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Karthikeyan et al. Nanocurcumin: A Promising Candidate for Therapeutic Applications effects on in vitro renal cancer cells. The results confirmed that CWAuNPs was an effective anticancer agent and induced apoptosis in the renal carcinoma cell line A498 (Liu et al., 2019). In a similar manner, curcumin-green synthesized gold nanoparticles (AuNP’s-Cur) evaluated at colon and breast cancer cell lines, HCT-116 and MCF-7 respectively. The study revealed that the AuNP’s-Cur have shown high antiproliferative and apoptotic activity against cancer cells, compared to native curcumin (Elbialy et al., 2019). Conjugates The complex formed from the joining of two or more molecules, especially by the covalent bond is referred to as conjugates. Curcumin conjugation with small molecules and hydrophilic polymers increase its solubility and oral bioavailability. Manju and Sreenivasan reported conjugation of curcumin with hyaluronic acid decreases gold nanoparticles (AuNPs) effects and improves its aqueous solubility and stability (Manju and Sreenivasan, 2011). Singh et al. demonstrated that curcumin conjugates piperic acid and glycine were prepared by esterifying the phenolic hydroxyls of 4 and 4 to increase its bioavailability and trigger apoptosis in MCF-7 and MDA-MB-231 cell lines through a mitochondrion based pathway (Singh et al., 2013a). Similarly, Muangnoi et al. prepared glutaric acid conjugate of curcumin, curcumin-glutaric acid (CurDG) prodrug through ester linkage and tested in mice. It revealed that solubility and antinociceptive properties were increased for CurDG compared to curcumin (Muangnoi et al., 2018). Recently, the gold nanoparticle–PVP–curcumin conjugate (PVP–C–AuNP) found to have obstructed the amyloid Ab (1–6) aggregation with high degree of curcumin bioavailabilty, loading efficiency (80%), and prolonged drug release. This formulation potential to treat Alzheimer’s disease (Brahmkhatri et al., 2018). Cyclodextrins Cyclodextrins [a-, b-, g-cyclodextrins (CD)] are multi- component hybrid, soluble carrier systems that bear on non- covalent bound drugs. They often used to enhance drug solubility and stability and to deliver drugs in their active form to the cancer cells. Cyclodextrins are bucket-shaped oligosaccharides consisting of six (a-), seven (b-), or eight (g-) D-glucopyranose units linked through a-1,4-glycosidic bond to form macrocycles (Szejtli, 1998; Ntoutoume et al., 2016). b-CD, g-CD, and its derivatives were widely used to deliver the drugs due to its low price, relatively easy synthesis and adaptability. Recently, the significance of cyclodextrin in the curcumin delivery system is demonstrated by many researchers (Guo, 2019). Yallapu et al. developed a b-CD mediated curcumin drug delivery system and showed that b-CD-curcumin increased the distribution of curcumin in prostate cancer cells compared to unformulated curcumin and enhanced its therapeutic value (Yallapu et al., 2010). Zhang et al. found that b-cyclodextrin-curcumin (CD15) formulation exhibited high cytotoxicity than normal curcumin through pro-apoptotic and cell cycle arrest activities of lung cancer cells (Zhang et al., 2016). Also, experimental data from this study suggested that CD15 was a potential system for optimizing the delivery of curcumin and its therapeutic efficacy in lung cancer. Nanoparticles were prepared using chitosan, hyaluronic acid, and sulfobutyl-ether-b- cyclodextrin and with or without curcumin and used to treat with intestinal epithelial and colorectal cancer cells. Curcumin nanoparticles showed great encapsulation efficiency and stability. It also decreases the curcumin cytotoxicity in normal intestinal epithelial cells and to reduce cancer cell proliferation (Abruzzo et al., 2016). Further, the water soluble complex of curcumin with cyclodextrins improved solubility and provided the sustained release of drugs in retinitis pigmentosa. The results helped to formulate the eye drops from naturally derived phytochemical (Nabih Maria et al., 2017). Solid Dispersions Molecular dispersion of two various compounds known as a solid dispersion. It is normally a hydrophobic drug (i.e., curcumin in a solid hydrophilic carrier or matrix) (Dhirendra et al., 2009; Flora et al., 2013). To release the drug, solid dispersions are being dissolved as minute colloidal particles of any aqueous media. It diminishes the particle size to nanorange with better wettability increasing the pharmacokinetic properties and oral biodistribution of the drugs. Solid dispersions are produced through fusion-melt, solvent-based methods, and also by combining both the solvent and fusion (hybrid) methods (Tihanyi and Vastag, 2011). Li et al. prepared a curcumin–Eudragit® PO solid dispersion through a solution mixing technique to increase the solubility and stability of curcumin water (Li et al., 2015). Besides, in vitro transdermal analysis was performed and confirmed the capability of Cur@ EPO as a vehicle to deliver curcumin in medicinal applications. In another study, curcumin-Gelucire®50/13 solid dispersion prepared by spray drying showed better solubility (3,600-fold) in water compared with the native curcumin. Besides, the bioavailability and anti-inflammatory activity of curcumin were highly improved by solid dispersion as a consequence of an increased gastrointestinal absorption (Teixeira et al., 2016). Similarly, curcumin solid dispersion-encapsulated temperature- sensitive in situ hydrogels (CSDG) effective for treatment for vaginal bacterial infection by stable and sustained release of curcumin (Zhang et al., 2019). Micelles Micelle is referred to as a set of amphiphilic surfactant molecules that spontaneously aggregate in water into a spherical vesicle. It is widely used to deliver poorly water-soluble drugs like curcumin (Rana et al., 2017). Liu et al. used a one-step solid dispersion approach to make curcumin encapsulated polymeric micelles (Cur-M) and studied the effectiveness of Cur-M in a breast tumor model. It was seen that, compared with unformulated curcumin, Cur-M was successful in obstructing the growth of breast tumors and spontaneous pulmonary metastasis of the lungs (Liu et al., 2013). Curcumin-poly (ethylene glycol) methyl ether (MPEG-PCL) micelles solid dispersion enhanced the antiangiogenesis and anti-tumor effect of curcumin. Results from this study also proposed that curcumin micelles may useful in pulmonary carcinoma treatment (Gong et al., 2013). Chang et al. evaluated the Frontiers in Pharmacology | www.frontiersin.org 9 May 2020 | Volume 11 | Article 487PDF Image | Nanocurcumin Promising Candidate for Therapeutic Applications
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