Programmable multistage drug delivery to lymph nodes

Abstract

Therapeutic delivery selectively to lymph nodes has the potential to address a variety of unmet clinical needs. However, owing to the unique structure of the lymphatics and the size-restrictive nature of the lymph node reticular network, delivering cargo to specific cells in the lymph node cortex and paracortex is difficult. Here, we describe a delivery system to overcome lymphatic and intra-lymph node transport barriers by combining nanoparticles that are rapidly conveyed to draining lymph nodes after administration in peripheral tissues with programmable degradable linkers. This platform enables the controlled release of intra-lymph-mobile small molecular cargo, which can reach vastly more immune cells throughout the lymph node than either the particles or free compounds alone. The release rate can be programmed, allowing access to different lymph node structures and thus, specific lymphocyte subpopulations. We are thereby able to alter the subtypes of drugged lymph node cells to improve immunotherapeutic effects.

Recent Advances in Nanocarrier-Assisted Therapeutics Delivery Systems

“…Efforts have also been made to improve the drug-releasing profile of polymeric micelles. Recently, Schudel et al developed a programmable multistage drug delivery system targeting at the lymph nodes [31]. They synthesized polymeric micelles that can be easily taken up by lymph nodes and added thiol-reactive oxanorbornadiene (OND) linkers to these nanoparticles [31].…”

“…Recently, Schudel et al developed a programmable multistage drug delivery system targeting at the lymph nodes [31]. They synthesized polymeric micelles that can be easily taken up by lymph nodes and added thiol-reactive oxanorbornadiene (OND) linkers to these nanoparticles [31]. Depending on different OND substituents, the half-life of the nanocarrier can be programed ranging from hours to days [31].…”

“…They synthesized polymeric micelles that can be easily taken up by lymph nodes and added thiol-reactive oxanorbornadiene (OND) linkers to these nanoparticles [31]. Depending on different OND substituents, the half-life of the nanocarrier can be programed ranging from hours to days [31]. Such multi-staged intra-lymphatic drug release can help in augmenting the immunotherapeutic effects compared to free drug delivery [31].…”

“…Depending on different OND substituents, the half-life of the nanocarrier can be programed ranging from hours to days [31]. Such multi-staged intra-lymphatic drug release can help in augmenting the immunotherapeutic effects compared to free drug delivery [31].…”

The Importance of Poly(ethylene glycol) and Lipid Structure in Targeted Gene Delivery to Lymph Nodes by Lipid Nanoparticles

“…For instance, antigen-presenting cells such as CD103 + dendritic cells must traffic to draining lymph nodes to present tumour antigens to T cells, which then proliferate and migrate to the tumour to kill cancer cells [22]. CD8 + dendritic cells and CD169 + macrophages play an important role in initiating the antibody production process but are resident only in lymph nodes [23]. As such, delivering nucleic acids to lymph nodes allows presenting tumour or virus antigens to immune cells more effectively, leading to increasing antibody production efficiency and reducing side effects due to off-target transfections [24].…”