title: Polymeric chloroquine as an inhibitor of cancer cell migration and experimental lung metastasis.
abstract: 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 a macromolecular drug with antimetastatic activity. The pCQ polymers 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.
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sleightholm
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China. Electronic address: david.oupicky@unmc.edu.
authors.forename: David
authors.initials: D
authors.lastname: Oupický
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002738:Chloroquine / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D016503:Drug Delivery Systems; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008807:Mice, Inbred BALB C; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D011108:Polymers; D019718:Receptors, CXCR4; D002738:Chloroquine; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: CXCR4; Chloroquine; Endosomal release; HPMA; Metastasis; Polymeric drug