Study On The Preparation Of CRGD Targeted Drug-loaded Nanomicrospheres And Their Anticancer Activity In Combined Therapy

Cancer has become one of the most urgent public health problems in the 21^st century,which greatly damages the human life and health.At present,the main clinically applied therapeutic methods are chemotherapy,surgery,etc.Nevertheless,these common treatments always have unavoidable defects,such as non-specific distribution of anticancer drugs,low concentration of drugs in tumor,intolerable side effects and incomplete curative effect,etc.,contributing to the unsatisfactory level.With the improvement of science and technology recently,the rising nanotechnology has brought new light to antitumor treatment,which is dedicated to the design and development of functional nanoscale drug delivery system and presents few side effects,high biocompatibility,perfect bioavailability and some other advantages.However,it still faces many problems need to be improved as to take place with traditional therapeutic strategies in clinical and benefit patients.Based on the above content and thinking,this paper mainly designed and prepared the nanoscale drug delivery systems with targeting transport and controlled release,which can realize the combined therapy for excellent antitumor effect.The work includes the following two aspects.In this study,a novel cytotoxic molecule was synthesized,coumarin-containing all-trans retinoic acid derivative?AC?,through linking ATRA with 7-hydroxy-4-trifluoromethyl coumarin?HTCM?for the first time,which enhanced toxicity against tumor cells.Furthermore,AC and ICG were simultaneously loaded into one nanocarrier modified with cRGD peptide.AC/ICG-TNPs have a desirable particle size,uniform monodispersity and good stability,which could release AC under mild acidic condition.On the basis of the active targeting mediated by overexpressed integrin?_v?₃ on the breast cancer cells MDA-MB-231,AC/ICG-TNPs could achieve the enhanced cellular uptake.Meanwhile,the encapsulated ICG could efficiently convert the NIR light into heat and generate ROS,which possesses the potential to simultaneously complete the phototherapy and photodynamic therapy.Furthermore,the investigation in vitro showed that when the concentration of AC was 120?M,the survival rate of MDA-MB-231 was as low as 3.16%,confirming that AC/ICG-TNPs had effective antitumor activity after NIR irradiation due to chemo/photothermal/photodynamic therapy.In addition,a permeable and targeting nanosystem cRGD@TAT-NPs was constructed by self-assembly for the first time,which could co-delivery DOX and ICG.Specially,TAT,as a kind of cell-penetrating peptide,could enhanced cellular internalization of cRGD@TAT-NPs and improved accumulation of DOX.Meanwhile,ICG-mediated nanosystem exhibited explosive temperature elevation and reactive oxygen species generation under NIR irradiation.And heat could promote the release of DOX due to lecithin in the framework of nanosystem.Thus realize the dual stimulus-response of pH and near-infrared light for cRGD@TAT-NPs.In vitro experiments,when the concentration of DOX was 10?g/mL,the survival rate of MDA-MB-231 and A549 were 5.4%and4.8%,which could confirm that cRGD@TAT-DINPs had excellent combined therapeutic effects on cancer cells MDA-MB-231 and A549.