Curcumin Nanocrystals Research Articles

Antibacterial Effects of Curcumin Nanocrystals against Porphyromonas gingivalis Isolated from Patients with Implant Failure.

Background. Despite their benefits, dental implants may sometimes fail for a diversity of causes; the most common reasons of failure are infection and bone loss. Porphyromonas gingivalis (P. gingivalis) bacteria show a major role in peri-implantitis infection and dental implant failure. Methods. In this study, the prevalence of P. gingivalis isolated from the gingival crevicular fluid (GCF) of fifteen Iranian patients with implant failure (more than 1/3 of the implant length), who had average oral and dental hygiene and no antibiotic use for at least one month, was determined. Moreover, the antimicrobial effects of curcumin nanocrystals against isolated P. gingivalis were investigated. The collected samples from patients were transferred to a microbiology laboratory to culture. The presence of P. gingivalis in the culture media was confirmed using a trypsin reagent test. An isolate from a patient with the highest colony count was selected to evaluate the antibacterial effects of curcumin nanoparticles. The inhibition zone diameter, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) were determined. Results. Out of fifteen patients, eight (53.33%) were positive for the presence of P. gingivalis. The results of the microbial tests showed that curcumin nanoparticles had an MIC of 6.25 µg/mL and an MBC of 12.5 µg/mL. Conclusions. The use of curcumin nanoparticles may control the bacterial infection around the implant.

Brain-Targeted Biomimetic Nanodecoys with Neuroprotective Effects for Precise Therapy of Parkinson's Disease.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates called Lewy bodies. Here, nanodecoys were designed from a rabies virus polypeptide with a 29 amino acid (RVG29)-modified red blood cell membrane (RBCm) to encapsulate curcumin nanocrystals (Cur-NCs), which could effectively protect dopaminergic neurons. The RVG29-RBCm/Cur-NCs nanodecoys effectively escaped from reticuloendothelial system (RES) uptake, enabled prolonged blood circulation, and enhanced blood–brain barrier (BBB) crossing after systemic administration. Cur-NCs loaded inside the nanodecoys exhibited the recovery of dopamine levels, inhibition of α-synuclein aggregation, and reversal of mitochondrial dysfunction in PD mice. These findings indicate the promising potential of biomimetic nanodecoys in treating PD and other neurodegenerative diseases.

Curcumin nanocrystals with tunable surface zeta potential: Preparation, characterization and antibacterial study

Curcumin (CUR) is a natural polyphenol with broad-spectrum antimicrobial efficacy, however, its use has been limited by low water solubility and poor stability. The aim of this study was to develop CUR nanocrystals (NCs) to improve its water solubility and stability, and investigate the effect of surface charge on its antibacterial activity. CUR NCs were prepared with different ratios of Pluronic F127 (F127) and hexadecyl trimethyl ammonium bromide (CTAB) as stabilizers to achieve tunable surface charge. The mean particle sizes of CUR NCs were around 150 nm, and zeta potentials were varied from −16.7 to 36.5 mV. Solubility and stability of CUR were significantly enhanced by processing into NCs. In vitro dissolution test showed that the dissolution rate of CUR NC was significantly higher than free CUR. Compared with free CUR, CUR NCs displayed low cytotoxicity against normal human kidney-2 cells. Moreover, comprehensive experiments (MIC, MBC, zone of inhibition and colony counting method) all demonstrate that CUR NCs with high positive surface charge exhibited excellent antibacterial activity than free CUR against E. coli and S. aureus, and SEM images showed that CUR NCs could destroy the surface of the bacteria cell to enhance the antibacterial activity. The overall results suggest that the CUR NC may be a promising antibacterial agent for pharmaceutical application.

