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

TY - JOUR

T1 - Metronomic chemotherapy using orally active carboplatin/deoxycholate complex to maintain drug concentration within a tolerable range for effective cancer management

AU - Mahmud, Foyez

AU - Chung, Seung Woo

AU - Alam, Farzana

AU - Choi, Jeong Uk

AU - Kim, Seong Who

AU - Kim, In-San

AU - Kim, Sang Yoon

AU - Lee, Dong Soo

AU - Byun, Youngro

PY - 2017/3/10

Y1 - 2017/3/10

N2 - 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 50 mg/kg oral dose was administered. Further findings of oral bioavailability during a low-dose daily administration of the complex (10 mg/kg) for 3 weeks 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 10 mg/kg (74.09% vs. control, P < 0.01) and 20 mg/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 10 mg/kg and 20 mg/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 10 mg/kg daily oral dose. Our study thus describes an effective and safe oral formulation of carboplatin as a metronomic chemotherapy.

AB - 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 50 mg/kg oral dose was administered. Further findings of oral bioavailability during a low-dose daily administration of the complex (10 mg/kg) for 3 weeks 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 10 mg/kg (74.09% vs. control, P < 0.01) and 20 mg/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 10 mg/kg and 20 mg/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 10 mg/kg daily oral dose. Our study thus describes an effective and safe oral formulation of carboplatin as a metronomic chemotherapy.

KW - Bile acids

KW - Carboplatin

KW - Metronomic dose

KW - Oral anticancer

KW - Oral drug delivery

UR - http://www.scopus.com/inward/record.url?scp=85010876878&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010876878&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2017.01.020

DO - 10.1016/j.jconrel.2017.01.020

M3 - Article

C2 - 28093298

AN - SCOPUS:85010876878

VL - 249

SP - 42

EP - 52

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -