Nano-carrier-facilitated delivery of bioactive molecules into lymph nodes (LNs) has found application in the treatment and diagnosis of numerous immune-related diseases. Much work has focused on optimization of physicochemical properties of the nano-carrier to enhance lymphatic drainage passively, whereas active modulation of the quantity and timing of lymphatic delivery remains a significant challenge. Here, inspired by the success of thermo-modulation of tumor targeting, we have developed a simple external temperature control strategy to regulate the distribution of thermo-sensitive nanomaterials between the injection site and draining LNs. To demonstrate feasibility of this strategy, we injected Rhodamine-B-labeled poly(N-isopropylacrylamide) (RhB-PNIPAm) (2.5 kDa) into the footpad of mice at different initial temperatures-either below or above the lower critical solution temperature (LCST), followed by physical cooling of the injection site. We show that RhB-PNIPAm drained efficiently into the popliteal and inguinal nodes (pLNs, iLNs, respectively) with low levels of accumulation in major internal organs. Within the first two hours post-injection the rate of drainage was primarily dependent on the initial temperature of RhB-PNIPAm. However, over the course of 24 h, temperature gradient due to local cooling affected significantly the draining of the injection site, resulting in differential accumulation of RhB-PNIPAm in the proximal (pLNs) versus the distal (iLNs) nodes. This study provides a new methodology and insights for modulating in vivo lymphatic distribution of thermo-sensitive nanomaterials with implications in immune regulation and immunotherapy.
Bibliographical noteFunding Information:
This project was supported by Special Program for High-Tech Leader & Team of Tianjin Government and Natural Science Foundation of Tianjin (17JCYBJC29100) awarded to Prof. Mingming Zhang. We thank Prof. Li Liu in the Institute of Polymer Chemistry, Nankai University, who provided PNIPAm-17k used in this work.