Surface stabilization determines macrophage uptake, cytotoxicity, and bioactivity of curcumin nanocrystals

Pharmaceutical nanocrystals represent a promising new formulation that combines the benefits of bulk crystalline materials and colloidal nanoparticles. To be applied in vivo, nanocrystals must meet several criteria, namely colloidal stability in physiological media, non-toxicity to healthy cells, avoidance of macrophage clearance, and bioactivity in the target tissue. In the present work, curcumin, a naturally occurring poorly water-soluble molecule with a broad spectrum of bioactivity has been considered a candidate substance for preparing pharmaceutical nanocrystals. Curcumin nanocrystals in the size range of 40–90 nm were prepared by wet milling using the following combination of steric and ionic stabilizers: Tween 80, sodium dodecyl sulfate, Poloxamer 188, hydroxypropyl methylcellulose, phospholipids (with and without polyethylene glycol), and their combination. Nanocrystals stabilized by a combination of phospholipids enriched with polyethylene glycol proved to be the most successful in all evaluated criteria; they were colloidally stable in all media, exhibited low macrophage clearance, and proved non-toxic to healthy cells. This curcumin nanoformulation also exhibited outstanding anticancer potential comparable to commercially used cytostatics (IC50 = 73 µM; 24 h, HT-29 colorectal carcinoma cell line) which represents an improvement of several orders of magnitude when compared to previously studied curcumin formulations. This work shows that the preparation of phospholipid-stabilized nanocrystals allows for the conversion of poorly soluble compounds into a highly effective “solution-like” drug delivery system at pharmaceutically relevant drug concentrations.

Particle Size Effect of Curcumin Nanocrystals on Transdermal and Transfollicular Penetration by Hyaluronic Acid-Dissolving Microneedle Delivery.

Microneedles are one promising penetration enhancement vehicle to overcome the stratum corneum skin barrier, which hampers the penetration of drug nanocrystals by transdermal delivery. In order to clarify the particle size effect of nanocrystals on transdermal delivery, 60 nm, 120 nm, and 480 nm curcumin nanocrystals were fabricated and incorporated into dissolving hyaluronic acid polysaccharide microneedles. The microneedles showed good mechanical strength with 1.4 N/needle, possessing the ability to insert into the skin. The passive permeation results showed that the smaller particle size of 60 nm curcumin nanocrystals diffused faster and deeper than the larger 120 nm and 480 nm curcumin nanocrystals with size-dependent diffusion behaviors. Thereafter, higher concentration gradients and overlap diffusional coronas also formed in the skin layers by the smaller-particle-size nanocrystals. Furthermore, the diffusion rate of the smaller particle size of curcumin nanocrystals to the hair follicle was also higher than that of the larger curcumin nanocrystals. In conclusion, the particle sizes of curcumin nanocrystals influenced the transdermal and transfollicular penetration in deeper skin layers

Preparation and Assessment of Physicochemical Possessions, Solubility, and Antimicrobial Properties of Dental Prosthesis Glass Ionomer Cement Containing Curcumin Nanocrystals

The physicochemical, antibacterial, and mechanical properties of the cement used in fixed dental prostheses show particular importance in the successful treatment. The objective of this in vitro study was to prepare glass ionomer cements (GIC) containing curcumin nanocrystals, as a sealant between the prepared tooth and crown. The prepared cements containing curcumin nanocrystals with concentration of 20% and 30% were evaluated by conventional physicochemical methods, and then, the effects of adding nanocrystals on the cement water solubility and sorption were measured. Finally, the antibacterial effects of the prepared cement were evaluated against three bacterial strains of Streptococcus mutans, Staphylococcus aureus, and Escherichia coli. The results showed that the solubility and sorption of both GIC containing curcumin nanocrystals did not change significantly compared with the control (p > 0.05). The cement containing 20% and 30% curcumin nanocrystals showed significant increase in antibacterial effect (p < 0.05). Considering the suitable physicochemical properties and worthy antibacterial result GIC containing curcumin nanocrystals, it seems that it can be a suitable restorative material.

