| Currently available nanoparticle preparation methods involve the use of heat, organic solvents and high shear forces which may compromise the stability of the entrapped drug. Thus, a novel nanoparticle system using milder processing conditions has been developed. This system employs the oppositely charged aqueous polymers, polyethylenimine (PEI) and dextran sulfate (DS), with zinc as a stabilizing agent. The polymers (under low shear force) spontaneously self-assemble to form nanoparticles through electrostatic interactions at room temperature. Under these mild conditions, a broad variety of drugs have been entrapped in this new nanoparticle system while maintaining their physicochemical and biological stabilities. Amphotericin B, insulin and plasmid DNA were loaded into the nanoparticles as model drugs as examples of small molecules, proteins and polynucleotides, respectively. Biological activities of all three classes of drugs were demonstrated in various test systems. Optimized nanoparticles contained PEI and DS in the weight ratio of approximately 1:2. Spherical particles of 200--250 nm mean diameter and polydispersity index of 0.2 (a relatively narrow size distribution) were achieved under optimal conditions. They possessed a zeta potential of approximately +18 to +30 mV. Very favorable drug entrapment efficacies in the range of 75--95% was routinely observed. Processing parameters such as the pH of the PEI solutions, ratio of the two polymers, as well as the concentrations of DS, PEI and zinc sulfate all played a significant role in controlling both particle size and particle toxicity. Dissolution studies demonstrated fast release kinetics suggesting that much of the associated drugs may be adsorbed on the particle's surface. This novel system is a promising drug delivery carrier since it offers many advantages including: (1) ease of manufacturing under mild preparation conditions; (2) employment of completely aqueous processing conditions; (3) the ability to lyophilize; (4) the ability to control particle size; (5) a high level of drug entrapment and (6) the ability to preserve the physicochemical and biological stability of loaded drugs. |
