Celecoxib Encapsulation in β-Casein Micelles: Structure, Interactions, and Conformation

Tanya Turovsky; Rafail Khalfin; Shifi Kababya; Asher Schmidt; Yechezkel Barenholz; Dganit Danino

doi:10.1021/acs.langmuir.5b01397

Celecoxib Encapsulation in β-Casein Micelles: Structure, Interactions, and Conformation

Tanya Turovsky, Rafail Khalfin, Shifi Kababya, Asher Schmidt, Yechezkel Barenholz, Dganit Danino^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

Abstract

β-Casein is a 24 kDa natural protein that has an open conformation and almost no folded or secondary structure, and thus is classified as an intrinsically unstructured protein. At neutral pH, β-casein has an amphiphilic character. Therefore, in contrast to most unstructured proteins that remain monomeric in solution, β-casein self-assembles into well-defined core-shell micelles. We recently developed these micelles as potential carriers for oral administration of poorly water-soluble pharmaceuticals, using celecoxib as a model drug. Herein we present deep and precise insight into the physicochemical characteristics of the protein-drug formulation, both in bulk solution and in dry form, emphasizing drug conformation, packing properties and aggregation state. In addition, the formulation is extensively studied in terms of structure and morphology, protein/drug interactions and physical stability. Particularly, NMR measurements indicated strong drug-protein interactions and noncrystalline drug conformation, which is expected to improve drug solubility and bioavailability. Small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) were combined for nanostructural characterization, proving that drug-protein interactions lead to well-defined spheroidal micelles that become puffier and denser upon drug loading. Dynamice light scattering (DLS), turbidity measurements, and visual observations complemented the analysis for determining formulation structure, interactions, and stability. Additionally, it was shown that the loaded micelles retain their properties through freeze-drying and rehydration, providing long-term physical and chemical stability. Altogether, the formulation seems greatly promising for oral drug delivery. (Chemical Equation Presented).

Original language	English
Pages (from-to)	7183-7192
Number of pages	10
Journal	Langmuir
Volume	31
Issue number	26
DOIs	https://doi.org/10.1021/acs.langmuir.5b01397
State	Published - 7 Jul 2015
Externally published	Yes

Access to Document

10.1021/acs.langmuir.5b01397

Cite this

@article{58e7632ec69d4080afe36c0505bca2e3,

title = "Celecoxib Encapsulation in β-Casein Micelles: Structure, Interactions, and Conformation",

abstract = "β-Casein is a 24 kDa natural protein that has an open conformation and almost no folded or secondary structure, and thus is classified as an intrinsically unstructured protein. At neutral pH, β-casein has an amphiphilic character. Therefore, in contrast to most unstructured proteins that remain monomeric in solution, β-casein self-assembles into well-defined core-shell micelles. We recently developed these micelles as potential carriers for oral administration of poorly water-soluble pharmaceuticals, using celecoxib as a model drug. Herein we present deep and precise insight into the physicochemical characteristics of the protein-drug formulation, both in bulk solution and in dry form, emphasizing drug conformation, packing properties and aggregation state. In addition, the formulation is extensively studied in terms of structure and morphology, protein/drug interactions and physical stability. Particularly, NMR measurements indicated strong drug-protein interactions and noncrystalline drug conformation, which is expected to improve drug solubility and bioavailability. Small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) were combined for nanostructural characterization, proving that drug-protein interactions lead to well-defined spheroidal micelles that become puffier and denser upon drug loading. Dynamice light scattering (DLS), turbidity measurements, and visual observations complemented the analysis for determining formulation structure, interactions, and stability. Additionally, it was shown that the loaded micelles retain their properties through freeze-drying and rehydration, providing long-term physical and chemical stability. Altogether, the formulation seems greatly promising for oral drug delivery. (Chemical Equation Presented).",

author = "Tanya Turovsky and Rafail Khalfin and Shifi Kababya and Asher Schmidt and Yechezkel Barenholz and Dganit Danino",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2015",

