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.

Synthesis and Evaluation of Chloroquine‐Containing DMAEMA Copolymers as Efficient Anti‐miRNA Delivery Vectors with Improved Endosomal Escape and Antimigratory Activity in Cancer Cells

“…These results clearly suggest that conjugation of CQ to the polycation results in a significant loss of autophagy inhibitory activity. Similar observation was also reported in our previous study …”

“…CQ inhibited CXCR4‐mediated invasion and proliferation of pancreatic cancer cells and improved overall survival of tumor‐bearing mice when combined with gemcitabine . More recently, our group developed CQ‐containing N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymers, which achieved greatly enhanced inhibition activity against cancer cell migration and tumor metastasis in vivo …”

Synthesis and biological characterization of clicked chloroquine copolymers as macromolecular inhibitors of cancer cell migration

“…According to our previous studies, CQ‐containing HPMA polymers inhibited migration and invasion of multiple types of cancer cells . We also found that the inhibitory activity of the polymer was broad and involved multiple signaling pathways responsible for cancer cell motility.…”

“…We have previously reported synthesis of CQ‐containing copolymers (pCQ1) by copolymerization of HPMA and methacryloyl‐HCQ (MA‐HCQ). The reported pCQ1 copolymers demonstrated unexpectedly enhanced inhibitory activity of cancer cell migration and experimental lung metastasis as polymeric drugs when compared to HCQ . However, HCQ was conjugated to the pCQ1 copolymers through ester bonds, which made them susceptible to degradation in vivo .…”

Chloroquine-Modified Hydroxyethyl Starch as a Polymeric Drug for Cancer Therapy

“…53, 54 However, the HPMA-based polymer demonstrated only limited ability to inhibit autophagy, one of the main mechanisms by which HCQ exerts its therapeutic actions. This led us to investigate other HCQ-modified polymers that better retained the autophagy inhibitory properties of HCQ for improved anticancer activity.…”