Emulsion-based colloidal nanosystems for oral delivery of doxorubicin: improved intestinal paracellular absorption and alleviated cardiotoxicity.
We have previously reported that the limited intestinal absorption via the paracellular pathway may be the primary cause of the low oral bioavailability of doxorubicin (DOX). In this study, we have formulated medium chain glycerides-based colloidal nanosystems to enhance the intestinal paracellular absorption of DOX and reduce its cardiotoxicity. The DOX formulations prepared by the construction of pseudo-ternary phase diagram were characterized in terms of their droplet size distribution, viscosity, drug loading, and drug release. Further evaluation was conducted by an in vitro Caco-2 transport study as well as in situ/in vivo intestinal absorption, bioavailability and toxicity studies. Compared with DOX solution, these formulations enhanced the absorptive transport of DOX across Caco-2 cell monolayers at least partly due to the paracellular-enhancing effects of their lipidic components. Moreover, the in situ intestinal absorption and in vivo oral bioavailability of DOX in rats were markedly enhanced. In addition, no discernible damage was observed in the rat jejunum after oral administration of these DOX formulations while the cardiac toxicity was significantly reduced when compared with intravenous DOX solution. Taken together, the medium chain glycerides-based colloidal nanosystems prepared in this study represent a potentially effective oral delivery system for DOX.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Ji-Eon
JE
Kim
College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Republic of Korea.
In-Soo
IS
Yoon
College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea.
Hyun-Jong
HJ
Cho
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Dong-Hwan
DH
Kim
College of Pharmacy, Dongguk University-Seoul, Gyeonggi 410-820, Republic of Korea.
Young-Hee
YH
Choi
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: ddkim@snu.ac.kr.
Dae-Duk
DD
Kim
D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D054715:Cardiotoxins / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D036103:Nanotechnology / Q000379:methods*; D051381:Rats
D054715:Cardiotoxins; D004655:Emulsions; D004317:Doxorubicin
Cardiotoxicity; Colloidal nanosystem; Doxorubicin; Intestinal paracellular absorption; Medium chain glyceride; Oral delivery