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Karthikeyan et al. Nanocurcumin: A Promising Candidate for Therapeutic Applications outcome of various sizes of curcumin encapsulated micelles on human colon carcinoma cells at in vitro condition for their cell uptake, intracellular localization, and cytotoxicity. The results suggest that small sized curcumin loaded micelles have potential to induce better cytotoxicity effect on the human colon carcinoma cells than larger micelles. Explaining thus that drug loading, micelle size and uptake/release kinetics are important considerations for the nanoparticle drug delivery (Chang et al., 2016). Recently, curcumin loaded into the zein-super hydrophilic zwitterionic polymers, poly(sulfobetaine methacrylate) (PSBMA) micelles had much better stability, cellular uptake, cytotoxicity to cancer cells, and pharmacokinetics compared with native curcumin (Chen S. et al., 2020). Nanospheres and Microcapsules Nanospheres are known as solid matrix particles wherein the main component (drug) is mixed, but microcapsule contains the internal core and outer polymeric shell. Arunraj et al. synthesized the surfactant-free curcumin nanospheres (CNSs) and detailed the evidence of CNSs anticancer effect on breast cancer and osteosarcoma cell lines (Arunraj et al., 2014). Smooth and spherical curcumin encapsulated PLGA nanospheres are potential for clinical application in prostate cancer. Cell viability analysis concluded that the curcumin encapsulated nanospheres were capable to exert a further strong activity against cancer cells compared with native curcumin (Mukerjee and Vishwanatha, 2009). Dimethyl curcumin encapsulated PLGA nanospheres (ASC-J9) were evaluated in breast cancer cells. It has been seen that PLGA nanospheres were potential of delivering ASC-J9 intracellularly, most important to arrest the growth of estrogen-dependent MCF-7 cancer cells (Verderio et al., 2014). Curcumin was successfully encapsulated into the poly(ethylene glycol)–poly(lactic acid) (PEG–PLA) nanospheres and delivered to HeLa and MDA-MB-231 cancer cells. This formulation improved curcumin solubility and stability than native curcumin and showed better cytotoxic effects against cancer cells (Liang et al., 2017). To enhance the bioavailability of curcumin, microcapsules containing a solid lipid nanoparticle and mesoporous silica shell were prepared (Kim et al., 2016). It is a promising drug delivery system and more suitable for poorly soluble drugs. Curcumin-polylactic acid (PLA) based microcapsules fabricated through the electrospray method (Mai et al., 2017). The study confirmed the excellent anti- microbial and antioxygenation activity and suggest that the PLA-based electrospray method joint with spherical microcapsules has effective for medicinal applications, particularly drug delivery. Huo et al. synthesized the selenium nanoparticles (Se NPs) encapsulated poly-lactide-co-glycolide (PLGA) nanospheres with curcumin. It decreased the amyloid-b load in Alzheimer’s disease mice, and greatly cured the memory deficiency of the model mice due to effective and targeted drug delivery (Huo et al., 2019) Miscellaneous Nanoformulations Nanogels, nanodisks, yeast cells, and metallo-complexes are other formulations to enhance curcumin’s biological activities. A nanogel is a nanoparticle (10 to 100 nm) composed of a hydrogel synthesized by either physical or chemical cross-linking of polymers under controlled conditions. The cross-linked structure of nanogel offers a strong base for drug storage and release. It is a possible technique to prepare and release active types of drugs to cells for remaining activity, improving stability, and prevent drug immunogenicity (Wang S. et al., 2018). Reeves et al. synthesized and examined a colloidal nanogel carrier system for encapsulation of curcumin to enhance its solubility and cytotoxicity. This curcumin-nanogel formulation was able to kill the tumor cells compared to curcumin alone (Reeves et al., 2015). Dandekar et al. formulated a curcumin loaded hydrogel nanoparticles by combining hydroxypropyl methylcellulose and polyvinyl pyrrolidone and tested the antimalarial activity in mice. It revealed a major action of curcumin-loaded hydrogel nanoparticles over unformulated curcumin (Dandekar et al., 2010). Curcumin loaded into gold nanoparticles-chitosan nanogels showed extent of cellular uptake and better cytotoxic effects on huh7 and MCF7 cell lines compared to native curcumin (Amanlou et al., 2019). In the goal of treating skin cancer, curcumin is delivered as self-assembled capsules with carboxymethyl cellulose and casein nanogels and fabricated with folic acid and casein by layer-by-layer (LbL) technique. The results showed better cellular uptake, cytotoxicity and apoptosis on melanoma cells (MEL-39) (Priya et al., 2020). Nanodisks are disk-shaped bilayers, apolipoprotein-stabilized and self-assembled. Ghosh et al. first used the nanodisk to boost the solubility and targeted the release of curcumin (Ghosh et al., 2011). Curcumin nanodisk formulations were shown effective strategy to treat MCL or other cancers (Singh et al., 2011). The interaction between curcumin nanodisk and glioblastoma multiforme cells facilitated by ApoE primes to increased curcumin uptake and improved biological activity (Ghosh and Ryan, 2014). Curcumin loading into the Saccharomyces cerevisiae cell membrane and other parts were found to be hydrogen- bonded to the cell wall (Paramera et al., 2011a). In another research, Paramera et al. determined the stability of yeast cell– loaded curcumin, it showed that yeast cells restricted the curcumin from environmental factors (i.e., light, humidity, and heat) (Paramera et al., 2011b). Curcumin prepared with Mn (II) and Fe (III) salts exhibited potent activity to Alzheimer’s disease in Swiss albino male rats (Bicer et al., 2018). Palladium (II) complexes with curcumin synthesized had exhibited a strong antitumor effect to MCF-7, HeLa, and A549 tumor cells (Li et al., 2018). COMPARATIVE CHARACTERISTICS AND EFFICACY OF NANOCURCUMIN AND CURCUMIN AS A DRUG For nanocurcumin, not only their chemical composition but also their physical properties determine their characteristics. Physical and chemical properties are playing a major role in the alteration of normal curcumin into the nanoform (Figure 3). Particle size, surface area, surface charge, and hydrophobicity are important Frontiers in Pharmacology | www.frontiersin.org 10 May 2020 | Volume 11 | Article 487PDF Image | Nanocurcumin Promising Candidate for Therapeutic Applications
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