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Preliminary Investigation of Histidine Grafted Poly (β-amino Ester)s as Novel Cationic Polymer Gene Vectors

Author: PengYao
Tutor: ChangJin
School: Tianjin University
Course: Materials Science
Keywords: gene vectors poly (β-amino ester)s histidine degradable buffering capacity
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Type: Master's thesis
Year: 2012
Downloads: 28
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Abstract


Intense attention has been focused on the design of multifunctional gene vectorswith low cytotoxicity, aimed at overcoming a variety of extracellular barriers andintracellular barriers to achieve high transfection efficiency in gene delivery. Hereinwell-designed biodegradable cationic polymer with buffering capacity wassynthesized and thoroughly evaluated utilized as gene vectors.In this article, poly (β-amino ester)s (PBAEs) containing degradable ester bondswere prepared firstly through the conjugation addition between1-amino4-butanol and1,4-butanediol diacrylate. Afterwards, histidine-grafted PBAEs (HGPAEs) weresynthesized by modification of PBAEs with histidine, which is capable of protonation.NMR, FTIR, GPC are employed to investigate the effect of polymerization conditionson the structure of PBAEs and HGPAEs, leading to the determination of optimumreaction conditions. Absorbance tests, titration tests, and complexation tests with poly(acrylic acid) demonstrated the pH dependent solubility of HGPAEs, that is, moreremarkable solubility was obtained at acidic conditions. It was also concluded thatHGPAEs was able to slow down the change of pH values in acidic environment, andnano-sized complexes could be formulated by integration of HGPAEs andpolyelectrolytes bearing negative charge. According to these results, HGPAEs couldbe an essentially promising candidate as gene vectors to complex withnegative-charged genes, promote escape from endosome and realize gene release.Subsequently, the interaction between HGPAEs and reporter gene plasmid DNA(pDNA) were investigated in detail. Agarose gel electrophoresis, TEM observations,and Zeta potential tests displayed the successful preparation of stable HGPAEs/pDNAcomplexes, with size ranging from50nm to150nm. The obtained complexes showedpositive surface charge with a tendency to increase as a function of vector/gene ratios.Moreover, complexes exhibited well-established stability in the presence of heparinsodium, and would logically offer efficient protection to pDNA. The complexesmaintained constant size under physiological pH, while much larger sizes wereobserved for complexes under acidic pH values, which might be attributed to thedissociation between HGPAEs and pDNA. Consequently, it was revealed that HGPAEs could perform as elegant gene vectors to condense pDNA into stablenanoparticles, providing effective protection onto pDNA and releasing pDNA underacidic environment.In addition, transfection efficiency of HGPAEs were evaluated by delivering GFPreporter genes into Miacapa-2cell lines. HGPAEs was proved to be able to mediateefficient gene transfection. MTT experiments were also conducted and revealed lowcytotoxicity of obtained HGPAEs.In short, HGPAEs are expected as promising cationic polymer gene vectors.

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