TY - JOUR
T1 - Multi-layer polymeric implants for sustained release of chemopreventives
AU - Aqil, Farrukh
AU - Jeyabalan, Jeyaprakash
AU - Kausar, Hina
AU - Bansal, Shyam S.
AU - Sharma, Ram J.
AU - Singh, Inder P.
AU - Vadhanam, Manicka V.
AU - Gupta, Ramesh C.
N1 - Funding Information:
This work was supported from the USPHS Grants CA-118114, CA-125152 and CA-90892, Kentucky Lung Cancer Research Program, and the Agnes Brown Duggan Endowment. R.C.G. holds the Agnes Brown Duggan Chair in Oncological Research. We thank Sabinsa Corp. (East Windsor, NJ) for generously providing curcumin, individual curcuminoids and standardized extract of W. somnifera . Mr. Adam Robinson, Associate Director of the University of Louisville Writing Center is acknowledged for editorial corrections.
PY - 2012/12/29
Y1 - 2012/12/29
N2 - 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 8weeks, 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/109 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.
AB - 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 8weeks, 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/109 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.
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U2 - 10.1016/j.canlet.2012.07.017
DO - 10.1016/j.canlet.2012.07.017
M3 - Article
C2 - 22820161
AN - SCOPUS:84866148275
SN - 0304-3835
VL - 326
SP - 33
EP - 40
JO - Cancer Letters
JF - Cancer Letters
IS - 1
ER -
