Construction And Evaluation Of Mesoporous Silica-based And Mesoporous Silica/Gold Nanorods-based Drug Delivery System For Tumor-targeted Therapy

Hollow mesoporous silica nanoparticles(HMSN),a new-style mesoporous silica-based inorganic nanoparticles,which possessed many advantages,including low density,high specific surface area,high loading capacity and strong stability,were equally suitable as carriers for use in cancer therapy.Unfortunately,some defects,such as the lackless of ligand-mediated targeting to tumor,and the rapid clearance by the Reticuloendothelial system(RES),greatly limit its drug delivery efficiency to tumor tissue in vivo.Photothermal therapy(PTT)is widely regarded as a promising technology for cancer treatment.Gold nanorods(GNRs),as an excellent PTT agent candidates,have shown high-performance photothermal conversion ability under laser irradiation,yet two major obstacle for its clinical application are the lack of selective accumulation in the tumor lesions following systemic administration and the greatly reduce of photothermal conversion efficiency caused by self-aggregating in aqueous environment.What's more,it is difficult to judge the optimal timing of laser treatment and the highest peaked accumulation of PTT agent in the targeted niduses.To address these critical issue and improve the druggability of HMSN and GNRs,by drawing on some of the latest research in multiple disciplines including Oncology,Molecular Biology,Material Science and Medical Imageology,in this research,we constructed and evaluated two new inorganic nanomaterials-based drug delivery systems(DDS).These study provide a theoretical and experimental foundation for the realization of enhanced active-targeting to tumor tissues and efficient PTT.The research contents may be conveniently divided into two categories.1.Construction and evaluation of tLyp-1 peptide modified HMSN as tumor targeting DDS:in this research,we synthesized HMSN through CSASE strategy.tHMSN nanoparticles were then obtained by covalently linked HMSN with PEG and tLyp-1.The HMSN nanoparticles were confirmed by TEM and nitrogen adsorption desorption analysis.And the tHMSN nanoparticles were confirmed by zeta potentiometric method,BCA,TGA,XPS analysis.Then,we chosed MDA-MB-231 cells and HUVEC cells as the model of tumor cells and tumor angiogenesis cell model,respectively.Several properties of tHMSN,such as targeting performance,vector toxicity,and endocytosis mechanism and cell-killing effect,were systematically studied.Through these studies,we demonstrated that tHMSN nanoparticles could significantly enhanced the cell killing effects of cargoes for its robust targeting ability to MDA-MB-231 and HUVEC cells.Therefore,we think that tHMSN is expected to be an effective active targeting carrier for drug delivery aganist breast cancer.2.Construction and evaluation of GNRs/MSN-based nanocomposite as theranostic agents:by using "seed growth method" and Stober method,gold nanorods and mesoporous silica coated gold nanorods(MSG)were de novo synthesized.TMSG nanoparticles were then obtained by covalently linked MSG with PEG and tLyp-1.The MSG nanopa rticles were confirmed by TEM,nitrogen adsorption desorption analysis and AAS.And the TMSG nanoparticles were confirmed by zeta potentiometric method,BCA,TGA,XPS analysis.Then,I-TMSG were obtained by embedded Indocyanine green as cargoes in the mesoporous of TMSG.Subsequently,several analytic technique,such as UV-visible spectrophotometry,fluorescence spectrophotometry,thermal imager,Calcein-AM/PI co-staining,Annexin V-FITC/PI double-staining,CCK-8 assay,small animal in vivo imaging,flow cytometry,confocal laser scanning microscope observation and so on,were performed to evulation the three core functions of TMSG,including PTT,near infrared(Nir)fluorescence imaging and active-targeting to tumor.And the endocytosis and PTT mechanism were also performed.Through these studies,we demonstrated that I-TMSG,as a kind of theranostic nanoparticles composed by MSG,ICG and tLyp-1 peptide,possessed several functions including effective PTT,robust active-targeting to tumor cells and molecular imaging.Therefore,we deemed that I-TMSG could be a targeting Nir fluorescence probe and PTT agent and have great potenital in the the application for the diagnosis and treatment of tumor.In conclusion,in this study,we successfully constructed and evaluated two kinds of nanostructural drug delivery carriers based on HMSNs and GNRs/MSNs nanocomposites,which could accomplish active targeting of anti-cancer agents to tumor and Nir fluorescence imaging guided PTT,respectively.These research results,as we report above,illustrated that we conducted many theoretical explorations on the enhancement of MSNs-based tumor-targeted DDS and the safety,effectiveness and controllability of PTT.Meanwhile,it also illustrated that we accumulated some useful experience on the original design of active-targeting DDS and theranostic nanosystem.