Polymeric Curcumin Research Articles

Polymeric curcumin nanospheres for lysozyme aggregation inhibition, antibacterial, and wound healing applications.

The present study reports highly stable polymeric nanoparticles comprising curcumin and polyvinylpyrrolidone, and then conjugated with gold nanoparticles, resulting in C-PVP and C-PVP-Au, respectively. The synthesized conjugates C-PVP and C-PVP-Au were investigated for amyloid aggregation inhibition activity, antimicrobial activity, and wound healing applications.The anti-amyloidogenic capacity of nanoconjugates were studied for model protein, hen egg-white lysozyme (HEWL). The ThT binding assay, fibril size measurement, and electron microscopy results revealed that conjugates suppress fibrillogenesis in HEWL. The highest amyloid inhibition activity obtained against C-PVP and C-PVP-Au was 31μg.mL-1 and 30μg.mL-1, respectively. The dissociation activity for amyloid aggregation was observed against Q-PVP and Q-PVP-Au at 29μg.mL-1 and 27μg.mL-1, respectively. The antibacterial studies show significant efficacy against Escherichia coli (E. coli) in the presence of C-PVP and C-PVP-Au. The substantial antibacterial potential of C-PVP@PVA and C-PVP-Au@PVA membranes shows promising wound healing applications. The PVA membranes with nanoparticles promote the antibacterial activity and wound healing activity in the Drosophila model. C-PVP-Au@PVA membrane healed the wound faster than the C-PVP@PVA, and it can be used for better results in wound healing. Thus, C-PVP-Au and C-PVP have higher bioavailability and stability and can act as multifunctional therapeutic agents for amyloid-related diseases and as wound healing agents. Graphical abstract C-PVP, and C-PVP-Au conjugates for inhibition of HEWL aggregation, antibacterial and wound healing activity.

Water‐soluble hyperbranched polymer with high curcumin content

AbstractCurcumin is one of the promising anticancer drugs but has the problems of poor water solubility and rapid degradation in aqueous solution. In this study, a hyperbranched curcumin polymer having many carboxylic end groups is synthesized. The polymer is highly water‐soluble and contains a high amount of curcumins. Remarkable improvement of stability toward degradation and aggregation in aqueous solution is achieved. Its cellular uptake and cytotoxicity are also confirmed.

Macrophage targeted polymeric curcumin nanoparticles limit intracellular survival of Mycobacterium tuberculosis through induction of autophagy and augment anti-TB activity of isoniazid in RAW 264.7 macrophages.

Rapid emergence of antibiotic resistance in tuberculosis has left us with limited resources to treat and manage multi drug resistant (MDR) cases of tuberculosis, prompting the development of novel therapeutics. Mycobacterium tuberculosis (MTB) perturbs the host protective pathways for its survival, therefore host directed therapeutic (HDT) interventions offer an attractive alternative strategy. Curcumin (CMN), the principle curcuminoid from Curcuma longa is known to have anti-TB activity against MDR strains of MTB in macrophages. We discovered that treatment of CMN induced autophagy in uninfected and MTB infected macrophages which was evident by conversion of LC3-I to LC3-II and degradation of p62. Inhibition of autophagy by a pharmacological inhibitor 3-MA resulted in significant inhibition of intracellular killing activity of CMN, suggesting the involvement of autophagy in intracellular clearance of MTB. Moreover, annexin v-FITC/PI staining data suggested induction of apoptosis in uninfected and MTB infected macrophages post CMN treatment. This finding was further corroborated by up-regulated expression of pro-apoptotic proteins, Bax, cleaved caspase-3 and PARP and diminished expression of anti-apoptotic protein Bcl-2 as evaluated by immunoblotting. Using GFP-MTB H37Rv and Lysotracker Red staining we demonstrated co-localization of GFP-MTB H37Rv containing phagosome to lysosome after CMN treatment, indicating enhanced phagosome lysosome fusion. Due to poor bioavailability of CMN, its clinical use is limited, therefore to overcome this issue, CMN was encapsulated in Poly(lactic-co-glycolic) acid (PLGA) shell, resulting in polymeric CMN nano particles (ISCurNP). Flow cytometric evaluation suggested >99% uptake of ISCurNP after 3h of treatment. In BALB/c mice, oral dose of ISCurNP resulted in 6.7-fold increase in the bioavailability compared to free CMN. Moreover, ISCurNP treatment resulted in significant decrease in the intracellular survival of MTB H37Rv through induction of autophagy. Adjunct action of ISCurNP and CMN in combination with isoniazid (INH) revealed >99% decrease in intracellular survival of MTB in macrophage as compared to ISCurNP, CMN or INH alone. In conclusion, our findings suggest the role of ISCurNP as novel host directed formulation to combat both sensitive and MDR strains of MTB by induction of autophagy.

