TY - JOUR
T1 - Controlled-release systemic delivery - a new concept in cancer chemoprevention
AU - Gupta, Ramesh C.
AU - Bansal, Shyam S.
AU - Aqil, Farrukh
AU - Jeyabalan, Jeyaprakash
AU - Cao, Pengxiao
AU - Kausar, Hina
AU - Russell, Gilandra K.
AU - Munagala, Radha
AU - Ravoori, Srivani
AU - Vadhanam, Manicka V.
N1 - Funding Information:
This work was supported from the USPHS grants CA-118114, CA-125152 and CA-90892, Kentucky Lung Cancer Research Program Cycles 7 and 10, and the Agnes Brown Duggan Endowment. P.C. and G.K.R. were supported, in part, from the NIEHS training grant T32-ES011564-07. R.C.G. holds the Agnes Brown Duggan Chair in Oncological Research and also the recipient of USHPS and Kentucky research grants listed. We thank Dr Harrell Hurst, University of Louisville for assisting in the GC–MS analysis of dichloromethane in polycaprolactone implants, Dr Robert Cooney, University of Hawaii for suggesting the use of tetrahydrofuran to dissolve highly lipophilic compounds and Dr Rajesh Singh, currently at Morehouse School of Medicine for his initial discussion on the choice of polymer. We also thank Sabinsa Corp. (East Windsor, NJ) for generously providing curcumin, the individual curcuminoids and enriched Withania somifera; Dr. Inder Pal Singh of National Institute of Pharmaceutical Education and Research, SAS Nagar, India for isolating withaferin A from enriched Withania somifera; Pharma Foods International Co., LTD (Kyoto, Japan) for polyphenon E (a standardized green tea extract). Ms Emily Freund of the University of Louisville Writing Center is acknowledged for editorial corrections.
PY - 2012/8
Y1 - 2012/8
N2 - Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo.
AB - Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo.
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U2 - 10.1093/carcin/bgs209
DO - 10.1093/carcin/bgs209
M3 - Article
C2 - 22696595
AN - SCOPUS:84865325440
SN - 0143-3334
VL - 33
SP - 1608
EP - 1615
JO - Carcinogenesis
JF - Carcinogenesis
IS - 8
ER -