Drug-Based Reversal of Drug Resistance in Hepatocellular Carcinoma (HCC) Using TPGS
Abstract
Hepatocellular carcinoma (HCC) is a cancer with high incidence and mortality rates worldwide. In the various treatment methods for HCC, the lack of cancer cell specificity and the development of multidrug resistance (MDR) are two major obstacles in the treatment of HCC. P-glycoprotein (P-gp) is an ATP-dependent drug efflux pump that can reduce the accumulation of drugs in cells and make cancer cells acquire drug resistance. D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or TPGS) can inhibit the activity of ATP-dependent P-gp and serves as an effective excipient for overcoming tumor multidrug resistance (MDR). TPGS has been approved by the FDA as a safe adjuvant and is widely used in drug delivery systems. The biological and physicochemical properties of TPGS provide multiple advantages for its application in drug delivery, such as high biocompatibility, enhanced drug solubility, improved drug permeation, and selective antitumor activity. In recent years, more and more studies have found that using TPGS-modified nanomaterials to load chemotherapy drugs to treat tumors can effectively reverse the drug resistance of tumors, including HCC. This review summarizes and discusses the role of TPGS in reversing tumor drug resistance and the therapeutic effects of TPGS-based drugs on drug-resistant HCC.
Introduction
With an annual incidence rate exceeding 660,000 cases, hepatocellular carcinoma (HCC) is the fifth most common malignant tumor worldwide and the third leading cause of cancer-related deaths [1]. Over 80% of HCC patients are diagnosed at an advanced stage, where treatment options such as local ablation, surgical resection, or liver transplantation have poor outcomes [2]. Chemotherapy is an important cancer treatment strategy; however, liver cancer cells typically exhibit a poor response to systemic chemotherapy drugs [3].
Studies have shown that the low sensitivity of HCC patients to chemotherapy may be mediated by multidrug resistance (MDR), a phenomenon where cancer cells develop resistance to anticancer drugs [4] [5]. Numerous cellular and molecular changes may contribute to the development of the MDR phenotype, one of the most well-known mechanisms being the efflux pump based on the function of the ABC transporter protein P-gp, a 170-kDa plasma membrane glycoprotein encoded by the human MDR1 gene [6] [7]. Known to use ATP as an energy source, P-gp can promote the extrusion of a variety of cytotoxic drugs, including anthracyclines, vinca alkaloids, epipodophyllotoxins, and taxanes [8]. P-gp is overexpressed in many chemotherapy-resistant tumors, such as liver cancer, colorectal cancer, renal cancer, pancreatic cancer, and adrenal cancer, and is upregulated after disease progression following chemotherapy in many other cancers [7]. Moreover, HCC patients with high levels of P-gp protein detectable in tumor sections have shorter disease-free intervals and survival times [9] [10]. Therefore, the study of P-gp inhibitors is essential for improving the outcomes of chemotherapy in HCC.
TPGS1000 is the most commonly used form of TPGS in nanomedical applications. D-α-tocopheryl polyethylene glycol 1000 succinate (briefly referred to as TPGS or Vitamin E TPGS) is a water-soluble derivative of natural Vitamin E (VE), formed by the esterification of Vitamin E succinate with polyethylene glycol 1000. When the molecular weight (Mw) of PEG is 1000, the product is denoted as TPGS1000, or simply TPGS. If the Mw of PEG varies, the name should reflect the Mw, such as TPGS450 (Mw = 450) and TPGS2K (Mw = 2000). Variations in PEG are also associated with physicochemical/biological properties, including the critical micelle concentration (CMC), hydrophilic-lipophilic balance (HLB) value, P-gp inhibitory activity, and even circulation time after intravenous administration.
TPGS is a quintessential multifunctional material that has gained increasing attention in nanomedical applications in recent years. Benefits of TPGS explored in nanomedical science include: 1) Safety. TPGS is an excipient approved by the FDA and CFDA for medicinal use, with an oral LD50 in adult rats of over 7 g/kg. 2) Universality. As a non-ionic surfactant, TPGS can be applied to a variety of different drug delivery systems (DDSs), such as micelles, liposomes, and nanoparticles (NPs). 3) P-gp inhibitory effect. While many non-ionic surfactants (e.g. Pluronic and Tween) can inhibit P-gp activity, TPGS is reportedly one of the most effective. Due to its special properties, TPGS can be used as an oral absorption enhancer and a drug to overcome tumor multidrug resistance (MDR). 4) Tumor cell toxicity. Studies have shown that TPGS exhibits cytotoxicity to tumor cells, potentially due to the production of reactive oxygen species (ROS) and mitochondria-related apoptosis [11]-[13].
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Following excipients are mentioned in the study besides other: Vitamin E TPGS
Xue, F. and Lu, L. (2024) Drug-Based Reversal of Drug Resistance in Hepatocellular Carcinoma (HCC) Using TPGS. Journal of Biosciences and Medicines, 12, 161-172. doi: 10.4236/jbm.2024.129016.
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