Journal
JOURNAL OF CONTROLLED RELEASE
Volume 244, Issue -, Pages 347-356Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2016.07.040
Keywords
Polymeric drug; Metastasis; Chloroquine; HPMA; CXCR4; Endosomal release
Funding
- University of Nebraska Medical Center, National Institutes of Health [EB015216, EB020308, EB019175]
- Changjiang Scholar Program
- Nebraska Research Initiative
- Fred and Pamela Buffett Cancer Center [P30CA036727]
- Institutional Development Award (IDeA) from the NIGMS [P30GM106397]
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Chloroquine (CQ) is a widely used antimalarial drug with emerging potential in anticancer therapies due to its apparent inhibitory effects on CXCR4 chemokine receptor, autophagy, and cholesterol metabolism. This study reports on polymeric CQ (pCQ) as amacromolecular drug with antimetastatic activity. The pCQpolymers were synthesized by copolymerization of methacryloylated hydroxy-CQ (HCQ) and N-(2-hydroxypropyl) methacrylamide (HPMA). The results show that pCQ is significantly more effective in inhibiting cancer cell migration and invasion when compared with the parent HCQ. The proposed mechanism of action at least partially relies on the ability of pCQ to inhibit cell migration mediated by the CXCR4/CXCL12 pathway. The pCQ also demonstrates superior inhibitory activity over HCQ when tested in a mouse model of experimental lung metastasis. Lastly, pCQ shows the ability to efficiently translocate to the cytoplasm while exhibiting lower cytotoxicity than HCQ. Overall, this study supports pCQ as a promising polymeric drug platform suitable for use in combination antimetastatic strategies and potential use in cytoplasmic drug delivery. (C) 2016 Elsevier B.V. All rights reserved.
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