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Synthesis of Aminated Poly(glycerol Methacrylate)s as Carriers for the Delivery Systems of Insulin and Oligonucleic Acid

Author: LuXueYou
Tutor: MaJianBiao; GaoHui
School: Tianjin University of Technology
Course: Applied Chemistry
Keywords: PGMA Polyelectrolyte Nanoparticle insulin Gene carrier
CLC: TQ460.1
Type: Master's thesis
Year: 2012
Downloads: 36
Quote: 0
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Abstract


Poly(glycidyl methacrylate)(PGMA) is biocompatible, possessing reactive epoxy groups.The PGMA was then modified with amines by ring-opening of the epoxide groups. Theresulting amino poly(glycerol methacrylate) have hydroxyl groups on its side chain, whichcould offer hydrogen-bonding interaction with biological molecules. Amino PGOHMAs asdrug carriers showed the following properties:(1) Amino PGOHMA can form nano-complexwith insulin by electrostatic interactions.(2) Amino PGOHMA can form nano-complex withantisense oligonucleotide (AON) by electrostatic and hydrogen bonding. Owing to thesynergy of hydrogen bonds, polymer can form complexes with AON at a lower N/P ratio.Thereby, the cellular toxicity becomes lower. Hydrogen bonding interactions not only makethe release of AON in the cell more easily but also increase gene transfection efficiency.Poly(glycidyl methacrylate) derivatives-amino PGOHMAs (L-E, L-B, L-D, S8-E, S8-B,S8-D. L and S8represent Linear and star polymer, respectively. E, B, D represent1,2-ethanediamine,1,4-butanediamine and diethylenetriamine respectively) was synthesizedby diamines or polyamines and PGMA. PGOHMAscan form polyelectrolyte complexes(PECs) with insulin. Parameters influencing complex formation were investigated by dynamiclight scattering (DLS). PECs in the size range of100-200nm were obtained under optimalconditions, i.e., the pH value of PECs was5.58-6.27, the concentration of NaCl was0.02mol/L, and insulin-polymer weight ratio was0.8. The insulin association efficiency (AE) ofcurrent system increased with zeta potentials of PECs. Circular dichroism (CD) analysiscorroborated that the structure of insulin in the PEC nanoparticles was preserved afterlyophilization. Fourier transform infrared (FT-IR) and X-ray diffraction (XRD) experimentsdemonstrated that weak physical interactions between insulin and amino PGOHMAs play animportant role in the formation of PECs. The release of insulin is depended on both structureand architecture of amino PGOHMAs.To improve the transfection activity and reduce cell cytotoxicity of polycations withantisense oligonucleotide (AON), poly(glycidyl methacrylate)s (PGMAs) were modified withdifferent amines, i.e., methylethylamine (MEA),2-amino-1-butanol (2-ABO) and4-amino-1-butanol (4-ABO). The amino PGOHMA could self-assemble with AON in a Trisbuffer solution, resulting in narrowly distributed polymer/AON complexes with a size of100-300nm at amine-group-of-polymer/phosphate-group-of-nucleotide ratio (N/P ratio) of0.5-3. Spherical nanoparticles of the complexes were visualized using atomic forcemicroscopy (AFM), and the gel electrophoresis and zeta potential assay evidenced theformation of complexes at relative low N/P ratio. Stability of the complexes towardsdissociation was tested using ethidium bromide displacement assy. Protection of theincorporated AON against DNase I degradation was also evaluated. Increased charge ratio and a synergistic effect of hydrogen bonding in this system were contributed to the increasedstability of the complex, which prevents the incorporated AON from nuclease degradation. Invitro cytotoxicity experiments on COS-7cells showed that all amino PGOHMAs displayedlower toxicity compared to the control PEI25k, except for the polymers with a relative highmolecular weight (30kDa). In addition, the MEA modified linear and star-shaped PGMA (Mnin the range of15-20kDa), as well as4-ABO modified linear PGMA complexes exhibitedhigher transfection efficiencies in vitro, compared to PEI25k. These results demonstrated thatamino PGOHMAs with suitable amine groups and molecular weight can be employed as safeand efficient AON delivery polymers.

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