Influence of Curcumin Nanocrystals on the Early Osteogenic Differentiation and Proliferation of Dental Pulp Stem Cells

Regenerative therapies are the developed method for regrowing, repairing, or exchanging damaged or diseased cells, tissues, or organs. Bone injury regeneration is a complicated procedure. For this reason, stimulation of the osteogenic differentiation impact on mesenchymal stem cells (MSCs) is a critical method. The goal of the current study was to test the biocompatibility and induction of early osteogenic differentiation by curcumin nanocrystals in human dental pulp stem cells (DPSCs) which are MSCs derived from dental pulp. In this study, curcumin nanocrystals were produced through the spray‐drying technique and then were characterized using conventional methods. Then, cytotoxicity and proliferative properties of curcumin nanocrystals were evaluated in different concentrations at 48 hours, 72 hours, and 7 days which were measured by the MTT test, and a special kit was used to determine the activity of alkaline phosphatase (ALP). The results of this study displayed that the prepared nanocurcumin with the mean particle size of 128 nm, spherical morphology, and the negative surface charge did not show a toxic effect on dental pulp cells in most concentrations for 48 and 72 hours and was toxic only at a concentration of 25 μM. Also, comparing the toxicity of different doses at 7 days showed that at concentrations of 2.5, 5, 10, and 25 μM, cell growth was significantly inhibited. ALP activity was increased in two weeks compared to one week and also compared to that of the control group significantly (p < 0.05). Considering the positive possessions of nanocurcumin on the osteogenic differentiation of DPSCs and its low toxicity, this substance can be considered in the planning of regenerative protocols.

The Preparation, the Physicochemical Assessment, and the Antimicrobial Action of Nanocurcumin‐Loaded Dental Temporary Restorative Material

Introduction. The aim of this study was to prepare a temporary restorative material containing curcumin nanocrystals and to evaluate the physicochemical properties and the antimicrobial action against Enterococcus faecalis (E. faecalis), Staphylococcus aureus (S. aureus), and Escherichia coli (E. coli). Materials and Methods. Dental temporary restorative material was physically mixed with curcumin nanocrystals at weight percentages of 80/20 and 70/30. The prepared materials were then subjected to the physicochemical tests: Fourier transmission infrared spectroscopy (FTIR) to investigate possible bonds, X‐ray diffraction (XRD) method to test the crystallinity pattern, and scanning electron microscopy (SEM) method to study the morphology of the prepared materials. Besides, the release pattern of nanocurcumin from the temporary material was evaluated using drug dissolution USP apparatus II and UV spectrophotometer. For microbial evaluation, the disk diffusion method was used against the mentioned bacteria. Results. The results showed the homogenous mixing of nanocurcumin with the temporary restorative material. Nanocurcumin showed a two‐stage release pattern from the temporary material, and both types of samples containing 20% and 30% nanocurcumin had antimicrobial action against all selected bacteria. Conclusion. Extensive cellular, animal, and clinical studies are needed to demonstrate the use of temporary restorative material containing antimicrobial nanoparticles.

Nanofiber-mediated sequential photothermal antibacteria and macrophage polarization for healing MRSA-infected diabetic wounds

BackgroundDiabetic wound healing remains a challenge because of its susceptibility to drug-resistant bacterial infection and its persistent proinflammatory state. Switching from proinflammatory M1 macrophages (Mφs) to proregenerative M2 dominant Mφs in a timely manner accelerates wound healing by coordinating inflammatory, proliferative, and angiogenic processes.MethodsWe propose a sequential photothermal antibacterial and subsequent M2 Mφ polarization strategy based on nanofibers (NFs) consisting of polydopamine (PDA) coating on curcumin (Cur) nanocrystals to treat Methicillin-resistant Staphylococcus aureus (MRSA)-infected diabetic wounds.ResultsThe PDA/Cur NFs showed excellent photothermal conversion and antibacterial effects due to the PDA shell under laser irradiation, consequently resulting in the release of the inner Cur with the ability to promote cell proliferation and reinforce the M2 Mφ phenotype in vitro. In vivo studies on MRSA-infected diabetic wounds showed that PDA/Cur NFs not only inhibited MRSA infection but also accelerated the wound regeneration process. Furthermore, the NFs displayed the ability to promote the M2 Mφ phenotype with enhanced collagen deposition, angiogenesis, and cell proliferation.ConclusionOverall, the NFs displayed great potential as promising therapeutics for healing infected diabetic wounds through a sequential photothermal antibacterial and M2 Mφ polarization strategy.Graphical abstract

Curcumin nanocrystals attenuate cyclophosphamide-induced testicular toxicity in mice

