Ocular Biodistribution of Spironolactone after a Single Intravitreal Injection of a Biodegradable Sustained-Release Polymer in Rats
Open accessAbstract
Sustained-release formulations for ocular delivery are of increasing interest given their potential to significantly improve treatment efficacy and patient adherence. The objectives of this study were (i) to develop a sustained-release formulation of spironolactone (SPL) using a biodegradable and injectable polymer, hexyl-substituted poly-lactic acid (hexPLA) and (ii) to investigate the ocular biodistribution and tolerability of SPL and its metabolites in rats in vivo over 1 month following a single intravitreal injection (IVT inj). The concentrations of SPL and its two principal active metabolites, 7α-thiomethylspironolactone and canrenone (CAN), in the different ocular compartments were determined at different time points (3, 7, and 31 days after IVT inj) using a validated ultra-high-performance liquid chromatography-mass spectrometry method. Systemic exposure following a single IVT inj of 5% SPL-hexPLA formulation was evaluated by quantifying SPL and its metabolites in the plasma. Ocular tolerability of the formulation was evaluated using in vivo retinal imaging and histology. In vitro release studies revealed a sustained release of SPL from 5% SPL-hexPLA for up to 65 days. In vivo studies showed that SPL and its metabolites were detected in all ocular tissues at 3 and 7 days post-IVT inj. At 31 days post-IVT inj, SPL and CAN were mainly detected in the retina. These results also highlighted the clearance pathway of SPL and its metabolite involving the anterior and posterior routes in the first week (days 3 and 7), then mainly the posterior segment in the last week (day 31). This study showed that a single IVT inj of 5% SPL-hexPLA in rats enabled sustained delivery of therapeutic amounts of SPL for up to 1 month to the retina without systemic exposure. This formulation may be of interest for the local treatment of diseases involving overactivation of the mineralocorticoid receptor in the chorioretina such as chronic central serous chorioretinopathy.
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The first small molecule-based polymeric nanoparticles for drug targeting and controlled release have moved from the bench to the bedside, laying the foundation for phase II clinical trials.
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From Smart nanoparticles for cancer therapy (2023) · cites this paper as [19]
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Smart nanoparticles for cancer therapy
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- Authors
- Dahmana, N., Kowalczuk, L., Gabriel, D., Behar-Cohen, F., Gurny, R., & Kalia, Y. N.
- Affiliations
- University of Geneva (CH)
- Hôpital Ophtalmique Jules-Gonin (CH)
- Apidel SA, Quai du Mont Blanc 29, 1201 Geneva, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 21, 1011 Lausanne, Switzerland
- Corresponding author
- Kalia, Yogeshvar N.
- Venue
- Molecular Pharmaceutics
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-11-21
- Volume
- 17
- Issue
- 1
- Pages
- 59-69
- ISSN
- 1543-8384 (ISSN-L)
- 1543-8392
- OpenAlex
- W2989849964
- Cited by
- 7
- References
- 53
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Molecular Pharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Soci?t? Acad?mique de Gen?ve
- Universit? de Gen?ve
- Kommission f?r Technologie und Innovation (19086.1 PFLS-LS)
- Apidel SA
- Fondation Ernst and Lucie Schmidheiny
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Ocular Infections and Treatments
- Keywords
- spironolactone, intravitreal injection, sustained-release formulation, biodegradable polymers, canrenone, mineralocorticoid receptor, retinal drug delivery, ocular tolerance, chronic central serous chorioretinopathy
- MeSH terms
- Animals, Canrenone, Chromatography, Liquid, Delayed-Action Preparations, Fundus Oculi, Polyesters, Retina, Mass Spectrometry, Spironolactone, Time Factors, Tissue Distribution, Rats, Wistar, Tomography, Optical Coherence, Rats, Intravitreal Injections
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