•Conjugation of resiquimod and bexarotene to HA allowed their coadministration.•The dual conjugate inhibited melanoma growth better than the single drug conjugates.