A Novel Loading Method for Doxycycline Liposomes for Intracellular Drug Delivery: Characterization of In Vitro and In Vivo Release Kinetics and Efficacy in a J774A.1 Cell Line Model of Mycobacterium smegmatis Infection
Identifieur interne : 001121 ( Main/Exploration ); précédent : 001120; suivant : 001122A Novel Loading Method for Doxycycline Liposomes for Intracellular Drug Delivery: Characterization of In Vitro and In Vivo Release Kinetics and Efficacy in a J774A.1 Cell Line Model of Mycobacterium smegmatis Infection
Auteurs : Rebekah K. Franklin ; Sarah A. Marcus ; Adel M. Talaat ; Butch K. Kukanich ; Ruth Sullivan ; Lisa A. Krugner-Higby ; Timothy D. HeathSource :
- Drug Metabolism and Disposition [ 0090-9556 ] ; 2015.
Abstract
Doxycycline (doxy) is used in treating intracellular and extracellular infections. Liposomal (LE) antibiotics allow low-frequency dosing and extended efficacy compared with standard (STD) formulations. We developed a novel sulfuric acid–loading method for doxycycline liposomes (LE-doxy). We hypothesized that a single s.c. injection of LE-doxy would be detectable in serum for at least 2 weeks at concentrations equal to or better than STD-doxy and would be bactericidal in an in vitro
Url:
DOI: 10.1124/dmd.115.063602
PubMed: 26033620
PubMed Central: 4518064
Affiliations:
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Novel Loading Method for Doxycycline Liposomes for Intracellular Drug Delivery: Characterization of In Vitro and In Vivo Release Kinetics and Efficacy in a J774A.1 Cell Line Model of <italic>Mycobacterium smegmatis</italic>
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<author><name sortKey="Marcus, Sarah A" sort="Marcus, Sarah A" uniqKey="Marcus S" first="Sarah A." last="Marcus">Sarah A. Marcus</name>
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<author><name sortKey="Talaat, Adel M" sort="Talaat, Adel M" uniqKey="Talaat A" first="Adel M." last="Talaat">Adel M. Talaat</name>
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<author><name sortKey="Kukanich, Butch K" sort="Kukanich, Butch K" uniqKey="Kukanich B" first="Butch K." last="Kukanich">Butch K. Kukanich</name>
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<author><name sortKey="Sullivan, Ruth" sort="Sullivan, Ruth" uniqKey="Sullivan R" first="Ruth" last="Sullivan">Ruth Sullivan</name>
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<author><name sortKey="Krugner Higby, Lisa A" sort="Krugner Higby, Lisa A" uniqKey="Krugner Higby L" first="Lisa A." last="Krugner-Higby">Lisa A. Krugner-Higby</name>
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<author><name sortKey="Heath, Timothy D" sort="Heath, Timothy D" uniqKey="Heath T" first="Timothy D." last="Heath">Timothy D. Heath</name>
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<series><title level="j">Drug Metabolism and Disposition</title>
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<front><div type="abstract" xml:lang="en"><p>Doxycycline (doxy) is used in treating intracellular and extracellular infections. Liposomal (LE) antibiotics allow low-frequency dosing and extended efficacy compared with standard (STD) formulations. We developed a novel sulfuric acid–loading method for doxycycline liposomes (LE-doxy). We hypothesized that a single s.c. injection of LE-doxy would be detectable in serum for at least 2 weeks at concentrations equal to or better than STD-doxy and would be bactericidal in an in vitro <italic>Mycobacterium smegmatis</italic>
infection of J774A.1 macrophage cells. Liposomes were encapsulated by sulfuric acid gradient loading, and release kinetics were performed in vitro and in vivo. LE-doxy made using 8.25 mg/ml doxycycline loaded for 24 hours achieved 97.77% capture in 1,2-dipalmitoyl-<italic>sn</italic>
-glycero-3-phosphocholine (DPPC) and 43.87% in sphingomyelin (sphing). Rats were injected s.c. with 50 mg/kg LE-doxy or 5 mg/kg STD-doxy, and serial blood samples were collected. Pharmacokinetics were analyzed using high-performance liquid chromatography. Liver and injection site skin samples were collected at euthanasia (4 weeks postinjection). Minimal histologic tissue reactions occurred after injection of STD (nonliposomal), DPPC, or sphing-doxy. DPPC-doxy had slightly faster in vitro leakage than sphing liposomes, although both were detectable at 264 hours. The mean residence time for DPPC was the highest (111.78 hours), followed by sphing (56.00 hours) and STD (6.86 hours). DPPC and sphing-doxy were detectable at 0.2 <italic>μ</italic>
g/ml in serum at 336 hours postadministration. LE-doxy was not toxic to J774A.1 cells in vitro and produced inhibition of viable <italic>Mycobacterium smegmatis</italic>
at 24 and 48 hours. LE-doxy will require further testing in in vivo infection models.</p>
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<tree><noCountry><name sortKey="Franklin, Rebekah K" sort="Franklin, Rebekah K" uniqKey="Franklin R" first="Rebekah K." last="Franklin">Rebekah K. Franklin</name>
<name sortKey="Heath, Timothy D" sort="Heath, Timothy D" uniqKey="Heath T" first="Timothy D." last="Heath">Timothy D. Heath</name>
<name sortKey="Krugner Higby, Lisa A" sort="Krugner Higby, Lisa A" uniqKey="Krugner Higby L" first="Lisa A." last="Krugner-Higby">Lisa A. Krugner-Higby</name>
<name sortKey="Kukanich, Butch K" sort="Kukanich, Butch K" uniqKey="Kukanich B" first="Butch K." last="Kukanich">Butch K. Kukanich</name>
<name sortKey="Marcus, Sarah A" sort="Marcus, Sarah A" uniqKey="Marcus S" first="Sarah A." last="Marcus">Sarah A. Marcus</name>
<name sortKey="Sullivan, Ruth" sort="Sullivan, Ruth" uniqKey="Sullivan R" first="Ruth" last="Sullivan">Ruth Sullivan</name>
<name sortKey="Talaat, Adel M" sort="Talaat, Adel M" uniqKey="Talaat A" first="Adel M." last="Talaat">Adel M. Talaat</name>
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