Metronomic chemotherapy using orally active carboplatin/deoxycholate complex to maintain drug concentration within a tolerable range for effective cancer management

• Published in: Journal of controlled release 2017-03, Vol.249, p.42-52
• Main Authors: Mahmud, Foyez, Chung, Seung Woo, Alam, Farzana, Choi, Jeong Uk, Kim, Seong Who, Kim, In-San, Kim, Sang Yoon, Lee, Dong Soo, Byun, Youngro
• Format: Article
• Language: English
• Subjects: Administration, Metronomic; Administration, Oral; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols; Bile acids; Carboplatin; Carboplatin - administration & dosage; Carboplatin - analogs & derivatives; Carboplatin - pharmacokinetics; Carboplatin - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Deoxycholic Acid - administration & dosage; Deoxycholic Acid - analogs & derivatives; Deoxycholic Acid - pharmacokinetics; Deoxycholic Acid - therapeutic use; Lung - drug effects; Lung - pathology; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Metronomic dose; Mice, Nude; Models, Molecular; Oral anticancer; Oral drug delivery; Rats, Sprague-Dawley
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.01.020

Metronomic chemotherapy has translated into favorable toxicity profile and capable of delaying tumor progression. Despite its promise, conventional injectable chemotherapeutics are not meaningful to use as metronomic due to the necessity of frequent administration for personalized therapy in long-term cancer treatments. This study aims to exploit the benefits of the oral application of carboplatin as metronomic therapy for non-small cell lung cancer (NSCLC). We developed an orally active carboplatin by physical complexation with a deoxycholic acid (DOCA). The X-ray diffraction (XRD) patterns showed the disappearance of crystalline peaks from carboplatin by forming the complex with DOCA. In vivo pharmacokinetic (PK) study confirmed the oral absorption of carboplatin/DOCA complex. The oral bioavailability of carboplatin/DOCA complex and native carboplatin were calculated as 24.33% and 1.16%, respectively, when a single 50mg/kg oral dose was administered. Further findings of oral bioavailability during a low-dose daily administration of the complex (10mg/kg) for 3weeks were showed 19.17% at day-0, 30.27% at day-7, 26.77% at day-14, and 22.48% at day-21, demonstrating its potential for metronomic chemotherapy. The dose dependent antitumor effects of oral carboplatin were evaluated in SCC7 and A549 tumor xenograft mice. It was found that the oral carboplatin complex exhibited potent anti-tumor activity at 10mg/kg (74.09% vs. control, P