The cancer therapy using cyclophosphamide (CP) has been associated with adverse effects on the testicular function that raises concerns about the future fertility potential among cancer survivors. Curcumin, a polyphenol, has shown to possess a plethora of biological functions including tissue protective effects. In the present study, we investigated the protective effects of curcumin nanocrystals (NC) in mitigation of CP-induced testicular toxicity. Healthy adult (8–10 week) and prepubertal (2 week) male Swiss albino mice were injected with a single dose of CP (200 mg/kg) intraperitoneally (i.p). NC (4 mg/kg, i.p.) was administered every alternate day, for 35 days in adult mice while, a single dose of NC was injected intraperitoneally to prepubertal mice 1 h prior to CP. Administration of multiple doses of NC ameliorated CP-induced testicular toxicity in adult mice, which was evident from the improved sperm functional competence, sperm chromatin condensation, seminiferous tubule architecture and decreased apoptosis in testicular cells. Further, administration of NC 1 h prior to CP in prepubertal mice modulated the expression of genes pertaining to proliferation, pluripotency, DNA damage and DNA repair in spermatogonial cells at 24 h after the treatment. Overall, these results suggest that NC could be a promising chemoprotective agent, which can have potential application in male fertility preservation.

Curcumin Nanocrystals: Production, Physicochemical Assessment, and In Vitro Evaluation of the Antimicrobial Effects against Bacterial Loading of the Implant Fixture

Background: This study aimed to prepare and study physicochemical properties as well as the antibacterial action of curcumin nanocrystals inside the implant fixture against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Enterococcus faecalis (E. faecalis). Methods: Curcumin nanocrystals were prepared via precipitation combined with the spray drying method. The produced curcumin nanocrystals were characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Moreover, the in vitro antimicrobial effect of curcumin nanocrystals inside the implant fixture was assessed against E. coli, S. aureus, and E. faecalis. All implant-abutment assemblies were immersed in bacterial suspensions and were incubated at 24, 48, and 72 h. The contents of each implant were cultured to count the colony of bacteria at 37 °C for 24 h. Results: The prepared curcumin nanocrystals with a mean particle size of 95 nm and spherical morphology exhibited a removal rate of 99.99% for all bacteria. In addition, the colony-forming unit (CFU) of bacteria in exposure to nanocrystals significantly was reduced (p < 0.010) by increasing the time. Conclusions: Curcumin nanocrystals can be used inside the implant fixture as an antimicrobial agent in order to more stabilization of the implant.

Hair Follicle Targeting and Dermal Drug Delivery with Curcumin Drug Nanocrystals-Essential Influence of Excipients.

Many active pharmaceutical ingredients (API) possess poor aqueous solubility and thus lead to poor bioavailability upon oral administration and topical application. Nanocrystals have a well-established, universal formulation approach to overcome poor solubility. Various nanocrystal-based products have entered the market for oral application. However, their use in dermal formulations is relatively novel. Previous studies confirmed that nanocrystals are a superior formulation principle to improve the dermal penetration of poorly soluble API. Other studies showed that nanocrystals can also be used to target the hair follicles where they create a drug depot, enabling long acting drug therapy with only one application. Very recent studies show that also the vehicle in which the nanocrystals are incorporated can have a tremendous influence on the pathway of the API and the nanocrystals. In order to elucidate the influence of the excipient in more detail, a systematic study was conducted to investigate the influence of excipients on the penetration efficacy of the formulated API and the pathway of nanocrystals upon dermal application. Results showed that already small quantities of excipients can strongly affect the passive dermal penetration of curcumin and the hair follicle targeting of curcumin nanocrystals. The addition of 2% ethanol promoted hair follicle targeting of nanocrystals and hampered passive diffusion into the stratum corneum of the API, whereas the addition of glycerol hampered hair follicle targeting and promoted passive diffusion. Propylene glycol was found to promote both pathways. In fact, the study proved that formulating nanocrystals to improve the bioefficacy of poorly soluble API upon dermal application is highly effective. However, this is only true, if the correct excipient is selected for the formulation of the vehicle. The study also showed that excipients can be used to allow for a targeted dermal drug delivery, which enables to control if API should be delivered via passive diffusion and/or as drug reservoir by depositing API in the hair follicles.

