Graduation Date

Summer 8-17-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dong Wang

Abstract

Macromolecular prodrug conjugate is a promising strategy for better diagnosis and treatment of musculoskeletal diseases. Our lab has pioneered this effort and has successfully developed multiple prodrug formulations. The general approach we have taken is to incorporate active ingredient (AI, including imaging probe or therapeutic agents) containing monomers into water-soluble and biocompatible polymers, such as N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers. Structural parameters of these polymeric prodrugs, such as molecular weight (MW), drug loading, prodrug activation mechanism and the selection of drug payload may greatly affect therapeutic efficacy and the safety of the macromolecular prodrugs. To investigate the impact of these structural parameters in my research, (1) We have synthesized a series of the HPMA copolymer-based dexamethasone prodrugs with different molecular weight and drug loading. After labeling with 125I or fluorescent dye, these prodrugs were administered to a murine implant loosening model. The in vivo/ex vivo pharmacokinetics and biodistribution of these polymers and in vitro and in vivo cellular internalization were analyzed and compared. (2) We designed and synthesized dexamethasone-containing monomers with different releasing chemistry and copolymerized with HPMA. The different in vitro releasing rates of these prodrugs were confirmed. When evaluated in an adjuvant induced arthritis rat model, these prodrugs demonstrated significantly different therapeutic efficacy and duration. (3) To understand if the design principle we learned from the dexamethasone prodrug can be extrapolated to other class of drugs, we replaced dexamethasone with Tofacitinib (Tofa, a disease-modifying antirheumatic drug or DMARD) in the prodrug design. The resulting prodrug (P-Tofa) was found to effectively ameliorate joint inflammation of the adjuvant-induced arthritis rat model. Collectively, the results from these systematic investigations provide us with more insight into the polymeric prodrug design principle and are instructive for the future development and clinical translation of the macromolecular prodrugs for musculoskeletal and other relevant diseases.

Download

Share

COinS