In Situ Hybridization of Polymeric Curcumin to Arginine-Derived Carbon Quantum Dots for Synergistic Treatment of Bacterial Infections.

Effective infectious keratitis treatment must eliminate the pathogen, reduce the inflammatory response, and prevent persistent damage to the cornea. Infectious keratitis is generally treated with broad-spectrum antibiotics; however, they have the risk of causing corneal epithelial cell damage and drug resistance. In this study, we prepared a nanocomposite (Arg-CQDs/pCur) from arginine (Arg)-derived carbon quantum dots (Arg-CQDs) and polymeric curcumin (pCur). Partial carbonization of arginine hydrochloride in the solid state by mild pyrolysis resulted in the formation of CQDs, which exhibited enhanced antibacterial activity. pCur was formed by the polymerization of curcumin, and further crosslinking reduced its cytotoxicity and improved antioxidative, anti-inflammatory, and pro-proliferative activities. The pCur in situ conjugated with Arg-CQDs to form the Arg-CQDs/pCur nanocomposite, which showed a minimum inhibitory concentration of ca. 10 μg mL-1, which was >100-fold and >15-fold lower than that of the precursor arginine and curcumin, respectively, against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The Arg-CQDs/pCur nanocomposite with combined antibacterial, antioxidative, anti-inflammatory, pro-proliferative properties, and long-term retention on cornea enabled synergistic treatment of bacterial keratitis. In a rat model, it can effectively treat P. aeruginosa-induced bacterial keratitis at a concentration 4000-fold lower than the commercially used drug, Sulmezole eye drops. Arg-CQDs/pCur nanocomposites have great potential for application in antibacterial and anti-inflammatory nanoformulations for clinical use to treat infectious diseases.

Curcumin–polymer conjugates with dynamic boronic acid ester linkages for selective killing of cancer cells

A phenylboronic acid (PBA)-containing copolymer was synthesized via the Hantzsch reaction and radical polymerization. Curcumin was dynamically included in this PBA-containing polymer to selectively kill cancer cells.

Acid-activatable polymeric curcumin nanoparticles as therapeutic agents for osteoarthritis

Curcumin, a primary active element of turmeric, has potent antioxidant and anti-inflammatory activity, but its low bioavailability is a major hurdle in its pharmaceutical applications. To enhance the therapeutic efficacy of curcumin, we exploited polymeric prodrug strategy. Here, we report rationally designed acid-activatable curcumin polymer (ACP), as a therapeutic prodrug of curcumin, in which curcumin was covalently incorporated in the backbone of amphiphilic polymer. ACP could self-assemble to form micelles that rapidly release curcumin under the acidic condition. The potential of ACP micelles as therapeutics for osteoarthritis was evaluated using a mouse model of monoidoacetic acid (MIA)-induced knee osteoarthritis. ACP micelles drastically protected the articular structures from arthritis through the suppression of tumor necrosis factor-alpha (TNF-α) and interleukin 1β (IL-1β). Given their pathological stimulus-responsiveness and potent antioxidant and anti-inflammatory activities, ACP micelles hold remarkable potential as a therapeutic agent for not only osteoarthritis but also various inflammatory diseases.

