Construction Of A Survivin Inhibitor Encapsulated Bionic Nanobubble With Potent Tumor Suppressing Activity Against Hepatoma Carcinoma

Hepatic carcinoma(HC)is the sixth most frequently occurring malignancies and the third leading cause of cancer death worldwide.Therefore,it is urgent to find safe and effective treatment for HC.The overexpression of survivin is a common feature of almost all types of malignant tumors.Survivin is an important member of the inhibitor of apoptosis(IAPs)family,which is required for fetal development but later became absent in terminally differentiated tissues such as adult liver,spleen,kidney,and other visceral organs.However,many studies have shown that survivin is significantly overexpressed and playing vital roles in a variety of malignancies,rending it an ideal potential target for cancer therapy.YM155 is a small molecule inhibitor of survivin,which can effectively inhibit the expression of survivin protein in a variety of malignant tumor cells.It has a broad-spectrum anticancer therapeutic effect in various xenograft models.However,the clinical application of YM155 is limited by its non-target release and short half life in blood.In recent years,the emergence of nano drug delivery system(DDS)provides a better technical means for the targeted delivery of antitumor drugs.However,clinical application of a great many DDSs is still significantly restricted because of limited tumor targeting,premature drug leakage,and nanomaterials’ prone to be engulfed by macrophages due to weak immunocompatibility,etc.To overcome these weaknesses,the biomimetic strategy with utilization of natural cell membrane camouflage technology has been widely employed in nano-drug preparations for tumor diagnosis and treatment.Inspired by the inherent immune escape and homologous adhesion characteristics of tumor cells,coating nanoparticles with homologous tumor cell membrane can improve its targeting ability and avoid the recognition and clearance of immune cells.Studies have found that the effect of simple chemotherapy-based treatment is limited.Therefore,it is urgent to explore and develop safe and efficient new combination therapy.Photothermal therapy(PTT)has become a promising cancer treatment strategy due to its non-invasiveness and small side effects.Graphene quantum dots(GQDs)with near-infrared response is considered as an emerging photothermal nanomaterial due to its favorable photothermal conversion ability,excellent optical stability and good biological safety.Herein,a SMMC-7721 cancer cell membranecloaked DDS was developed for co-encapsulation of YM155 and GQDs(named as i M7721@GQD-YM),and its application in combined chemotherapeutic/photothermal therapy was explored.Firstly,GQDs with near-infrared response were synthesized by one-step hydrothermal molecular fusion method.The results showed that GQDs contained abundant hydroxyl and amino groups,which proved that GQDs had good water solubility.The absorption spectrum of GQDs covers the visible to near-infrared region,showing good photothermal performance after near-infrared irradiation(NIR).After calculation,the photothermal conversion efficiency is as high as 52.4%.In vitro cell imaging results showed that GQDs exhibited good fluorescence properties and could be used as biological fluorescent probes.In order to prepare YM155 bionic DDS,we extracted the SMMC-7721 cell membrane,and then hybridized it with DSPE-PEG-i RGD.After that,GQDs and YM155 were co-encapsulated by liposomal extruder to construct i M7721@GQD-YM system for the treatment of homologous liver cancer.The results showed that HC cytomembrane coating endowed i M7721@GQD-YM with effective targeting ability to homologous tumors,excellent biocompatibility and immunocompatibility for in vivo application.Surface decoration of i RGD further enhanced its tumor targeting activity by i RGD-integrin recognition between biomimetic DDS and cancer cells.In addition,under near-infrared radiation,GQDs can directly kill tumors through photothermal effect,and cause cell membrane rupture,accurately releasing YM155 at tumor sites.The physicochemical properties,in and ex vivo anti-tumor efficacy and mechanisms of i M7721@GQD-YM nanobubbles were systematically investigated in this work.The experimental results clearly indicated that the versatile biomimetic DDS i M7721@GQD-YM hold great potential for the treatment of homologous hepatic carcinoma,which merits further investigation in both pre-clinical and clinical studies.