Multi-Stage Drug Delivery System for Enhanced Payload Delivery to Lymph Node Cells | AIChE

Multi-Stage Drug Delivery System for Enhanced Payload Delivery to Lymph Node Cells


Thomas, S. - Presenter, Georgia Institute of Technology
Schudel, A., Georgia Institute of Technology
Higginson, C., Georgia Institute of Technology
Finn, M. G., Georgia Institute of Technology
Targeted drug delivery to lymph nodes (LN), tissues where organized lymphocyte accumulation in the body occurs, has the potential to improve the treatment of a variety of pathologies, such as B and T cell malignancies and immunodeficiency viral infections, as well as enhance the efficacy of vaccines and cancer immunotherapy. To date, size-based principles of lymphatic-mediated transport have emerged as an effective means to achieve facile LN delivery of formulated agents after injection in the periphery. However, within the LN, solutes and particulates are filtered based on size, with smaller molecules penetrating more deeply into LN follicles and the paracortex than large particulates by virtue of their increased diffusivity and uptake within LN conduits. Herein, we report the design and implementation of a multistage lymphatic delivery and payload release system combining 30 nm thiolated poly(propylene sulfide) nanoparticles that exhibit prodigious uptake into lymphatics after administration with the thiol-reactive oxanorbornadiene (OND) linkage chemistry that degrades in a pH- and polarity-insensitive manner at programmable half-lives ranging from hours to days to release small-molecule cargo. Post administration in the skin, nanoparticle tethering dramatically enhances model cargo accumulation within LN draining the site of injection that when released via the OND penetrates deeply throughout the collagenous LN interstitium due to its increased diffusivity relative to polymer nanoparticles. As a result, small molecule cargo is delivered to cell subtypes localized within the LN cortex and paracortex at high levels, a 10- to 1000-fold relative to free cargo alone or cargo tethered to the nanoparticles via an irreversible linkage. These data suggest that by utilizing an engineered multi-stage system to overcome barriers to both lymphatic and lymph node uptake, payload can be delivered to previously undruggable cell subpopulations resident within lymph nodes and has the potential to dramatically enhance drug bioactivity and resulting therapeutic effect.