Prodrug Nanosensitizer Overcomes the Radiation Resistance of Hypoxic Tumor.
Lili QianQian LiZhenshan DingKejun LuoJiamin SuJiawei ChenGuangying ZhuZhihua GanQingsong YuPublished in: ACS applied materials & interfaces (2022)
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.
Keyphrases
- cell cycle
- dna damage
- dna repair
- cancer therapy
- cell proliferation
- radiation therapy
- induced apoptosis
- pet ct
- room temperature
- randomized controlled trial
- oxidative stress
- systematic review
- dengue virus
- cell cycle arrest
- gene expression
- magnetic resonance imaging
- drug delivery
- locally advanced
- zika virus
- rectal cancer
- quality improvement
- risk assessment
- squamous cell carcinoma
- computed tomography
- signaling pathway
- anti inflammatory
- human health
- diffusion weighted imaging