High Amplification of the Antiviral Activity of Curcumin through Transformation into Carbon Quantum Dots.

It is demonstrated that carbon quantum dots derived from curcumin (Cur-CQDs) through one-step dry heating are effective antiviral agents against enterovirus 71 (EV71). The surface properties of Cur-CQDs, as well as their antiviral activity, are highly dependent on the heating temperature during synthesis. The one-step heating of curcumin at 180 °C preserves many of the moieties of polymeric curcumin on the surfaces of the as-synthesized Cur-CQDs, resulting in superior antiviral characteristics. It is proposed that curcumin undergoes a series of structural changes through dehydration, polymerization, and carbonization to form core-shell CQDs whose surfaces remain a pyrolytic curcumin-like polymer, boosting the antiviral activity. The results reveal that curcumin possesses insignificant inhibitory activity against EV71 infection in RD cells [half-maximal effective concentration (EC50 ) >200 µg mL-1 ] but exhibits high cytotoxicity toward RD cells (half-maximal cytotoxic concentration (CC50 ) <13 µg mL-1 ). The EC50 (0.2 µg mL-1 ) and CC50 (452.2 µg mL-1 ) of Cur-CQDs are >1000-fold lower and >34-fold higher, respectively, than those of curcumin, demonstrating their far superior antiviral capabilities and high biocompatibility. In vivo, intraperitoneal administration of Cur-CQDs significantly decreases mortality and provides protection against virus-induced hind-limb paralysis in new-born mice challenged with a lethal dose of EV71.

In vivo evaluation of enhanced drug carrier efficiency and cardiac anti-hypertrophy therapeutic potential of nano-curcumin encapsulated photo-plasmonic nanoparticles combined polymerized nano-vesicles: A novel strategy

Curcumin, a naturally derived polyphenolic compound has potent activities against cardiac disease like reducing hypertrophy, increasing antioxidant activity, maintaining hormone levels and blood pressure etc. Polymeric curcumin nanoparticles is a solemn concern nowadays in accordance to improve the beneficial properties of curcumin by diminishing its disadvantages like hydrophobic nature thereby results in maximum delivery of drug curcumin at the target. This study demonstrated the application of curcumin capped gold loaded poly (lactic-co-glycolic acid) nanoparticles (CAu-PLGA Nps) for the inhibition of cardiac hypertrophy by preserving myocardial functions of Wister rat model. Rat models were arbitrarily divided into five groups and observation period was 10 weeks; 1. Control 2. Enalopril (EP), an hypertropic agent induced group 3. EP and Curcumin (C) 4. EP and Curcumin capped gold (CAu) Nps and 5. EP and CAu-PLGA Nps injected group. CAu-PLGA Nps was first synthesized from double emulsion-solvent evaporation method and were characterized by its adoptable techniques such as FT-IR, XRD, SEM and TEM analysis. These analyses demonstrate the encapsulation of curcumin capped gold nanoparticles into PLGA there confirms the successful synthesis of CAu-PLGA Nps. Animals studies illustrates that the CAu-PLGA Nps has significantly produced cardiac anti-hypertrophy and drug delivery when compared to the other groups. CAu-PLGA Nps exhibit increased survival rate, improved cardiac functions like cardiac systolic and diastolic function, maintaining heart weight and left ventricle pressure at the controlled level. Beneficiary activities of CAu-PLGA Nps were associated with its cardiovascular functions like anti-inflammatory, antioxidant, controls cardiomycete growth, increased drug delivery, prevents accumulation of cholesterol and prevents myocardial infarction.

Polymeric curcumin nanoparticles by a facile in situ method for macrophage targeted delivery.