Hair follicle targeting with curcumin nanocrystals: Influence of the formulation properties on the penetration efficacy

Nanocrystals are a universal formulation approach for improved drug delivery of poorly water-soluble drug substances. Besides oral application, also topical application of the nanocrystals is feasible, because the increased kinetic solubility of the nanocrystals results in an increased concentration gradient, thus fostering passive, dermal penetration. Nanocrystals are also promising for targeting drug substances into the hair follicle. After penetration into the hair follicle, the nanocrystals could form a depot from which the active is released into the hair follicle. Thus, leading to a long-lasting and very efficient dermal drug delivery. The efficacy of nanocrystals to penetrate the hair follicles and the influence of the vehicle in which the nanocrystals are suspended was not yet investigated. Therefore, in this study curcumin nanocrystals with a size of about 300 nm were produced and incorporated into gels with different properties. The efficacy to penetrate the hair follicles, as well as the passive, dermal penetration, was assessed on the ex-vivo pig ear model. Nanocrystals were efficiently taken up by the hair follicles and reached the lower part of the infundibulum. This region is optimal for efficient drug delivery because the barrier of the lower infundibulum is not fully developed and thus more permeable, which results in a less hindered passive diffusion of drug substances. The penetration efficacy of the nanocrystals into the hair follicles was not affected by the different types of vehicles, which represented either oleogels or hydrogels that varied in viscosity as well as in the type and the concentration of the gelling agent. All gels possessed a shear-thinning flow behavior and it is hypothesized that all gels fluidized during the skin massage, whereby leading to similarly low viscosities than the aqueous nanosuspension and thus to similar penetration results. The passive, dermal penetration of curcumin was different for the different gels and the main driving parameter leading to good passive diffusion was caused by good skin hydrating properties of the vehicle. The best passive penetration was achieved from hydrogels that contained a humectant. However, the addition of the humectant reduced the efficacy of the nanocrystals to penetrate the hair follicle. Data so far, therefore, suggest that hair follicle targeting with nanocrystals that are suspended in water or simple, shear-thinning gels is highly effective. However, the addition of other excipients, e.g. humectants, to these vehicles might cause changes in the penetration profiles. More research in this regard is needed to understand these observations in more detail.

Curcumin Nanocrystal/pH-Responsive Polyelectrolyte Multilayer Core-Shell Nanoparticles for Inflammation-Targeted Alleviation of Ulcerative Colitis.

In this study, we developed oral core-shell nanoparticles composed of curcumin nanocrystals in the core and chitosan/alginate multilayers in the shell for inflammation-targeted alleviation of ulcerative colitis (UC). The release rate of curcumin from the core-shell nanoparticles was low at a pH mimicking the stomach and small intestine, whereas it was higher at a pH mimicking the colon. Further, biodistribution studies in the gastrointestinal tract of mice showed that distribution of nanoparticles was significantly higher in the colon than that in the stomach and small intestine. Quantitative analysis of drugs in colonic tissues and confocal imaging of colons revealed preferential accumulation of nanoparticles in inflamed tissues than that in healthy tissues. In vivo anti-inflammatory studies revealed that nanoparticles exhibit enhanced efficacy in alleviating inflammation-related symptoms in a mouse colitis model. The results suggest that the core-shell nanoparticles presented here can be exploited as efficient colon-targeted drug delivery systems for UC therapy.

Optimization of Curcumin Nanocrystals as Promising Strategy for Nose-to-Brain Delivery Application.

Intranasal (IN) drug delivery is recognized to be an innovative strategy to deliver drugs to the Central Nervous System. One of the main limitations of IN dosing is the low volume of drug that can be administered. Accordingly, two requirements are necessary: the drug should be active at a low dosage, and the drug solubility in water must be high enough to accommodate the required dose. Drug nanocrystals may overcome these limitations; thus, curcumin was selected as a model drug to prepare nanocrystals for potential IN administration. With this aim, we designed curcumin nanocrystals (NCs) by using Box Behnken design. A total of 51 formulations were prepared by the sonoprecipitation method. Once we assessed the influence of the independent variables on nanocrystals’ mean diameter, the formulation was optimized based on the desirability function. The optimized formulation was characterized from a physico-chemical point of view to evaluate the mean size, zeta potential, polidispersity index, pH, osmolarity, morphology, thermotropic behavior and the degree of crystallinity. Finally, the cellular uptake of curcumin and curcumin NCs was evaluated on Olfactory Ensheathing Cells (OECs). Our results showed that the OECs efficiently took up the NCs compared to the free curcumin, showing that NCs can ameliorate drug permeability.

