Butyrate Modification Promotes Intestinal Absorption and Hepatic Cancer Cells Targeting of Ferroptosis Inducer Loaded Nanoparticle for Enhanced Hepatocellular Carcinoma Therapy

Abstract

Sorafenib is an oral‐administered first‐line drug for hepatocellular carcinoma (HCC) treatment. However, the therapeutic efficacy of sorafenib is relatively low. Here, an oral delivery platform that increases sorafenib uptake by HCC and induces potent ferroptosis is designed. This platform is butyrate‐modified nanoparticles separately encapsulated with sorafenib and salinomycin. The multifunctional ligand butyrate interacts with monocarboxylate transporter 1 (MCT‐1) to facilitate transcytosis. Specifically, MCT‐1 is differentially expressed on the apical and basolateral sides of the intestine, highly expressed on the surface of HCC cells but lowly expressed on normal hepatocytes. After oral administration, this platform is revealed to boost transepithelial transport effectively and continuously in the intestine, drug accumulation in the liver, and HCC cell uptake. Following drug release in cancer cells, sorafenib depletes glutathione peroxidase 4 and glutathione, consequently initiating ferroptosis. Meanwhile, salinomycin enhances intracellular iron and lipid peroxidation, thereby accelerating ferroptosis. In vivo experiments performed on the orthotopic HCC model demonstrate that this combination strategy induces pronounced ferroptosis damage and ignites a robust systemic immune response, leading to the effective elimination of tumors and establishment of systemic immune memory. This work provides a proof‐of‐concept demonstration that an oral delivery strategy for ferroptosis inducers may be beneficial for HCC treatment.

Drug delivery system for the extended-release of larotrectinib based on a biocompatible Fe-based metal-organic framework: synthesis, characterization, in vitro release properties and antitumor evaluation

“…Meanwhile, the number of drug administrations is reduced and the toxic side effects of the drug are reduced ( Lazar et al, 2023 ; Shen et al, 2023 ). Therefore, using Fe-MOF carriers to protect drugs from gastric acid inactivation and to achieve uniform high-concentration drug distribution in various segments of the gastrointestinal tract by prolonged retention and slow release of the anticancer drug Lar through the gastrointestinal tract not only increases patient compliance and improves treatment efficacy, but also reduces the total amount of drug required ( Fukumori et al, 2023 ; Yu et al, 2023 ).…”

HGFK1 Enhances the Anti-Tumor Effects of Angiogenesis Inhibitors via Inhibition of CD90+ CSCs in Hepatocellular Carcinoma

“…PH1 Polymeric Nanoparticle-Mediated pORF-HGFK1, pORF-Endo, and Combined pORF-HGFK1+pORF-Endo Gene Therapies for the Treatment of HCC Based on the development of effective liver-and tumor-targeting gene delivery polymeric nanoparticle systems, we studied the efficacy of two anti-angiogenesis genes, Endostatin and HGFK1, on the treatment of the orthotopic HCC-bearing mice. Orthotopic HCC-bearing mice were established by injecting mouse HCC ML-1 cells into BALB/c mice, as described previously [19]. The mice were divided into four groups and treated via the i.p.…”

Green Synthesis of Gold Nanoparticles from Polygahatous Polysaccharides and Their Anticancer Effect on Hepatic Carcinoma through Immunoregulation

“…In recent years, an increasing number of nanomaterials have been studied for the treatment of hepatic carcinoma, and these materials can deliver small molecular substances such as chemotherapeutics, polysaccharides, and therapeutic agents; increase dispersion, solubility, and stability; and change pharmacokinetics. − Uptake of the anticancer cargo inside the cells remains a major challenge in the application of nanomaterials; membrane potential and receptor-mediated uptake of nanoparticles are important factors, and receptor-mediated approach has been confirmed as a useful method to increase the uptake of nanomaterial drugs inside hepatic cancer cells. , Gold nanoparticles (AuNPs) are the most widely studied type of nanoparticle, and they can be easily combined with drugs and increase the stability of drugs due to their optical, plasmon resonance, and biological conjugation properties . AuNPs possess advantages, including low toxicity, slowing drug degradation, and reducing the dosage and toxicity of drugs used .…”