Targeting macrophages is a promising strategy for improved therapy of intracellular infections as macrophages exhibit rapid phagocytosis of particles >200 nm. Entrapment of Curcumin (CUR) in nanocarriers could provide bioenhancement and macrophage targeting. We present a simple and facile in situ nanoprecipitation approach for instantaneous and on‐site generation of curcumin nanoparticles (ISCurNP). ISCurNP optimised by Box‐Behnken design exhibited average size of 208.25 ± 7.55 nm and entrapment efficiency of 90.16 ± 1.17%. Differential scanning calorimetry and X‐Ray diffraction confirmed amorphization of CUR in ISCurNP. Sustained release was observed over 72 hr in vitro at lysosomal pH 4.5. Rapid and high uptake in RAW 264.7 macrophages was confirmed by flow cytometry and high performance liquid chromatography. Confocal microscopy established localisation of ISCurNP in lysosomal compartment. The facile in situ nanoprecipitation method provides simple, scalable technology to enable macrophage targeted delivery of CUR, with great promise for improved therapy of intracellular infections.

A Self-degradable Curcumin Polymer with Anti-cancer Activity.

Curcumin is a widely researched and utilized natural product used for a variety of ailments including as a gastrointestinal aide and an anticancer agent. Curcumin however suffers from poor bioavailability. A strategy to circumvent poor bioavailability is to administer with an adjuvant or by synthetic modification. Herein we demonstrate the incorporation of curcumin into a self-degradable polymer by condensation with N,N'-di-Boc-L-cystine. The polymer is made self-degradable upon deprotection of the cystine amines. Degradation is confirmed by thermogravimetric analysis and differential scanning calorimetry. Curcumin retains its anti-cancer activity within the polymer showing activity against HT29 human colon cancer cells and DU-145 prostate cancer cells. The self-degrading polymer showed enhanced activity against HT29 cells compared to that of curcumin.

Curcumin polymer coated, self-fluorescent and stimuli-responsive multifunctional mesoporous silica nanoparticles for drug delivery

We reported the facile preparation of self-fluorescent mesoporous silica nanoparticles based on a triple-role curcumin polymer shell as stimuli-responsive multifunctional nanocarriers for drug delivery. This curcumin polymer shell integrates multiple function of acting as fluorescent agents, increasing the drug loading ratio of curcumin, and controlling the open and close of the pores in a “smart” way. This novel drug nanocarrier will inspire the development of smart and self-fluorescent drug nanocarrier to achieve imaging and therapeutic goals for cancer therapy.

Orally delivered polycurcumin responsive to bacterial reduction for targeted therapy of inflammatory bowel disease

Inflammatory bowel disease (IBD) such as Crohn’s disease and ulcerative colitis is a chronic autoimmune disease affecting nearly five million people worldwide. Among all drug delivery system, oral administration is the most preferable route for colon-specific targeting and the treatment of IBD. Herein, an amphiphilic curcumin polymer (PCur) composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic curcumin (Cur) linked by disulfide bond was synthesized and characterized. The sufficient solubility, nano-scaled size and close to the neutral surface potential of PCur lead to preferential accumulation of the active drug in the inflamed regions of the gut. Moreover, PCur showed limited drug release and enhanced robustness under the physiological pH of the gastrointestinal tract (GIT), and a significantly elevated release was observed when responding to a bacterial reduction in the colon. Furthermore, cellular studies confirmed PCur had low cytotoxicity and increased transmembrane permeability, resulting in improved oral bioavailability evidenced by in vivo pharmacokinetics of rats. Finally, with DSS-induced murine model of IBD, we demonstrated that orally administered PCur ameliorated the inflammatory progression in the colon and could protect mice from IBD. In conclusion, it is illustrated that the developed PCur conjugate could potentially be employed as a colon-specific candidate for IBD treatment.

