Modified curcumin with hyaluronic acid: Combination of pro-drug and nano-micelle strategy to address the curcumin challenge
Introduction
Curcumin [(E,E)-1,7-bis(4-hydroxy-3-methoxy-phenyl)-1,6-heptadiene-3,5-ione] is a natural phenolic compound isolated from the perennial herb Curcuma longa (turmeric) (Ramawat & Goyal, 2008). Turmeric has been consumed as food stuff and nutritional supplement in Indian and other oriental countries for thousands of years. Recently, numerous articles were released discussing the health beneficial effects of curcumin such as antioxidant, anti-inflammatory, anti-cancer and many others (Kuo et al., 1996, Eliaz and Szoka, 2001, Gota et al., 2010, Ishida et al., 2007, Kakkar et al., 2011, Surh and Chun, 2007). However, the pleiotropic activities of curcumin are not fully realized due to its low water solubility, low stability and low bioavailability when using conventional administrative methods (Onoue et al., 2010). In the past decades, researchers have explored several ways to solve these problems of curcumin. Among them, the nano-system and pro-drug strategies attracted much attention.
The nano-system, such as liposome, micelle, solid lipid particle and emulsion, has been developed to encapsulate curcumin and enhance its bioavailability (Yallapu, Jaggi & Chauhan, 2012). In our previous research, curcumin was loaded into chitosan-coated nano-liposome which showed higher mucin adsorption ability (Shin, Chung, Kim, Joung & Park, 2013). Lei Liu and co-workers studied the anti-tumor activity of a polymeric micelle loaded with curcumin (Liu et al., 2013). Many researchers also encapsulated curcumin into solid lipid particle formulation and reported the increased bioavailability and pharmacokinetics parameters (Menon and Sudheer, 2007, Misra et al., 2011). Recently, silica nanoparticle was also studied as carrier to delivery curcumin (Tikekar, Pan & Nitin, 2013). Nevertheless, the need of novel nano-system which circumvents some of the inherent problems, such as complex preparation procedures, low stability, and low loading efficiency, are still there (Bansal, Goel, Aqil, Vadhanam & Gupta, 2011).
On the other hand, the pro-drug method also got great success to increase the water solubility of curcumin. Curcumin molecule has one hydroxyl group attached on each of the two benzene rings as depicted in Fig. 1. The hydroxyl group is highly reactive with carboxyl group as it tends to lose the proton under proper conditions. Hydrophilic polymers are usually used to conjugate with curcumin in the pro-drug approach. Synthetic polymers such as polyethylene glycol, poly (lactic acid) were reported as the hydrophilic moieties (Murphy et al., 2012, Naksuriya et al., 2014). Even though the synthetic polymers achieved certain breakthrough, the safety concern about them always limits their applications (Ishida, Wang, Shimizu, Nawata, & Kiwada, 2007). On the contrary, naturally occurred polymers show much better biodegradability and biocompatibility than their synthetic counterparts (Boztas et al., 2013). Among the naturally occurred polymers, hyaluronic acid (HA) owns particular features such as specific reaction with certain receptors (CD44 and RHAMM) which are over-expressed on the surface of many tumor cells (Misra et al., 2011, Eliaz and Szoka, 2001). In fact, it has long been hypothesized that HA conjugated with anti-cancer drugs can work as the ‘smart bullet’ in the anti-cancer therapy (Misra et al., 2011). The carboxyl group on HA is usually the main target in the modification reaction because it can react with hydroxyl and amino groups of other compounds under the catalysis of carbodiimide reagents (Kong, Chen, & Park, 2011). In one recent publication, S. Manju and K. Sreenivasan reported the direct reaction between HA and curcumin in the DMSO/water (1:1) system (Manju & Sreenivasan, 2011). However, the reaction efficiency seems to be low as suggested by the results of their another recent released publication (Dey & Sreenivasan, 2014). So here, we conducted the similar reaction in pure DMSO which homogenously dissolved HA and curcumin. With the aim of combining the nano-micelle and pro-drug method, after the synthesis, we loaded curcumin again into the nano-micelle formed by the modified curcumin. The HA modified curcumin (HMC) dissolved in water with yellowish color and formed nano size micelle with low PDI. Curcumin was loaded into the core of the micelle using vortexing and sonication method and the loading capability was found to be high. After that, we also examined the antioxidant activity using DPPH radical scavenging and reducing power assay. The HMC not only increased the water solubility and antioxidant activity but also worked as carrier for curcumin which is promising to overcome its prime limitation.
