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Karthikeyan et al. Nanocurcumin: A Promising Candidate for Therapeutic Applications INTRODUCTION Curcuma longa commonly referred to as turmeric is an ancient perennial herb belonging to the family Zingiberaceae and native to India. Curcuma has developed by incessant cross-breeding and selection. To date, over 100 known species are reported in the species of Curcuma (Esatbeyoglu et al., 2012). Besides, the widespread Curcuma longa (syn. Curcuma domestica), Curcuma aromatica, and Curcuma xanthorrhiza are other common species (Itokawa et al., 2008). It is grown in tropical and subtropical areas of the world, extensively cultivated in Asian countries, viz., India, Burma, Bangladesh, China, Indonesia, Japan, Taiwan, Thailand, and Vietnam (Chattopadhyay et al., 2004; Damalas, 2011). Curcuma species exhibit inter and intraspecific differences in the biologically active principles combined with morphological differences in the above-ground vegetative and floral characteristics and the under-ground rhizome characteristics (Sasikumar, 2005). Curcuma has a strong relationship with the socio-cultural life of the people of Asia, using it as a medicine, nutritional spice, and food preservative. Curcumin is an important bioactive ingredient isolated from the rhizomes of C. longa (Tayyem et al., 2006; Heger et al., 2014). In the middle of the 20th century, researchers described the biological features of curcumin. Three sovereign research teams identified various features of curcumin in the 1970s, including cholesterol-lowering (Patil and Srinivasan, 1971), antidiabetic (Srinivasan, 1972), anti-inflammatory (Srimal and Dhawan, 1973), and anti-oxidant (Sharma, 1976) activities. Curcumin has been shown to control various signaling molecules at the molecular level based on the target and cell background. It can trigger up or down-regulation. Thus, it acts on multiple targets in cellular pathways creating an agent that able to complete multiple actions (Paulraj et al., 2019). In human, the biological activity of curcumin relies on its bioavailability. Studies of bioavailability have detailed the amount and concentration at which curcumin is engrossed, occurs in the plasma, and entering its target location. In the recent three decades, researchers have worked on curcumin for its various functional and biological features viz., anti-inflammatory, anti-oxidant, anti-mutagenic, antimicrobial activity, anti-tumoral, wound healing, and antiangiogenesis effects (Mahady et al., 2002; Aggarwal and Harikumar, 2009; Akbik et al., 2014; Hu et al., 2015; Fernández-Bedmar and Alonso-Moraga, 2016; Da Silva et al., 2018; Imran et al., 2018; Willenbacher et al., 2019). Existing research data provide evidence to support the curcumin’s beneficial effects on different human diseases including cancer (Adiwidjaja et al., 2017), diabetes (Shome et al., 2016), lung and chronic kidney diseases (Gupta et al., 2013; Trujillo et al., 2013), neurological disorders (Aggarwal and Sung, 2009), metabolic disease (Panahi et al., 2016), liver problems (Nabavi et al., 2014), cardiovascular disease (Bhullar et al., 2013), digestive disorders (Debjit Bhowmik et al., 2009), and other inflammatory diseases (Beevers and Huang, 2011). Despite its reported benefits, multiple factors often limit the practical applications of curcumin. For instance, poor water solubility and physicochemical instability, low pharmacokinetics and bioavailability, poor bioactive absorption, rapid metabolization, low penetration and targeting efficacy, sensitivity to alkaline conditions, metal ions heat and light (Flora et al., 2013). However, these obstacles being solved by encapsulating curcumin into nanoformulations (nanocurcumin) (Yallapu et al., 2012a). Integrating curcumin into nanocarriers through various methods is an appropriate and fruitful choice to upsurge the biological activity of curcumin, which increases its bioavailability and solubility, long time circulation, and retention in the body, and overcome physiological barriers of curcumin (Sahu et al., 2008; Das et al., 2010; Li et al., 2013; Bhatia et al., 2016; Fonseca-Santos et al., 2016). Also, it can reduce the unintended toxicity to surrounding normal cells/tissues by diffusing the indent tissues. So far, many researchers showed the feasibility of using nanoformulation based approaches to improve curcumin application in both in vitro and in vivo studies that involve the use of liposomes, polymers, conjugates, cyclodextrins, micelles, dendrimers, and nanoparticles (Ghalandarlaki et al., 2014; Naksuriya et al., 2014; Yallapu et al., 2015). Of these, some curcumin nanoformulations have extended clinical studies and applications. Since 2011, more than 1,500 publications related to curcumin nanoparticles were available in the NCBI PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez, accessed 6th March 2020). In the beginning, many researchers worked mainly to improve bioavailability but later also focused on effective curcumin targeting in the diseased area with peptide mediation, aptamer, and antibody support. Curcumin was encapsulated into poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) and oral bioavailability was examined. Results showed a nine-fold increase in nanocurcumin over the native curcumin (Shaikh et al., 2009). Experimental data also support that nanoform of curcumin produced an effective result against liver and heart problems (Shimatsu et al., 2012), cancers (Mohanty and Sahoo, 2010), and brain tumors (Lim et al., 2011). In this review first, we briefly discuss chemistry and molecular targets of curcumin and methods for synthesis of curcumin nanoformulation. In the next section, different curcumin nanoformulations, comparative characteristics of curcumin and nanocurcumin, and nanocurcumin implications in various therapeutic applications are summarized and discussed. In the final section of this review, we discussed the status of ongoing clinical trials and patents, the research gap, and future research directions needed to propose curcumin as a promising therapeutic candidate. CHEMICAL STRUCTURE AND MOLECULAR TARGETS OF CURCUMIN The probable chemical composition of curcumin was described by many researchers in the eighteenth century. Curcumin’s International Union of Pure and Applied Chemistry (IUPAC) name is (1E,6E)-1,7-bis(4-hydroxy-methoxyphenyl)-1,6- heptadiene-3,5-dione (Miłobȩdzka et al., 1910). Chemical formula Frontiers in Pharmacology | www.frontiersin.org 2 May 2020 | Volume 11 | Article 487PDF Image | Nanocurcumin Promising Candidate for Therapeutic Applications
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