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Published on: February 8, 2017
Lipid-Saporin Nanoparticles for the Intracellular Delivery of Cytotoxic Protein to Overcome ABC Transporter-Mediated
Guan-Nan Zhang1, Pranav Gupta1, Ming Wang2
1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Abstract:
Although the judicious use of anticancer drugs that target one or more receptor tyrosine kinases constitutes an effective strategy to attenuate tumor growth, drug resistance is commonly encountered in cancer patients. The ATP-binding cassette transporters are one of the major contributors to the development of multidrug resistance as their overexpression significantly decreases the intracellular concentration and thus, the efficacy of certain anticancer drugs. Therefore, the development of treatment strategies that would not be susceptible to efflux or excretion by specific ABC transporters could overcome resistance to treatment. Here, we investigated the anticancer efficacy of saporin, a ribosome-inactivating protein. Since saporin has poor permeability across the cell membrane, it was encapsulated in a lipid-based nanoparticle system (EC16-1) that effectively delivered the formulation (EC16-1/saporin) intracellularly and produced anti-cancer efficacy. EC16-1/saporin, at nanomolar concentrations, significantly inhibited the cellular proliferation of parental and ABCB1- and ABCG2-overexpressing cancer cells. EC16-1/saporin did not significantly alter the subcellular localization of ABCB1 and ABCG2. In addition, EC16-1/saporin induced apoptosis in parental and ABCB1- and ABCG2-overexpressing cancer cells. In a murine model system, EC16-1/saporin significantly inhibited the tumor growth in mice xenografted with parental and ABCB1- and ABCG2-overexpressing cancer cells. Our findings suggest that the EC16-1/saporin combination could potentially be a novel therapeutic treatment in patients with parental or ABCB1- and ABCG2-positive drug-resistant cancers.
Insights
This study shows that EC16-1/saporin, a novel nanoparticle formulation, effectively inhibits cancer cell proliferation and tumor growth. It offers a potential new treatment for drug-resistant cancers, including those overexpressing ABCB1 and ABCG2 transporters.
Area of Science:
- Biochemistry
- Molecular Biology
- Nanotechnology
Background:
- Anticancer drug resistance is a major clinical challenge, often mediated by ATP-binding cassette (ABC) transporters.
- Overexpression of ABCB1 and ABCG2 transporters reduces intracellular drug concentrations, leading to treatment failure.
- Novel therapeutic strategies are needed to overcome multidrug resistance in cancer.
Purpose of the Study:
- To investigate the anticancer efficacy of saporin encapsulated in a lipid-based nanoparticle system (EC16-1/saporin).
- To evaluate the effectiveness of EC16-1/saporin against cancer cells with and without overexpression of ABCB1 and ABCG2 transporters.
- To assess the therapeutic potential of EC16-1/saporin in a preclinical cancer model.
Main Methods:
- Saporin was encapsulated in EC16-1 nanoparticles for intracellular delivery.
- Anticancer efficacy was assessed by measuring cellular proliferation and apoptosis in parental and ABCB1/ABCG2-overexpressing cancer cells.
- Tumor growth inhibition was evaluated in a murine xenograft model.
Main Results:
- EC16-1/saporin demonstrated significant anticancer efficacy at nanomolar concentrations.
- The formulation inhibited proliferation and induced apoptosis in both parental and multidrug-resistant cancer cells.
- In vivo studies showed significant tumor growth inhibition in mice treated with EC16-1/saporin.
Conclusions:
- EC16-1/saporin is a promising therapeutic agent against drug-resistant cancers.
- This nanoparticle formulation effectively overcomes resistance mediated by ABCB1 and ABCG2 transporters.
- EC16-1/saporin represents a potential novel treatment for patients with ABCB1/ABCG2-positive drug-resistant cancers.
