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WIREs Nanomed Nanobiotechnol
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Promise of chemokine network‐targeted nanoparticles in combination nucleic acid therapies of metastatic cancer

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Chemokines and chemokine receptors play key roles in cancer progression and metastasis. Although multiple chemokines and chemokine receptors have been investigated, inhibition of CXCR4 emerged as one of the most promising approaches in combination cancer therapy, especially when focused on the metastatic disease. Small RNA molecules, such as small interfering RNA (siRNA) and microRNA (miRNA), represent new class of therapeutics for cancer treatment through RNA interference‐mediated gene silencing. However, the clinical applicability of siRNA and miRNA is severely limited by the lack of effective delivery systems. There is a significant therapeutic potential for CXCR4‐targeted nanomedicines in combination with the delivery of siRNA and miRNA in cancer. Recently developed CXCR4‐targeted polymeric drugs and nanomedicines, including cyclam‐ and chloroquine‐based polymeric CXCR4 antagonists are introduced here and their ability to deliver functional siRNA and miRNA is discussed.

This article is categorized under:

  • Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
  • Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Main approaches utilizing CXCR4 in cancer nanomedicine
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Chloroquine containing polycation for improving endosome escape of delivered miRNA and inhibiting cell migration. (Reprinted with permission from Xie et al. (). Copyright 2018 Wiley‐VCH)
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Proposed mechanisms of PCX/RNA polyplexes. (1) Excess PCX of the polyplexes formulation is responsible for the immediate CXCR4 antagonism. (2) The disassembly of polyplex releases both small RNA and PCX. Functional small RNA silences oncogene through RNAi mechanism. These released PCX results in delayed CXCR4 inhibition effect via binding intracellular CXCR4 during recycling or via PCX excretion from the cells and binding the plasma membrane CXCR4 on cancer cells. (3) In case of intracellularly bioreducible PCX (rPCX), the small molecule degradation products containing the CXCR4‐binding cyclam moieties further contribute to the CXCR4 inhibition
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(a) Proposed mechanism of action of PCX/miR‐200c polyplexes. (b) Combined inhibition of cancer cell migration. (Reprinted with permission from Xie et al. (). Copyright 2016 American Chemical Society) (c) Chemical structure of an HPMA‐based self‐immolative polymeric prodrug of a CXCR4 antagonist, AMD3465 (P‐SS‐AMD). (Reprinted with permission from Peng et al. (). Copyright 2017 American Chemical Society)
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Mechanism of action of PCX/siNCOA3 polyplexes in pancreatic cancer therapy. (Reprinted with permission from Wang, Kumar, et al. (). Copyright 2016 Elsevier)
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Chemical structure of (a) AMD3100 and cyclam‐based polymeric CXCR4 antagonists (PCX) and (b) hydroxychloroquine and chloroquine‐based CXCR4 antagonists (PCQ) (red color indicates the CXCR4‐binding repeating unit in the polymers)
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Gene silencing mechanisms of siRNA and miRNA. (Reprinted with permission from Lam and Chow (). Copyright 2015 American Society of Gene & Cell Therapy)
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Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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