We are collaborating with the Hubbell group to develop materials and molecular strategies for drug delivery to immature dendritic cells of the lymph node, and to explore the mechanisms of dendritic cell activation or tolerance induction. Our approach exploits interstitial flow to access the lymphatic system as a low resistance delivery route that leads to lymph nodes. The lymphatic system constantly drains fluid and macromolecules from the interstitial space, creating small interstitial flows in the order of 0.1-1 µm/sec. We take advantage of this basic physiological phenomenon using nanoparticle platforms of specific sizes:
- Ultra-small (25 nm) particles are convected by interstitial flow through the extracellular matrix into the draining lymphatic capillary bed
- Larger (100 nm) particles enter the lymphatics much less efficiently than ultra-small nanoparticles and therefore are likely to target peripheral more than lymph node-resident DCs.
We showed that adjuvants conjugated to small particles were highly effective at inducing immune responses against pathogens and tumors. A better understanding of the mechanisms involved in such responses is critical for a deeper understanding of lymph node targeting and for the strategic development of therapies.
- “Vaccine nanocarriers: Coupling intracellular pathways and cellular biodistribution to control CD4 vs CD8 T cell responses,” Rincon-Restrepo M, Mayer A, Hauert S, Bonner DK, Phelps EA, Hubbell JA, Swartz MA, Hirosue S. Biomaterials, 2017
- “6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice”, Jeanbart L, Kourtis IC, van der Vlies AJ, Swartz MA, Hubbell JA. Cancer Immunology Immunotherapy, 2015
- “Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes”, Jeanbart L, Ballester M, de Titta A, Corthésy P, Romero P, Hubbell JA, Swartz MA. Cancer Immunology Research, 2014
- “Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response”, Thomas SN, Vokali E, Lund AW, Hubbell JA, Swartz MA. Biomaterials, 2014
- “Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity and memory recall at low dose”, de Titta A, Ballester M, Julier Z, Nembrini C, Jeanbart L, van der Vlies AJ, Swartz MA, Hubbell JA. PNAS, 2013
- “Exploiting lymphatic transport and complement activation in nanoparticle vaccines”, Reddy ST, van der Vlies AJ, Simeoni E, Angeli V, Randolph GJ, O'Neil CP, Lee LK, Swartz MA, Hubbell JA. Nature Biotechnology, 2007.
- “Engineering opportunities in cancer immunotherapy”, Jeanbart L and Swartz MA. PNAS, 2015.
- “Engineering synthetic vaccines using cues from natural immunity”, Irvine DJ, Swartz MA, Szeto GL. Nature Materials, 2013.
- “Materials engineering for immunomodulation”, Hubbell JA, Thomas SN, Swartz MA. Nature, 2009.