Curcumin is a bioactive molecule extracted from Turmeric roots that has been recognized to possess a wide variety of important biological activities. Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. We have formulated this hydrophobic compound into stable polymeric nanoparticles (nano-curcumin) to enhance its oral absorption. Pharmacokinetic analysis after oral delivery of nano-curcumin in mice demonstrated approximately 20-fold reduction in dose requirement when compared to unformulated curcumin to achieve comparable plasma and central nervous system (CNS) tissue concentrations. This investigation corroborated our previous study of curcumin functionality of attenuating opioid tolerance and dependence, which shows equivalent efficacy of low-dose (20mg/kg) nano-curcumin and high-dose (400mg/kg) pure curcumin in mice. Furthermore, the highly selective and validated liquid chromatography-mass spectrometry (LC-MS) method was developed to quantify curcumin glucuronide, the major metabolite of curcumin. The results suggest that the presence of curcumin in the CNS is essential for prevention and reversal of opioid tolerance and dependence.

We describe the use of an amphiphilic macromolecular brush based on poly(ethylene glycol) (PEG) and poly(D,L-lactide) (PLA) as a stabilizer of hydrophobic solutes. The brush, which in solution adopted an extended backbone conformation consequent with excluded volume effects of the side chains, retained an elongated character in water following the hydrophobic collapse of PLA and the backbone triggered by a rapid change in solvent quality. However, in the presence of hydrophobic solutes at low concentrations in a homogeneous environment, the brush formed spherical unimolecular nanoparticles achieving high solute encapsulation efficiency. As solute content increased and exceeded what appears to be a limit for intramolecular solubilization, intermolecular assembly took place along with the formation of large aggregates, the properties of which were highly dependent on the solute. This first observation of the solute-triggered unimolecular collapse of an amphiphilic macromolecular brush should find important applications for the design of polymeric drug carriers whose properties can be conveniently modified at the single molecule level.

A large group of functional nanomaterials employed in biomedical applications, including targeted drug delivery, relies on amphiphilic polymers to encapsulate therapeutic payloads via self-assembly processes. Knowledge of the micelle structures will provide critical insights into design of polymeric drug delivery systems. Core-shell micelles composed of linear diblock copolymers poly(ethylene glycol)-b-poly(caprolactone) (PEG-b-PCL), poly(ethylene oxide)-b-poly(lactic acid) (PEG-b-PLA), as well as a heterografted brush consisting of a poly(glycidyl methacrylate) backbone with PEG and PLA branches (PGMA-g-PEG/PLA) were characterized by dynamic light scattering (DLS) and small angle X-ray scattering (SAXS) measurements to gain structural information regarding the particle morphology, core-shell size, and aggregation number. The structural information at this quasi-equilibrium state can also be used as a reference when studying the kinetics of polymer micellization.

Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca 21 /calmodulin-dependent protein kinase II a (CaMKIIa), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA)-curcumin nanoparticles (nanocurcumin) to overcome the drug's poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGAcurcumin nanoparticles reduced the dose requirement by 11-to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dosedependent manner, with ED 50 values of 3.9 and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED 50 5 12.6 mg/kg p.o.) and dependence (ED 50 5 3.1 mg/kg p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1-10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIa activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIa activity.

We have formulated hydrophobic curcurmin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] into stable nanoparticle suspensions (nano-curcumin) to overcome its relatively low bioavailability, high rate of metabolism and rapid elimination and clearance from the body. Employing the curcumin nanoformulations as the platform, we discovered that curcumin has the potential to alleviate morphine tolerance. The two types of stable polymeric nanoparticles - poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) - and the hybrid of the two were generated using flash nanoprecipitation integrated with spray drying. The optimized formulations have high drug loading (>45%), small particles size with narrow distribution, 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. Compared with PEGylated nano-curcumin, negatively charged PLGA nanoparticles showed better functionality.