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Theranostic CuS/ALA Nanoprobes Modulate Drug Efflux Pumps and Synergize the Photoacoustics-Guided Photothermal Breast
Nidhi Parihar1, Prathamesh Mahadev Patil1, Santimoy Sen1
1Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam 781101, India.
Abstract:
Breast cancer remains a clinical hurdle despite technoclinical advancements, primarily due to drug resistance mechanisms, from overexpression of drug efflux pumps. Modulating drug efflux/influx transporters like ABCG2 and HCP-1 can improve anticancer therapeutic approaches. Our study reports CuS-ALA metal-organic nanoprobes combining 5-aminolevulinic acid (5-ALA), a tumor targeting biomolecule, and near-infrared (NIR) light-absorbing copper sulfide (CuS) nanoparticles. These ALA-CuS nanoprobes (NPs) had excellent near-infrared (NIR) absorption properties along with high photothermal profile, stability, photoacoustic and fluorescence imaging properties. In vitro studies in breast cancer cell lines revealed uniform internalization and exhibited a synergistic cytotoxic effect in the case of ALA-CuS NPs when exposed to a NIR 808 nm light. Further mechanistic studies have revealed that these nanoprobes could target and modulate drug transporters, such as ABCG2 and HCP1, indicating their efficient role in targeted downregulation of resistance pathways and activating photodynamic and photothermal therapies-mediated intrinsic apoptotic cell death pathways in breast cancer. Furthermore, the ALA-CuS NPs were effective for the photoacoustic image-guided delivery when evaluated in a preclinical 4T1 syngeneic breast tumor model. The fluorescence biodistribution profile revealed that these nanoprobes were preferentially accumulated in the tumor, liver, and kidneys and revealed negligible toxic effects. However, following the NIR irradiation, the ALA-CuS NPs treated tumors were effectively ablated without obvious tumor recurrence within 21 days. Moreover, they reduced hypoxia, promoting tumor regression when combined with NIR light. Overall, the proposed ALA-CuS NPs could be a promising translational formulation for targeting drug resistance and aiding in synergizing multimodal theranostics-based breast cancer therapy.
Insights
This study introduces novel copper sulfide-5-aminolevulinic acid nanoprobes (ALA-CuS NPs) that overcome breast cancer drug resistance. These nanoprobes effectively target tumors, reduce resistance, and enable image-guided therapy with minimal toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Breast cancer treatment faces challenges due to drug resistance, often caused by efflux pump overexpression.
- Modulating drug transporters like ABCG2 and HCP1 presents a therapeutic strategy to enhance anticancer treatments.
Purpose of the Study:
- To develop and evaluate novel CuS-ALA metal-organic nanoprobes (ALA-CuS NPs) for targeted breast cancer therapy.
- To investigate the efficacy of ALA-CuS NPs in overcoming drug resistance and enabling multimodal theranostics.
Main Methods:
- Synthesized ALA-CuS nanoprobes combining 5-aminolevulinic acid (5-ALA) and copper sulfide (CuS) nanoparticles.
- Evaluated NIR absorption, photothermal profile, photoacoustic and fluorescence imaging properties.
- Assessed in vitro cytotoxicity and drug transporter modulation (ABCG2, HCP1) in breast cancer cell lines.
- Conducted in vivo studies using a 4T1 syngeneic breast tumor model for image-guided delivery, biodistribution, and therapeutic efficacy.
Main Results:
- ALA-CuS NPs demonstrated excellent NIR absorption, photothermal effects, and imaging capabilities.
- In vitro studies showed synergistic cytotoxicity and modulation of ABCG2/HCP1 transporters upon NIR irradiation.
- In vivo studies confirmed image-guided tumor ablation, preferential tumor accumulation, and reduced hypoxia.
- Treated tumors showed significant regression and negligible recurrence within 21 days post-NIR irradiation with minimal toxic effects.
Conclusions:
- ALA-CuS nanoprobes are a promising theranostic formulation for overcoming breast cancer drug resistance.
- This approach synergizes photodynamic and photothermal therapies for effective tumor ablation.
- The nanoprobes facilitate image-guided delivery and demonstrate a favorable safety profile.
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