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We have demonstrated that the novel family of functionalized poly(amido amine)s containing repetitive disulfide linkages in their main chain have very promising characteristics for the development of highly potent and nontoxic gene carriers

Novel bioreducible poly(amido amine)s for highly efficient gene delivery.

BIOCONJUGATE CHEMISTRY, no. 1 (2007): 138-145

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摘要

A series of novel bioreducible poly(amido amine)s containing multiple disulfide linkages (SS-PAAs) were synthesized and evaluated as nonviral gene vectors. These linear SS-PAAs could be easily obtained by Michael-type polyaddition of various primary amines to the disulfide-containing cystamine bisacrylamide. The SS-PAA polymers are relati...更多

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简介
  • A prerequisite for the success of human gene therapy is the availability of safe and efficient gene delivery systems [1,2,3].
  • Improvements have been aimed at developing polymeric vectors that are hydrolytically degradable [10,11,12,13,14,15], and a particular example of that approach is the large library of linear poly( -amino ester)s synthesized and screened by Langer and co-workers [16,17,18]
  • These hydrolyzable carrier systems generally display decreased cytotoxicity by avoiding the accumulation of positively charged high molecular weight polymers in cells.
  • Polymers which are very sensitive for hydrolysis may give difficulties in vector handling and further modification [20]
重点内容
  • A prerequisite for the success of human gene therapy is the availability of safe and efficient gene delivery systems [1,2,3]
  • Cationic polymers have emerged as important synthetic alternatives, as they have many potential advantages such as absence of specific immune response, large DNA loading capacity, and the ease of large-scale production [4,5,6]
  • We report a novel family of linear poly(amido amine)s containing repetitive disulfide linkages in their main chain (SS-Poly(amido amine)s (PAAs)) as highly efficient intracellularly degradable gene delivery vectors
  • For use as control polymers, three poly(amido amine)s lacking the disulfide linkages were prepared from polyaddition of histamine (HIS) to N,N′-methylenebisacrylamide (MBA), 1,4-bis(acryloyl)piperazine (BAP), and N,N′-hexamethylenebisacrylamide (HMBA), respectively (Scheme 2)
  • Since the addition polymerization is a stepwise process, equal monomer ratios were used in the synthesis in order to obtain PAAs of highest theoretical molecular weight
  • We have demonstrated that the novel family of functionalized poly(amido amine)s containing repetitive disulfide linkages in their main chain (SS-PAAs) have very promising characteristics for the development of highly potent and nontoxic gene carriers
结果
  • 3.1 Synthesis and Characterization of SS-PAAs. Seven different bioreducible poly(amido amine) polymers with repetitive disulfide linkages in their main chain (SS-PAAs) were synthesized via Michael addition of the corresponding primary amine monomers to N,N′-cystamine bisacrylamide (Scheme 2).
  • In the final stage of the reaction, an excess of the amine monomer was added in order to ensure that all potentially toxic acrylamide end groups are consumed and the polymers have only amino end groups.
  • Gel permeation chromatography (GPC) measurements showed that the weight-average molecular weights (Mw) of these
结论
  • The authors have demonstrated that the novel family of functionalized poly(amido amine)s containing repetitive disulfide linkages in their main chain (SS-PAAs) have very promising characteristics for the development of highly potent and nontoxic gene carriers
  • Their easy and versatile synthesis is compatible with the use of a large variety of functionalized amine monomers, allowing large variation in the structure of the polymers.
  • This material is available free of charge via the Internet at http://pubs.acs.org
总结
  • Introduction:

    A prerequisite for the success of human gene therapy is the availability of safe and efficient gene delivery systems [1,2,3].
  • Improvements have been aimed at developing polymeric vectors that are hydrolytically degradable [10,11,12,13,14,15], and a particular example of that approach is the large library of linear poly( -amino ester)s synthesized and screened by Langer and co-workers [16,17,18]
  • These hydrolyzable carrier systems generally display decreased cytotoxicity by avoiding the accumulation of positively charged high molecular weight polymers in cells.
  • Polymers which are very sensitive for hydrolysis may give difficulties in vector handling and further modification [20]
  • Results:

    3.1 Synthesis and Characterization of SS-PAAs. Seven different bioreducible poly(amido amine) polymers with repetitive disulfide linkages in their main chain (SS-PAAs) were synthesized via Michael addition of the corresponding primary amine monomers to N,N′-cystamine bisacrylamide (Scheme 2).
  • In the final stage of the reaction, an excess of the amine monomer was added in order to ensure that all potentially toxic acrylamide end groups are consumed and the polymers have only amino end groups.
  • Gel permeation chromatography (GPC) measurements showed that the weight-average molecular weights (Mw) of these
  • Conclusion:

    The authors have demonstrated that the novel family of functionalized poly(amido amine)s containing repetitive disulfide linkages in their main chain (SS-PAAs) have very promising characteristics for the development of highly potent and nontoxic gene carriers
  • Their easy and versatile synthesis is compatible with the use of a large variety of functionalized amine monomers, allowing large variation in the structure of the polymers.
  • This material is available free of charge via the Internet at http://pubs.acs.org
表格
  • Table1: Characteristics of Poly(amido amine)s: Weight-Average
Download tables as Excel
基金
  • All SS-PAAs, except pDMEA, showed excellent buffer capacity ranging from 42% to 75% protonation, which is significantly higher than that of pEI (24%)
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