title: Multi-layer polymeric implants for sustained release of chemopreventives.
abstract: Poor oral bioavailability limits the use of many chemopreventives in the prevention and treatment of cancer. To overcome this limitation, we report an improvised implant formulation ("coated" implants) using curcumin, individual curcuminoids, withaferin A and oltipraz. This method involves the coating of blank polycaprolactone implants with 20-30 layers of 10-20% polycaprolactone solution in dichloromethane containing 0.5-2% of the test agent. The in vitro release showed that while oltipraz was released with almost zero-order kinetics over 8 weeks, curcumin, individual curcuminoids and withaferin A were released with some initial burst. The in vivo release was determined by grafting implants subcutaneously in A/J mice. When delivered by coated implants, oltipraz significantly diminished lung DNA adducts in mice treated with dibenzo[a,l]pyrene compared with sham treatment (28 ± 7 versus 54 ± 17 adducts/10(9) nucleotides). Withaferin A also diminished DNA adducts, but it was insignificant. Curcumin and individual curcuminoids were ineffective. Analysis of lung, liver and brain by UPLC-fluorescence showed the presence of the three test curcuminoids indicating effectiveness of the implant delivery system. Further, based on its known antitumor activity in vivo, withaferin A given via the implants significantly inhibited human lung cancer A549 xenograft in athymic nude mice, while it was ineffective when the same total dose was administered i.p. and required over 2-fold higher dose to elicit effectiveness. Together, our data suggest that coated polymeric implants can accommodate heat-labile compounds, can furnish sustained release for long duration, and elicit DNA damage-inhibiting and anti-tumor activities.
authors: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors: Farrukh
authors: F
authors: Aqil
authors: Jeyaprakash
authors: J
authors: Jeyabalan
authors: Hina
authors: H
authors: Kausar
authors: Shyam S
authors: SS
authors: Bansal
authors: Ram J
authors: RJ
authors: Sharma
authors: Inder P
authors: IP
authors: Singh
authors: Manicka V
authors: MV
authors: Vadhanam
authors: Ramesh C
authors: RC
authors: Gupta
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000633:toxicity; D001682:Biological Availability; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage; D003474:Curcumin / Q000008:administration & dosage; D018736:DNA Adducts; D005260:Female; D006801:Humans; D015918:Infusion Pumps, Implantable / Q000009:adverse effects; D051379:Mice; D008819:Mice, Nude; D011091:Polyesters / Q000008:administration & dosage*; D011108:Polymers / Q000008:administration & dosage*; D011719:Pyrazines / Q000008:administration & dosage; D013871:Thiones; D013876:Thiophenes; D014018:Tissue Distribution; D054358:Withanolides / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D016588:Anticarcinogenic Agents; D020099:Coated Materials, Biocompatible; D018736:DNA Adducts; D011091:Polyesters; D011108:Polymers; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D054358:Withanolides; C016240:polycaprolactone; C026209:oltipraz; D003474:Curcumin; C009684:withaferin A