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Published on: November 1, 2017
Enhanced Efficacy against Drug-Resistant Tumors Enabled by Redox-Responsive Mesoporous-Silica-Nanoparticle-Supported
Shuoye Yang1,2, Beibei Zhang1, Xiangguo Zhao1
1School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China.
Abstract:
Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects.
Insights
This study developed novel nanocarriers to overcome multidrug resistance (MDR) in cancer. The nanocarriers effectively delivered chemotherapy drugs, inhibited drug efflux pumps, and enhanced tumor treatment in preclinical models.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Drug Delivery
Background:
- Multidrug resistance (MDR) in cancer, often due to P-glycoprotein (P-gp) overexpression, limits chemotherapy efficacy.
- Nanodelivery systems offer a promising strategy to overcome MDR and improve therapeutic outcomes.
Purpose of the Study:
- To develop and characterize a novel dual pH/reduction responsive nanodelivery system (HT-LMSNs-SS@DOX) for overcoming MDR.
- To evaluate the efficacy of HT-LMSNs-SS@DOX in vitro and in vivo for treating drug-resistant cancer.
Main Methods:
- Synthesis of mesoporous silica nanoparticles (MSNs) coated with lipid bilayers, functionalized with TPGS and HA, and loaded with doxorubicin (DOX).
- Characterization of nanocarrier properties, including dispersity, biocompatibility, drug loading, and responsive drug release.
- In vitro studies assessing cellular uptake, P-gp inhibition, apoptosis induction, cell cycle arrest, and reactive oxygen species (ROS) generation.
- In vivo evaluation of anti-tumor efficacy and biosafety in tumor-bearing mice.
Main Results:
- HT-LMSNs-SS@DOX demonstrated good dispersity, biocompatibility, and drug-loading capacity.
- The nanocarrier exhibited efficient cellular uptake via clathrin-mediated endocytosis and dual pH/reduction responsive drug release.
- In vitro, HT-LMSNs-SS@DOX effectively inhibited P-gp, increased apoptosis, arrested cell cycle, and elevated ROS levels in drug-resistant cancer cells.
- In vivo studies showed superior tumor growth inhibition and good biosafety of HT-LMSNs-SS@DOX compared to other treatments.
Conclusions:
- The developed HT-LMSNs-SS@DOX nanodelivery system effectively overcomes MDR by targeted delivery and redox-responsive drug release.
- This nanoplatform shows significant potential for enhancing chemotherapy efficacy against resistant tumors.
