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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F17%3A10362240" target="_blank" >RIV/00216208:11110/17:10362240 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1021/acs.molpharmaceut6b00969" target="_blank" >http://dx.doi.org/10.1021/acs.molpharmaceut6b00969</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.molpharmaceut6b00969" target="_blank" >10.1021/acs.molpharmaceut6b00969</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

Itraconazole (ITZ) is arr 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 &quot;stealth sheath&quot; 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 incorporation info 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-palmitoyl2-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.

Název v anglickém jazyce

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

Popis výsledku anglicky

Itraconazole (ITZ) is arr 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 &quot;stealth sheath&quot; 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 incorporation info 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-palmitoyl2-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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10600 - Biological sciences

Projekt

<a href="/cs/project/GBP302%2F12%2FG157" target="_blank" >GBP302/12/G157: Dynamika a organizace chromosomů během buněčného cyklu a při diferenciaci v normě a patologii</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Molecular Pharmaceutics

ISSN

1543-8384

e-ISSN

—

Svazek periodika

14

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

1057-1070

Kód UT WoS článku

000398426100009

EID výsledku v databázi Scopus

2-s2.0-85019028641