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Supramolecular self-assemblies of H6/doxorubicin reverse P-gp-mediated multidrug resistance in breast cancer
Qingquan Sun1, Yan Wei1, Baoyuan Sun1
1School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, 30 Qingquan Road, Yantai 264005, Shandong, People's Republic of China.
Abstract:
Tumor multidrug resistance (MDR) remains a major cause of chemotherapy failure. Inhibiting the P-glycoprotein (P-gp)-mediated excessive efflux of chemotherapeutic drugs represent an effective strategy to overcome MDR. Conventional P-gp inhibitors are limited in clinical use due to systemic toxicity and risks of normal tissue dysfunction. In this study, we constructed a self-assembled system based on H6, the α-hederagenin derivative with potent MDR reversal activity, and the chemotherapeutic agent doxorubicin (DOX). Guided by the CREKA peptide, this system specifically targets fibronectin in tumor tissues, thereby enhancing drug accumulation at the lesion site. The combination therapy of H6 and DOX exhibited a combination index (CI) of 0.16 (CI < 1), indicating strong synergistic effects. Both in vitro and in vivo experiments demonstrated that H6 interferes with ATP production and effectively inhibits P-gp efflux function. In a breast cancer MDR model, this strategy achieved a tumor inhibition rate of 81.7%, offering a promising approach to combat tumor MDR.
Insights
This study introduces a novel drug delivery system combining H6 and doxorubicin to overcome tumor multidrug resistance (MDR). The targeted system shows strong synergistic effects, significantly inhibiting tumor growth in a breast cancer model.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Tumor multidrug resistance (MDR) is a primary reason for chemotherapy failure.
- P-glycoprotein (P-gp) efflux of drugs contributes significantly to MDR.
- Existing P-gp inhibitors have limitations due to systemic toxicity.
Purpose of the Study:
- To develop a targeted self-assembled system to overcome MDR.
- To investigate the synergistic effects of H6 and doxorubicin (DOX).
- To evaluate the efficacy of the system in a breast cancer MDR model.
Main Methods:
- Construction of a self-assembled system using H6 (α-hederagenin derivative) and DOX.
- Incorporation of CREKA peptide for fibronectin targeting in tumors.
- In vitro and in vivo evaluation of P-gp inhibition and synergistic effects (Combination Index, CI).
Main Results:
- The H6-DOX system demonstrated strong synergistic effects (CI < 1).
- H6 was shown to inhibit P-gp efflux by interfering with ATP production.
- The targeted therapy achieved an 81.7% tumor inhibition rate in a breast cancer MDR model.
Conclusions:
- The CREKA-peptide-guided H6-DOX self-assembled system effectively targets tumors and overcomes MDR.
- This approach offers a promising strategy to enhance chemotherapy efficacy against resistant cancers.
- The study highlights the potential of H6 as a P-gp inhibitor in combination therapy.
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