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

Abstract

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 poly-_L-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 T₁-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-PEI-PLL(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-_L-lysine 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 chemo-chemodynamic therapy. And Mn²⁺ could be used for T₁-weighted magnetic resonance imaging.

Keywords: Combined cancer therapy; Controlled release; Fenton-like reaction; Hollow manganese dioxide; Multi-stimuli responsive.