Ocular permeability, intraocular biodistribution of lipid nanocapsule formulation intended for retinal drug delivery

Recently, cGMP analogues have been investigated for the treatment of inherited retinal degenerations (IRD) using intravitreal injections. However, higher vitreous elimination rates limit the possibility to treat the retina with small molecule drugs. Here, we investigated the potential of lipid nanocapsules (LNCs) as vehicles to reduce clearance and prolong the delivery of cGMP analogue, CN03 to the retinal photoreceptors. Initially LNCs were investigated for both topical/periocular and intravitreal administration routes. While LNC-mediated drug permeation through the cornea proved to be too low for clinical applications, intravitreal application showed significant promise. Intravitreally administered LNCs containing fluorescent tracer in ex vivo porcine eyes showed complete intravitreal dispersal within 24 h. Ocular bio-distribution on histological sections showed that around 10 % of the LNCs had reached the retina, and 40 % accumulated in the ciliary body. For comparison, we used fluorescently labeled liposomes and these showed a different intraocular distribution with 48 % accumulated in the retina, and almost none were in the ciliary body. LNCs were then tested in retinal explants prepared from wild-type (WT) and rd1 mouse. In WT retina LNCs showed no significant toxic effects up to a concentration of 5 mg/mL. In rd1 retina, the LNC/CN03 formulation protected rd1 photoreceptors with similar efficacy to that of free CN03, demonstrating the usefulness of LNC/CN03 formulation in the treatment of IRD. Overall, our results indicate the suitability of LNCs for intraocular administration and drug delivery to both the retina and the ciliary body.

2. Materials

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt) (DSPE-PEG₂₀₀₀), 3,3′-Dioctadecyl-oxacarbocyanin-perchlorate, dioctadecyl-3,3,3,3 Tetramethylindodicarbocyanine (DiO), Float-A-Lyzer® G2 dialysis devices (MWCO 100 kDa), chloroform, PBS, 4 % paraformaldehyde in PBS (PFA), sucrose and sodium chloride were obtained from Sigma Aldrich. Labrafac™ lipophile WL 1349 (Medium chain triglycerides, Ph. Eur. Grade), Kolliphor® HS 15 (polyethylene glycol (15)-hydroxystearate, Ph. Eur. Grade), and Phospholipon® 90 H (hydrogenated phosphatidylcholine ≥ 90 %) were obtained from Gattefossé (France), BASF and, Lipoid (Germany) respectively. The CN03 (also referred to as DF003 in previous publications) drug compound (R_P-8-Br-PET-cGMPS) was synthesized internally by RISE Research Institutes of Sweden [19].

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Gustav Christensen, Dileep Urimi, Laura Lorenzo-Soler, Nicolaas Schipper, François Paquet-Durand, Ocular permeability, intraocular biodistribution of lipid nanocapsule formulation intended for retinal drug delivery, European Journal of Pharmaceutics and Biopharmaceutics, 2023, ISSN 0939-6411,
https://doi.org/10.1016/j.ejpb.2023.04.012.