In-situ crosslinking hydrogels for combinatorial delivery of chemokines and siRNA-DNA carrying microparticles to dendritic cells.
Polymer-based, injectable systems that can simultaneously deliver multiple bioactive agents in a controlled manner could significantly enhance the efficacy of next generation therapeutics. For immunotherapies to be effective, both prophylactically or therapeutically, it is not only critical to drive the antigen (Ag)-specific immune response strongly towards either T helper type 1 (Th1) or Th2 phenotype, but also to promote recruitment of a high number of antigen-presenting cells (APCs) at the site of immunization. We have recently reported a microparticle-based system capable of simultaneously delivering siRNA and DNA to APCs. Here we present an in-situ crosslinkable, injectable formulation containing dendritic cell (DC)-chemo-attractants and dual-mode DNA-siRNA loaded microparticles to attract immature DCs and simultaneously deliver, to the migrated cells, immunomodulatory siRNA and plasmid DNA antigens. These low crosslink density hydrogels were designed to degrade within 2-7 days in vitro and released chemokines in a sustained manner. Chemokine carrying gels attracted 4-6 folds more DCs over a sustained period in vitro, compared to an equivalent bolus dose. Interestingly, migrated DCs were able to infiltrate the hydrogels and efficiently phagocytose the siRNA-DNA carrying microparticles. Hydrogel embedded microparticles co-delivering Interleukin-10 siRNA and plasmid DNA antigens exhibited efficient Interleukin-10 gene knockdown in migrated primary DCs in vitro.
Singh
Ankur
A
Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
Suri
Shalu
S
Roy
Krishnendu
K
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000008:administration & dosage* / Q000276:immunology; D003432:Cross-Linking Reagents; D004247:DNA / Q000008:administration & dosage* / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D055785:Gene Knockdown Techniques; D020100:Hydrogels / Q000737:chemistry*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000276:immunology
D018925:Chemokines; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D020100:Hydrogels; D034741:RNA, Small Interfering; D016753:Interleukin-10; D004247:DNA