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Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery

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ABSTRACT

Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm2) and penetration through the skin (13.38±2.26 μg/cm2). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.

No MeSH data available.


The morphology of FK506–HA–Chol–NPs–NIC observed by AFM at room temperature.Abbreviations: AFM, atomic force microscope; FK506–HA–Chol–NPs–NIC, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide.
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f4-ijn-11-4037: The morphology of FK506–HA–Chol–NPs–NIC observed by AFM at room temperature.Abbreviations: AFM, atomic force microscope; FK506–HA–Chol–NPs–NIC, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide.

Mentions: NPs were prepared by the sonication method. The morphology of NPs characterized by AFM was uniformly spherical (Figure 4). The particle size and zeta potential of HA–Chol–NPs with different DSs were examined by dynamic light scattering, and the results are shown in Table 3. The average size of HA–Chol–NPs in the absence of NIC was larger than that in the presence of NIC, and the size of HA–Chol–NPs with NIC ranged from 160.5 nm to 208.0 nm, and the zeta potential ranged from −31.5 mV to −41.9 mV. With the increase in Chol DS, the particle size was decreased due to the increasing hydrophobic interaction. The negative zeta potential was attributed to the negative charge of the carboxylic group of HA backbone. The high zeta potential might prevent the aggregation of NPs in solution by electrostatic repulsion.


Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery
The morphology of FK506–HA–Chol–NPs–NIC observed by AFM at room temperature.Abbreviations: AFM, atomic force microscope; FK506–HA–Chol–NPs–NIC, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4998035&req=5

f4-ijn-11-4037: The morphology of FK506–HA–Chol–NPs–NIC observed by AFM at room temperature.Abbreviations: AFM, atomic force microscope; FK506–HA–Chol–NPs–NIC, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide.
Mentions: NPs were prepared by the sonication method. The morphology of NPs characterized by AFM was uniformly spherical (Figure 4). The particle size and zeta potential of HA–Chol–NPs with different DSs were examined by dynamic light scattering, and the results are shown in Table 3. The average size of HA–Chol–NPs in the absence of NIC was larger than that in the presence of NIC, and the size of HA–Chol–NPs with NIC ranged from 160.5 nm to 208.0 nm, and the zeta potential ranged from −31.5 mV to −41.9 mV. With the increase in Chol DS, the particle size was decreased due to the increasing hydrophobic interaction. The negative zeta potential was attributed to the negative charge of the carboxylic group of HA backbone. The high zeta potential might prevent the aggregation of NPs in solution by electrostatic repulsion.

View Article: PubMed Central - PubMed

ABSTRACT

Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm2) and penetration through the skin (13.38±2.26 μg/cm2). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.

No MeSH data available.