Prodrug Nanosensitizer Overcomes the Radiation Resistance of Hypoxic Tumor

Abstract

Clinical radiation therapy (RT) is often hindered by the low radiation energy absorption coefficient and the hypoxic features of tumor tissues. Among the tremendous efforts devoted to overcoming the barriers to efficient RT, the application of hypoxic radiosensitizers and cell-cycle-specific chemotherapeutics has shown great potential. However, their effectiveness is often compromised by their limited bioavailability, especially in the hypoxic region, which plays a major role in radioresistance. Herein, to simultaneously improve the delivery efficacy of both hypoxic radiosensitizer and cell-cycle-specific drug, a gambogic acid (GA) metronidazole (MN) prodrug (GM) was designed and synthesized based on GA, a naturally occurring chemotherapeutic and multiple pathway inhibitor, and MN, a typical hypoxic radiosensitizer. In combination with MN-containing block copolymers, the prodrug nanosensitizer (NS) of GM was obtained. Owing to the bioreduction of MN, the as-designed prodrug could be efficiently delivered to hypoxic cells and act on mitochondria to cause the accumulation of reactive oxygen species. The strong G 2 /M phase arrest caused by the prodrug NS could further sensitize treated cells to external radiation under hypoxic conditions by increasing DNA damage and delaying DNA repair. After coadministration of the NS with a well-established tissue-penetrating peptide, efficient tumor accumulation, deep tumor penetration, and highly potent chemoradiotherapy could be achieved.

Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment

“…Nitroimidazoles, which are widely employed as tumor radiosensitizers, can not only imitate O 2 to solidify DNA damage in hypoxic conditions, but they can also undergo a hydrophobicity–hydrophilicity shift, which speeds up NPs disintegration. Yu et al fabricated a gambogic acid metronidazole NPs by coencapsulating gambogic acid (chemotherapeutic and multiple pathway inhibitor) and metronidazole (hypoxic radiosensitizer) to achieve efficient delivery to hypoxic cells and deep tumor penetration by the bioreduction of metronidazole . The prodrug NPs can significantly arrest the G2/M phase and further sensitize treated cells to external radiation, allowing for extremely effective chemoradiotherapy under hypoxic settings by increasing DNA damage and delaying DNA repair.…”

Implantable, 3D-Printed Alginate Scaffolds with Bismuth Sulfide Nanoparticles for the Treatment of Local Breast Cancer via Enhanced Radiotherapy

“…The main therapeutic effect of radiotherapy is to induce cellular damage or apoptosis through direct or indirect interactions between cancer cell internal components and high-energy ionizing radiation (IR). , Increasing the maximum dose accumulation in tumor tissues while at the same time reducing the damage to normal tissues is the main limitation of radiotherapy . Nanotechnology provides a variety of therapeutic strategies that can be used to overcome the radiation resistance of tumor tissue, enhance the radiation tolerance of normal tissues, increase the radiosensitivity of tumor tissues, limit the accumulation of radiation doses in the tumor volume, and balance side effects. , Nanomaterials, which are being intensively studied and investigated to be integrated into cancer therapy, can be used as potential candidates to achieve the main optimization of radiotherapy and enhanced radiation therapy.…”

Janus ACSP Nanoparticle for Synergistic Chemodynamic Therapy and Radiosensitization

“…Radiotherapy (RT) serves as a valid common treatment modality for postoperative or neoadjuvant cancer treatment in the clinic. − The radiotherapy efficacy is determined by the direct damage of tumor cell DNA owing to the high-energy hydrated electrons without depth limitation and indirect damage of the generated reactive oxygen species (ROS), , and is influenced by multiple factors, such as irradiation resistance and DNA damage repair capability. , The key issue in radiotherapy is the relatively high dose of X-rays, leading to side effects on peripheral normal tissues. , Hypoxic tumor cells are not sensitive to ionizing radiation. − The mild damaged DNA can be repaired through nonhomologous end joining and homologous recombination (HR) repair pathways, , protecting the tumor cells from necrosis and apoptosis.…”