Curcumin Nanocrystals as Photodynamical Sensor Monitoring Ultraviolet Accelerated Aging of HDPE

In this work, curcumin nanocrystals (CCN) was used as fluorescence probes for monitoring the accelerated aging of high density polyethylene (HDPE) used in insulation of high-voltage cables. CCN has been synthesized and incorporated into HDPE matrix using hydrothermal process (HydP) at 202.65 kPa and temperatures of 60 °C and 120 °C. The apparent activation energy (EA) for CCN incorporation into HDPE matrix was 54.4 kJ/mol. The resulting nanocomposite HDPE-CCN has been characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and fluorescence spectroscopy (FS). The crystallinity of HDPE and HDPE-CCN determined by DSC were 71.27% and 70.30% respectively, suggesting that the presence of CCN does not modify significantly the microstructure of HDPE. Accelerated aging of HDPE-CCN samples was carried out and the stress to break ( $\varepsilon _{\mathrm {b}}$ ), Young’s modulus (E) and fluorescence intensity (FI) were used as measurements of HDPE degradation. Mechanical properties ( $\varepsilon _{\mathrm {b}},\mathrm {E}$ ) and FI measurements do correlate with age-related material degradation on the HDPE samples examined.

Hyaluronic acid hydrophilic surface rehabilitating curcumin nanocrystals for targeted breast cancer treatment with prolonged biodistribution.

Due to its high therapeutic efficiency and low systemic toxicity, natural bioactive curcumin has attracted more and more attention as a potential antineoplastic drug. Although the emergence of a carrier-free nanocrystalline technology could improve the solubility and guarantee the high drug loading of curcumin, uncontrollable drug release and fast systemic metabolism are definite obstacles that hinder its further application in cancer treatment. Here, hyaluronic acid (HA) modification was carried out on the surface of curcumin nanocrystals (Cur-NC) to obtain surface reformed hydrophilic HA@Cur-NCs that exhibit prolonged biodistribution. Besides this, HA@Cur-NC shows enhanced intracellular uptake in CD44 overexpressing MDA-MB-231 cells, but reduced uptake when pre-treated with HA. The apoptotic effects, confirmed by flow cytometry, suggest that HA@Cur-NC could achieve high anticancer activity against MDA-MB-231 cells. In vivo pharmacokinetic studies suggest that the t1/2 and mean residence time (MRT) of Cur are significantly extended after the intravenous administration of HA@Cur-NC in normal rats. Moreover, HA@Cur-NC demonstrated superior anticancer effects in a murine 4T1 orthotopic breast cancer model compared with free drug and Cur-NC. Overall, these results show the potential of HA@Cur-NC as a suitable formula for use in breast cancer therapy.

Size effect of curcumin nanocrystals on dissolution, airway mucosa penetration, lung tissue distribution and absorption by pulmonary delivery

Nanocrystals (NCs) have been introduced for use in pulmonary delivery in recent decades. Although the deposition and bioavailability have been extensively studied, little is known about the biofate, which influences the drug release and absorption process of NCs. In this study, we fabricated three different sized curcumin NCs by adjusting the parameters of mill machine using a wet milling method and studied the size effect on pulmonary absorption. The small nanocrystals (NC-S, 246.16 ± 21.98 nm) exhibited a faster dissolution rate and higher diffusion percentage in vitro compared with middle (NC-M, 535.26 ± 50.33 nm) and large nanocrystals (NC-L, 1089.53 ± 194.34 nm). Multiple particle tracking experiments revealed that NC-S had larger mean squared displacement during diffusion in simulated mucus of 0.5% hydroxyethyl cellulose solution. Moreover, enhanced cellular uptake and transport efficiency were achieved by NC-S in Calu-3 cells and an air-liquid interface culturing model. NCs were mainly absorbed in the dissolved drug form, as assessed by using the Förster resonance energy transfer (FRET) technique. In vivo lung retention and distribution revealed that few smaller sized nanocrystals were retained in the lung after intratracheal administration. The pharmacokinetic study showed that the AUC(0-t) values of small sized nanocrystals were 1.75- and 3.32-fold greater than NC-M and NC-L, respectively. In conclusion, this study demonstrated that smaller sized nanocrystals were more easily absorbed into the blood system by increasing the dissolution rate.

