Beta-casein nanoparticles as an oral delivery system for chemotherapeutic drugs: impact of drug structure and properties on co-assembly.
OBJECTIVE
To develop a novel oral drug delivery system comprising a hydrophobic chemotherapeutic drug entrapped within beta casein (β-CN), a major milk protein, which self-associates into micelles in aqueous solutions. The efficient gastric digestibility of β-CN suggests possible targeting to gastric cancers.


METHODS
Antitumor drug entrapment was performed by stirring its dimethyl-sulfoxide solution into a phosphate-buffered saline containing β-CN. The association of drugs to β-CN was characterized by spectrophotometry and Trp143 fluorescence quenching; particle-size by dynamic light scattering, and colloidal stability by zeta potential.


RESULTS
The optimal drug-to-β-CN molar loading-ratios for paclitaxel and vinblastine at 1 mg/ml β-CN were found to be 7.3 ± 1.2 and 5.3 ± 0.6 and the association constants were (6.3 ± 1.0) x 10(3) M(-1) and (2.0 ± 0.3) x 10(4) M(-1), respectively. Zeta potential analysis suggested that nanoencapsulation by β-CN stabilized all studied drugs in aqueous solution. The initial drug-β-CN association was apparently governed by hydrophobic interactions and at higher drug concentrations, also by electrostatic interactions. Up to the optimal drug:β-CN loading-ratio, ~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.


CONCLUSIONS
Beta-CN forms colloidally-stable nanovehicles of hydrophobic anticancer drugs, and may be used for oral-delivery of chemotherapeutics.
Shapira
Alina
A
Russell Berrie Nanotechnology Institute, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Assaraf
Yehuda G
YG
Epstein
Dikla
D
Livney
Yoav D
YD
D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D002364:Caseins / Q000737:chemistry*; D003102:Colloids; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D000077146:Irinotecan; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D010316:Particle Size; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry; D014747:Vinblastine / Q000008:administration & dosage / Q000737:chemistry
D000970:Antineoplastic Agents; D002364:Caseins; D003102:Colloids; D004337:Drug Carriers; D043823:Taxoids; D000077143:Docetaxel; D014747:Vinblastine; D000077146:Irinotecan; D017239:Paclitaxel; D002166:Camptothecin