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Quercetin, a flavonoid compound rich in hydroxyl groups, possesses antioxidant properties, whereas its poor water solubility limits its bioavailability. In pursuit of addressing the water solubility of quercetin and comprehending the impact of nanocrystal particle size on antioxidant efficacy, we prepared three different-sized quercetin nanocrystals, namely small (50 nm), medium (140 nm), and large (360 nm), using a nanosuspension method in this study. Within the in vitro setting, assessments employing solubility and radical scavenging assays revealed that quercetin nanocrystals displayed superior solubility (26, 21, and 13 fold corresponding to small, medium, and large particle sizes) and antioxidant performance compared to the coarse quercetin. Furthermore, quercetin nanocrystals of three particle sizes all demonstrated significant protection effects on the survival rate of H2O2-treated zebrafish at 72 h (77.78%, 73.33%, and 66.67% for small, medium, and large particle sizes, respectively), while the coarse quercetin group exhibited a low survival rate (53.3%) similar to the H2O2-treated group (47.8%). Moreover, all quercetin nanocrystals exhibited potent antioxidant capacity on both the antioxidants and enzymatic antioxidant system in H2O2-treated zebrafish to restore zebrafish to a normal state under oxidative stress. For instance, the levels of reactive oxygen species were reduced to 101.10%, 108.83%, and 109.77% of the normal levels for small, medium, and large particle-sized quercetin nanocrystals, respectively. In conclusion, quercetin nanocrystals demonstrated enhanced solubility, robust antioxidant capacity, and protective effects in zebrafish compared to coarse quercetin. [ABSTRACT FROM AUTHOR]

Hyaluronidase is clinically used in treating many skin diseases due to its good permeability-promoting effect, which may motivate the diffusion and absorption of drugs. To verify the penetration osmotic effect of hyaluronidase in microneedles, 55 nm-size curcumin nanocrystals were fabricated and loaded into microneedles containing hyaluronidase in the tip. Microneedles with bullet shape and backing layer of 20% PVA + 20% PVP K30 (w/v) showed excellent performance. The microneedles were able to pierce the skin effectively with a skin insert rate of 90% and demonstrated good mechanical strength. In the in vitro permeation assay, with the increase of hyaluronidase concentration at the tip of the needle, the cumulative release of curcumin increased, as well as the skin retention decreased. In addition, compared with the microneedles without hyaluronidase, the microneedles containing hyaluronidase in the tip exhibited a larger drug diffusion area and deeper diffusion depth. In conclusion, hyaluronidase could effectively promote the transdermal diffusion and absorption of the drug. [ABSTRACT FROM AUTHOR]

Melanin is a kind of dark insoluble pigment that can cause pigmentation and free-radical clearance, inducing melasma, freckles, and chloasma, affecting the quality of life of patients. Due to poor water solubility and low safety, the absorption of poorly water-soluble drugs is limited by the hinderance of a skin barrier. Therefore, it is necessary to develop new, safe, and highly efficient drugs to improve their transdermal absorption efficiency and thus to inhibit the production of melanin. To address these issues, we developed a new nicotinamide (NIC)-stabilized phloretin nanocrystals (PHL-NCs). First, NC technology significantly increased the solubility of PHL. The in vitro release results indicated that at 6 h, the dissolution of the PHL-NIC-NCs was 101.39% ± 2.40% and of the PHL-NCs was 84.92% ± 4.30%, while that of the physical mixture of the two drugs was only 64.43% ± 0.02%. Second, NIC acted not only as a stabilizer to enlarge the storage time of PHL-NIC-NCs (improved to 10-day in vitro stability) but also as a melanin transfer inhibitor to inhibit melanin production. Finally, we verified the melanin inhibition effect of PHL-NIC-NCs evaluated by the zebrafish model. It showed that 0.38 mM/L PHL-NIC-NCs have a lower tyrosinase activity at 62.97% ± 0.52% and have less melanin at 36.57% ± 0.44%. The inhibition effect of PHL-NCs and PHL-NIC-NCs was stronger compared to the positive control arbutin. In conclusion, the combination of NIC and PHL achieves better inhibition of tyrosinase and inhibition of melanin production through synergism. This will provide a direction to the subsequent development of melanin-inhibiting drugs and the combined use of pharmaceutical agents. [ABSTRACT FROM AUTHOR]

