Response of pH-Sensitive Doxorubicin Nanoparticles on Complex Tumor Microenvironments by Tailoring Multiple Physicochemical Properties

Cellular internalization, delivery efficiency, and therapeutic efficacy of nanoparticles vary according to the micro-environmental complexity for tumor types. Adjusting their physicochemical properties, such as surface properties and size, has significant potential for dealing with such complexities. Herein, we prepare four types of pH-sensitive doxorubicin nanoparticles (DOX-D1, DOX-D2, DOX-W1, and DOX-W2 Nano) using simply changing reaction medium or reactant ratio. DOX-D1 and DOX-D2 Nano exhibit similar surface characteristics (surface coating and targeting ligand content) and different size, while both DOX-W Nano examples present similar surface characteristics and size. And they can re-self-assemble into smaller particles in blood-mimic conditions and the order of size is as follows: DOX-D1> DOX-D2 approximate to DOX-W Nano, and DOX-W Nano has a higher targeting ligand content than DOX-D Nano. Thus, the bioactivities in vitro and tumor microenvironment responses of DOX-D1, DOX-D2, and DOX-W1 are further investigated due to their different physicochemical properties. DOX-W1 Nano exhibits a higher cellular uptake, a stronger antiproliferation than DOX-D1 and DOX-D2 Nano attributed to its smaller size, and a higher targeting moiety content. Despite the similar sizes of DOX-W1 and DOX-D2, DOX-D2 Nano shows a greater in vitro blood-brain barrier (BBB) permeability related to its surface coating. Interestingly, DOX-D1 with suitable size and surface property can efficiently bypass the BBB and deliver to an intracranial glioma; in comparison DOX-W1 Nano has excellent targeting efficiency in subcutaneous tumors (glioma and breast cancer). Accordingly, DOX-D1 Nano is preferential for the treatment of intracranial glioma while DOX-W1 Nano exhibits potent killing ability for subcutaneous tumors. Our work suggests tailoring multiple physicochemical properties of nanoparticles can play a significant role in addressing tumor microenvironment complexity.