Lauren F. Sestito

BME Ph.D. Proposal Presentation

Date & Time: Monday, November 25, 2019 at 12:00pm

Location:  UAW 3115 (McIntire Room) 

Advisor: 

Susan N. Thomas, PhD

Committee:

Julia Babensee, PhD

Julie Champion, PhD

Brandon Dixon, PhD

Johnna Temenoff, PhD

Title: Engineered biomaterial nanoparticle systems for lymphatic-targeted drug delivery

Abstract:

The lymphatic system plays a critical role in both fluid balance and the immune response, and its dysfunction is implicated in a wide variety of pathologies including cardiac disease, cancer, and lymphedema. While this makes lymphatic tissues promising therapeutic targets, lymphatic drug delivery is challenging as small molecule drugs show poor lymphatic vessel uptake by any delivery route. Once drugs have entered lymphatic vessels, access to therapeutically relevant cells within the lymph node (LN) is further restricted by cellular and physical barriers. There is a clear need for delivery methods to enhance drug access to therapeutic targets in lymphatic tissues, including both lymphatic vessels and lymph nodes. As such, the overall objective of the proposed research is to employ engineered nanoparticle (NP) systems to enhance and control drug delivery to the lymphatics. These biomaterial systems will be employed to enhance small molecule drug accumulation in target lymphatic tissues, enabling study and therapeutic modulation of 1) the lymph node and lymph node-resident cells and 2) intrinsic pumping in collecting lymphatic vessels. To this end, two model small molecule drugs will be employed. In aim 1, the highly reactive small molecule nitric oxide (NO) will be conjugated to NP to evaluate the role of NO in lymphatic transport, with focus on its effects on drug distribution within the LN. In aim 2, S-(-)-Bay K8644 (BayK), a calcium channel modulator, will be encapsulated in a NP and delivered to target lymphatic muscle cells within lymphatic collecting vessels for the treatment of lymphedema. The central hypothesis of this work is that nanoparticle formulation will improve the lymphatic availability of these small molecule drugs and enable their application for therapeutic modulation of both lymph node and lymphatic collecting vessel function. Upon completion, this work will demonstrate the effectiveness of these NP systems for drug delivery to lymphatic tissue targets, highlight a mechanism for enhancing drug access to typically restricted LN cell types, and reveal a novel treatment for lymphedema and other diseases characterized by lymphatic dysfunction.