A7: Controlled Drug Delivery


Sudhir Ranganath1,2,3,4,5,6, Zhixiang Tong3,4,5, Oren Levy3,4,5, Keir Martyn3,4,5, Jeffrey Karp3,4,5, Maneesha Inamdar2,6 

1Siddaganga Institute of Technology, India;
2Jawaharlal Nehru Center for Advanced Scientific Research, India;
3Brigham & Women’s Hospital, USA
4Harvard Medical School, USA;
5Harvard–MIT Program of Health Sciences and Technology, USA;
6Institute for Stem Cell Biology and Regenerative Medicine, India 

Cell therapy using exogenous mesenchymal stem cells (MSCs) has gained limelight recently given its secretome-mediated paracrine effects, especially via potent immunomodulatory and antiinflammatory secretome. However, the complex host microenvironment is a major hindrance to controlling the MSC secretome post-transplantation. The resultant unpredictable MSC response hinders their clinical efficacy and often contributes to highly variable clinical outcomes. While genetically engineered MSCs have non-transient effects and regulatory hurdles towards clinical translation, the drug/cytokine preconditioned MSCs have highly transient effects post transplantation. To address these, we developed an intracellular controlled drug delivery approach to non-genetically and transiently modulate the pro-inflammatory secretome in human MSCs (hMSCs). Poly-L-lactideco-glycolide (PLGA) polymer was used to synthesize microparticles (~ 900 nm in size) and surface functionalized with a cationic polymer (poly-L-lysine) to enhance internalization kinetics into hMSCs. Under simulated inflammatory condition (stimulation by TNF-alpha), we demonstrate that intracellularly delivered TPCA-1 (a small molecule NF-kB inhibitor) via PLGA microparticles (TPCA-μPs) can attenuate secretion of pro-inflammatory factors from hMSCs for at least six days in vitro. On the contrary, soluble TPCA-1 preconditioning has a very transient effect on hMSC secretome. Conditioned medium (CM) derived from TPCA-μP-loaded hMSCs also showed reduced ability to attract human monocytes and prevented differentiation of human cardiac fibroblasts to myofibroblasts, compared to CM from untreated or TPCA-1-preconditioned hMSCs. In addition, Conditioned medium derived from TPCA-μP-loaded hMSCs attenuated collagen secretion from human and mouse cardiac myofibroblasts. These results demonstrate the potential utility of the microparticleengineered hMSCs in the inhibition of cardiac fibrosis. Thus, we provide a broadly applicable bioengineering solution to facilitate intracellular sustained release of agents that modulate cell signaling. We propose that this approach could be harnessed to improve control over MSC secretome post-transplantation, especially to prevent adverse remodeling post-myocardial infarction.

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