Multifunctional Tumor pH-Sensitive Self-Assembled Nanoparticles for Bimodal Imaging and Treatment of Resistant Heterogeneous Tumors

TLDR

Nanoparticle-based diagnosis–therapy integrative systems are emerging for cancer treatment, yet challenges such as limited diagnostic sensitivity, treatment efficacy, bioavailability, tumor heterogeneity, and drug resistance hinder clinical implementation. This study reports the fabrication of tumor pH‑sensitive magnetic nanogrenades (PMNs) composed of self‑assembled iron oxide nanoparticles and pH‑responsive ligands. PMNs target tumors through surface‑charge switching in acidic microenvironments and disassemble in acidic subcellular compartments to activate MR contrast, fluorescence, and photodynamic therapeutic activity. In mice, PMNs enabled early detection of small tumors via pH‑responsive T1‑MR contrast and fluorescence without targeting agents, generated singlet oxygen for selective photodynamic therapy, and achieved superior efficacy against highly heterogeneous drug‑resistant tumors, indicating strong clinical potential.

Abstract

Nanoparticle-based diagnosis–therapy integrative systems represent an emerging approach to cancer treatment. However, the diagnostic sensitivity, treatment efficacy, and bioavailability of nanoparticles as well as the heterogeneity and drug resistance of tumors pose tremendous challenges for clinical implementation. We herein report on the fabrication of tumor pH-sensitive magnetic nanogrenades (termed PMNs) composed of self-assembled iron oxide nanoparticles and pH-responsive ligands. These PMNs can readily target tumors via surface-charge switching triggered by the acidic tumor microenvironment, and are further disassembled into a highly active state in acidic subcellular compartments that "turns on" MR contrast, fluorescence and photodynamic therapeutic activity. We successfully visualized small tumors implanted in mice via unique pH-responsive T1MR contrast and fluorescence, demonstrating early stage diagnosis of tumors without using any targeting agents. Furthermore, pH-triggered generation of singlet oxygen enabled pH-dependent photodynamic therapy to selectively kill cancer cells. In particular, we demonstrated the superior therapeutic efficacy of PMNs in highly heterogeneous drug-resistant tumors, showing a great potential for clinical applications.