Multi-layer polymeric implants for sustained release of chemopreventives

作者：Aqil Farrukh; Jeyabalan Jeyaprakash; Kausar Hina; Bansal Shyam S; Sharma Ram J; Singh Inder P; Vadhanam Manicka V; Gupta Ramesh C^*

来源：Cancer Letters, 2012, 326(1): 33-40.

DOI：10.1016/j.canlet.2012.07.017

• Polycaprolactone
• Curcumin
• Withaferin A
• Oltipraz
• DNA adducts
• Lung tumor xenograft
• Bioavailability
• Drug delivery
• Curcuminoids

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 (%26quot;coated%26quot; 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.

• 出版日期2012-12-29