Abstract

Development of versatile nanoplatforms that simultaneously integrate therapeutic and diagnostic features for stimuli-responsive delivery to tumors remains a great challenge. In this work, we report a novel intelligent redox-responsive hybrid nanosystem composed of MnO₂ nanoparticles (NPs) and doxorubicin (DOX) co-loaded within poly(N-vinylcaprolactam) nanogels (PVCL NGs) for magnetic resonance (MR) imaging-guided and ultrasound-targeted microbubble destruction (UTMD)-promoted tumor chemotherapy.

Methods: PVCL NGs were first synthesized via a precipitation polymerization method, decorated with amines using ethylenediamine, and loaded with MnO₂ NPs through oxidation with permanganate and DOX via physical encapsulation and Mn-N coordination bonding. The as-prepared DOX/MnO₂@PVCL NGs were well characterized. UTMD-promoted cellular uptake and therapeutic efficacy of the hybrid NGs were assessed in vitro, and a xenografted tumor model was used to test the NGs for MR imaging and UTMD-promoted tumor therapy in vivo.

Results: The as-prepared DOX/MnO₂@PVCL NGs with a size of 106.8 nm display excellent colloidal stability, favorable biocompatibility, and redox-responsiveness to the reductive intracellular environment and tumor tissues having a relatively high glutathione (GSH) concentration that can trigger the synchronous release of Mn²⁺ for enhanced T₁-weighted MR imaging and DOX for enhanced cancer chemotherapy. Moreover, the DOX/MnO₂@PVCL NGs upon the UTMD-promotion exhibit a significantly enhanced tumor growth inhibition effect toward subcutaneous B16 melanoma owing to the UTMD-improved cellular internalization and tumor penetration.

Conclusion: Our work thereby proposes a promising theranostic nanoplatform for stimuli-responsive T₁-weighted MR imaging-guided tumor chemotherapy.

Keywords: nanogels, manganese dioxide nanoparticles, ultrasound-targeted microbubble destruction, magnetic resonance imaging, chemotherapy