The dose threshold for nanoparticle tumour delivery
Ben Ouyang, Wilson Poon, Yi-Nan Zhang, Zachary P. Lin, Benjamin R. Kingston, Anthony J. Tavares, Yuwei Zhang, Juan Chen, Michael S. Valic, Abdullah M. Syed, Presley MacMillan, Julien Couture-Senécal, Gang Zheng & Warren C. W. Chan
Nanoparticle delivery to solid tumours over the past ten years has stagnated at a median of 0.7% of the injected dose. Varying nanoparticle designs and strategies have yielded only minor improvements. Here we discovered a dose threshold for improving nanoparticle tumour delivery: 1 trillion nanoparticles in mice. Doses above this threshold overwhelmed Kupffer cell uptake rates, nonlinearly decreased liver clearance, prolonged circulation and increased nanoparticle tumour delivery. This enabled up to 12% tumour delivery efficiency and delivery to 93% of cells in tumours, and also improved the therapeutic efficacy of Caelyx/Doxil. This threshold was robust across different nanoparticle types, tumour models and studies across ten years of the literature. Our results have implications for human translation and highlight a simple, but powerful, principle for designing nanoparticle cancer treatments.