Multi-stimuli responsive hollow MnO2-based drug delivery system for magnetic resonance imaging and combined chemo-chemodynamic cancer therapy

The exploration and application of hollow manganese dioxide nanoparticle (HMDN) for biosensing and biomedicine has gained significant research attention in the past decade. In this study, a type of biodegradable HMDN is prepared for multi-stimuli responsive tumor-targeted drug delivery, which was successfully loaded with doxorubicin hydrochloride (DOX). Then, the drug-loaded HMDN is functionalized with polyethyleneimine (PEI) as a gatekeeper followed by citraconic anhydride (cit) functionalized polyL-lysine (PLL(cit)) as a charge reversal moiety successively to yield the resultant DOX@HMDN-PEI-PLL(cit) nanoparticles. In vitro study showed that DOX@HMDN-PEI-PLL(cit) exhibited a stealthy'' property under physiological conditions and enhanced cellular uptake activity in response to the mild acidic tumor microenvironment due to the departure of cit. In vitro release profiles proved that the decomposition of HMDN to Mn2+ under acidic condition/high glutathione (GSH) concentration triggered the release of DOX and Fenton-like reaction for improved therapeutic effect. And Mn2+ could also act as a T-1-weighted magnetic resonance imaging (MRI) contrast agent. In vivo studies further proved with both the charge reversal and combined therapy properties, DOX@HMDN-PEI-PLL(cit) showed a good tumor enrichment ability and therapeutic effect with few side effects to the mice. These results demonstrate that DOX@HMDN-PEIPLL(cit) nanoparticles are promising drug delivery systems for targeted cancer therapy. Statement of significance Traditional chemotherapy based on anticancer drugs such as doxorubicin hydrochloride (DOX) shows limited efficacy with serious side effects. We employed hollow manganese dioxide nanoparticle (HMDN) to loaded DOX and coated it with polyethyleneimine and then citraconic anhydride functionalized poly- Llysine to endow it with a charge reversal property to obtain a multi-stimuli responsive drug delivery system named DOX@HMDN-PEI-PLL(cit). It was stealthy'' with low cellular uptake capability by normal cells, but could be acid-activated in tumors for endocytosis by cancer cells to reduce side effects. HMDN could be decomposed to Mn2+ under acidic conditions/high glutathione concentration to release DOX intracellular. DOX and Mn2+ catalyzed Fenton-like reaction could achieve a combined chemochemodynamic therapy. And Mn2+ could be used for T-1-weighted magnetic resonance imaging. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

The research focuses on the exploration and application of hollow manganese dioxide nanoparticles (HMDN) for biosensing and biomedicine, particularly in tumor-targeted drug delivery. The prepared DOX@HMDN-PEI-PLL(cit) nanoparticles have shown promising results in vitro and in vivo studies, demonstrating their potential as a drug delivery system for targeted cancer therapy. The nanoparticles exhibit a stealthy property under physiological conditions and enhanced therapeutic effects with minimal side effects, showcasing their potential for future applications in cancer treatment.