Application Of Self-assembled Selenopeptides In The Treatment Of Atherosclerosis

Cardiovascular diseases（CVDs）are the leading cause of death in the world,and their pathogenesis is closely related to atherosclerosis（AS）.At present,due to the complex pathological and evolutionary mechanism of AS,it is difficult to reverse the development of plaque by drugs.Antioxidant therapy can reduce oxidative stress by reducing the level of reactive oxygen species（ROS）in plaques,which is an effective way to treat AS.Nowdays,nanotechnology combined with drug delivery strategy has extended circulation time,improved bioavailability and reduced toxicity,showing great application prospects in the medical field.However,the application of traditional nanomedicine carriers is still limited due to the lack of targeting.Therefore,the development of targeted and functional nanodrug carriers to achieve precise treatment of diseases is currently an effective means to improve the therapeutic effect.In this study,a selenopeptide self-assembly drug-loading nanodrug（Se P-Nps）with active targeting and ROS responsiveness is developped.Selenopeptide nanocarriers（Se P）have hydrophobic alkyl chains and hydrophilic heads,which self-assemble into nanomicelles in water depending on hydrophilic interaction,and their hydrophobic cores can encapsulate lipid-soluble drugs.Se P-Nps targets the endothelial vascular cell adhesion molecule（VCAM-1）by the peptide（VHPKQHR）.And Se P-Nps accurately delivers simvastatin to the inflammatory plaque,where it is absorbed and accumulated by endothelial cells to achieve enrichment in the lesion.At the same time,under the stimulation of high ROS level at the lesion,Se P-NPs can produce ROS response,reduce ROS level at the lesion,release statins,and achieve accurate and efficient treatment of AS.Herein,the Se P with antioxidant activity has been synthesized.Then,the critical micelle concentration（CMC）and antioxidant capacity of Se P have been tested with CMC of 5.57μM.In the presence of H₂O₂,80%of Sep has been oxidized within 3 h,and the scavenging rate of H₂O₂ could reach 100%.Furthermore,Sep-Nps based on Se P have been prepared and their drug loading performance,ROS response ability,drug stability and drug release curve have been measured.Its inclusion rate could reach 17%,and it could stably exist in PBS within 12 h.Under the stimulation of 100μM H₂O₂,Se P showed sensitive H₂O₂ response staphylastic bond and could release 80%simvastatin within 3 h,showing sensitive drug release ability.Then,the targeting and antioxidant capacity of Se P-Nps on inflammatory endothelial cells were investigated at the cellular level.Se P-Nps could be effectively phagocytosed by endothelial cells by laser confocal detection.The ROS scavenging and antiapoptotic ability of Se P-Nps were verified by flow cytometry.And the therapeutic effect of peptide nanomedicine on AS was evaluated in vivo.Se P-Nps showed prolonged pharmacokinetic performance,good aortic plaque enrichment ability and anti-AS restenosis in periodic treatment of AS model mice.In addition,Se P-Nps has no obvious toxic and side effects in vivo and in vitro experiments,showing good biosafety.To sum up,Se P-Nps with active targeting and ROS response has been designed and prepared in this study,which provides a new idea for the treatment of AS and further promotes the development of therapeutic means for cardiovascular and cerebrovascular diseases.