Polyamidoamine gene delivery

Huang R, Ke W, Liu Y, Jiang C, Pei Y (2008) The use of lactoferrin as a ligand for targeting the polyamidoamine-based gene delivery system to the brain. Biomaterials 29 238-246... 

Interest in dendritic polymers (dendrimers) has grown steadily over the past decade due to use of these molecules in numerous industrial and biomedical applications. One particular class of dendrimers, Starburst polyamidoamine (PAMAM) polymers, a new class of nanoscopic, spherical polymers that appears safe and nonimmunogenic for potential use in a variety of therapeutic applications for human diseases. This chapter will focus on investigations into PAMAM dendrimers for in vitro and in vivo nonviral gene delivery as these studies have progressed from initial discoveries to recent animal trials. In addition, we will review other applications of dendrimers where the polymers are surface modified. This allows the opportunity to target-deliver therapeutics or act as competitive inhibitors of viral or toxin attachment to cells. 

While the dendrimer architecture is the most popular form of polyamidoamine polymers for gene delivery, linear polyamidoamines have also been evaluated for their effectiveness as gene transfer agents to... 

Tang, M.X., Redemann, C.T. and Szoka, F.C. (1996) In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjug. Chem., 7, 703-714. 

Peptide-based gene delivery, 334 Peptide nucleic acid (PNA), 73,252 Pharmacokinetics, 409 Polyethyleneimine (PEI), 369 Peptides with thiol groups, 348 Persistence of gene expression, 10,463 Physiological Pharmacokinetics, 423 PNA binding affinity, 75 Poly anion interchange, 179 Poly cations, 164 Polymeric gel, 447 Polyamidoamine (PAMAM), 376 Polyaminomethacrylates, 379 Poly(L-lysine), 336, 369 Poly(vinyl pyrrolidone) (PVP), 382 Prophylactic vaccines, 474... 

Synthetic polymer. Among the cationic synthetic polymers used for gene delivery are polyethylenimine (PEI), polyamidoamine dendrimers, and poly(2-dimethylaminoethyl methacrylate).161-164 Depending on the flexibility (or rigidity) of the polymers, they form either a small (<100 nm) DNA polyplex or a large (>1 to 10 pm) DNA polyplex.165 More detailed physicochemical properties and their transfection efficacy are to be discussed. 

Dendrimers used for DNA delivery most commonly have positive net surface charges. The most well studied molecules for gene delivery are those based on an ethylene diamine or ammonia core with polyamidoamine (PAMAM) dendrites or those based on bufylenediamine cores and polypropylenimine (PPI) dendrites. Solubility of PAMAM dendrimers can be enhanced by partial acetylation of the reactive amino groups and they can be conjugated with various targeting entities such as folic acid to target receptors on specific cancer cells (42). 

Rudolph C, Lausier J, Naundorf S, Muller RH, Rosenecker J. In vivo gene delivery to the lung using polyethylenimine and fractured polyamidoamine dendrimers. J Gene Med 2000, 2, 269-278. 

Liu et al. presented the synthesis of polyamidoamine-functionalized mul-tiwalled carbon nanotubes (PAA-g-MWNTs) and their application as a novel gene delivery system. The PAA-g-MWNTs showed comparable or even higher transfection efficiency than PAA and PEI at optimal w/w ratio. Intracellular trafficking of Cy3-labeled pGL-3 indicated that a large number of Cy3-labeled pGL-3 were attached to the nucleus membrane, the majority of which was localized in the nucleus after incubation with cells for 24 h (Figure 3.20). 

Qin et al. also modified MWNTs with polyamidoamine (PAMAM) to increase the CNTs gene loading, and eventually to improve the transfection performance of CNTs. However, though the MWNT-PAMAM hybrid could deliver the GFP gene into cultured HeLa cells more efficiently than the unmodified CNTs, the efficiency was much lower than Lipofectamine 2000. The surfaces of SWNTs were also functionalized with cationic glycopolymers, and the copolymer modified SWNTs were found to be biocompatible and exhibit transfection efficiencies that are comparable to the commercially available agent Lipofectamine 2000. Various modified CNTs were tested in different cell lines for gene delivery. ... 

Dendrimers are polymeric molecules composed of multiple branched monomers radially emanating from a central core. Dendrimers based on polymers such as polyamidoamines (PAMAMs) and poly(propylene imine) can form compact polycations under physiological conditions and, therefore, have been of interest to researchers for use in gene delivery both in vivo and in vitro [78,89,90]. They can also be functionalized with other molecules such as a-cyclodextrin [91], PEG [92], etc. to enhance gene integration and expression. However, the use of dendrimers for in vitro gene delivery into somatic and stem cells has not yet been demonstrated. 

Several of the most effective polymeric delivery systems were polyamidoamine den-drimers (220) and polyethyleneimines (PEI) (221). Being non-biodegradable, these synthetic polymers posed a potential toxicity to cell therefore, biodegradable polypeptides like PLL and protamine were used for condensation and delivery of gene, but they had limited efficacy in transfection (222, 223). They were usually used with cationic lipids to obtain enhanced transfection activity (178,201). Among the biodegradable polymers, chitosan... 

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