Controlled-release systemic delivery - a new concept in cancer chemoprevention

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 issue...

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Bibliographic Details
Published in:Carcinogenesis (New York) 2012-08, Vol.33 (8), p.1608-1615
Main Authors: GUPTA, Ramesh C, BANSAL, Shyam S, AQIL, Farrukh, JEYABALAN, Jeyaprakash, PENGXIAO CAO, KAUSAR, Hina, RUSSELL, Gilandra K, MUNAGALA, Radha, RAVOORI, Srivani, VADHANAM, Manicka V
Format: Article
Language:English
Subjects:
Animals
Anticarcinogenic Agents - administration & dosage
Anticarcinogenic Agents - pharmacokinetics
Biological and medical sciences
Biological Availability
Carcinogenesis, carcinogens and anticarcinogens
Chemical agents
Delayed-Action Preparations
Drug Implants
Female
Humans
Lung Neoplasms - prevention & control
Medical sciences
Mice
Mice, Nude
Original Manuscript
Rats
Rats, Sprague-Dawley
Tissue Distribution
Tumors
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Summary: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.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgs209