Ultrasound-triggered doxorubicin targeted delivery for liver cancer treatment: Reduced toxicity and improved efficacy
Remya Radha, Shabana Anjum, Rand Hasan Abusamra, Vinod Paul, William G. Pitt, Ghaleb A. Husseini, Mohammad H. Al-Sayah
Abstract
Liver cancer, especially hepatocellular carcinoma (HCC), remains a major global health challenge, causing high mortality worldwide. Conventional chemotherapy often results in severe side effects due to its systemic distribution, which limits its effectiveness in targeting cancer cells specifically. The development of targeted drug delivery systems can enhance the precision and efficacy of chemotherapeutic agents while reducing their side effects.
Introduction
Liver cancer continues to be a significant global public health challenge, with Hepatitis B (HBV) and Hepatitis C (HCV) infections being the primary risk factors [1]. Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, accounted for around 830,180 deaths worldwide in 2020, making it the fourth leading cause of cancer-related mortality globally [2]. This trend is projected to worsen, with disease and deaths from liver cancer expected to increase by over 55% by 2040, driven by factors such as chronic hepatitis infections (hepatitis B and C), excessive alcohol consumption, and rising rates of obesity, metabolic disorders and fatty liver disease [2,3].
Materials and methods
2.1. Chemicals/materials
Lactobionic acid, cholesterol (≥99%), Sephadex® G-25, chloroform, HEPES sodium salt, ammonium ferrothiocyanate, phosphate-buffered saline (PBS) and 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) were purchased from Sigma-Aldrich (St. Louis, MO, USA) and supplied by Labco LLC (Dubai, UAE).
Results
The combination of drug delivery systems with the use of external physical triggers, such as ultrasound, holds great promise for enhancing the specificity and therapeutic efficacy of chemotherapy. In this study, we focus on the design of LA-conjugated liposomes (LL) for the targeted delivery of DOX to HCC cells, a major form of liver cancer, in combination with ultrasound to mediate controlled and targeted drug release.
Discussion
Chemotherapy is essential in cancer treatment, but its side effects, such as cardiac toxicity, adversely affect patient quality of life and challenge healthcare systems [24,54]. Current drug delivery methods often fail to target cancer cells efficiently, worsening these challenges and widening healthcare disparities. This study presents a novel therapeutic approach that integrates ligand-targeted liposomal drug delivery with external ultrasound stimulation to enhance chemotherapeutic efficacy in HCC.
Acknowledgments
The authors acknowledge the technical support of the Chemical and Biological Engineering Department, Office of Research, Department of Biology, Chemistry and Environmental Sciences at the American University of Sharjah, UAE. We acknowledge Mr. Manju Nidagodu Jayakumar, Research Institute for Medical and Health Sciences, University of Sharjah, for his assistance with the flow cytometry analyses for the apoptosis assay and support for phase contrast microscopy.
Citation: Radha R, Anjum S, Abusamra RH, Paul V, Pitt WG, Husseini GA, et al. (2026) Ultrasound-triggered doxorubicin targeted delivery for liver cancer treatment: Reduced toxicity and improved efficacy. PLoS One 21(3): e0345161. https://doi.org/10.1371/journal.pone.0345161
Editor: Lei Zhang, University of Waterloo, CANADA
Received: August 19, 2025; Accepted: March 3, 2026; Published: March 24, 2026
Copyright: © 2026 Radha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This study was financially supported by the American University of Sharjah (https://www.aus.edu) in the form of grants received by GAH (FRG20-L-E48 and FRG22-C-E08), MHA (FRG24-C-S08), and the OAP program award received by GAH.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0345161#ack
