Degradation Of Mutant P53 Proteins By Engineered Nanomaterials In Tumor Therapy

Cancer is a serious disease that affects human life and health.As a common tumor suppressor gene,p53 plays an important role in preventing cancer.However,over 50% of human tumors harbor p53 mutations,leading to cellular accumulation of highly stabilized mutant p53(mutp53)proteins,which not only lose the ability to act as a tumor suppressor gene,but also promote tumors development due to gain-of-function(GOF).The high level of mutp53 in tumors is a huge problem for cancer therapy,and depletion of mutp53,through inducing either autophagic or proteasomal degradation,is an effective strategy for the therapy of p53-mutated cancer.Although a variety of small molecule degradation inducers have been developed,no relevant drugs have been officially approved for clinical use.Nanomaterials show excellent prospects for disease diagnosis and treatment because of their unique physical and chemical properties.Therefore,we developed two engineered nanomaterials to degrade mutp53 by regulating ubiquitin proteasome pathway and autophagy lysosomal pathway for p53-mutant tumors treatment.This paper is mainly divided into the following two parts:(1)Based on the regulation of the mutp53 homeostasis by zinc ions and responsive release of zinc ion by ZIF-8,we developed ZIF-8 nanomaterial for degrading mutp53 in tumor cells through ubiquitin-proteasome pathway.First,we demonstrated that ZIF-8 decomposed and released zinc ions in acidic endosomes,decreased the intracellular reduced glutathione(GSH):oxidized glutathione(GSSG)ratio,promoted glutathionylation and ubiquitination of mutp53,and then degraded by proteasome pathway.Subsequently,we modified ZIF-8 with an Z1-RGD peptide,exhibiting enhanced cellular internalization and improved decomposition behavior,and demonstrated remarkable therapeutic efficacy in a ES-2 ovarian cancer model as well as in a patient-derived xenograft(PDX)breast cancer model.(2)Based on the principle of selective autophagy,we developed a biomimetic "nano receptors"(NRs)system that simulates key receptor proteins of selective autophagy.It is composed of biodegradable maleimide polyethylene glycol acid(MAL-PEG-PLA)and cationic lipid DOTAP that induces autophagy to form nanoparticles,and modify mutp53-targeted binding peptide(MBP)on its surface.Subsequently,we proved that NRs can bind mutp53 with high affinity and induce the formation of autophagosome,therefore lead to ubiquitination and degradation of mutp53 via autophagy-lysosomal pathway.At the same time,we confirmed the degradation of mutp53 by the NRs abrogated mutp53-conferred gain-of-function(GOF)phenotypes and enhanced sensitivity to cisplatin.Last,we demonstrated that NRs/Pt,consisting of Pt(IV)prodrug encapsulated in the NRs,showed outstanding synergistic antitumor effects in a ES-2 ovarian cancer model as well as in a patient-derived xenograft(PDX)ovarian cancer model.In conclusion,this paper shows that intervening intracellular degradation pathway by nanotechnology to regulate the homeostasis of mutp53 is an effective strategy for the treatment of p53 mutant tumors,which provides a new idea for the precise treatment of tumors.