Study On Hyperbranched Polyglycerol Derivatives For Drug/gene Delivery

Hyperbranched polymers are one of the most valuable materials for construction of drug/gene carriers due to their special physicochemical properties and simple synthetic processes.Hyperbranched polyglycidyl ether(HPG)is a polyether polyol polymer with multifunctional modifiable groups,low toxicity,high thermal stability,oxidation resistance,and even better biocompatibility than PEG,and its application value in the field of drug/gene carrier has attracted much attention.HPG can not only load the hydrophobic drugs by the introduction of hydrophobic structure,but also can be modified into cationic polymers,which have the ability to condense the negatively charged DNA/siRNA into nanoparticle for gene delivery.In this thesis,HPG was used as the building block to build new types of efficient,low toxicity,biocompatibility drug/gene carriers,which include two parts as followed: 1.Study on ?-CD-HPG as a drug carrier and its anti-tumor effectThe development of hydrophobic drug carriers with good biocompatibility is still an urgent problem in cancer treatment.In this study,we design and synthesis a drug delivery system based on HPG modified ?-CD(?-CD-HPG)by conjugating HPG branches onto ?-CD core.Its physical and chemical properties are well analyzed by 1H NMR,Fourier transform infrared(FTIR)spectrum,Gel permeation chromatography(GPC),Dynamic light scattering(particle size and zeta potential),TEM and so on.The results shows that HPG modification not only enhanced the solubility of ?-CD,but also endowed ?-CD-HPG with excellent cytocompatibility and hemocompatibility.An anti-cancer drug,docetaxel,was effectively encapsulated into ?-CD-HPG which was confirmed by DSC analysis.This copolymers could form nanoparticles with small size(?200 nm)and exhibited better DTX loading capacity and more slowly release kinetics without initial burst release behavior compared with ?-CD.Furthermore,antitumor assay in vitro show that ?-CD-HPG/DTX effectively inhibited proliferation of human breast adenocarcinoma cells.In conclusion,?-CD-HPG can act as a potential hydrophobic drug carrier for cancer therapy.2.Study on PEI-CD/HPG-Fc as gene carrier for anti-tumor therapyIn order to explore the relationship between the assembled molecular weight of polycation and the efficiency of gene transfection,we designed the ferrocene-modified HPG as the core,assembly with the different molecular weight PEI modified ?-CD to construct a star supramolecular cationic aggregate by the host-guestinteraction.The physicochemical properties of the polymer showed that the particle size of the polymer was decreased,while the zeta potential increasedafter the supramolecular assembly.Gel electrophoresis results showed that the polymer had the ability to condense DNA.Meanwhile,the cytotoxicity test showed that the cytotoxicity of the supramolecular polycationic assembly decreased with the decreasement of the molecular weight of the assembled PEI.Transfection results showed that there was no significant difference in the maximum transfection efficiency of different molecular weight polycationic assemblies,indicating the transfection efficiency depends on the spherical structure with outer positive charged,rather than the molecular weight of the assembled polycation.However,aggregate assembled with low molecular weight PEI(600Da bPEI)showed relatively lowtoxicity,we put forward a point of view that: The gene transfection with high molecular weight polycation can be achieved by assembly of low molecular weight polycaric and hyperbranched biocompatible polymers.This work provides a new idea to design polymer gene carriers.