Graduation Date

Fall 12-14-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dong Wang

Abstract

Chronic pain afflicts millions of people worldwide. Particularly, the inflammatory conditions in the incurable disease rheumatoid arthritis (RA) generate persistent pain in its sufferers, for which a number of different analgesics have been prescribed, such as glucocorticoids (GCs) and opioids. However, administration of these pain- mitigating pharmaceutics is implicated in the development of adverse systemic effects due to their non-specific tissue distribution and quick excretion, eliciting the need for high dosing frequencies. To address this issue, this thesis is focused on the development of prodrugs based on a macromolecular design approach to instill preferential inflammation-targeting and retentive properties to common analgesics. Previously within our lab, an HPMA copolymer prodrug of the common GC dexamethasone (P-Dex) was tested for its antirheumatic properties in a rodent model of adjuvant-induced arthritis (AIA). The first part of this project, therefore, involved further evaluation of the pain-alleviating properties of P-Dex. We demonstrated that a single systemically-administered dose of the prodrug significantly reduced the pain response for a duration of twenty-one days, versus equivalent doses of free Dex given daily. It was confirmed that both the sustained analgesia and anti-inflammatory effects conferred by P-Dex is due to its enhanced uptake within inflamed tissue and subsequent retention by phagocytosing immune cells within the arthritic synovium and synovial cavity. Moreover, the macromolecular P-Dex copolymer greatly tempered the co-morbidity of enhanced bone turnover, as is often observed in RA. To expand the clinical repertoire of improved analgesic therapies for RA, we then synthesized and tested the pain-alleviating properties of an HPMA copolymer of the opioid hydromorphone (HMP), a very potent drug that has been implicated in deleterious effects on the central nervous system (CNS) by crossing the blood-brain barrier (BBB). Though the analgesic effects lasted only throughout the dosing day, there was sustained presence of this prodrug (P-HMP) for up to seven days within the AIA knee joint, confirmed to be mediated by the resident inflammatory cells. In contrast to the free drug, the spinal cord analgesic effects of P-HMP were greatly attenuated. Therefore, it can be reasoned that opioid-induced CNS depressive effects could be mitigated by way of the polymeric scaffold’s inability to cross the BBB.

Though there remain optimization strategies to be implemented in the design of these macromolecular analgesics, we have successfully demonstrated their improved therapeutic efficacies in the treatment of pain related to RA. Through instilling arthrotropic and retentive properties to small molecule drugs, the prodrug approach can not only more effectively relieve pain versus free drugs alone, but may also curtail harmful systemic side effects associated with off-target biodistribution. In conclusion, macromolecular prodrugs demonstrate great potential as a clinically-relevant approach to mitigate the pain accompanying such chronic inflammatory conditions as those present in the pathology of RA.

Available for download on Friday, December 04, 2020

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