With the wide application of nanotechnology to drug delivery systems, a simple, dynamic and visual in vivo model for high-throughput screening of novel formulations with fluorescence markers across biological barriers is desperately needed. In vitro cell culture models have been widely used, although they are far from a complimentary in vivo system. Mammalian animal models are common predictive models to study transport, but they are costly and time consuming. Zebrafish ( Danio rerio ), a small vertebrate model, have the potential to be developed as an “intermediate” model for quick evaluations. Based on our previously established coumarin 6 nanocrystals (C6-NCs), which have two different sizes, the present study investigates the transportation of C6-NCs across four biological barriers, including the chorion, blood brain barrier (BBB), blood retinal barrier (BRB) and gastrointestinal (GI) barrier, using zebrafish embryos and larvae as in vivo models. The biodistribution and elimination of C6 from different organs were quantified in adult zebrafish. The results showed that compared to 200 nm C6-NCs, 70 nm C6-NCs showed better permeability across these biological barriers. A FRET study suggested that intact C6-NCs together with the free dissolved form of C6 were absorbed into the larval zebrafish. More C6 was accumulated in different organs after incubation with small sized NCs via lipid raft-mediated endocytosis in adult zebrafish, which is consistent with the findings from in vitro cell monolayers and the zebrafish larvae model. C6-NCs could be gradually eliminated in each organ over time. This study demonstrated the successful application of zebrafish as a simple and dynamic model to simultaneously assess the transport of nanosized drug delivery systems across several biological barriers and biodistribution in different organs, especially in the brain, which could be used for central nervous system (CNS) drug and delivery system screening. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Nanocrystals are characterized by high drug loading, low carrier toxicity, and great structural stability. Therefore, they are a promising and versatile strategy for enhancing the local delivery of insoluble drugs. They achieve this by improving skin adhesion, concentration gradients, and hair follicle accumulation, as well as generating corona diffusion (which forms through the overlap of dissolved drug molecules around a nanocrystal). The development of suitable formulations for enhancing the passive diffusion and/or follicular targeting of nanocrystals is of great importance to clinical practice. We sought to elucidate the influence of particle size, a penetration enhancer, and delivery vehicles on the follicular accumulation and passive dermal permeation of nanocrystals. For this purpose, curcumin nanocrystals (particle size: 60, 120, and 480 nm) were incorporated into xanthan gum gels (delivery vehicles) with propylene glycol (penetration enhancer). This evaluation was performed in a porcine skin model. The results showed that xanthan gum reduced the follicular penetration and passive skin accumulation of curcumin nanocrystals. The propylene glycol enhanced the skin penetration and retention of curcumin nanocrystals in vitro for 24 h. The curcumin nanocrystals of smaller particle size (i.e., 60 and 120 nm) displayed higher passive skin penetration versus those with larger particle size (i.e., 480 nm); however, the latter type showed deeper follicular accumulation. In conclusion, the delivery vehicles, penetration enhancer, and particle sizes examined in this study affect the dermal penetration and accumulation of curcumin nanocrystals. Hence, their effects should be adequately considered when designing formulations of such nanocrystals. [Display omitted] • Multiple factors influence the skin penetration of curcumin nanocrystals. • Xanthan gum gels reduce the skin permeation of curcumin nanocrystals. • Smaller curcumin nanocrystals (<100 nm) show better passive skin permeation. • Propylene glycol exhibits a time-dependent skin permeation effect on nanocrystals. [ABSTRACT FROM AUTHOR]

The aim of this study was to fabricate 20(S)-protopanaxadiol (PPD) nanocrystals to improve PPD’s oral bioavailability and brain delivery. PPD nanocrystals were fabricated using an anti-solvent precipitation approach where d -α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was optimized as the stabilizer. The fabricated nanocrystals were nearly spherical with a particle size and drug loading of 90.44 ± 1.45 nm and 76.92%, respectively. They are in the crystalline state and stable at 4 °C for at least 1 month. More than 90% of the PPD could be rapidly released from the nanocrystals, which was much faster than the physical mixture and PPD powder. PPD nanocrystals demonstrated comparable permeability to solution at 2.52 ± 0.44 × 10 −5 cm/s on MDCK monolayers. After oral administration of PPD nanocrystals to rats, PPD was absorbed quickly into the plasma and brain with significantly higher C max and AUC 0– t compared to those of the physical mixture. However, no brain targeting was observed, as the ratios of the plasma AUC 0– t to brain AUC 0– t for the two groups were similar. In summary, PPD nanocrystals are a potential oral delivery system to improve PPD’s poor bioavailability and its delivery into the brain for neurodegenerative disease and intracranial tumor therapies in the future. [ABSTRACT FROM AUTHOR]