Triggered-release polymeric conjugate micelles for on-demand intracellular drug delivery
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Nanoscale drug delivery platforms have been developed over the past four decades that have shown promising clinical results in several types of cancer and inflammatory disorders. These nanocarriers carrying therapeutic payloads are maximizing the therapeutic outcomes while minimizing adverse effects. Yet one of the major challenges facing drug developers is the dilemma of premature versus on-demand drug release, which influences the therapeutic regiment, efficacy and potential toxicity. Herein, we report on redox-sensitive polymer-drug conjugate micelles for on-demand intracellular delivery of a model active agent, curcumin. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a disulfide bond or ester bond (control), respectively. The self-assembled redox-sensitive micelles exhibited a hydrodynamic size of 115.6 ± 5.9 (nm) with a zeta potential of -10.6 ± 0.7 (mV). The critical micelle concentration was determined at 6.7 ± 0.4 (μg mL(-1)). Under sink conditions with a mimicked redox environment (10 mM dithiothreitol), the extent of curcumin release at 48 h from disulfide bond-linked micelles was nearly three times higher compared to the control micelles. Such rapid release led to a lower half maximal inhibitory concentration (IC50) in HeLa cells at 18.5 ± 1.4 (μg mL(-1)), whereas the IC50 of control micelles was 41.0 ± 2.4 (μg mL(-1)). The cellular uptake study also revealed higher fluorescence intensity for redox-sensitive micelles. In conclusion, the redox-sensitive polymeric conjugate micelles could enhance curcumin delivery while avoiding premature release, and achieving on-demand release under the high glutathione concentration in the cell cytoplasm. This strategy opens new avenues for on-demand drug release of nanoscale intracellular delivery platforms that ultimately might be translated into pre-clinical and future clinical practice.Keywords:
Nanocarriers
Conjugate
Zeta potential
Dithiothreitol
Treatment of chymotrypsin A α with dithiothreitol (10 mM) at pH 9.2 in the presence of 8 M urea results in the complete reduction of the disulfide linkages of the protein. Reduction of a single disulfide bond of the enzyme can be achieved by treatment with 10 mM dithiothreitol at pH 9.2 in the presence of 100 mM hydrocinnamate. No such disulfide cleavage occurs in the case of indoleacryloyl chymotrypsin upon treatment with dithiothreitol.
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Curcumin is a natural molecule with proved anticancer efficacy on several human cancer cell lines. However, its clinical application has been limited due to its poor bioavailability. Nanocarrier-based drug delivery approaches could make curcumin dispersible in aqueous media, thus overtaking the limits of its low solubility. The aim of this study was to increase the bioavailability and the antitumoral activity of curcumin, by entrapping it into nanostructured lipid carriers (NLCs). For this purpose here we describe the preparation and characterization of three kinds of curcumin-loaded NLCs. The nanosystems allowed the achievement of a controlled release of curcumin, the amounts of curcumin released after 24 h from Compritol-Captex, Compritol-Miglyol, and Compritol NLCs being, respectively, equal to 33, 28, and 18% w/w on the total entrapped curcumin. Considering the slower curcumin release profile, Compritol NLCs were chosen to perform successive in vitro studies on ovarian cancer cell lines. The results show that curcumin-loaded NLCs maintain anticancer activity, and reduce cell colony survival more effectively than free curcumin. As an example, the ability of A2780S cells to form colonies was decreased after treatment with 5 μM free curcumin by 50% ± 6, whereas, at the same concentration, the delivery of curcumin with NLC significantly (p < 0.05) inhibited colony formation to approximately 88% ± 1, therefore potentiating the activity of curcumin to inhibit A2780S cell growth. The obtained results clearly suggest that the entrapment of curcumin into NLCs increases curcumin efficacy in vitro, indicating the potential use of NLCs as curcumin delivery systems.
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Dithiothreitol
Hemin
Proteostasis
Reducing agent
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The previously described kinetic method of the substrate reaction during irreversible inhibition of enzyme activity [Tsou (1988) Adv. Enzymol. Relat. Areas Mol. Biol. 61 . 381–436] has been used to study the inactivation kinetics of aminoacylase by dithiothreitol (DTT) and 2‐mercaptoethanol (MET). The results show that the inactivation of aminoacylase by DTT or MET is competitive slow‐reversible inhibition. The microscopic rate constants for the inactivation reaction were determined. Removal of these inhibitors by dialysis can lead to complete recovery of enzymatic activity. The present results also show that the presence of equimolar Zn 2+ to DTT gives complete protection of the enzyme against the inactivation by DTT. Moreover, addition of equimolar amounts of Zn 2+ to DTT can induce recovery of the enzymatic activity of DTT‐inactivated enzyme. It is known that aminoacylase from pig kidney contains no disulfide bonds. Therefore, it may be suggested that inactivation of aminoacylase by dithiothreitol or 2‐mercaptoethanol is not due to the reduction of disulfide bonds, and is a competitive slow‐reversible inhibition.
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The major impediment towards the use of Curcumin for health benefits is its poor availability in the blood and tissues. This problem can be trounced by our innovative Curcumin preparation. The formulation treats curcumin as it occur inside the turmeric rhizome, where curcumin is more available in the blood. A human study conducted, where the innovative curcumin found to absorb ~15 times more as that of the normal curcumin. This Bio available curcumin was branded as “cureit” and its anti oxidant potential established. The study proves that “cureit” could be good source of natural antioxidant.
