Carcinogenesis. 2012 Jun 13. [Epub ahead of print]
Controlled-release systemic delivery - a new concept in cancer chemoprevention.
Gupta RC, Bansal S, Aqil F, Jeyabalan J, Cao P, Kausar H, Russell G, Munagala R, Ravoori S, Vadhanam MV.
Source
University of Louisville, Pharmacology and Toxicology/James Graham Brown Cancer Center, Baxter II, Room 304E, 580 S. Preston Street, Louisville, Kentucky, United States, 40202, 502-852-3682.
Abstract
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 cancerA549 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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