Controlling Disassembly of Paramagnetic Prodrug and Photosensitizer Nanoassemblies for On-Demand Orthotopic Glioma Theranostics.

Abstract

Controlling delivery and release of therapeutic agents to accomplish on-demand synergistic therapy of orthotopic gliomas is desired but challenging. Here, we report a glioma targeting and redox activatable theranostic nanoprobe (<b>Co-NP-RGD</b>_<b>1/1</b>) for magnetic resonance (MR) and fluorescence (FL) bimodal imaging-guided on-demand synergistic chemotherapy/photodynamic therapy (Chemo-PDT) of orthotopic gliomas. <b>Co-NP-RGD</b>_<b>1/1</b> is formed via molecular coassembly of two paramagnetic and fluorogenic small-molecule probes <b>CPT-RGD</b> and <b>PPa-RGD</b> at an optimized molar ratio of 1/1, which shows a high longitudinal relaxivity (<i>r</i>₁ = 17.0 ± 0.6 mM^-1 s^-1, 0.5 T) but weak FL emissions and low Chemo-PDT activity. Upon reduction by endogenous glutathione (GSH), <b>Co-NP-RGD</b>_<b>1/1</b> disassemble and release small molecules 2-RGD, chemodrug camptothecin (CPT), and near-infrared (NIR) photosensitizer (PS) PPa-SH that further binds to endogenous albumin to form PPa-SH-albumin complex, allowing to turn on FL, chemotherapeutic efficacy, and PDT activity for synergistic Chemo-PDT of orthotopic U87MG or U251 gliomas in living mice. Moreover, <b>Co-NP-RGD</b>_<b>1/1</b> can also allow noninvasive detection and monitoring of orthotopic brain tumor growth via FL and MR imaging. Findings suggest the potential of cascade coassembly and stimuli-controlled intracellular disassembly strategy for constructing targeted and activatable nanoagents for improving combinational cancer theranostics.