About 15% of breast cancers are diagnosed as TNBC. TNBC does not express common therapeutic targets and their non-responsiveness to receptor-targeted treatments has increasingly led to attempts to develop novel and effective specific targeted therapy. One of the promising strategies is the conjugation of ligands to nanoparticle platforms for the targeted delivery of therapeutic agents to the tumour tissue. However, conventional nanoparticle platforms are not so effective in terms of the selectivity and transfection efficiency. To overcome this problem, Professor Gordon Xu’s research team in the Australian Institute for Bioengineering and Nanotechnology at The University of Queensland have developed a dual-target drug/gene delivery system based on lipid-coated calcium phosphate (LCP) nanoparticles (NPs) that significantly enhances siRNA in vivo and in vitro delivery efficiency, making them promising nanocarriers for biomedical applications.
“In this project, single-target and dual-target LCP NP-based drug/gene delivery systems were engineered by conjugating folic acid and/or EGFR-specific ABX-EGF scFv for enhanced delivery to MDA-MB-468 human breast tumour both in vitro and in vivo. The optimal density of single-target ABX-EGF scFv and folic acid on each LCP NP surface was first determined regarding the delivery efficacy and growth inhibition of human breast cancer cells in vitro. Based on this optimal density information, co-conjugation with both ligands — each with a sub-optimal density on the LCP NP surface — synergistically enhanced the cellular delivery to MDA-MB-468 human breast tumour and achieved higher tumour accumulation in vivo,” explained Ms Jie Tang, first author of this research.
“The confocal images taken using ANFF-Q’s Zeiss LSM 710 provided important information on the influence of the conjugated ligand density on cellular uptake, which helped to finally design the optimal ligand density on the surface of the delivery system for enhanced siRNA delivery,” said Jie.
“Our results demonstrate that conjugation of either ABX-EGF scFv or folic acid improves the delivery to MDB-MA-468 cancer cells; there is an optimal density of ABX-EGF scFv and folic acid on each NP surface in terms of the delivery efficacy; and co-conjugation of 75 ABX-EGF scFv and 50 folic acid on each LCP NP further enhance the delivery efficacy. This gene/drug carrier also achieves higher tumour accumulation in vivo. Therefore, the new dual ligand LCP NPs may be a valuable targeting system for human breast cancer diagnosis and therapy,” explained Professor Gordon Xu.
“The dual ligand modified LCP NPs would be useful for early diagnosis and treatment of triple negative breast cancer. Moreover, these LCP NPs with suitable modification are potential nano-platforms for efficient delivery through various targeting strategies for imaging diagnosis and combined therapy of breast cancers,” said Gordon. “Future work on this project will involve further enhancing the in vivo anti-tumour therapies by loading the targeting nanoparticles with anti-cancer siRNA and drugs to evaluate the in vivo therapeutic results. We may continue using the confocal microscopes at ANFF-Q for cell and tissue observations.”