Delivery of nano‐formulated drugs to solid tumours is selectively increased by co‐application of the vascular disrupting agent CA4P

BACKGROUND AND PURPOSE: Nano-formulated chemotherapeutics prolong systemic availability of drugs and can reduce systemic toxicity, but their accumulation in solid tumours is often limited and unpredictable. Broadly applicable strategies to selectively enhance tumour delivery are lacking. We investigated whether subtherapeutic vascular disruption could be repurposed to transiently enhance tumour delivery of nano-formulated agents. EXPERIMENTAL APPROACH: Fluorescent reporter nanoparticles and the clinically approved nano-formulations Caelyx (doxorubicin) and Onivyde (irinotecan) were administered in combination with subtherapeutic doses of the vascular disrupting agent (VDA) combretastatin A4-phosphate (CA4P). Biodistribution, pharmacokinetics and therapeutic efficacy were assessed using longitudinal in vivo imaging and drug quantification via LC-MS/MS (liquid chromatography-tandem mass spectrometry) in syngeneic murine 4T1 breast cancer models. KEY RESULTS: Co-administration of CA4P increased tumour accumulation of nano-formulated agents by up to threefold without increasing exposure in healthy organs. This effect was observed across reporter particles and both chemotherapeutic formulations but was not retained after repeated treatments. Consequently, CA4P co-treatment did not improve tumour growth inhibition under standard multi-dose therapeutic regimens. CONCLUSIONS AND IMPLICATIONS: Low-dose vascular disruption can transiently and selectively enhance tumour delivery of nano-formulated agents but does not improve therapeutic efficacy with repeated dosing. This strategy may therefore be best suited to single-dose applications, such as diagnostic imaging or delivery studies, rather than sustained cancer therapy.