Design,Synthesis And Bioactivity Evaluation Of Bola-Amphiphilic Dendrimer

Bola-amphiphilic dendrimers are a novel class of functionalized molecules which contain two hydrophilic dendrons linked covalently via a hydrophobic chain.By taking the structural advantages of dendrimers and bolaamphiphiles,bola-amphiphilic dendrimers have the precisely controlled structure,nanoscale size,multiple functional groups on the surface and multivalence.Moreover,their unique “dumbbell-like” bipolar structures endow such denrimers with excellent self-assembly properties.In recent years,the bola-amphiphilic dendrimers have been used to construct supramolecular dendrimers for mimicking convalent dendrimers in high generation,thus to avoid the complicated synthesis and difficult purification of high-generation dendrimers.Importantly,more and more studies have showed that these bola dendrimers also exhibit promising application in biomedical fields,such as nucleic acid delivery,drug delivery and anticancer drug discovery.Therefore,with the aim to expand the varieties and applications of this family of dendrimers,the main work of this thesis is to develop a series of novel bolaamphiphilic dendrimers and study their self-assembly properties and biological activities.In the first part of this thesis,we designed and synthesized the bola-amphiphilic dendrimers with different cationic terminals as the novel non-viral vectors for nucleic acid delivery.The bola-amphiphilic cationic dendrimers bearing tertiary amine(series I)and biguanide(series Ⅱ)were prepared by introducing the ionizable tertiary amine and electron-delocalized biguanide to the terminals of the bola dendrimers,respectively.By evaluating their critical aggregation concentration(CAC),we further proved that both bola-dendrimer Ⅰ and Ⅱ could effectively self-assemble in water.Additionally,compared to the bola dendrimers with primary amine terminals,the tertiary amine dendrimer Ⅰ and biguanide dendrimer Ⅱ displayed much lower cytotoxicity.In addition,some of the synthesized bola-amphiphilic cationic dendrimers could deliver siRNA efficiently in vitro.Among them,the siRNA delivery system constructed by dendrimer Ⅰ-2a displayed relatively good gene silencing effect,which suggested that these bola-amphiphilic cationic dendrimers are potential vector with low toxicity for nucleic acid delivery.In the second part,we have developed a series of bola-amphiphilic glycodendrimers and studied their ability for targeting carbohydrate-binding proteins as carbohydrate mimics.These bola glycodendrimers have β-D-glucose(series Ⅲ)or α-D-mannose(series Ⅳ)in the terminals aiming to target glucose transporters(GLUTs)and mannose receptors(MRs),respectively.Moreover,our studies showed that these glycodendrimers possessed of good self-assembly ability and biocompatibility.Further results demonstrated that glycodendrimer Ⅳ with mannose terminal could effectively recognize and bind to concanavin A(ConA,a carbohydrate-binding protein),while glycodendrimer Ⅲ containing glucose moieties did not,indicating the importance of the sugar configuration in receptor recognition and binding.Notably,bola glycodendrimer Ⅳ-2a displayed stronger binding affinity to ConA than the non-bola glycodendrimers,which further highlighted the unique advantages of the bola glycodendrimers in binding with carbohydrate-binding proteins.Furthermore,dendrimer Ⅲ-2a and Ⅳ-2a were able to target various cancer cells overexpressed GLUTs and MRs suggesting their great potential in targeted drug delivery.The third part of this thesis focuses on the synthesis and biological study of bola dendrimer-gemcitabine conjugates for the purpose of improving the pharmacokinetic properties and antitumor activity of gemcitabine.We prepared the dendrimer-gemcitabine conjugates by covalently conjugating gemcitabine to the terminals of the bola dendrimers.Besides having satisfactory self-assembly properties,these conjugates could release gemcitabine efficiently in pH-and enzyme-responsive manner.Further antiproliferation and cell uptake studies in cancer cells showed that different from free gemcitabine,the conjugates were uptaken via endocytosis rather than nucleoside transporter and then exhibited potential antiproliferation activities.Taken together,these bola dendrimergemcitabine conjugates can be developed as novel nano self-assembled prodrug delivery systems.In conclusion,we have successfully designed and synthesized various kinds of novel bola-amphiphilic dendrimers as well as explored their self-assembly properties and biological activities.Our research work hence has expanded the diversity and applications of bola-amphiphilic dendrimers,which provids a new prospective in development of multifunctional nanocarriers for drug delivery.