Abstract 4631: Sustained-release, multi-layer polymeric implants for heat-labile compounds

Abstract

Abstract Many naturally-occurring compounds have elicited chemotherapeutic activity in various cancer models. However, due to the limited bioavailability, the effective dose is either not translatable or has rendered only limited effectiveness despite high doses. We previously reported a novel concept in which polycaprolactone:F68 (PCL:F68) implants embedded with test agents provide sustained low doses. While tested successfully for various agents, this formulation (“extrusion” method) does not apply to heat-labile compounds; further, it also renders an initial burst release for many compounds. To overcome these limitations, we now report an improvised formulation (“coated” implants). The method involves i) preparation of blank PCL:F68 implants (1.2 mm dia), and ii) coating of 20-40 layers by dipping blank implants, with intermittent drying, in 10-20% PCL solution in dichloromethane (DCM) containing 0.5-2% of test agent in DCM or another appropriate solvent. The coated implants of oltipraz, withaferin A and curcumin when tested for in vitro release showed that i) the burst release was minimal, and ii) the release was largely sustained for three weeks. To determine their efficacy, female A/J mice were treated with dibenzo[a,l]pyrene (DBP) by subcutaneous polymeric implants alone or together with coated implants of oltipraz, withaferin A and curcumin (two, 15 mm long, 2.5 mm dia; 10%, 5% and 10% loads, respectively). Three weeks later animals were euthanized. Analysis of the target (lung) DNA by 32P-postlabeling showed significant inhibition of DNA adducts (adducts/109 nucleotides) by oltipraz implants (28 ± 7) compared with sham treatment (54 ± 17); withaferin A (45 ± 26) and curcumin (71 ± 17) revealed no significant effect. The oltipraz-mediated inhibition of DNA adducts is consistent with the inhibition of CYP1A1, 1A2 and1B1 activity with oltipraz. Measurement of the residual compounds in the implants recovered from the animals showed that the total amounts of oltipraz (3.1 mg), curcumin (6.1 mg) and withaferin A (1.9 mg) administered was 10 to 20-fold lower than the typical dietary doses reported. To determine if the implant delivery concept would lower the effective dose in a tumor model, nude mice were inoculated with human lung cancer A549 cells (3×106 cells), and then treated with withaferin A coated implants. Two additional groups were treated i.p. with vehicle or withaferin A (8 mg/kg, on alternate days). Four weeks into the study, withaferin A treatment has shown nearly 50% reduction in tumor burden irrespective of the route of the treatment, except that the implant route cut down the effective dose significantly. Together, our data suggest that coated polymeric implants can accommodate heat-labile compounds, furnish more sustained release, and can elicit DNA damage-inhibiting and anti-tumor activities in animal models (Supported from the USPHS grants CA-118114, CA-125152, KLCRP and the Duggan Endowment). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4631. doi:10.1158/1538-7445.AM2011-4631