Entwicklung von Nanokapseln für die zielgerichtete Anwendung von Medikamenten in der Neuroretina

• Antragsteller: Professor Dr. Francois Paquet-Durand
• Fachliche Zuordnung: Augenheilkunde ; Molekulare und zelluläre Neurologie und Neuropathologie
• Förderung: Förderung von 2019 bis 2022
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 426861724

• Erstellungsjahr: 2023

Zusammenfassung der Projektergebnisse

Hereditary retinal degenerations (RD) are a major cause of blindness in the developed world. These diseases are at present untreatable, due to an important extent to a lack of suitable systems that can deliver drugs to the neuroretina in vivo. The project therefore investigated the potential of liposomal nanocapsules to efficiently deliver compounds to the neuroretina. The preferred drug administration route was intravitreal injection. Different liposomal and LNC formulations were produced, characterized, and tested in a variety of test systems, ranging from human cell cultures, to ex vivo porcine eyes, to in vitro murine retinal explant cultures. Eventually, this work led to the identification of pyruvateconjugated liposomes that exhibited a favourable toxicity profile and that could selectively deliver encapsulated drug candidates to the photoreceptors of the retina. The liposomal formulation of an inhibitory cGMP-analogue was significantly more efficient in protecting rd1 retina photoreceptors when compared with free compound. Overall, our study indicates that pyruvate-liposomes are useful as a drug delivery system for the active targeting of photoreceptors. Combined with a suitable drug, this delivery approach may be very promising for the development of new treatments for chronic retinal diseases, notably for RD and possibly also for cone degeneration diseases such as achromatopsia or age-related macular degeneration (AMD). The data and ideas generated during the project have led to several new grant applications. Apart from this, the project to date has led to the nine peer-reviewed, scientific articles, published in international scientific journals, one patent application, and the successful conclusion of a PhD thesis.

Projektbezogene Publikationen (Auswahl)

• Long-Term, Serum-Free Cultivation of Organotypic Mouse Retina Explants with Intact Retinal Pigment Epithelium. Journal of Visualized Experiments, 165.
  Belhadj, Soumaya; Tolone, Arianna; Christensen, Gustav; Das, Soumyaparna; Chen, Yiyi & Paquet-Durand, François
  
• Cytotoxicity of β-Cyclodextrins in Retinal Explants for Intravitreal Drug Formulations. Molecules, 26(5), 1492.
  Prajapati, Manisha; Christensen, Gustav; Paquet-Durand, François & Loftsson, Thorsteinn
  
• Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems. Pharmaceutics, 13(7), 1013.
  Christensen, Gustav; Barut, Leon; Urimi, Dileep; Schipper, Nicolaas & Paquet-Durand, François
  
• The role of cGMP-signalling and calcium-signalling in photoreceptor cell death: perspectives for therapy development. Pflügers Archiv - European Journal of Physiology, 473(9), 1411-1421.
  Das, Soumyaparna; Chen, Yiyi; Yan, Jie; Christensen, Gustav; Belhadj, Soumaya; Tolone, Arianna & Paquet-Durand, François
  
• In vitro Model Systems for Studies Into Retinal Neuroprotection. Frontiers in Neuroscience, 16.
  Zhu, Yu; Cao, Bowen; Tolone, Arianna; Yan, Jie; Christensen, Gustav; Arango-Gonzalez, Blanca; Ueffing, Marius & Paquet-Durand, François
  
• Visualizing Cell Death in Live Retina: Using Calpain Activity Detection as a Biomarker for Retinal Degeneration. International Journal of Molecular Sciences, 23(7), 3892.
  Belhadj, Soumaya; Hermann, Nina Sofia; Zhu, Yu; Christensen, Gustav; Strasser, Torsten & Paquet-Durand, François
  
• Glutathione Coating of Liposomes Enhances the Delivery of Hydrophilic Cargo to the Inner Nuclear Layer in Retinal Cultures. Advances in Experimental Medicine and Biology, 467-471. Springer International Publishing.
  Christensen, Gustav & Paquet-Durand, François
  
• Ocular permeability, intraocular biodistribution of lipid nanocapsule formulation intended for retinal drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 187, 175-183.
  Christensen, Gustav; Urimi, Dileep; Lorenzo‐Soler, Laura; Schipper, Nicolaas & Paquet-Durand, François
  
• Pyruvate-conjugation of PEGylated liposomes for targeted drug delivery to retinal photoreceptors. Biomedicine & Pharmacotherapy, 163, 114717.
  Christensen, Gustav; Chen, Yiyi; Urimi, Dileep; Zizmare, Laimdota; Trautwein, Christoph; Schipper, Nicolaas & Paquet-Durand, François