Ionically-crosslinked milk protein nanoparticles as flutamide carriers for effective anticancer activity in prostate cancer-bearing rats

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 85; no. 3; pp. 444 - 451
• Main Authors: Elzoghby, Ahmed O., Saad, Noha I., Helmy, Maged W., Samy, Wael M., Elgindy, Nazik A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2013
• Subjects: Animals; Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - chemistry; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis - drug effects; Casein; Caseins - chemistry; Caspase 3 - metabolism; Cross-Linking Reagents - chemistry; Delayed-Action Preparations; Drug Carriers - chemistry; Drug Delivery Systems; Flutamide - administration & dosage; Flutamide - pharmacology; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; In vivo anti-tumor activity; Ionic-crosslinking; Male; Nanoparticles; Particle Size; Polyphosphates - chemistry; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Rats; Rats, Sprague-Dawley; Sustained release; Nanoparticles; In vivo anti-tumor activity; Sustained release; Casein; Ionic-crosslinking; Prostate cancer
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2013.07.003

In this study, casein (CAS) nanoparticles were used to encapsulate the hydrophobic anticancer drug, flutamide (FLT), aiming at controlling its release, enhancing its anti-tumor activity, and reducing its hepatotoxicity. The nanoparticles were prepared by emulsification of CAS, at pH below its isoelectric point, and stabilized via ionic-crosslinking with sodium tripolyphosphate (TPP). The nanoparticles were spherical and positively charged with a size below 100nm and exhibited a sustained drug release up to 4days. After intravenous administration into prostate cancer-bearing rats for 28days, FLT-loaded CAS nanoparticles showed a higher anti-tumor efficacy as revealed by a significantly higher % reduction in PSA serum level (75%) compared to free FLT (55%). Moreover, the nanoparticles demonstrated a marked reduction in the relative weights of both prostate tumor and seminal vesicle (43% and 32%) compared to free FLT (12% and 18%), respectively. A significantly higher anti-proliferative, anti-angiogenic, and apoptotic effects was demonstrated by the nanoparticles compared to drug solution as evidenced by their ability to decrease the expression of the proliferative marker (Ki-67) and reduce the level of tumor angiogenic markers (VEGF and IGF-1) as well as their ability to activate caspase-3 with subsequent induction of apoptosis in prostate cancer cells. Conclusively, these novel ionically-crosslinked milk protein nanovehicles offer a promising carrier to allow controlled intravenous delivery of hydrophobic anticancer drugs.