Preparation Of Nano-prodrug Carrier Based On ROS-responsive For "Sequential Induction" Synergistic Anti-tumor

According to statistics,tens of millions of people die of cancer every year.Traditional treatment methods have problems such as incomplete treatment and large side effects.In order to solve these problems,nano drug delivery systems have been used to efficiently deliver drugs.chemodynamic therapy（CDT）has a wide range of applications in cancer therapy.CDT could utilizes iron-initiated Fenton reaction to destroy tumor cells by converting endogenous H₂O₂ into highly toxic hydroxyl radical（·OH）without additional energy stimulation.Therefore,this paper designsed ROS responsive nanoparticles based on the change of the tumor microenvironment,and achieved the sequential induction process by CDT.The specific contents include:（1）The two diblock molecules mPEG-AcMH and PAsp-AcMH were designed and synthesized to form primary micelles by self-assembly and further aggregated into nanoparticles to promote drug co-delivery.The positively charged nitrogen mustard prodrug was adsorbed in the PAsp segment by electrostatic action.β-lapachone was coated in the primary micelle core by hydrophobic action.The nanoparticles enter the tumor cells by endocytosis.The weak acid environment in the lysosome breaks the acetal bond,causing the nanoparticles to disintegrate and release nitrogen mustard prodrug andβ-lapachone.Theβ-lapachone released in the tumor cells induces a large amount of H₂O₂ by NQO1,and the nitrogen mustard prodrug was activated by H₂O₂ to form activated nitrogen mustard to leads to tumor cells apoptosis.The size of the nanoparticles was around 100 nm measured by transmission electron microscopy（TEM）.Cytotoxicity experiments showed that nitrogen mustard andβ-lapachone were almost non-toxic when used alone within a certain concentration range,but had good inhibition of tumor cells when used in combination.Animal experiments further demonstrated that the nanoparticles have good anti-tumor effects.（2）The triblock molecules mPEG-PAsp-AcMH wes designed and synthesized to form multi-enzyme nanocatalyst by self-assembly.Glucose oxidase（GOD）and surface negatively charged Fe₃O₄ were adsorbed in the PAsp segment by electrostatic action.The multi-enzyme nanocatalyst enter the tumor cells by endocytosis.The weak acid environment breaks the acetal bond,causing the multi-enzyme nanocatalyst to disintegrate and release the GOD and Fe₃O₄.The GOD consumed glucose to produce a large amount of H₂O₂,and then H₂O₂ were catalyzed by the Fenton reaction of Fe₃O₄ to produce toxic·OH under the acidic condition in the tumor cells,which induces tumor cell apoptosis.This sequential induction process greatly reduces toxic side effects and damage to normal tissues.The size of the nanoparticles was around 150 nm measured by transmission electron microscopy（TEM）.Cytotoxicity experiments showed that GOD and Fe₃O₄ were almost non-toxic when used alone,but had good inhibition of tumor cells when used in combination.