Development of injectable liposomes and drug-in-cyclodextrin-in-liposome formulations encapsulating estetrol to prevent cerebral ischemia of premature babies

Claudio Palazzo, Julie Laloy, Anne Sophie Delvigne, Gwenael Nys, Marianne Fillet, Jean Michel Dogne, Christel Pequeux, Jean Michel Foidart, Brigitte Evrard, Geraldine Piel

Research output: Contribution to journalArticle

Abstract

Neonatal Hypoxic-Ischemic Encephalopathy (HIE), a brain disease due to brain hypoxia along with ischemia and reduced cerebral blood flow, is one of the primary reasons of severe injury among babies prematurely born. No efficacy treatment is available to the present day. Estetrol (E4), a major estradiol metabolite, has an important role in the brain development and protection. The aim of this study is to develop new injectable liposome and drug-in-cyclodextrin-in-liposome (DCL) formulations, encapsulating E4 in order to enhance its crossing through the blood-brain barrier (BBB). Liposome and DCL formulations were prepared and were physiochemically characterized. Stability in foetal bovine serum (FBS) was evaluated. LDH and MTS tests on endothelial, neuronal and BBB model cells, as well as hemocompatibility of the nanovectors were performed in vitro. In vitro BBB passage was evaluated using human BBB cell line (hCMEC/D3). All the formulations had average particle size below 150 nm, polydispersity index below 0.10 and ζ potential around +30 mV. The encapsulation efficacy for liposomes was between 3% and 10% while those of DCL are between 15% and 35%. The effect of liposome and DCL formulations on cell viability and integrity was evaluated. The results showed no toxic effects on all the tested cell lines. Hemocompatibility tests showed no hemolysis, platelet aggregation or effects on coagulation, confirming the possibility of the formulations to be intravenously administrated. BBB passage tests highlighted the capability of the formulations to pass the BBB and reach the brain. Therefore, the formulations are promising drug delivery system to target estrogens to the brain, due to their physiochemical characteristics.

Original languageEnglish
Pages (from-to)52-59
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Volume127
DOIs
Publication statusPublished - 15 Jan 2019

Fingerprint

Estetrol
Cyclodextrins
Brain Ischemia
Liposomes
Blood-Brain Barrier
Injections
Pharmaceutical Preparations
Cerebrovascular Circulation
Brain
Brain Hypoxia-Ischemia
Brain Hypoxia
Cell Line
Poisons
Brain Diseases
Drug Delivery Systems
Hemolysis
Platelet Aggregation
Particle Size
Estradiol
Cell Survival

Keywords

  • Blood-brain barrier
  • Cerebral ischemia
  • Drug-in-Cyclodextrin-in-liposome
  • Estetrol
  • Hemocompatibility
  • Liposome

Cite this

Palazzo, Claudio ; Laloy, Julie ; Delvigne, Anne Sophie ; Nys, Gwenael ; Fillet, Marianne ; Dogne, Jean Michel ; Pequeux, Christel ; Foidart, Jean Michel ; Evrard, Brigitte ; Piel, Geraldine. / Development of injectable liposomes and drug-in-cyclodextrin-in-liposome formulations encapsulating estetrol to prevent cerebral ischemia of premature babies. In: European Journal of Pharmaceutical Sciences. 2019 ; Vol. 127. pp. 52-59.
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Development of injectable liposomes and drug-in-cyclodextrin-in-liposome formulations encapsulating estetrol to prevent cerebral ischemia of premature babies. / Palazzo, Claudio; Laloy, Julie; Delvigne, Anne Sophie; Nys, Gwenael; Fillet, Marianne; Dogne, Jean Michel; Pequeux, Christel; Foidart, Jean Michel; Evrard, Brigitte; Piel, Geraldine.

In: European Journal of Pharmaceutical Sciences, Vol. 127, 15.01.2019, p. 52-59.

Research output: Contribution to journalArticle

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T1 - Development of injectable liposomes and drug-in-cyclodextrin-in-liposome formulations encapsulating estetrol to prevent cerebral ischemia of premature babies

AU - Palazzo, Claudio

AU - Laloy, Julie

AU - Delvigne, Anne Sophie

AU - Nys, Gwenael

AU - Fillet, Marianne

AU - Dogne, Jean Michel

AU - Pequeux, Christel

AU - Foidart, Jean Michel

AU - Evrard, Brigitte

AU - Piel, Geraldine

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Neonatal Hypoxic-Ischemic Encephalopathy (HIE), a brain disease due to brain hypoxia along with ischemia and reduced cerebral blood flow, is one of the primary reasons of severe injury among babies prematurely born. No efficacy treatment is available to the present day. Estetrol (E4), a major estradiol metabolite, has an important role in the brain development and protection. The aim of this study is to develop new injectable liposome and drug-in-cyclodextrin-in-liposome (DCL) formulations, encapsulating E4 in order to enhance its crossing through the blood-brain barrier (BBB). Liposome and DCL formulations were prepared and were physiochemically characterized. Stability in foetal bovine serum (FBS) was evaluated. LDH and MTS tests on endothelial, neuronal and BBB model cells, as well as hemocompatibility of the nanovectors were performed in vitro. In vitro BBB passage was evaluated using human BBB cell line (hCMEC/D3). All the formulations had average particle size below 150 nm, polydispersity index below 0.10 and ζ potential around +30 mV. The encapsulation efficacy for liposomes was between 3% and 10% while those of DCL are between 15% and 35%. The effect of liposome and DCL formulations on cell viability and integrity was evaluated. The results showed no toxic effects on all the tested cell lines. Hemocompatibility tests showed no hemolysis, platelet aggregation or effects on coagulation, confirming the possibility of the formulations to be intravenously administrated. BBB passage tests highlighted the capability of the formulations to pass the BBB and reach the brain. Therefore, the formulations are promising drug delivery system to target estrogens to the brain, due to their physiochemical characteristics.

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