• Je něco špatně v tomto záznamu ?

Effects of Membrane PEGylation on Entry and Location of Antifungal Drug Itraconazole and Their Pharmacological Implications

M. Dzieciuch-Rojek, C. Poojari, J. Bednar, A. Bunker, B. Kozik, M. Nowakowska, I. Vattulainen, P. Wydro, M. Kepczynski, T. Róg,

. 2017 ; 14 (4) : 1057-1070. [pub] 20170307

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc18016749

Itraconazole (ITZ) is an antifungal agent used clinically to treat mycotic infections. However, its therapeutic effects are limited by low solubility in aqueous media. Liposome-based delivery systems (LDS) have been proposed as a delivery mechanism for ITZ to alleviate this problem. Furthermore, PEGylation, the inclusion in the formulation of a protective "stealth sheath" of poly(ethylene glycol) around carrier particles, is widely used to increase circulation time in the bloodstream and hence efficacy. Together, these themes highlight the importance of mechanistic and structural understanding of ITZ incorporation into liposomes both with and without PEGylation because it can provide a potential foundation for the rational design of LDS-based systems for delivery of ITZ, using alternate protective polymers or formulations. Here we have combined atomistic simulations, cryo-TEM, Langmuir film balance, and fluorescence quenching experiments to explore how ITZ interacts with both pristine and PEGylated liposomes. We found that the drug can be incorporated into conventional and PEGylated liposomes for drug concentrations up to 15 mol % without phase separation. We observed that, in addition to its protective properties, PEGylation significantly increases the stability of liposomes that host ITZ. In a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer without PEGylation, ITZ was found to reside inside the lipid bilayer between the glycerol and the double-bond regions of POPC, adopting a largely parallel orientation along the membrane surface. In a PEGylated liposome, ITZ partitions mainly to the PEG layer. The results provide a solid basis for further development of liposome-based delivery systems.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc18016749
003      
CZ-PrNML
005      
20180515103533.0
007      
ta
008      
180515s2017 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1021/acs.molpharmaceut.6b00969 $2 doi
035    __
$a (PubMed)28234487
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Dzieciuch-Rojek, Monika $u Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
245    10
$a Effects of Membrane PEGylation on Entry and Location of Antifungal Drug Itraconazole and Their Pharmacological Implications / $c M. Dzieciuch-Rojek, C. Poojari, J. Bednar, A. Bunker, B. Kozik, M. Nowakowska, I. Vattulainen, P. Wydro, M. Kepczynski, T. Róg,
520    9_
$a Itraconazole (ITZ) is an antifungal agent used clinically to treat mycotic infections. However, its therapeutic effects are limited by low solubility in aqueous media. Liposome-based delivery systems (LDS) have been proposed as a delivery mechanism for ITZ to alleviate this problem. Furthermore, PEGylation, the inclusion in the formulation of a protective "stealth sheath" of poly(ethylene glycol) around carrier particles, is widely used to increase circulation time in the bloodstream and hence efficacy. Together, these themes highlight the importance of mechanistic and structural understanding of ITZ incorporation into liposomes both with and without PEGylation because it can provide a potential foundation for the rational design of LDS-based systems for delivery of ITZ, using alternate protective polymers or formulations. Here we have combined atomistic simulations, cryo-TEM, Langmuir film balance, and fluorescence quenching experiments to explore how ITZ interacts with both pristine and PEGylated liposomes. We found that the drug can be incorporated into conventional and PEGylated liposomes for drug concentrations up to 15 mol % without phase separation. We observed that, in addition to its protective properties, PEGylation significantly increases the stability of liposomes that host ITZ. In a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer without PEGylation, ITZ was found to reside inside the lipid bilayer between the glycerol and the double-bond regions of POPC, adopting a largely parallel orientation along the membrane surface. In a PEGylated liposome, ITZ partitions mainly to the PEG layer. The results provide a solid basis for further development of liposome-based delivery systems.
650    _2
$a antifungální látky $x chemie $7 D000935
650    _2
$a chemie farmaceutická $x metody $7 D002626
650    _2
$a systémy cílené aplikace léků $x metody $7 D016503
650    _2
$a fluorescence $7 D005453
650    _2
$a itrakonazol $x chemie $7 D017964
650    _2
$a lipidové dvojvrstvy $x chemie $7 D008051
650    _2
$a liposomy $x chemie $7 D008081
650    _2
$a membrány $x chemie $7 D008566
650    _2
$a fosfatidylcholiny $x chemie $7 D010713
650    _2
$a polyethylenglykoly $x chemie $7 D011092
650    _2
$a polymery $x chemie $7 D011108
650    _2
$a ochranné látky $x chemie $7 D020011
650    _2
$a rozpustnost $7 D012995
650    _2
$a povrchové vlastnosti $7 D013499
655    _2
$a časopisecké články $7 D016428
700    1_
$a Poojari, Chetan $u Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland.
700    1_
$a Bednar, Jan $u Université de Grenoble Alpes/CNRS, Institut Albert Bonniot , UMR 5309, 38042 CEDEX 9 Grenoble, France. First Faculty of Medicine, Laboratory of Biology and Pathology of the Eye, Institute of Inherited Metabolic Disorders, Charles University in Prague , KeKarlovu 2, 12800 Prague 2, Czech Republic.
700    1_
$a Bunker, Alex $u Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
700    1_
$a Kozik, Bartłomiej $u Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
700    1_
$a Nowakowska, Maria $u Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
700    1_
$a Vattulainen, Ilpo $u Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland. Department of Physics, University of Helsinki , P.O. Box 64, FI-00014 Helsinki, Finland. MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark , Odense, Denmark.
700    1_
$a Wydro, Paweł $u Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
700    1_
$a Kepczynski, Mariusz $u Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Kraków, Poland.
700    1_
$a Róg, Tomasz $u Department of Physics, Tampere University of Technology , P.O. Box 692, FI-33101 Tampere, Finland. Department of Physics, University of Helsinki , P.O. Box 64, FI-00014 Helsinki, Finland.
773    0_
$w MED00008279 $t Molecular pharmaceutics $x 1543-8392 $g Roč. 14, č. 4 (2017), s. 1057-1070
856    41
$u https://pubmed.ncbi.nlm.nih.gov/28234487 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20180515 $b ABA008
991    __
$a 20180515103706 $b ABA008
999    __
$a ok $b bmc $g 1300373 $s 1013589
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2017 $b 14 $c 4 $d 1057-1070 $e 20170307 $i 1543-8392 $m Molecular pharmaceutics $n Mol Pharm $x MED00008279
LZP    __
$a Pubmed-20180515

Najít záznam

Citační ukazatele

Možnosti archivace