Iridium Complex-Loaded Sorafenib Nanocomposites for Synergistic Chemo-photodynamic Therapy of Hepatocellular
Weinire Abuduwaili1,2, Xiang Wang3, An-Tian Huang1,2
1Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai 200032, China.
Abstract:
Although sorafenib, a multi-kinase inhibitor, has provided noteworthy benefits in patients with hepatocellular carcinoma (HCC), the inevitable side effects, narrow therapeutic window, and low bioavailability seriously affect its clinical application. To be clinically distinctive, innovative drugs must meet the needs of reaching tumor tissues and cause limited side effects to normal organs and tissues. Recently, photodynamic therapy, utilizing a combination of a photosensitizer and light irradiation, was selectively accumulated at the tumor site and taken up effectively via inducing apoptosis or necrosis of cancer cells. In this study, a nano-chemo-phototherapy drug was fabricated to compose an iridium-based photosensitizer combined with sorafenib (IPS) via a self-assembly process. Compared to the free iridium photosensitizer or sorafenib, the IPS exhibited significantly improved therapeutic efficacy against tumor cells because of the increased cellular uptake and the subsequent simultaneous release of sorafenib and generation of reactive oxygen species production upon 532 nm laser irradiation. To evaluate the effect of synergistic treatment, cytotoxicity detection, live/dead staining, cell proliferative and apoptotic assay, and Western blot were performed. The IPS exhibited sufficient biocompatibility by hemolysis and serum biochemical tests. Also, the results suggested that IPS significantly inhibited HCC cell proliferation and promoted cell apoptosis. More importantly, marked anti-tumor growth effects via inhibiting cell proliferation and promoting tumor cell death were observed in an orthotopic xenograft HCC model. Therefore, our newly proposed nanotheranostic agent for combined chemotherapeutic and photodynamic therapy notably improves the therapeutic effect of sorafenib and has the potential to be a new alternative option for HCC treatment.
Insights
This study developed a novel nano-chemo-phototherapy drug combining an iridium photosensitizer with sorafenib for hepatocellular carcinoma (HCC). This new treatment significantly improved therapeutic efficacy and reduced tumor growth in preclinical models.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Oncology
Background:
- Sorafenib, a multi-kinase inhibitor, offers benefits for hepatocellular carcinoma (HCC) but has limitations including side effects and low bioavailability.
- Photodynamic therapy (PDT) offers targeted cancer cell destruction via photosensitizers and light, inducing apoptosis or necrosis.
- Developing innovative therapies with improved tumor targeting and reduced systemic toxicity is crucial for effective HCC treatment.
Purpose of the Study:
- To fabricate and evaluate a novel nano-chemo-phototherapy agent for HCC treatment.
- To combine an iridium-based photosensitizer with sorafenib (IPS) using a self-assembly process.
- To assess the synergistic therapeutic efficacy and biocompatibility of the developed nanotheranostic agent.
Main Methods:
- Fabrication of an iridium-based photosensitizer combined with sorafenib (IPS) via self-assembly.
- In vitro evaluation including cytotoxicity, live/dead staining, proliferation, and apoptosis assays.
- In vivo assessment using an orthotopic xenograft HCC model and biocompatibility tests (hemolysis, serum biochemical tests).
Main Results:
- The IPS formulation demonstrated significantly enhanced cellular uptake and therapeutic efficacy compared to free sorafenib or photosensitizer.
- Upon laser irradiation, IPS induced simultaneous sorafenib release and reactive oxygen species (ROS) generation, leading to inhibited HCC cell proliferation and promoted apoptosis.
- In vivo studies showed marked anti-tumor effects, with significant inhibition of tumor growth and promotion of cancer cell death, alongside good biocompatibility.
Conclusions:
- The developed nanotheranostic agent (IPS) offers improved therapeutic efficacy for HCC by combining chemotherapy and photodynamic therapy.
- This novel approach enhances sorafenib's therapeutic effect and presents a potential new treatment option for hepatocellular carcinoma.
- The findings highlight the potential of synergistic nano-chemo-phototherapy in advancing cancer treatment strategies.
