Optimized Carbohydrate-Based Nanogel Formulation to Sensitize Hypoxic Tumors

Abstract

Solid tumors are often poorly vascularized, which impairs oxygen supply and drug delivery to the cells. This often leads to genetic and translational adaptations that promote tumor progression, invasion, metastasis, and resistance to conventional chemo-/radiotherapy and immunotherapy. A hypoxia-directed nanosensitizer formulation of a hypoxia-activated prodrug (HAP) was developed by encapsulating iodoazomycin arabinofuranoside (IAZA), a 2-nitroimidazole nucleoside-based HAP, in a functionally modified carbohydrate-based nanogel, facilitating delivery and accrual selectively in the hypoxic head and neck and prostate cancer cells. Although IAZA has been reported as a clinically validated hypoxia diagnostic agent, recent studies have pointed to its promising hypoxia-selective anti-tumor properties, which make IAZA an excellent candidate for further exploration as a multimodal theranostic of hypoxic tumors. The nanogels are composed of a galactose-based shell with an inner core of thermoresponsive (di­(ethylene glycol) methyl ethyl methacrylate) (DEGMA). Optimization of the nanogels led to high IAZA-loading capacity (≅80–88%) and a slow time-controlled release over 50 h. Furthermore, nanoIAZA (encapsulated IAZA) displayed superior in vitro hypoxia-selective cytotoxicity and radiosensitization in comparison to free IAZA in the head and neck (FaDu) and prostate (PC3) cancer cell lines. The acute systemic toxicity profile of the nanogel (NG1) was studied in immunocompromised mice, indicating no signs of toxicity. Additionally, growth inhibition of subcutaneous FaDu xenograft tumors was observed with nanoIAZA, demonstrating that this nanoformulation offers a significant improvement in tumor regression and overall survival compared to the control.

Tumor Microenvironment Responsive RNA Drug Delivery Systems: Intelligent Platforms for Sophisticated Release

“…To inhibit the expression of the CDC20 gene, siRNA was encapsulated in nanoparticles (HRNP) consisting of self-assembled 2-nitroimidazole (NI)-modified peptides and cationic lipid compounds. Since NI can be reduced to 2-aminoimidazole (AI) under tumor cell hypoxia, it subsequently leads to the decomposition of HRNP and the rapid release of cargo (Figure A) . It was subsequently demonstrated that silencing CDC20 had an effect on the proliferation of tumor cells, and the results showed that HRNP/siCDC20 significantly inhibited cell proliferation compared with that of the untreated group and the free genome (Figure B).…”

Galactose: A Versatile Vector Unveiling the Potentials in Drug Delivery, Diagnostics, and Theranostics

“…The optimization of nanogels mentioned above was conducted by Diaz-Dussan in a recently published paper [ 58 ]. The study focuses on the development of a hypoxia-directed nanosensitizer formulation for the treatment of solid tumors.…”

Highly Stretchable, Self-Healing, Injectable and pH Responsive Hydrogel from Multiple Hydrogen Bonding and Boron-Carbohydrate Interactions

“…These glycopolymers are known for their ease of preparation and low cytotoxicity. These glycopolymers were found to be promising in drug/gene delivery, surface coatings, hydrogels and tissue engineering [ 28 , 32 , 52 , 53 , 54 , 55 ]. A hydrophilic polymer with sugar moieties was designed and prepared as the hydrogel precursor.…”