Section snippets
Materials
Hyaluronic acid sodium salt form with molecular weight of 10 kDa was provided by Kewpie Corporation (Tokyo, Japan). Curcumin with 98% purity was purchased from Acros Organics (New Jersey, USA). 1-Hydroxybenzotriazole hydrate (HOBt), 1,1-di-phenyl-2-picrylhydrazyl (DPPH), Folin–Ciocalteu's reagent (FCR) and gallic acid were from Sigma-Aldrich (Missouri, USA). N,N′-Dicyclohexylcarbodiimide (DCC) was from TCI (Tokyo, Japan). Dimethyl sulfoxide (DMSO) was purchased from Duksan Pure Chemicals
Modification of curcumin with hyaluronic acid
Hyaluronic acid (HA) was conjugated to curcumin through the carbodiimide reaction as illustrated in Fig. 1. In order to facilitate the reaction, HA and curcumin should be dissolved homogenously in the reaction solvent. Before it reacted with curcumin, HA was transformed to DMSO soluble form according to our patented method. HA sodium salt form was mixed with HCl which helped to acidify HA. Sodium ion was removed along with chloride ion by washing with 75% ethanol, 95% ethanol and diethyl ether
Conclusion
In this study, we tried to combine the pro-drug and nano-micelle approaches to increase the water solubility and antioxidant activity of curcumin. Hyaluronic acid was conjugated with curcumin using the carbodiimide chemistry reaction. FT-IR spectra and UV–vis analysis indicated that the reaction happened successfully with DS about 0.71%. HMC formed nano-micelle spontaneously when dissolved in water and encapsulated curcumin again in the core of the micelle. Moreover, HMC and CHMC greatly
Acknowledgements
This research was supported by a grant from the Institute of Biomedical Science and Food Safety, Korea University and by the International Research & Development Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) of Korea (Grant number: 2012K1A3A1A20031356).
References (37)
- et al.
Conjugation of curcumin onto alginate enhances aqueous solubility and stability of curcumin
Carbohydrate Polymers
(2014) - et al.
Lyophilised ready-to-use formulations of PEG-PCL-PEI nano-carriers for siRNA delivery
International Journal of Pharmaceutics
(2012) - et al.
PEGylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner
Journal of Controlled Release
(2007) - et al.
Flocculation and coalescence of micron-size emulsion droplets
Colloids and Surfaces, A: Physicochemical and Engineering Aspects
(1999) - et al.
Structural and antioxidant properties of gamma irradiated hyaluronic acid
Food Chemistry
(2008) - et al.
Design and investigation of nanoemulsified carrier based on amphiphile-modified hyaluronic acid
Carbohydrate Polymers
(2011) - et al.
Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells
Biochimica et Biophysica Acta (BBA) — Molecular Basis of Disease
(1996) - et al.
Curcumin loaded polymeric micelles inhibit breast tumor growth and spontaneous pulmonary metastasis
International Journal of Pharmaceutics
(2013) - et al.
Conjugation of curcumin onto hyaluronic acid enhances its aqueous solubility and stability
Journal of Colloid and Interface Science
(2011) - et al.
Reproductive effects of a pegylated curcumin
Reproductive Toxicology
(2012)
Curcumin nanoformulations: A review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment
Biomaterials
Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability
Journal of Pharmaceutical Sciences
Fate of curcumin encapsulated in silica nanoparticle stabilized Pickering emulsion during storage and simulated digestion
Food Research International
Studies on curcumin and curcuminoids: XXXI. Symmetric and asymmetric curcuminoids: Stability, activity and complexation with cyclodextrin
International Journal of Pharmaceutics
Curcumin nanoformulations: A future nanomedicine for cancer
Drug Discovery Today
Curcumin loaded mixed micelles composed of Pluronic P123 and F68: Preparation, optimization and in vitro characterization
Colloids and Surfaces B: Biointerfaces
Curcumin and genistein coloaded nanostructured lipid carriers: In vitro digestion and antiprostate cancer activity
Journal of Agricultural and Food Chemistry
A comparative study of PNIPAM nanoparticles of curcumin, demethoxycurcumin, and bisdemethoxycurcumin and their effects on oxidative stress markers in experimental stroke
Protoplasma
Cited by (81)
Unlocking the potential of hyaluronic acid: Exploring its physicochemical properties, modification, and role in food applications
2023, Trends in Food Science and TechnologyHyaluronic acid-based nanodelivery systems for food bioactive compounds
2023, Trends in Food Science and TechnologyCurcumin-Incorporated Biomaterials: In silico and in vitro evaluation of biological potentials
2023, Coordination Chemistry ReviewsRecent developments in natural biopolymer based drug delivery systems
2023, RSC AdvancesDetecting different amorphous – Amorphous phase separation patterns in co-amorphous mixtures with high resolution imaging FTIR spectroscopy
2022, European Journal of Pharmaceutics and BiopharmaceuticsTumor homing dextran and curcumin derived amphiphilic functional polymer self-assembling to tubustecan nanoarchitectures: A strategy of adorning the golden spice (curcumin) for taming the red devil (Dox)
2022, Journal of Drug Delivery Science and Technology