Dual-action CXCR4-targeting liposomes in leukemia: function blocking and drug delivery

Research output: Contribution to journalArticle

  • External authors:
  • Catriona Mccallion
  • Anna Peters
  • Andrew Booth
  • Karen Rees-Unwin
  • Julie Adams
  • Raisa Rahi
  • Claire Hutchinson

Abstract

The C-X-C chemokine receptor CXCR4 is overexpressed by a broad range of hematological disorders, and its interaction with the chemokine CXCL12 is of central importance in the retention and chemoprotection of neoplastic cells in the bone marrow and lymphoid organs. In this paper we describe the biological evaluation of a new CXCR4-targeting and antagonizing molecule, BAT1, designed by the authors, and show that when incorporated into a liposomal drug delivery system, BAT1 can be used to deliver cancer therapeutics at high levels to chronic lymphocytic leukemia (CLL) cells. CXCR4-targeting and antagonism by BAT1 were demonstrated both alone and following its incorporation into liposomes. Antagonism of BAT1 against the CXCR4/CXCL12 interaction was demonstrated through both signaling inhibition and function-blocking: BAT1 reduced ERKphosphorylation and cell migration to levels equivalent to those seen in the absence of CXCL12 stimulation (p < 0.001). Specific uptake of BAT1-liposomes and delivery of a therapeutic cargo to the cell nucleus was seen within 3 hours of incubation, and induced significantly more CLL cell death after 24 h than control liposomes (p = 0.004). The BAT1 drug delivery system we describe is modular, versatile and highly clinically relevant – incorporating elements of proven clinical efficacy. The combined capabilities to block CXCL12-induced migration and intracellular signaling while simultaneously delivering therapeutic cargo mean that the BAT1-liposome drug delivery system could be a timely and relevant treatment for a range of hematological disorders, particularly as the therapeutic cargo can be tailored to the disease being treated.

Bibliographical metadata

Original languageEnglish
Pages (from-to)2069-2081
Number of pages12
JournalBlood Advances
DOIs
Publication statusPublished - 23 Jul 2019