Chloroquine-Containing HPMA Copolymers as Polymeric Inhibitors of Cancer Cell Migration Mediated by the CXCR4/SDF-1 Chemokine Axis

Yu, Zhi Qiang; Xie, Ying; Wang, Yan; Peng, Zheng Hong; Li, Jing; Oupický, David

doi:10.1021/acsmacrolett.5b00857

Cited by 26 publications

(28 citation statements)

References 27 publications

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“…We recently reported synthesis of pCQ (Scheme 1) as a potential polymeric drug that takes advantage of the multivalency effect to enhance the ability of CQ to inhibit CXCR4-mediated invasion of lymphoma and leukemia cells [25]. We found that pCQ with 10 and 16.7 mol% of MA-CQ exhibited the most favorable activity profile in leukemia and lymphoma cells in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…This inhibition of CXCL12 binding then prevents CXCR4 receptor internalization and suppresses activation of the related downstream signaling cascades. CQ and HCQ on the other hand, appear to promote internalization of the surface CXCR4 receptors and their sequestration in the lysosomes, which then makes the receptors inaccessible for binding with extracellular CXCL12 chemokine molecules [15, 25]. …”

Section: Resultsmentioning

confidence: 99%

“…The pCQ copolymers with different CQ content were synthesized as previously reported (Scheme 1) [25]. Briefly, HCQ·HCl was converted to a base form using ammonium hydroxide and HCQ was extracted into DCM and dried.…”

Section: Methodsmentioning

confidence: 99%

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Polymeric chloroquine as an inhibitor of cancer cell migration and experimental lung metastasis

Xie

et al. 2016

Journal of Controlled Release

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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 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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Polymeric chloroquine as an inhibitor of cancer cell migration and experimental lung metastasis

Xie

et al. 2016

Journal of Controlled Release

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“…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 …”

Section: Introductionmentioning

confidence: 99%

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

Xie

Tang

et al. 2017

Macromolecular Bioscience

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Chloroquine-containing 2-(dimethylamino)ethyl methacrylate (DMAEMA) copolymers (PDCs) were synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Systematic evaluation was performed to test the hypothesis that presence of chloroquine (CQ) in the PDC structure will improve miRNA delivery due to enhanced endosomal escape while simultaneously contribute to anticancer activity of PCD/miRNA polyplexes through inhibition of cancer cell migration. Our results showed that miRNA delivery efficiency was dependent both on the molecular weight and CQ. The best performing PDC/miRNA polyplexes showed effective endosomal escape of miRNA. PDC polyplexes with therapeutic miR-210 showed promising anticancer activity in human breast cancer cells. PDC/miRNA polyplexes showed excellent ability to inhibit migration of cancer cells. Overall, this study supports the use of PDC as a promising polymeric drug platform for use in combination antimetastatic and anticancer miRNA therapeutic strategies.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Sleightholm

Yang

et al. 2017

Biomacromolecules

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Hydroxyethyl starch (HES) is a clinically used polysaccharide colloidal plasma volume expander. The goal of this study was to synthesize HES modified with hydroxychloroquine (HCQ) as a novel polymeric drug with the ability to inhibit the invasive character of pancreatic cancer (PC) cells. HES was conjugated with HCQ using a simple carbonyldiimidazole coupling to prepare Chloroquine-modified HES (CQ-HES). CQ-HES with various degrees of HCQ substitution were synthesized and characterized. Atomic force microscopy was used to demonstrate a pH-dependent assembly of CQ-HES into well-defined nanoparticles. In vitro studies in multiple PC cell lines showed CQ-HES to have a similar toxicity profile as HCQ. Confocal microscopy revealed the propensity of CQ-HES to localize to lysosomes and mechanistic studies confirmed the ability of CQ-HES to inhibit autophagy in PC cells. Further studies demonstrated a greatly enhanced ability of CQ-HES to inhibit the migration and invasion of PC cells when compared with HCQ. The enhanced inhibitory actions of CQ-HES compared to HCQ appeared to arise in part from the increased inhibition of ERK and Akt phosphorylation. We found no significant HCQ release from CQ-HES, which confirmed that the observed activity was due to the action of CQ-HES as a polymeric drug. Due to its promising ability to block cancer cell invasion and the ability to form nanoparticles, CQ-HES has the potential as a drug delivery platform suitable for future development with chemotherapeutics to establish novel antimetastatic treatments.

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Chloroquine-Containing HPMA Copolymers as Polymeric Inhibitors of Cancer Cell Migration Mediated by the CXCR4/SDF-1 Chemokine Axis

Cited by 26 publications

References 27 publications

Polymeric chloroquine as an inhibitor of cancer cell migration and experimental lung metastasis

Polymeric chloroquine as an inhibitor of cancer cell migration and experimental lung metastasis

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

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

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