Tumor progress intercept by intervening in Caveolin-1 related intercellular communication via ROS-sensitive c-Myc

Xueqing Zhou1, Xuan Liu1, Xiqin Yang1

  • 1College of Pharmaceutical Science, Zhejiang University, Hangzhou, 310058, China.

Biomaterials
|June 15, 2021
PubMed

Insights

This study developed a dual-targeted nanocarrier delivering a c-Myc inhibitor (JQ1) to tumor cells and macrophages. This strategy effectively inhibited tumor growth and metastasis with reduced toxicity.

Area of Science:

  • Oncology
  • Nanomedicine
  • Immunology

Background:

  • Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) significantly influence tumor progression through cytokine secretion and direct cell communication.
  • Targeting TAMs presents an attractive therapeutic strategy for cancer treatment.
  • The oncogene c-Myc is implicated in various aspects of tumor cell oncogenesis and macrophage activation.

Purpose of the Study:

  • To develop a dual-targeted delivery system for the c-Myc inhibitor JQ1, targeting both tumor cells and TAMs.
  • To investigate the therapeutic potential of this system in inhibiting tumor growth, metastasis, and M2 macrophage polarization.
  • To explore the mechanism by which JQ1 inhibits tumor cell migration mediated by M2 macrophage-derived exosomes.

Main Methods:

  • Construction of a glycolipid nanocarrier (CSOPOSA) with ROS-responsive peroxalate linkages for drug release.
  • Modification of the nanocarrier with Ex 26, a selective sphingosine 1-phosphate receptor 1 (S1PR1) antagonist (Ex 26-CSOPOSA), for dual targeting.
  • Delivery of the c-Myc inhibitor JQ1 via S1PR1, which is overexpressed on tumor cells and TAMs.
  • Assessment of JQ1's effect on tumor cell apoptosis, M2 macrophage polarization, and tumor cell migration induced by exosomes.
  • Investigation of the role of Caveolin-1, lncRNA H19, and miR-107 in exosome-mediated intercellular communication.

Main Results:

  • The Ex 26-CSOPOSA nanocarrier successfully achieved dual-targeted delivery of JQ1.
  • JQ1 induced tumor cell apoptosis and inhibited M2 polarization of macrophages.
  • JQ1 effectively suppressed tumor cell migration induced by M2 macrophage-derived exosomes by disrupting exosome exchange via lncRNA H19 and miR-107.
  • In vivo studies demonstrated significant inhibition of tumor growth and metastasis with reduced systemic toxicity.

Conclusions:

  • The developed dual-targeted delivery strategy using Ex 26-CSOPOSA nanocarriers shows significant potential for effective cancer treatment.
  • This approach offers a promising method for simultaneously targeting tumor cells and TAMs, leading to enhanced therapeutic outcomes.
  • The findings highlight the intricate role of exosome communication in tumor metastasis and provide a novel therapeutic avenue targeting this pathway.

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