Synthesis, Formulation and Characterization of Immunotherapeutic Glycosylated Dendrimer/cGAMP Complexes for CD206 Targeted Delivery to M2 Macrophages in Cold Tumors

Article Article scientifique Article Synthesis, Formulation and Characterization of Immunotherapeutic Glycosylated Dendrimer/cGAMP Complexes for CD206 Targeted Delivery to M2 Macrophages in Cold Tumors eng 2022-09-06 2022-09-06 author Petrovic Marija 0000-0002-5372-5959 881974 author Porcello Alexandre 0000-0003-1603-2704 802436 author Tankov Stoyan 888058 author Majchrzak Oliwia Barbara 0009-0002-4532-1134 938120 author Kiening Martin 0000-0001-9535-3308 893181 author Laingoniaina Annick Clara 920917 author Jbilou Tayeb 514478 author Walker Paul Richard 0000-0001-8999-6366 104900 author Borchard Gerrit 0000-0001-6268-2586 635281 author Jordan Olivier 0000-0003-3752-2198 133859 1883 10.3390/pharmaceutics14091883 36145631 1999-4923 PMC9503622 https://www.mdpi.com/1999-4923/14/9/1883 <p>Anti-tumor responses can be achieved via the stimulation of the immune system, a therapeutic approach called cancer immunotherapy. Many solid tumor types are characterized by the presence of immune-suppressive tumor-associated macrophage (TAMs) cells within the tumor microenvironment (TME). Moreover, TAM infiltration is strongly associated with poor survival in solid cancer patients and hence a low responsiveness to cancer immunotherapy. Therefore, 2′3′ Cyclic GMP-AMP (2′3′ cGAMP) was employed for its ability to shift macrophages from pro-tumoral M2-like macrophages (TAM) to anti-tumoral M1. However, cGAMP transfection within macrophages is limited by the molecule’s negative charge, poor stability and lack of targeting. To circumvent these barriers, we designed nanocarriers based on poly(amidoamine) dendrimers (PAMAM) grafted with D-glucuronic acid (Glu) for M2 mannose-mediated endocytosis. Two carriers were synthesized based on different dendrimers and complexed with cGAMP at different ratios. Orthogonal techniques were employed for synthesis (NMR, ninhydrin, and gravimetry), size (DLS, NTA, and AF4-DLS), charge (DLS and NTA), complexation (HPLC-UV and AF4-UV) and biocompatibility and toxicity (primary cells and hen egg chorioallantoic membrane model) evaluations in order to evaluate the best cGAMP carrier. The best formulation was selected for its low toxicity, biocompatibility, monodispersed distribution, affinity towards CD206 and ability to increase M1 (STAT1 and NOS2) and decrease M2 marker (MRC1) expression in macrophages.</p> CD206 M2 macrophage-targeted delivery PAMAM Nanoparticle orthogonal characterization cGAMP Dewey 615 31 Section des sciences pharmaceutiques 17 false 879 Biopharmacie Pharmaceutics 14 9 a01dbc63-8916-49a9-a0b9-49fdbdde0dc0 Article (Published version) Public Article-scientifique-from-crossref.pdf 4767238 application/pdf openAccess Faculté des sciences / Section des sciences pharmaceutiques

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Synthesis, Formulation and Characterization of Immunotherapeutic Glycosylated Dendrimer/cGAMP Complexes for CD206 Targeted Delivery to M2 Macrophages in Cold Tumors	Pharmaceutics			2022	257	112

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