Targeted Delivery of Immunomodulators to Lymph Nodes

• Published in: Cell reports (Cambridge) 2016-05, Vol.15 (6), p.1202-1213
• Main Authors: Azzi, Jamil, Yin, Qian, Uehara, Mayuko, Ohori, Shunsuke, Tang, Li, Cai, Kaimin, Ichimura, Takaharu, McGrath, Martina, Maarouf, Omar, Kefaloyianni, Eirini, Loughhead, Scott, Petr, Jarolim, Sun, Qidi, Kwon, Mincheol, Tullius, Stefan, von Andrian, Ulrich H., Cheng, Jianjun, Abdi, Reza
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - pharmacology; Antigens, Surface - metabolism; Cell Proliferation - drug effects; Cytokines - metabolism; Disease Models, Animal; Drug Delivery Systems; Graft Survival - drug effects; Heart Transplantation; Immunologic Factors - pharmacology; Immunosuppressive Agents - pharmacology; Lymph Nodes - drug effects; Lymph Nodes - metabolism; Membrane Proteins - metabolism; Mice, Inbred BALB C; Mice, Inbred C57BL; Microspheres; Neoplasm Transplantation; Polyesters - chemistry; Tacrolimus - pharmacology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.04.007

Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node addressin molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo. [Display omitted] •The MECA79 antibody binds peripheral lymph node addressin (PNAd)•Tacrolimus-loaded microparticles coated with MECA79 target lymph nodes•Microparticles accumulate in draining lymph nodes after intravenous delivery•Targeted delivery of tacrolimus prolonged allograft survival Azzi et al. show the targeted delivery of microparticles containing tacrolimus to the draining lymph nodes of recipients following organ transplantation via intravenous administration. Microparticles containing tacrolimus coated with an antibody against peripheral lymph node addressin are trafficked to the draining lymph nodes, resulting in a significant prolongation of murine heart allograft survival.