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Curcuminoid
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Curcumin, a non-nutritive yellow pigment derived from the rhizome of Curcuma longa (turmeric), is considered to be an established nutraceutical with anticancer activity. Turmeric contains three principal components, curcumin, demethoxycurcumin and bisdemethoxycurcumin, of which curcumin is most abundant and potent. The concurrence of a high consumption of turmeric and a low incidence of prostate cancer in Asian countries may suggest a role for curcumin in chemoprevention. Curcumin has been identified to exhibit anti-inflammatory, anti-oxidative and anticarcinogenic properties. Since the compound does not exhibit side effects, curcumin has been designated for several clinical trials as a treatment for human cancers. The pro-apototic, antioxidant and anti-inflammatory characteristics of curcumin are implicated in its anticancer activity, yet the mechanism of action of curcumin remains unknown. To achieve an effective pharmacological outcome, curcumin must reach and sustain appropriate levels at the site of action. However, the main disadvantage of curcumin is its high metabolic instability and poor aqueous solubility that limits its systemic bioavailability. To overcome this difficulty, the present study tested the anticancer activity of new curcumin-like compounds (E21cH and Q012095H). Also, the use of new medicaments requires an understanding of their pharmacokinetic profiles and targets. Thus, molecular modeling methods were used to identify the targets of curcumin and curcumin-like compounds compared with other anticancer drugs (Q012138 and Q012169AT), which were used as the controls. The present study identified several enzymes that are targeted by curcumin, aldo-keto reductase family 1 member B10 (AKR1B10), serine/threonine-protein kinase, protein kinase C, matrix metalloproteinase (MMP), cyclooxygenase and epidermal growth factor receptor, which were tested as targets for these anticancer chemicals. All the examined small compounds demonstrated anticancer activity in the in vitro experiments and may impact cancer cells by acting on AKR1B10, MMP-9 and their targets.
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Curcumin (1,7‐bis (4‐hydroxy‐3‐methoxyphenyl)‐1,6‐heptadiene‐3,5‐dione) is a major yellow‐orange pigment found in turmeric, and has been used widely as a food ingredient. Curcumin has been associated with many health benefits, but its health‐promoting potential is limited by its poor bioavailability. This is due to the fact that curcumin is poorly absorbed, and absorbed curcumin is subject to extensive biotransformation. The detailed understanding of biotransformation of curcumin is needed to facilitate the elucidation of its biological significance. This study was aimed to establish the metabolic fate of curcumin in the gastrointestinal (GI) tract. The male CD‐1 mice were fed with curcumin in diet (0.05% w/w) for 5 weeks. The entire GI tract and its content were harvested for LC‐MS analysis. Our results demonstrated that curcumin underwent phase I metabolism in the small intestine to yield two major metabolites, namely hexahydro‐curcumin and octahydro‐curcumin. Curcumin, hexahydro‐curcumin and octahydro‐curcumin were all subject to phase II metabolism that converted them to their corresponding glucuronides and sulfates. The majority of curcumin, hexahydro‐curcumin and octahydro‐curcumin exist as phase II conjugates in the small intestine. However, due to the action of gut microbiota, curcumin, hexahydro‐curcumin and octahydro‐curcumin almost exclusively existed in the non‐conjugated forms in the cecum and colon. Furthermore, our results suggested that gut microbiota could break down curcumin, hexahydro‐curcumin and octahydro‐curcumin to produce different fission products. In summary, our results determined the metabolic fate of curcumin in the GI tract, which can help understand the biological effects of curcumin in the GI tract as well as other related organs. Support or Funding Information This study was partially supported by fund from USDA.
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Curcumin is the major yellow pigment extracted from turmeric, a commonly used spice in Asian cuisine and extensively employed in ayurvedic herbal remedies. A number of studies have shown that curcumin can be a prevention and a chemotherapeutic agent for colon, skin, oral and intestinal cancers. Curcumin is also well known for its antiinflammatory and antioxidant properties, showing high reactivity towards peroxyl radicals, and thus acting as a free radical scavenger. Recently, experimental studies have demonstrated that curcumin might be used in the prevention and the cure of Alzheimer's disease. Indeed, curcumin injected peripherally in vivo into aged Tg mice crossed the blood-brain barrier and bound to amyloid plaques, reducing amyloid levels and plaque formation decisively. The present review will resume the most recent developments in the medicinal chemistry of curcumin and curcumin-like molecules. Keywords: Amyloid, anti-inflammatory molecules, antioxidant, cancer, curcumin, neuroprotective.
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Curcumin is a polyphenolic compound with multiple beneficial effects in human health. It has shown a remarkable anti-inflammatory, antibacterial, antifungal, anticancer, and antioxidant effects. The limitations of curcumin are primarily in its bioavailability. Curcumin nanoparticles is suggested to reduce the limitation of bulk curcumin and probably enhance its desired effect. Curcumin was turned into nanoparticles by using simple wet-milling method. The characterization of curcumin nanoparticles indicated the presence of curcumin in size less than 100 nm. The effect of both curcumin and curcumin nanoparticles on wound healing was investigated in rabbits, in paraffin wax. Rabbits whom under curcumin and curcumin nanoparticles have shown faster healing from day 5 compared to control rabbits whom showed a proximate advancement after day 7. On day 14, rabbits whom treated with bulk and nanosized curcumin have shown a perfect healing with no sign of infection. Furthermore, both bulk and nanosized curcumin have shown a comparable antioxidant effect with ascorbic acid. Furthermore, curcumin nanoparticles were exhibited a slightly powerful antioxidant effect compared to curcumin.
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