Construction Of Multifunctional Nanocarrier Based On Ferrocenium For Drug/siRNA Co-Delivery

Cancer chemotherapy has often been impeded by adverse side effects in healthy cells and multidrug resistance in cancer cells.To overcome these obstacles,one promising way is the development of versatile drug/siRNA transporters,which not only possess the ability to penetrate cell membrane rapidly and respond to the specific microenvironment changes to release the drug quickly in cancer cells,but also can knock down drug resistance genes to restore effective chemotherapy by encapsulating siRNA.Up to now,different materials and methods have been used to construct the transporters.However,further applications were usually limited by the restriction to a single function,the low/variable transport efficiency,high cytotoxicity or the need for modification.For clinical translation,nanostructures with higher transport efficiency and integrated functions should be developed.1.Cationic vesicles based on amphiphilic pillar[5]arene capped with ferrocenium: a redox-responsive system for drug/siRNA co-deliveryA novel ferrocenium capped amphiphilic pillar[5]arene(FCAP)was synthesized and self-assembled to cationic vesicles in aqueous solution.The cationic vesicles,displaying low cytotoxicity and significant redox-responsive behavior due to the redox equilibrium between ferrocenium cations and ferrocenyl groups,allow to build an ideal glutathione(GSH)-responsive drug/siRNA co-delivery system for rapid drug release and gene transfection in cancer cells where higher GSH concentration exists.This is the first report of redox-responsive vesicles assembled by pillararene for drug/siRNA co-delivery,which can not only enhance the bioavailability of drugs for cancer cells and reduce the adverse side effects for normal cells,but also overcome drug resistance of cancer cells.As we know,ferrocenium is first used as GSH-responsive structual units in drug delivery system.This work provides a good example of rationale design for effective drug/siRNA co-delivery system with responsiveness to stimuli existing specially in microenvironment of cancer cells.2.Multivalent glyco nanofibers based on small molecular carbohydrates for highly efficient drug/siRNA co-deliveryA novel type of self-assembling multivalent glyco nanofibers(GNFs)was obtained through ionic self-assembly(ISA)of siRNA and cationic glyco vesicles,where the vesicles were self-assembled by an amphiphilic lactose derivative capped with cationic ferrocenium.In addition to excellent biocompatibility,the unique bio-interactions of lactose cluster and biomimicking architecture of fibers enabled enhanced cell permeability and highly efficient drug/siRNA transport synergistically.Through co-delivery of multidrug resistance protein siRNA and anticancer drug,drug resistance of cancer cells was overcome.Furthermore,the redox-responsive property based on ferrocenium allowed for reduced adverse side effects in normal cells.It is the first time introducing ISA strategy to produce multivalent GNFs,which supplies an effective method for controlling the complicated self-assembly of small molecule carbohydrates.We believe the ISA strategy and the multivalent GNFs created can broaden the scope of versatile transporter in drug/siRNA co-delivery to overcome drug resistance and reduce adverse side effects in cancer chemotherapy.Above all,a novel GSH responsive unit and ionic self-assembly strategy was developed.Based on these,a cationic vesicles and glyco nanofibers were constructed and applied for drug/siRNA co-delivery.In addition to reducing adverse side effects in healthy cells and overcoming multidrug resistance in cancer cells,enhanced efficiency and safety were obtained,which were significant for further clinical translation.