Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems
There is a strong need for innovative and efficient drug delivery systems for ocular therapy development. However, testing intravitreal drug delivery systems without using live animals is challenging. Ex vivo animal models offer an interesting alternative. We analyzed the potential of using fresh po...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/13/7/1013 |
| _version_ | 1797526369614168064 |
|---|---|
| author | Gustav Christensen Leon Barut Dileep Urimi Nicolaas Schipper François Paquet-Durand |
| author_facet | Gustav Christensen Leon Barut Dileep Urimi Nicolaas Schipper François Paquet-Durand |
| author_sort | Gustav Christensen |
| collection | DOAJ |
| description | There is a strong need for innovative and efficient drug delivery systems for ocular therapy development. However, testing intravitreal drug delivery systems without using live animals is challenging. Ex vivo animal models offer an interesting alternative. We analyzed the potential of using fresh porcine eyes obtained from the local slaughterhouse as a model for testing the intravitreal biodistribution and retention of liposomes with or without polyethylene glycol (PEG) conjugation and with different surface charges. The histology of the eyes was analyzed to localize the liposomes, and it was found that liposomes with PEG absorbed rapidly on the retina (within 1 h), with positively charged and PEG-coated liposomes being retained for at least 24 h. In parallel, fluorophotometry was employed on intact eyes, to determine the pharmacokinetics of the fluorophore calcein, as a substitute for a small hydrophilic therapeutic compound. We found a 4.5-fold increase in the vitreous half-life of calcein loaded in liposomes, compared with the free solution. Retinal toxicity was addressed using murine-derived retinal explant cultures. Liposomes were non-toxic up to 500 µg/mL. Toxicity was observed at 5 mg/mL for anionic and cationic liposomes, with 2-fold and 2.5-fold increased photoreceptor cell death, respectively. Overall, we could show that important ocular drug delivery considerations such as pharmacokinetics and biodistribution can be estimated in ex vivo porcine eyes, and may guide subsequent in vivo experiments. |
| first_indexed | 2024-03-10T09:28:14Z |
| format | Article |
| id | doaj.art-2125a8e32aba4fc4bc5b934ed27ca091 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T09:28:14Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-2125a8e32aba4fc4bc5b934ed27ca0912023-11-22T04:40:43ZengMDPI AGPharmaceutics1999-49232021-07-01137101310.3390/pharmaceutics13071013Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery SystemsGustav Christensen0Leon Barut1Dileep Urimi2Nicolaas Schipper3François Paquet-Durand4Institute for Ophthalmic Research, University of Tübingen, Elfriede-Aulhorn Straße 5-7, 72076 Tübingen, GermanyInstitute for Ophthalmic Research, University of Tübingen, Elfriede-Aulhorn Straße 5-7, 72076 Tübingen, GermanyDivision Bioeconomy and Health, Chemical Process and Pharmaceutical Development, RISE Research Institutes of Sweden, Forskargatan 18, 151 36 Södertälje, SwedenDivision Bioeconomy and Health, Chemical Process and Pharmaceutical Development, RISE Research Institutes of Sweden, Forskargatan 18, 151 36 Södertälje, SwedenInstitute for Ophthalmic Research, University of Tübingen, Elfriede-Aulhorn Straße 5-7, 72076 Tübingen, GermanyThere is a strong need for innovative and efficient drug delivery systems for ocular therapy development. However, testing intravitreal drug delivery systems without using live animals is challenging. Ex vivo animal models offer an interesting alternative. We analyzed the potential of using fresh porcine eyes obtained from the local slaughterhouse as a model for testing the intravitreal biodistribution and retention of liposomes with or without polyethylene glycol (PEG) conjugation and with different surface charges. The histology of the eyes was analyzed to localize the liposomes, and it was found that liposomes with PEG absorbed rapidly on the retina (within 1 h), with positively charged and PEG-coated liposomes being retained for at least 24 h. In parallel, fluorophotometry was employed on intact eyes, to determine the pharmacokinetics of the fluorophore calcein, as a substitute for a small hydrophilic therapeutic compound. We found a 4.5-fold increase in the vitreous half-life of calcein loaded in liposomes, compared with the free solution. Retinal toxicity was addressed using murine-derived retinal explant cultures. Liposomes were non-toxic up to 500 µg/mL. Toxicity was observed at 5 mg/mL for anionic and cationic liposomes, with 2-fold and 2.5-fold increased photoreceptor cell death, respectively. Overall, we could show that important ocular drug delivery considerations such as pharmacokinetics and biodistribution can be estimated in ex vivo porcine eyes, and may guide subsequent in vivo experiments.https://www.mdpi.com/1999-4923/13/7/1013liposomesintravitrealocular drug deliveryretinal explants |
| spellingShingle | Gustav Christensen Leon Barut Dileep Urimi Nicolaas Schipper François Paquet-Durand Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems Pharmaceutics liposomes intravitreal ocular drug delivery retinal explants |
| title | Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems |
| title_full | Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems |
| title_fullStr | Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems |
| title_full_unstemmed | Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems |
| title_short | Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems |
| title_sort | investigating ex vivo animal models to test the performance of intravitreal liposomal drug delivery systems |
| topic | liposomes intravitreal ocular drug delivery retinal explants |
| url | https://www.mdpi.com/1999-4923/13/7/1013 |
| work_keys_str_mv | AT gustavchristensen investigatingexvivoanimalmodelstotesttheperformanceofintravitrealliposomaldrugdeliverysystems AT leonbarut investigatingexvivoanimalmodelstotesttheperformanceofintravitrealliposomaldrugdeliverysystems AT dileepurimi investigatingexvivoanimalmodelstotesttheperformanceofintravitrealliposomaldrugdeliverysystems AT nicolaasschipper investigatingexvivoanimalmodelstotesttheperformanceofintravitrealliposomaldrugdeliverysystems AT francoispaquetdurand investigatingexvivoanimalmodelstotesttheperformanceofintravitrealliposomaldrugdeliverysystems |