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 microenvironmental 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 ≈ 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.