ORCID ID

0000-0003-2989-053X

Graduation Date

Fall 12-20-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Ram I. Mahato

Abstract

Type 1 diabetes is one of the most challenging chronic autoimmune diseases. The destruction and dysfunction of insulin-secreting β cells are the results of inflammatory infiltration and the synergistic effect of multiple immune cells. The aim of this dissertation is to develop novel and reliable therapeutic approaches to advance the treatment of T1D: including chemical modification of a broad-spectrum immunosuppressant, co-application of small molecule based immune intervention and siRNA based β cell preservative therapy, and administration of a PI3K-δ/γ dual inhibitor to specifically target immune cells, utilizing synthetic polymeric micelles or natural produced multi-functional exosomes derived from human bone marrow mesenchymal stem cells (hBMSCs).

Chapter 1 is a comprehensive overview of the background, pathogenesis, current and advanced therapeutic strategies of T1D. At the end of the chapter, questions and future perspectives are raised, which may shed light on the future development and clinical translation of T1D treatment.

Chapter 2 describes the chemical modification of a broad-spectrum immunosuppressant mycophenolic acid by conjugating to quinic acid, which exhibits potent anti-inflammatory effect, via amide bonds to attenuate the non-specific toxicity while maintaining therapeutic efficacy. The resultant compound MQ4 may be a novel promising immunosuppressant to minimize immune rejection after islet transplantation.

Chapter 3 utilized cationic copolymers to co-deliver sunitinib, a tyrosine kinase inhibitor, and siRNA against Alox15 which is crucial for T1D pathogenesis by generating toxic and inflammatory lipids/ROS, to reverse the new-onset of T1D in a NOD mouse model. The encouraging results demonstrated the reliability and safety of this approach in the field of T1D.

Chapter 4 explored the therapeutic role of a novel PI3K-δ/γ dual inhibitor IPI-145, which specifically targeted immune cells, and the transportation potential as well as the trophic function of hBMSC-derived exosomes, which hypothetically carrying intrinsic immunoregulatory ability, paracrine effect, and migration tendency to inflamed pancreatic islets, for T1D treatment.

Chapter 5 is the summary of key findings of each chapter, and the discussion of the remaining concerns and future directions.

Available for download on Saturday, August 21, 2021

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