Functionalized Laponite Nanodisks As A Platform For Anticancer Drug Delivery And Molecular Imaging

One of the main objectives in nanomedicine is to create innovative drug delivery systems(DDS)that is able to deliver drugs into a specific position with high efficiency.In the improvement of DDS,some primary properties are required,such as biocompatibility,drug release profile.Furthermore,an ideal DDS should be capable to deliver a drug in a controlled manner and minimize its side effects.These two objectives are still a challenge for researchers all around the world.An excellent vehicle is required in drug delivery and several other applications.Moreover of our goals is to synthesize innovative nanoparticles as contrast agents for CT or MR imaging.The main goals of this project was firstly to synthesize dendrimer-functionalized Laponite(LAP)nanodisks for loading and delivery of anticancer drug doxorubicin(DOX);secondly to synthesize a novel iodinated CT contrast agent,Diatrizoic acid(DTA)-modified onto Laponite(LAP)nanodisks pre-modified with aminopropyldimethylethoxysilane(APMES),(LM-NH2)for X-ray computed tomography(CT)imaging applications;finally synthesize dendrimer-functionalized LAP for in vitro and in vivo MR imaging of cancer cells.The main aims were to investigate the new synthesis procedure using dendrimer modified LAP as a novel platform for anticancer drug delivery.In this study,LAP nanodisks were silanized to have amine groups and then modified with succinic anhydride(SAH)to render them with abundant carboxyl groups on the surface,and finally conjugated with amine-terminated poly(amidoamine)(PAMAM)dendrimers of generation 2(G2).Anticancer drug DOX was then loaded on the LM-G2 with an impressively high drug loading efficiency of 98.4% and could be released in a p Hsensitive and sustained manner.Moreover,cell viability assay results indicate that LM-G2/DOX complexes could more effectively inhibit the proliferationof KB cells(a human epithelial carcinoma cell line)than free DOX at the same drug concentration.Flow cytometry analysis and confocal laser scanning microscope demonstrated that LMG2/DOX could be uptaken by KB cells more effectively than free DOX.Considering the exceptional high drug loading efficiency and the abundant dendrimer amine groups on the surface that can be further modified,the developed LM-G2 nanodisks may hold a great promise to be used as a novel platform for anticancer drug delivery.Another study aimed to design and synthesize dendrimer-functionalized LAP for in vitro and in vivo MR imaging of cancer cells.LAP was modified with silane coupling agents and succinic anhydride to deliver abundant carboxyl groups on the surface of LAP.Then,PAMAM dendrimer of generation 2(G2)were combined to form LM-G2 nanodisks,then diethylenetriaminepentaacetic acid(DTPA)was modified ontothe LMG2 nanodisks for gadolinium(Gd)chelatingfor MRimaging of tumors.The designed LMG2-DTPA(Gd)complexes were characterized via different techniques.CCK-8 assay shows that the formed LM-G2-DTPA(Gd)complexes were non-cytotoxic to He La cells at a concentration up to 200 ?g/m L.LM-G2-DTPA(Gd)complexeswere demonstrated to have high r1 relaxivity,which is beneficial for enhanced MR imaging of the liver and bladder of a mouse within a time from 15 min,30 min,45 min,and 60 min.Furthermore,in vivo biodistribution studies reveal that the LM-G2-DTPA(Gd)have an extended blood circulation time and can be cleared from the major organs within 24 h.Moreover in vitro and in vivo MR imaging experiments show that the developed multifunctional LM-G2-DTPA(Gd)can be used for T1-weighted MR imaging of tumors.Our results obviously indicate that the way to forming LM-G2-DTPA(Gd)could be expanded for fabricating other active NPs for T1-weighted MR imaging of other biological systems with high precision.Final study aims to synthesize a novel iodinated CT contrast agent using silanized LAP conjugated with DTA.We designed DTA-modified LM-NH2 NPs as a contrast agent for CT imaging of main organs and tumors in vivo.DTA molecules were modified on the surface of LAP.Then,the prepared LM-NH2-DTA NPs was acetylated to improve their biocompatibility.In this study,the LM-NH2 nanoparticles(NPs)were conjugated with DTA via1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDC)coupling chemistry,followed by the acetylation of the remaining amines of LM-NH2-DTA NPs to improve their biocompatibility.The formed LM-NHAc-DTA NPs were characterized via different techniques.The results of cell viability reveal that the LM-NHAc-DTA NPs are cytocompatible in the given concentration range of 0.1-1.0 mg/m L.The measurements of X-ray attenuation coefficient demonstrate that the CT value of LM-NHAc-DTA NPs is much higher than that of the commercial iodine-based contrast agent at the same iodine concentration.Notably,the acetylated LM-NHAc-DTA NPs showed high performance in CT imaging of the major organs(heart,liver,kidney,and bladder)and tumors in vivo.