(734a) Self-Assembled Polymeric Nanoparticles Encapsulating Hydrophobic Curcumin to Attenuate Morphine Tolerance

Magdalena Szymusiak¹, Hao Shen¹, Xiaoyu Hu², Zaijie Jim Wang^2,*, and Ying Liu^1,2,*

¹ Department of Chemical Engineering, University of Illinois at Chicago, Chicago, IL 60607, USA

² Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA

* To whom correspondence should be addressed:  liuying@uic.edu, zjwang@uic.edu

Abstract

Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is the active constituent of  Curcuma longa - a yellow-colored traditional herb. It was recently found to have a wide spectrum of pharmacological activities, including antioxidant, cancer chemopreventive, anti-inflammatory, neuro-protective and antinociceptive actions. However, curcumin’s bioavailability is limited by low solubility, high rate of metabolism, and rapid clearance from the body. We have formulated this hydrophobic compound into stable nanoparticle suspensions (nano-curcumin) to overcome these difficulties. Employing the curcumin nanoformulations as the platform, we also discovered that curcumin has the potential to alleviate morphine tolerance. The three types of stable polymeric nanoparticles: (1) poly(lactic-co-glycolic acid) (PLGA), (2) poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA), and (3) the hybrid of the two were generated using flash nanoprecipitation integrated with spray or freeze drying. The process is scalable and reproducible, and the optimized formulations have high drug loading (50%), small particle size (100-200nm), and controlled surface properties. Mice behavioral studies (tail-flick and hot-plate tests) were conducted to verify the effects of nano-curcumin on attenuating morphine tolerance. Significant analgesia was observed in mice during both tail-flick and hot-plate tests using orally administrated nano-curcumin following subcutaneous injections of morphine. However, unformulated curcumin at the same dose showed no effect. Furthermore, the initial pharmacokinetic analysis revealed that nano-curcumin increased the oral bioavailability of the compound in blood plasma more than 80 fold.

Keywords: curcumin, polymeric nanoparticles, flash nanoprecipitation, oral delivery, drug tolerance