title: Metronomic chemotherapy using orally active carboplatin/deoxycholate complex to maintain drug concentration within a tolerable range for effective cancer management.
abstract: 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<0.01) and 20mg/kg dose (86.22% vs. control, P<0.01) in A549 tumor. The number of TUNEL positive cells in the tumor sections was also significantly increased during oral therapy (3.95% in control, whereas 21.37% and 32.39% in 10mg/kg and 20mg/kg dose, respectively; P<0.001). The enhanced anti-tumor efficacy of oral metronomic therapy was attributed with its antiangiogenic mechanism where new blood vessel formation was notably decreased. Finally, the safety of oral complex was confirmed by three weeks toxicity studies; there were no significant systemic or local abnormalities found in mice at 10mg/kg daily oral dose. Our study thus describes an effective and safe oral formulation of carboplatin as a metronomic chemotherapy.
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Foyez
authors.initials: F
authors.lastname: Mahmud
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Farzana
authors.initials: F
authors.lastname: Alam
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Jeong Uk
authors.initials: JU
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, South Korea.
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea.
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, South Korea.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea; Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 110-744, South Korea.
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea. Electronic address: yrbyun@snu.ac.kr.
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D059250:Administration, Metronomic; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D008958:Models, Molecular; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D003840:Deoxycholic Acid; D016190:Carboplatin
keywords: Bile acids; Carboplatin; Metronomic dose; Oral anticancer; Oral drug delivery