Biocleavable Polycationic Micelles as Highly Efficient Gene Delivery Vectors

An amphiphilic disulfide-containing polyamidoamine was synthesized by Michael-type polyaddition reaction of piperazine to equimolar N, N′-bis(acryloyl)cystamine with 90% yield. The polycationic micelles (198 nm, 32.5 mV), prepared from the amphiphilic polyamidoamine by dialysis method, can condense foreign plasmid DNA to form nanosized polycationic micelles/DNA polyelectrolyte complexes with positive charges, which transfected 293T cells with high efficiency. Under optimized conditions, the transfection efficiencies of polycationic micelles/DNA complexes are comparable to, or even higher than that of commercially available branched PEI (Mw 25 kDa)

New poly(amidoamine)s containing disulfide linkages in their main chain

Novel poly(amidoamine)s (PAAs) containing disulfide linkages regularly arranged along their backbones were synthesized by the stepwise polyaddition of 2-methylpiperazine to N,N'-bis(acryloyl)cystamine (BACy1) or N,N'-bis(acryloyl)-(L)cystine (BACy2). Both bisacrylamides had, in turn, been obtained by the reaction of acryloyl chloride with the corresponding amines. All the products were characterized with 1H and 13C NMR spectroscopy, and the average molecular weights of the polymers were determined by size exclusion chromatography. Both PAAs showed different solubility properties. In particular, PAA-Cy1, derived from BACy1, was sparingly soluble in water, whereas PAA-Cy2, derived from BACy2, was very soluble in aqueous media. The polymerization rates were investigated with 1H NMR spectroscopy. In both cases, the experimental data were consistent with pseudo-second-order kinetics. The calculated kinetic constants were 5.96 × 10-3 and 5.90 × 10-2 min-1 L mol-1 for the polyaddition of BACy1 and BACy2, respectively. The observed hydrolytic degradation rate of PAA-Cy2 in a pH 7.4 tris(hydroxymethyl)aminomethane (TRIS) buffer was comparable to that of conventional amphoteric PAAs, that is, PAAs containing carboxyl groups in their repeating unit. Degradation experiments carried out in the presence of 2-mercaptoethanol with both PAAs demonstrated that the disulfide groups contained in its repeating units were susceptible to reductive cleavage in the presence of thiols

A Biodegradable Polymeric Carrier Based on PEG for Drug Delivery

A biodegradable copolymer (PEG-fum), based on poly(ethylene glycol) (PEG) and fumarate (fum) units, was synthesised and studied as a drug carrier. PEG and fum were linked together by ester bonds to confer biodegradability to the polymeric backbone in vivo. Hence, this copolymer can be used with molecular weights above the kidney clearance threshold for PEG without body accumulation. The PEG-fum was designed to be a high drug loading carrier due to the fumarate units, thus, overcoming the limitations of linear PEGs. Suitable reactive groups for drug coupling were added by reacting fumarate with tioglycolic acid (TGA). The pendant TGA carboxylic groups were conjugated to the camptothecin derivative, SN38, taxol and epirubicin, respectively. The SN38 and taxol linked to the PEG-fum-(TGA) increased their solubility 15 and 100 fold, respectively. The rate of 2 SN38 release in plasma was adequate for prolonged circulation in vivo, while taxol was rapidly hydrolysed. This relatively fast degradation could hamper the conjugate from accumulating in the tumor tissue by enhanced permeability and retention effect (EPR). Instead, EPR effect could be exploited with the epirubicin conjugate coupled by means of a hydrazone bond. This linkage provides good blood stability, while readily cleaved in acidic environment like those in endosomes and lysosomes. Therefore, the drug is released intercellularly in its active form only after, thus reducing toxic effects