month = jul,

day = "7",

doi = "10.1021/acs.langmuir.5b01397",

language = "英语",

volume = "31",

pages = "7183--7192",

journal = "Langmuir",

issn = "0743-7463",

publisher = "American Chemical Society",

number = "26",

}

TY - JOUR

T1 - Celecoxib Encapsulation in β-Casein Micelles

T2 - Structure, Interactions, and Conformation

AU - Turovsky, Tanya

AU - Khalfin, Rafail

AU - Kababya, Shifi

AU - Schmidt, Asher

AU - Barenholz, Yechezkel

AU - Danino, Dganit

PY - 2015/7/7

Y1 - 2015/7/7

N2 - β-Casein is a 24 kDa natural protein that has an open conformation and almost no folded or secondary structure, and thus is classified as an intrinsically unstructured protein. At neutral pH, β-casein has an amphiphilic character. Therefore, in contrast to most unstructured proteins that remain monomeric in solution, β-casein self-assembles into well-defined core-shell micelles. We recently developed these micelles as potential carriers for oral administration of poorly water-soluble pharmaceuticals, using celecoxib as a model drug. Herein we present deep and precise insight into the physicochemical characteristics of the protein-drug formulation, both in bulk solution and in dry form, emphasizing drug conformation, packing properties and aggregation state. In addition, the formulation is extensively studied in terms of structure and morphology, protein/drug interactions and physical stability. Particularly, NMR measurements indicated strong drug-protein interactions and noncrystalline drug conformation, which is expected to improve drug solubility and bioavailability. Small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) were combined for nanostructural characterization, proving that drug-protein interactions lead to well-defined spheroidal micelles that become puffier and denser upon drug loading. Dynamice light scattering (DLS), turbidity measurements, and visual observations complemented the analysis for determining formulation structure, interactions, and stability. Additionally, it was shown that the loaded micelles retain their properties through freeze-drying and rehydration, providing long-term physical and chemical stability. Altogether, the formulation seems greatly promising for oral drug delivery. (Chemical Equation Presented).

AB - β-Casein is a 24 kDa natural protein that has an open conformation and almost no folded or secondary structure, and thus is classified as an intrinsically unstructured protein. At neutral pH, β-casein has an amphiphilic character. Therefore, in contrast to most unstructured proteins that remain monomeric in solution, β-casein self-assembles into well-defined core-shell micelles. We recently developed these micelles as potential carriers for oral administration of poorly water-soluble pharmaceuticals, using celecoxib as a model drug. Herein we present deep and precise insight into the physicochemical characteristics of the protein-drug formulation, both in bulk solution and in dry form, emphasizing drug conformation, packing properties and aggregation state. In addition, the formulation is extensively studied in terms of structure and morphology, protein/drug interactions and physical stability. Particularly, NMR measurements indicated strong drug-protein interactions and noncrystalline drug conformation, which is expected to improve drug solubility and bioavailability. Small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) were combined for nanostructural characterization, proving that drug-protein interactions lead to well-defined spheroidal micelles that become puffier and denser upon drug loading. Dynamice light scattering (DLS), turbidity measurements, and visual observations complemented the analysis for determining formulation structure, interactions, and stability. Additionally, it was shown that the loaded micelles retain their properties through freeze-drying and rehydration, providing long-term physical and chemical stability. Altogether, the formulation seems greatly promising for oral drug delivery. (Chemical Equation Presented).

UR - http://www.scopus.com/inward/record.url?scp=84936797803&partnerID=8YFLogxK

U2 - 10.1021/acs.langmuir.5b01397

DO - 10.1021/acs.langmuir.5b01397

M3 - 文章

C2 - 26068530

AN - SCOPUS:84936797803

SN - 0743-7463

VL - 31

SP - 7183

EP - 7192

JO - Langmuir

JF - Langmuir

IS - 26

ER -

Celecoxib Encapsulation in β-Casein Micelles: Structure, Interactions, and Conformation

Abstract

Access to Document

Other files and links

Fingerprint

Cite this