Hierarchical Responsive Nanoplatform with Two-Photon Aggregation-Induced Emission Imaging for Efficient Cancer Theranostics.

Theranostic nanoplatforms haev been proven to be a feasible strategy against cancer for convenient diagnosis, efficient drug release, and reduced side effects. However, the drug leakage during blood circulation, poor cellular uptake of drug-loaded nanoparticles, and insufficient drug release still remain to be overcome. Herein, a hierarchical pH and reactive oxygen species (ROS)-responsive nanoplatform is constructed labeling with a two-photon fluorophore developed by us, aiming for a programmed drug delivery and an intensive two-photon bioimaging. With the capecitabine (Cap) conjugated, the prodrug polymer PMPC-b-P[MPA(Cap)-co-TPMA]-PAEMA (PMMTAb-Cap) can be self-assembled into the core-shell structured micelles, which can stay stable in the blood stream. Once the micelles accumulate at the tumor tissue, the outside PMPC shell can be desquamated while the inner PAEMA become hydrophilic and electropositive under the acidic extracellular tumor microenvironment, leading to a shrunken micellar size for the better penetration along with enhanced endocytosis. After cellular internalization, the overexpressed intracellular ROS can eventually trigger the drug delivery for an accurate tumor therapy, which is confirmed by the in vivo antitumor experiments. Furthermore, the in vivo micellar biodistribution can be traced by a deep tissue imaging up to 150 μm because of the aggregation-induced emission active two-photon fluorophore. As a theranostic nanoplatform with two-photon bioimaging and hierarchical responsiveness, these PMMTAb-Cap micelles can be a potential candidate for tumor theranostical applications.