Liver cancer is a prevalent health issue globally, with more than a million cases predicted by 2025. The primary type of liver cancer is hepatocellular carcinoma (HCC). The most common risk factors are hepatitis B and C viruses and non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes [1]. Conventional treatments for liver cancer include chemotherapy, radiotherapy, surgery, transplantation, chemoembolization, and targeted therapy. Although these approaches can increase survival rates, they are expensive, have side effects, and may be ineffective due to drug resistance, metastasis, recurrence, genetic variability, and cancer heterogeneity [2]. Doxorubicin chemotherapy, the conventional treatment for HCC, is restricted by the emergence of tumor resistance. Doxorubicin primarily functions by inducing double-stranded DNA breaks through topoisomerase, resulting in DNA damage that leads to cell cycle arrest and the activation of apoptosis pathways. In other words, Dox damages the DNA of cancer cells, causing them to stop growing and eventually die [3]. New therapies, such as drug delivery systems with lower toxicity and greater efficacy, are being developed to overcome these limitations. These offer benefits by addressing or reducing the drawbacks observed in conventional therapy, enhancing transport to cellular levels, optimize the concentration and release kinetics of drugs in circulating or other biological fluids, alter the pharmacokinetic and pharmacodynamic properties of drugs, and providing effective and safe treatment with varying chemotherapy drug doses [2,4]. Magnetic nanoparticles are widely used for diagnostics, drug delivery, and hyperthermia and can be synthesized using Fe ions, which cells can reuse via normal biochemical pathways. In addition, MNP has low toxicity, excellent magnetic properties, biodegradability, and biocompatibility that can be achieved by adjusting their size and shape [5].

Besides using physical and passive methods to target tumors, nanoparticles can be combined with targeting ligands that attach to receptors in high numbers of tumor cells. This approach can help deliver drugs more selectively and efficiently to the tumor cells, thereby potentially overcoming drug resistance in these cells. Drug resistance can occur when the tumor cells remove the drug from within using multidrug-resistant mechanisms [6]. For this reason, the asialoglycoprotein receptor (ASGPR) is known to be highly expressed in liver cancer. ASGPRs mediate extracellular glycoproteins’ binding, internalization, and degradation with exposed terminal galactose, lactose, or N-acetyl-galactosamine residues [7]. Arabinogalactan is a highly branched natural polysaccharide from the Larix tree. It can be used in drug delivery systems due to its high water solubility, biocompatibility, and biodegradable properties [8]. In the project, it is planned that arabinogalactan will serve multifunctionally as a targeting molecule within the particulate system structure and as a targeting molecule for ASGPR.

The objective of this research was to develop magnetic nanoparticles to deliver drugs for the treatment of hepatocellular carcinoma, with improved targeting capabilities through arabinogalactan and enhanced cytotoxicity by adsorbing Dox. Dox onto arabinogalactan-conjugated magnetic nanoparticles (DANPs) were synthesized using the co-precipitation method. Arabinogalactan (AG) was employed for targeted delivery; moreover, 2-aminoethyl phosphonic acids (APA) served as linkers to anchor the nanoparticles on the MNP surface. The study is encompassed comprehensive characterization, investigations into drug release profiles, and an assessment of stability. In the reviewed literature, studies employing arabinogalactan as a ligand for hepatocellular carcinoma treatment have shown a preference for lipid-based or organic-based nanoparticles[[9], [10], [11], [12], [13]]. Our research, on the other hand, concentrated on producing iron oxide nanoparticles, mainly used as contrast agents for imaging systems or hyperthermia treatment [[14], [15], [16], [17], [18]]. Considering the literature research conducted, our study has introduced a pioneering approach by developing a magnetically responsive and ASGPR receptor-selective drug delivery system to enhance the efficacy of doxorubicin for treating hepatocellular carcinoma. For this reason, a patent application has been filed for this research (application number: 2024/001489)