Nano-drug delivery system with enhanced tumour penetration and layered anti-tumour efficacy.

The low delivery efficiency of nano-drugs and limited tumour penetration are still huge challenges in treating solid tumours. Herein, we developed a pH-responsive nano-drug delivery system, CALS/PDMA@DOX, with a size conversion-layered delivery function. The system is composed of a pH-responsive cationic liposome loaded with DOX (CALS) and a polyamidoamine dendrimer loaded with DOX (PAMAM@DOX) modified with 2,3-dimethylmaleic anhydride (PDMA@DOX) using electrostatic adsorption. In the tumour microenvironment, the positively-charged large-size CALS and the positively-charged small-size PAMAM@DOX were dissociated to exert anti-tumour effects. CALS preferentially targeted tumour angiogenesis endothelial cells. Because of its small size and positive charge, PAMAM@DOX showed excellent tumour penetration. Significant tumour suppression by the system in vivo was confirmed in a 4T1 tumour xenograft mouse model. This pH-triggered size-switching layered delivery nanosystem is a safe and effective cancer treatment delivery platform that improves drug permeability and therapeutic efficacy.