| With the continuous development of nanotechnology and the emergence of a large number of new nanomaterials, several functional nanomaterials have been used as drug delivery carriers and show great advantages. Among a variety of anticancer drug carrier systems, delivery systems using dendritic macromolecules as a platform are becoming the hotspot of research. We used the poly(amidoamine)(PAMAM) dendrimers of generation5(G5) as a drug carrier to build up a single and a dual drug delivery system for cancer treatment, respectively. We covalently attached different functional groups to the surface of dendrimer to improve its biocompatibility, and endow it with the function of cancer cell targeting for specific drug delivery. The dendrimer platform was loaded with different anticancer drugs via either physical entrapment within dendrimer interior or chemical linking on the surface of dendrimer periphery for targeted drug delivery applications.In this study, antitumor drug alpha-tocopheryl succinate (a-Tos) was first covalently attached onto the surface of G5PAMAM dendrimer. Followed by partial acetylation of the dendrimer terminal amines, then fluorescein isothiocyanate (FI) and targeting reagent folic acid (FA) were sequentially covalently linked to the remaining G5PAMAM dendrimer terminal amines, respectively. The obtained G5.NHAcn-α-Tos-FI-FA conjugate was characterized via different techniques.1H NMR and UV-vis spectroscopic results indicate the successful preparation of the G5.NHAcn-α-Tos-FI-FA conjugate. Combined MTT assay, cell morphological observation, confocal microscopy, and flow cytometry results show that the antitumor efficacy of the dendrimer-α-Tos complex is only related to the conjugated u-Tos drug itself, and FA-modified G5.NHAcn-α-Tos-FI-FA can specifically target to FA receptor-overexpressing KB cells and display targeted anti-tumor activity.Next, antitumor drug a-Tos and doxorubicin (DOX) were loaded onto the PAMAM dendrimer carrier by chemical bond and physical encapsulation, respectively. In this case, the prior formed G5.NHAcn-α-Tos-FI-FA conjugate was then physically loaded with DOX to form a dendrimer-based double delivery system (G5.NHAcn-a-Tos-FI-FA/DOX).’H NMR and UV-Vis spectroscopic results reveal that each PAMAM dendrimer can load5a-Tos and4.1DOX, respectively. In vitro MTT assay and cell morphology observation results show that the antitumor efficacy of the double drug-loaded G5.NHAcn-α-Tos-FI-FA/DOX is much higher than that of the single drug complex of G5.NHAcn-FI-FA/DOX under similar DOX concentration, demonstrating the desirable role of dual drug delivery system. In vitro drug release kinetics results show that DOX can be released from complex in a sustained manner. Confocal microscopy, flow cytometry, and MTT assay results show that the double drug delivery system G5.NHAcn-α-Tos-FI-FA/DOX can target to the FA receptor-overexpressing KB cells and show the specific therapeutic effect. Our results show that building up a dual drug delivery system enables enhanced anticancer treatment. |
