A novel synthetic analog of curcumin, the active ingredient in the commonly used spice turmeric, was recently synthesized. The drug shows promise, both as an anti-proliferative agent against restenosis in bare-metal stents and as a cytotoxin against ovarian cancer, following direct administration. However, a major limitation is its insolubility in aqueous media, and limited solubility in most organic solvents. The inability to safely deliver this drug in a soluble form presents a major challenge to further in vivo validation and eventual clinical applicability.
Poly(lactic-co-glycolic acid) (PLGA) is a well-known biodegradable polymer that is widely used as a sustained-release vehicle for various drugs. We hypothesized that the controlled release of the drug from a PLGA matrix would provide an alternative route for its administration in vivo. To improve dosage while limiting systemic cytotoxicity, localized release from disease-specific constructs was proposed, in which the mode of delivery is adapted to suit the different pathologies presented by the disease in vivo. Hence, drug-eluting films, PLGA-coated drug-eluting stents and drug-encapsulating nanoparticles were developed for evaluation in proliferative cardiovascular disease and ovarian cancer.
Fourier transform infrared spectroscopy and electron paramagnetic resonance spectroscopy were used for physical characterization of the biodegradable constructs. Additionally, dynamic light scattering and transmission electron microscopy were used for size characterization of the drug-encapsulating nanoparticles. Viability assays established the dose- and time-dependent anti-proliferative and cytotoxic effects of the biodegradable constructs. Western blot analysis on drug-eluting PLGA films and PLGA-coated PET matrices validated that the cellular mechanism of the action of the drug was conserved between direct administration and sustained release. TEM studies confirmed the internalization of the nanoparticles in vitro. Nanoparticles directly injected into murine ovarian cancer xenograft tumors in vivo were tracked for 14 days without any evidence of systemic toxicity.
These results validate the hypothesis that the sustained release of the drug from a PLGA matrix conserves its pharmacological action when compared to direct administration. This study established proof-of-concept for the localized and sustained release of a novel curcumin analog from biodegradable constructs, thus paving the way for its use as an effective therapeutic in two diseases of clinical significance.