Nanocrystals for dermal penetration enhancement – Effect of concentration and underlying mechanisms using curcumin as model

Nanocrystals have received considerable attention in dermal application due to their ability to enhance delivery to the skin and overcome bioavailability issues caused by poor water and oil drug solubility. The objective of this study was to investigate the effect of nanocrystals on the mechanism of penetration behavior of curcumin as a model drug. Curcumin nanocrystals were produced by the smartCrystals® process, i.e. bead milling followed by high pressure homogenization. The mean particle size of the curcumin crystals was about 200nm. Stabilization was performed with alkyl polyglycoside surfactants. The distribution of curcumin within the skin was determined in vitro on cross-sections of porcine skin and visualized by fluorescent microscopy. The skin penetration profile was analyzed for the curcumin nanosuspension with decreasing concentrations (2%, 0.2%, 0.02% and 0.002% by weight) and compared to nanocrystals in a viscous hydroxypropylcellulose (HPC) gel. This study demonstrated there was minor difference between low viscous nanosuspension and the gel, but low viscosity seemed to favor skin penetration. Localization of curcumin was observed in the hair follicles, also contributing to skin uptake. Looking at the penetration of curcumin from formulations with decreasing nanocrystal concentration, formulations with 2%, 0.2% and 0.02% showed a similar penetration profile, whereas a significantly weaker fluorescence was observed in the case of a formulation containing 0.002% of curcumin nanocrystals. In this study we have shown that curcumin nanocrystals prepared by the smartCrystal® process are promising carriers in dermal application and furthermore, we identified the ideal concentration of 0.02% nanocrystals in dermal formulations. The comprehensive study of decreasing curcumin concentration in formulations revealed that the saturation solubility (Cs) is not the only determining factor for the penetration. A new mechanism based also on the concentration of the nanocrystals on skin surface was proposed.

C-Jun N-terminal kinase-dependent apoptotic photocytotoxicity of solvent exchange-prepared curcumin nanoparticles.

Indian spice curcumin is known for its anticancer properties, but the anticancer mechanisms of nanoparticulate curcumin have not been completely elucidated. We here investigated the in vitro anticancer effect of blue light (470nm, 1W)-irradiated curcumin nanoparticles prepared by tetrahydrofuran/water solvent exchange, using U251 glioma, B16 melanoma, and H460 lung cancer cells as targets. The size of curcumin nanocrystals was approximately 250nm, while photoexcitation induced their oxidation and partial agglomeration. Although cell membrane in the absence of light was almost impermeable to curcumin nanoparticles, photoexcitation stimulated their internalization. While irradiation with blue light (1-8min) or nanocurcumin (1.25-10μg/ml) alone was only marginally toxic to tumor cells, photoexcited nanocurcumin displayed a significant cytotoxicity depending both on the irradiation time and nanocurcumin concentration. Photoexcited nanocurcumin induced phosphorylation of c-Jun N-terminal kinase (JNK), mitochondrial depolarization, caspase-3 activation, and cleavage of poly (ADP-ribose) polymerase, indicating apoptotic cell death. Accordingly, pharmacologial inhibition of JNK and caspase activity rescued cancer cells from photoexcited nanocurcumin. On the other hand, antioxidant treatment did not reduce photocytotoxicity of nanocurcumin, arguing against the involvement of oxidative stress. By demonstrating the ability of photoexcited nanocurcumin to induce oxidative-stress independent, JNK- and caspase-dependent apoptosis, our results support its further investigation in cancer therapy.