Polysorbate-80-coated, polymeric curcumin nanoparticles for in vivo anti-depressant activity across BBB and envisaged biomolecular mechanism of action through a proposed pharmacophore model

Depression is a modern world epidemic. Its main causative factor is oxidative stress, as reported in study subjects. Natural products are yet to show significant therapeutic effects in comparison with synthetic drugs. Current study deals with the preparation of brain-targeted polysorbate-80-coated curcumin PLGA nanoparticles (PS-80-CUR-NP), and their characterisation via Spectral and optical methods. PS-80-CUR-NP were evaluated against the oxidative stress-mediated depressant (OSMD) activity via Force despair, Tail suspension tests and stress biomarker assay (SOD and catalase activity). A significant reduction in immobility (p < 0.01) in force despair and tail suspension test and a significant increase (p < 0.001 and p < 0.01) in SOD and catalase activity was found and compared with stress control, which confirmed the OSMD activity of PS-80-CUR-NP at 5 mg equivalent dose. Further, AUC(0.5–15 h) curve of brain homogenates estimated the curcumin concentration of 1.73 ng/g C max at T max 3 h via HPLC technique.

Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions

Curcumin (CUR) was used as a poorly soluble drug whereas polyvinyl pyrrolidone K90 (PVP), Eudragit EPO (EPO), hydroxypropyl methylcellulose E5 (HPMC) and polyethylene glycol 8000 (PEG) were used as hydrophilic polymers. CUR polymer miscibility was evaluated by solubility parameter, melting point depression and glass transition temperature (Tg) measurements. Molecular interactions between CUR and polymers were determined by Fourier-transform infrared spectroscopy (FTIR) and Raman. Amorphous solid dispersions were prepared with CUR–polymer ratio of 70:30 (w/w) by solvent evaporation technique and were evaluated for dissolution enhancement using USP II method. Physical states of solid dispersions were characterized by X-ray diffraction (XRD) whereas thermal behaviors were investigated using modulated differential scanning calorimetry (MDSC). CUR–EPO system showed good miscibility through all the approaches, whereas immiscibility was found in other CUR–polymer systems. CUR–EPO and CUR–HPMC systems showed significant molecular interactions whereas CUR–PVP and CUR–PEG showed no molecular interactions. All solid dispersions showed significant dissolution enhancement with CUR–EPO showing highest dissolution rate during first 1h whereas CUR–HPMC was effective in maintaining high CUR concentrations for 6h. The study highlights the importance of investigating and correlating drug polymer miscibility and molecular interactions by various approaches for successful formulation of amorphous solid dispersions.

Curcumin Implants, Not Curcumin Diet, Inhibit Estrogen-Induced Mammary Carcinogenesis in ACI Rats

Curcumin is widely known for its antioxidant, anti-inflammatory, and antiproliferative activities in cell-culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvent oral bioavailability issues, and tested their potential against 17β-estradiol (E2)-mediated mammary tumorigenesis. Female Augustus Copenhagen Irish (ACI) rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2 cm; 200 mg each; 20% drug load) 4 days before grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Curcumin implants were changed after 4.5 months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months, and after the tumor incidence reached >80% (~6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2 ± 1 vs. 5 ± 3; P = 0.001) and tumor volume (184 ± 198 mm(3) vs. 280 ± 141 mm(3); P = 0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity, whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in the presence of E2. Because CYP1A and CYP3A4 metabolize most of the E2 to its noncarcinogenic 2-OH metabolite, and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by high-performance liquid chromatography showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered.

Curcumin amorphous solid dispersions: the influence of intra and intermolecular bonding on physical stability

We have investigated the physical stability of amorphous curcumin dispersions and the role of curcumin–polymer intermolecular interactions in delaying crystallization. Curcumin is an interesting model compound as it forms both intra and intermolecular hydrogen bonds in the crystal. A structurally diverse set of amorphous dispersion polymers was investigated; poly(vinylpyrrolidone), Eudragit E100, carboxymethyl cellulose acetate butyrate, hydroxypropyl methyl cellulose (HPMC) and HPMC-acetate succinate. Mid-infrared spectroscopy was used to determine and quantify the extent of curcumin–polymer interactions. Physical stability under different environmental conditions was monitored by powder X-ray diffraction. Curcumin chemical stability was monitored by UV-Vis spectroscopy. Isolation of stable amorphous curcumin was difficult in the absence of polymers. Polymers proved to be effective curcumin crystallization inhibitors enabling the production of amorphous solid dispersions; however, the polymers showed very different abilities to inhibit crystallization during long-term storage. Curcumin intramolecular hydrogen bonding reduced the extent of its hydrogen bonding with polymers; hence most polymers were not highly effective crystallization inhibitors. Overall, polymers proved to be crystallization inhibitors, but inhibition was limited due to the intramolecular hydrogen bonding in curcumin, which leads to a decrease in the ability of the polymers to interact at a molecular level.

