Graduation Date

Fall 12-15-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupicky

Abstract

Abstract

Development of Chloroquine-containing HPMA Copolymers for Drug Delivery

Fei Yu, Ph.D.

University of Nebraska Medical Center, 2018

Supervisor: David Oupický, Ph.D.

Synthetic polymers have been extensively explored for improved delivery of anticancer agents. Polymers can be designed as either carriers of existing drugs or as polymeric drugs with intrinsic pharmacological activity. Advantages of such polymeric drugs include common positive features of polymer-drug conjugates, such as targeted delivery of drugs, altered pharmacokinetic and biodistribution, improved drug safety, but also favorable pharmacological activities due to multivalent receptor-ligand interactions.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are safe drugs that have been in clinical use for longer than six decades. In addition to their antimalarial and antirheumatoid use, CQ and HCQ are known to synergistically enhance the activity of multiple anticancer drugs via complementary mechanisms of action so that they are applied in numerous clinical trials. In this study, we proposed that using the polymeric drug concept in the development of CQ-containing polymers will allow us to improve the pharmacological activity.

We first synthesized copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) and methacryloyl-hydroxychloroquine (MA-CQ) as pCQ that exhibited lowered cytotoxicity, enhanced inhibition of cancer cell migration and invasion, improved antimetastatic activity in vivo, and prolonged animal survival when compared with parent HCQ. These results suggest the potential of pCQ used for combination anticancer therapy to achieve simultaneous antimetastasis effect. Therefore, we then developed reduction-responsive camptothecin (CPT)-pCQ copolymers as pCQCPT that were used for codelivery of CPT and pCQ. The in vivo study showed that pCQCPT exhibited significantly enhanced inhibitory activity on tumor growth and antimetastasis activity when compared to CPT. In addition, we investigated the role of the linkage between CQ and polymer backbone by using ester in pCQ and a stable amide and triazole ring by copolymerization of HPMA and methacrylamido methyl triazole chloroquine (MA-tCQ) as NpCQ. NpCQ showed similar inhibitory activity of pCQ on cancer cell migration, suggesting that pCQ functions as a pharmacologically active polymer drug that does not require the release of the small molecule HCQ. Overall, this study provides clear impetus for further development of pCQ as a new class of antimetastatic polymer agents with possibly unique mechanism of action that is not found in HCQ.

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