Cisplatin-activated and hemoglobin-mediated injectable hydrogel system for antitumor chemodynamic and chemotherapy

• Published in: Biomedicine & pharmacotherapy Vol. 175; p. 116713
• Main Authors: Tsen, Hsun-Tzu, Sun, Tzu-Chieh, Lai, To-Kai, Huang, Wei-Yuan, Wang, Huan-Chih, Lu, Tsai-Te, Wang, Tzu-Wei
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.06.2024; Elsevier
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Chemodynamic therapy; Chemotherapy; Cisplatin - administration & dosage; Cisplatin - pharmacology; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Hemoglobin; Hemoglobins - metabolism; Hemoglobins - pharmacology; Humans; Hydrogels - chemistry; Hydrogen Peroxide - metabolism; Injectable hydrogel; Injections; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles - chemistry; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry; Reactive oxygen species; Reactive Oxygen Species - metabolism; Xenograft Model Antitumor Assays; Hemoglobin; Reactive oxygen species; Chemotherapy; Chemodynamic therapy; Injectable hydrogel; Glioblastoma
• DOI: 10.1016/j.biopha.2024.116713
• ISSN: 0753-3322; 1950-6007

Low specificity and hypoxia-induced drug resistance are significant challenges in traditional cancer treatment. To enhance the anticancer efficacy, an injectable hydrogel system is developed through the formation of dynamic covalent bonds in hyaluronic acid, allowing for localized controlled release of drugs. This system also utilizes double-stranded DNA sequences for the intercalation delivery of the chemotherapeutic drug, enabling a multifaceted approach to therapy. Cisplatin not only serves as a chemotherapy drug but also acts as a catalyst for chemodynamic therapy (CDT) to initiate CDT cascades by creating hydrogen peroxide for the Fenton reaction. Hemoglobin, enclosed in PLGA nanoparticles, provides ferrous ions that react with hydrogen peroxide in an acidic environment, yielding hydroxyl radicals that induce cancer cell death. Additionally, oxygen released from hemoglobin mitigates hypoxia-induced chemoresistance, bolstering overall anticancer efficacy. Results demonstrate the shear-thinning properties and injectability of the hydrogel. Cisplatin elevates intracellular hydrogen peroxide levels in tumor cells, while hemoglobin efficiently releases ferrous ions and generates reactive oxygen species (ROS) in the presence of hydrogen peroxide. In in vitro and in vivo study, the combinational use of chemo- and chemodynamic therapies achieves a synergistic anticancer effect on combating glioblastoma. In summary, our CDT-based hydrogel, activated by endogenous cues and mediated by chemo drugs, spontaneously produces ROS and ameliorates the adverse tumor microenvironment with rational and selective antitumor strategies. [Display omitted] •Cisplatin-activated chemodynamic cascades and hemoglobin-mediated Fenton reaction work synergistically and logically for antitumor effect.•Bioinspired hemoglobins serve as CDT agent for the Fenton reaction and deliver oxygen to reverse hypoxic microenvironment.•Cisplatin-based CDT is depth-independent treatment using endogenous stimuli to generate free radicals in site-specific manner.•This hydrogel system responds to the physiochemical-based surrounding changes with high-level control and precision.