Design And Evaluation Of Nanodrugs For Simultaneous Chemoradiotherapy With Enhanced Endogenous Hypoxia

Cancer is the second leading cause of human death,and its treatment has been widely studied.In recent years,with the rapid development of radiotherapy technology,a variety of new radiotherapy techniques have gradually been used in clinical practice.However,dose limiting toxicity has always been the main limiting factor of radiotherapy efficacy,and the existence of anoxic heterogeneous microenvironment in solid tumors has obvious resistance to radiotherapy.In order to overcome radiotherapy dose limitation toxicity and radiotherapy resistance in hypoxic microenvironment,the use of radiotherapy sensitizers has become an important trend.Metronidazole（MN）,as a widely studied radiosensitizer for hypoxic tumor,is also a good hypoxic sensitive material.However,the lack of bioavailability and the existence of adverse reactions limit its clinical application.Tirapazamine（TPZ）,as a hypoxic-activated prodrug,can be reduced to produce free radicals to kill tumor cells under hypoxia conditions,possessing potential hypoxic sensitization ability.However,oxygen-depleted tumor areas are often far away from blood vessels,which makes it difficult for oxygen-depleted drugs to activate effectively in tumors,severely limiting their application effect.In order to overcome the restriction effect of hypoxic heterogeneity of solid tumors on concurrent chemoradiotherapy,the modification of hypoxic tumor microenvironment becomes a potential means.Focusing on this goal,based on the properties of NQO1 efficient substrate that consumes oxygen and produces reactive oxygen species under the action of overexpressed NQO1 in tumor tissues,this paper proposes to construct endogenousoxygen-deficientsynchronouschemoradiotherapy nanotherapeutic drugs with self-enhancement ability.Nano drugs are easy to accumulate near tumor blood vessels,and targeted consumption of peripheral oxygen of tumor tissue can achieve the purpose of enhancing the overall hypoxic level of tumor,so that hypoxic activating drugs can be activated efficiently without deep penetration to sensitize hypoxic concurrent chemoradiotherapy.Around this goal,this paper has achieved the following research results:（1）The amphiphilic macromolecular polymer PEG_5K-PMNZ was successfully prepared by means of radiotherapy sensitizer Metronidazole（MN）and polyethylene glycol(PEG_5k).PEG-PMNZ was prepared with hydrogenated soybean phospholipids（HSPC）and cholesterol by microfluidic method.The hydrophobic drug KP372-1 and hydrophilic drug TPZ were also embedded in the vesicles.By characterizing the particle size,Hypoxic responsiveness,stability and other physicochemical properties of drug-carrying vesicles,it was found that the particle size of the vesicles was about 100 nm,which had good stability and anoxic responsiveness.（2）The oxygen-deficient responsive drug release,oxygen-deficient radiotherapy capacity of drug-carrying vesicles and their interaction with cells were evaluated through in vitro cell experiments.The authors found that drug-carrying vesicles could be quickly taken up by pancreatic cancer cells to kill cancer cells,especially under hypoxia conditions,drug-carrying vesicles showed stronger tumor killing effect.DNA damage and cell colony experiments also demonstrated the sensitization effect of the drug-carrying vesicles.（3）The study on the biological distribution of drug-carrying vesicles in vivo confirmed that the nanovesicles had good tumor targeting and tumor enrichment ability.The tumor inhibition experiment on the subcutaneous model of mouse pancreatic cancer showed that the nanodrug itself can effectively inhibit tumor growth,and combined with radiotherapy can further enhance the tumor inhibition effect in vivo,confirming that the oxygen-poor auto-enhancement strategy proposed by the author has important potential in the radiation sensitization of oxygen-poor tumors.