Beta-casein Nanoparticles as an Oral Delivery System for Chemotherapeutic Drugs: Impact of Drug Structure and Properties on Co-assembly

To develop a novel oral drug delivery system comprising a hydrophobic chemotherapeutic drug entrapped within beta casein (beta-CN), a major milk protein, which self-associates into micelles in aqueous solutions. The efficient gastric digestibility of beta-CN suggests possible targeting to gastric cancers. Antitumor drug entrapment was performed by stirring its dimethyl-sulfoxide solution into a phosphate-buffered saline containing beta-CN. The association of drugs to beta-CN was characterized by spectrophotometry and Trp143 fluorescence quenching; particle-size by dynamic light scattering, and colloidal stability by zeta potential. The optimal drug-to-beta-CN molar loading-ratios for paclitaxel and vinblastine at 1 mg/ml beta-CN were found to be 7.3 +/- 1.2 and 5.3 +/- 0.6 and the association constants were (6.3 +/- 1.0)center dot 10(3) M-1 and (2.0 A +/- 0.3)center dot 10(4) M-1, respectively. Zeta potential analysis suggested that nanoencapsulation by beta-CN stabilized all studied drugs in aqueous solution. The initial drug-beta-CN association was apparently governed by hydrophobic interactions and at higher drug concentrations, also by electrostatic interactions. Up to the optimal drug:beta-CN loading-ratio, similar to 80% of the particles were below 100 nm in diameter. At higher drug concentrations, particle diameter increased, and bi- or tri-modal particle distributions were observed. Beta-CN forms colloidally-stable nanovehicles of hydrophobic anticancer drugs, and may be used for oral-delivery of chemotherapeutics.