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Multistage O2-producing liposome for MRI-guided synergistic chemodynamic/chemotherapy to reverse cancer multidrug
Yan Liang1, Ping-Yu Wang2, You-Jie Li2
1Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, QingDao, ShanDong 266071, PR China.
Abstract:
Reduced drug uptake and elevated drug efflux are two major mechanisms in cancer multidrug resistance (MDR). In the present study, a new multistage O2-producing liposome with NAG/R8-dual-ligand and stimuli-responsive dePEGylation was developed to address the abovementioned issues simultaneously. The designed C-NAG-R8-PTXL/MnO2-lip could also achieve magnetic resonance imaging (MRI)-guided synergistic chemodynamic/chemotherapy (CDT/CT). In vitro and in vivo studies showed that C-NAG-R8-PTXL/MnO2-lip enhanced circulation time by PEG and targeted the tumor site. After tumor accumulation, endogenous l-cysteine was administered, and the PEG-attached disulfide bond was broken, resulting in the dissociation of PEG shells. The previously hidden positively charged R8 by different lengths of PEG chains was exposed and mediated efficient internalization. In addition, the oxygen (O2) generated by C-NAG-R8-PTXL/MnO2-lip relieved the hypoxic environment within the tumor, thus reducing the efflux of chemotherapeutic drug. O2 was able to burst liposomes and triggered the release of PTXL. The toxic hydroxyl radical (·OH), which was produced by H2O2 and Mn2+, strengthened CDT/CT. C-NAG-R8-PTXL/MnO2-lip was also used as MRI contrast agent, which blazed the trail to rationally design theranostic agents for tumor imaging.
Insights
This study presents a novel O2-producing liposome to combat cancer multidrug resistance (MDR) by enhancing drug uptake and reducing efflux. The theranostic agent enables targeted chemotherapy, chemodynamic therapy, and MRI-guided tumor imaging.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Cancer multidrug resistance (MDR) is a significant challenge, primarily driven by reduced drug uptake and increased drug efflux.
- Developing effective drug delivery systems that overcome MDR and provide diagnostic capabilities is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To develop a novel multistage, oxygen-producing liposome (C-NAG-R8-PTXL/MnO2-lip) designed to simultaneously address reduced drug uptake and elevated drug efflux in cancer MDR.
- To create a theranostic agent capable of magnetic resonance imaging (MRI)-guided synergistic chemodynamic therapy (CDT) and chemotherapy (CT).
Main Methods:
- Fabrication of a stimuli-responsive, PEGylated liposome incorporating NAG/R8-dual-ligand and MnO2 nanoparticles.
- Evaluation of liposome circulation time, tumor targeting, and stimuli-responsive dePEGylation triggered by endogenous l-cysteine.
- Assessment of oxygen generation to alleviate tumor hypoxia, enhance drug internalization, and trigger drug release.
- Investigation of MnO2-mediated chemodynamic therapy (generation of hydroxyl radicals) and paclitaxel (PTXL) chemotherapy.
- Utilizing the MnO2 component as an MRI contrast agent for tumor imaging.
Main Results:
- The C-NAG-R8-PTXL/MnO2-lip demonstrated enhanced circulation time and effective tumor targeting.
- Stimuli-responsive dePEGylation upon l-cysteine administration exposed R8 ligands, mediating efficient cellular internalization.
- Generated oxygen relieved tumor hypoxia, reducing drug efflux and bursting liposomes to release paclitaxel.
- Synergistic CDT/CT was achieved through hydroxyl radical generation, enhancing therapeutic efficacy.
- The liposome functioned as an effective MRI contrast agent for tumor visualization.
Conclusions:
- The developed C-NAG-R8-PTXL/MnO2-lip effectively overcomes cancer MDR by enhancing drug uptake and reducing efflux.
- This theranostic system offers a promising platform for MRI-guided synergistic CDT/CT, improving tumor treatment and imaging.
- The rational design of this agent paves the way for advanced theranostic nanomedicine in oncology.
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