Polymeric curcumin nanoparticle pharmacokinetics and metabolism in bile duct cannulated rats.

The objective of this study was to compare the pharmacokinetics and metabolism of polymeric nanoparticle-encapsulated (nanocurcumin) and solvent-solubilized curcumin formulations in Sprague-Dawley (SD) rats. Nanocurcumin is currently under development for cancer therapy. Since free, unencapsulated curcumin is rapidly metabolized and excreted in rats, upon intravenous (i.v.) administration of nanocurcumin only nanoparticle-encapsulated curcumin can be detected in plasma samples. Hence, the second objective of this study was to utilize the metabolic instability of curcumin to assess in vivo drug release from nanocurcumin. Nanocurcumin and solvent-solubilized curcumin were administered at 10 mg curcumin/kg by jugular vein to bile duct-cannulated male SD rats (n = 5). Nanocurcumin increased the plasma Cmax of curcumin 1749 fold relative to the solvent-solubilized curcumin. Nanocurcumin also increased the relative abundance of curcumin and glucuronides in bile but did not dramatically alter urine and tissue metabolite profiles. The observed increase in biliary and urinary excretion of both curcumin and metabolites for the nanocurcumin formulation suggested a rapid "burst" release of curcumin. Although the burst release observed in this study is a limitation for targeted tumor delivery, nanocurcumin still exhibits major advantages over solvent-solubilized curcumin, as the nanoformulation does not result in the lung accumulation observed for the solvent-solubilized curcumin and increases overall systemic curcumin exposure. Additionally, the remaining encapsulated curcumin fraction following burst release is available for tumor delivery via the enhanced permeation and retention effect commonly observed for nanoparticle formulations.

Gold nanoparticles generated and stabilized by water soluble curcumin–polymer conjugate: Blood compatibility evaluation and targeted drug delivery onto cancer cells

Curcumin (Cur) shows low anticancer activity in vivo due to its reduced systemic bioavailability stemmed from its poor aqueous solubility and instability. Suitably functionalized nanocarriers designed to empty the drug specifically at tumor sites can potentially enhance the antitumor activity of Cur. We devised a simple method for the fabrication of water soluble Cur conjugated gold nanoparticles to target various cancer cell lines. Cur was conjugated to hyaluronic acid (HA) to get a water soluble conjugate (HA–Cur). We generated gold nanoparticles (AuNPs) by reducing chloroauric acid using HA–Cur, which played the dual role of a reducing and stabilizing agent and subsequently anchored folate conjugated PEG. These entities were probed using different analytical techniques, assayed the blood compatibility and cytotoxicity. Their interaction with cancer cell lines (HeLa cells, glyoma cells and Caco 2 cells) was followed by flow cytometry and confocal microscopy. Blood–materials interactions studies showed that the nanoparticles are highly hemocompatible. Flow cytometry and confocal microscopy results showed significant cellular uptake and internalization of the particles by cells. HA–Cur@AuNPs exhibited more cytotoxicity comparing to free Cur. The strategy, we adopted here, resulted the formation blood compatible Cur conjugated AuNPs with enhanced targeting and improved efficacy.

Selenium-Containing Curcumin Polymer for Anti-Liver Fibrosis

A new selenium-containing curcumin polymer was synthesized by polycondensation of curcumin with dihydride, polyethylene glycol, and selenium amino acid monomers. The polymer was stable, water soluble, and injectable with a molecular weight of 6.1x104Da. The in vivo anti-liver fibrosis efficacy of the polymer was investigated with Sprague Dawley rats. The results showed the curcumin polymer had strong anti-hepafibrosis activity.