Date on Master's Thesis/Doctoral Dissertation

8-2011

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Committee Chair

Gupta, Ramesh

Author's Keywords

Curcumin; Chemoprevention; Polymeric implants; Breast cancer; Drug delivery; Bio-compatibility

Subject

Drug delivery systems; Curcumin--Therapeutic use--Administration

Abstract

Curcumin, a plant derived compound has shown significant potency against various chronic diseases like cancer in cell culture and animal studies. However, the introduction of this compound into clinical setting is limited by its poor oral bioavailability and thereby requires high doses for efficacy. We hypothesized that localized/systemic delivery of curcumin by polymeric implants can improve its efficacy by bypassing the oral route and by restricting majority of the drug at the tumor site. Therefore, we developed a polymeric implantable drug delivery system using poly (E-caprolactone) as the polymer and optimized it with respect to polymer molecular weight, drug load and formulation additives both under in vitro as well as under in vivo conditions so as to obtain a desired drug release profile. Drug release was found to be proportional to surface area and drug load for up to 10% concentration. The presence of water-soluble polymers like polyethylene glycol (PEG) at 35% w/w composition was also found to increase the drug release with in vivo release being 1.8-2 fold higher than in vitro release. Higher plasma and brain curcumin concentrations with almost similar levels in liver were observed by these implants but at 25-30 fold lower doses than dietary curcumin even after 3 months. Furthermore, these implants were found to provide a controlled/predictable release ranging from months to years. Analysis of biochemical parameters of liver and kidney function revealed non-toxicity of the implant formulation as well as of curcumin administered continuously into systemic circulation by these implants. Although a mild to moderate inflammatory reaction was observed at the local site of implantation, yet no toxic effect on health or physical well being of rats was observed. Moreover, systemically administered high doses of curcumin (by implants) were found to be more efficacious in modulation of cytochrome P450 enzymes like CYP1A1, CYP3A4 and CYP1B1 as well as in inhibiting Ermediated mammary tumorigenesis in ACI rats. These implants were found to reduce the tumor burden significantly by 35% and tumor multiplicity by 70% via favorable alteration of E2 metabolism suggestive of curcumin's potent chemopreventive activity when delivered via implants as compared to diet.

Download

Share

COinS