Poly(amidoamine) (PAA) networks that are obtained by the use of cystamine as a cross-linking agent in the reaction with 2,2'-dithiodipyridine turn into linear PAAs with dithiopyridyl side groups that easily undergo an exchange reaction with thiocholesterol. The resultant products represent the first examples of amphiphilic PAA-cholesterol conjugates in which lipophilic cholesterol moieties are linked to the hydrophilic PAA chain by S-S bonds that are stable in blood but cleavable inside cells. In aqueous media, these conjugates self-assemble into nanoaggregates whose inner cores consist of lipophilic cholesterol domains. A series of PAA-cholesterol conjugates that are derived from two different bis-acrylamides, namely 2,2-bis(acrylamido)acetic acid and 1,4-bis(acryloyl)piperazine, and that have different cholesterol contents were obtained. All products were characterized by (1)H and (13)C NMR spectroscopy, and the average molecular weights of the soluble polymers were determined by size exclusion chromatography. In all instances, the segregation of cholesterol residues from the aqueous medium was revealed by the comparison of their NMR spectra in CDCl3 and D2O, respectively. The TEM analysis of the PAA-cholesterol aggregates in aqueous buffers revealed homogeneous round nanospheres whose dimensions and dimension distributions were determined by DLS. Preliminary cytocompatibility tests demonstrated that all prepared PAA-cholesterol samples are cytocompatible and thus show potential for biotechnological applications.
The polyaddition kinetics of 2-methylpiperazine to 1,4-bisacryloylpiperazine was determined in water, methanol, ethylene glycol, formamide, and dimethylformamide, respectively. In the protic solvents, the polyaddition proceeded through a two-step mechanism, each step involved one of the two different secondary amino groups; the difference in amine reactivity was ascribed to the different steric hindrance by the neighbouring groups. Each step followed pseudo-second-order kinetics; the kinetic constants included the catalytic protonic species. In the case of dimethylformamide, the polyaddition proceeded through third-order kinetics; this accounted for the autocatalytic activity of the amino groups. The apparent kinetic constants in the protic solvents increased with the increase in the autoprotolysis constant values and decreased with the increase of the dipole moment.
One of the principal problems facing nucleic acid delivery systems using polyplexes is the instability of the complexes in the presence of proteins and high salt concentrations. We have used a cross-linking polymer to overcome this problem. Pendant thiol moieties have been incorporated into a PAA (polyamidoamine) homopolymer and a PEG [poly(ethylene glycol)]-PAA-PEG copolymer reported previously as a self-assembling system. When mixed with DNA, small monodisperse sterically stabilized particles are formed in quantitative yields. Optimization of the formulation resulted in nanoparticles which are stable in seawater. This cross-linked formulation has been successfully tested in both freshwater and estuarine field trials as a water tracer. Future work will develop these particles as a groundwater tracer and also for therapeutic applications of nucleic acid delivery.
Summary:Poly(amidoamine)s are biocompatible biodegradable polymers, which can be easily functionalized with a number of bioactive and biomimetic compounds. Co‐polymerization of these polymers with 4‐aminobutyl guanidine (agmatine) leads to an RGD mimicking structure. Hydrogels based on this structure showed an enhanced cell adhesion and could be chemically linked to a glass substrate to create a bioadhesive support for cell growth. Preliminary optimization and cell adhesion tests on Madin‐Darby Canine Kidney cells were performed, both on functionalized and non‐functionalized structures, with promising results.
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