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Publications (10 of 14) Show all publications
Perez, O., Stanzani, A., Huang, L., Schipper, N., Loftsson, T., Bollmark, M. & Marigo, V. (2024). New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration. Journal of Medicinal Chemistry, 67(10), 8396
Open this publication in new window or tab >>New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration
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2024 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 67, no 10, p. 8396-Article in journal (Refereed) Published
Abstract [en]

Retinitis pigmentosa (RP) is a form of retinal degeneration affecting a young population with an unmet medical need. Photoreceptor degeneration has been associated with increased guanosine 3′,5′-cyclic monophosphate (cGMP), which reaches toxic levels for photoreceptors. Therefore, inhibitory cGMP analogues attract interest for RP treatments. Here we present the synthesis of dithio-CN03, a phosphorodithioate analogue of cGMP, prepared using the H-phosphonothioate route. Two crystal modifications were identified as a trihydrate and a tetrahydrofuran monosolvates. Dithio-CN03 featured a lower aqueous solubility than its RP-phosphorothioate counterpart CN03, a drug candidate, and this characteristic might be favorable for sustained-release formulations aimed at retinal delivery. Dithio-CN03 was tested in vitro for its neuroprotective effects in photoreceptor models of RP. The comparison of dithio-CN03 to CN03 and its diastereomer SP-CN03, and to their phosphate derivative oxo-CN03 identifies dithio-CN03 as the compound with the highest efficacy in neuroprotection and thus as a promising new candidate for the treatment of RP. 

Place, publisher, year, edition, pages
American Chemical Society, 2024
National Category
Clinical Medicine
Identifiers
urn:nbn:se:ri:diva-73318 (URN)10.1021/acs.jmedchem.4c00586 (DOI)2-s2.0-85192143394 (Scopus ID)
Note

European Union: MSCA-ITN-2017−765441 (transMed) andEuropean Union’s Horizon 2020 research and innovationprogramme under the EJP RD COFUND-EJP N° 825575,grant # 101 (TreatRP).

Available from: 2024-06-03 Created: 2024-06-03 Last updated: 2024-06-03Bibliographically approved
Perez, O., Schipper, N., Leandri, V., Svensson, P. H., Bohlin, M., Loftsson, T. & Bollmark, M. (2023). Crystal Modifications of a Cyclic Guanosine Phosphorothioate Analogue, a Drug Candidate for Retinal Neurodegenerations. ChemistryOpen, 12(12), Article ID e202300141.
Open this publication in new window or tab >>Crystal Modifications of a Cyclic Guanosine Phosphorothioate Analogue, a Drug Candidate for Retinal Neurodegenerations
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2023 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 12, no 12, article id e202300141Article in journal (Refereed) Published
Abstract [en]

In contribution to the pharmaceutical development of cyclic guanosine monophosphorothioate analogue cGMPSA as a potential active pharmaceutical ingredient (API) for the treatment of inherited retinal degenerations (IRDs), its neutral form (cGMPSA-H) and salts of sodium (-Na), calcium (-Ca), ammonium (-NH4), triethylammonium (-TEA), tris(hydroxymethyl)aminomethane (-Tris), benethamine (-Bnet), and benzathine (-BZ) were prepared. Their solid-state properties were studied with differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy, and dynamic vapor sorption, and their solubilities were measured in deionized H2O as well as aqueous HCl and NaOH buffers. A total of 21 crystal modifications of cGMPSA were found and characterized by X-ray powder diffraction. Despite their crystalline character, no API forms featured any observable melting points during thermal analyses and instead underwent exothermic decomposition at ≥163 °C. Both the vapor sorption behavior and solubility were found to differ significantly across the API forms. cGMPSA-BZ featured the lowest aqueous solubility and hygroscopicity, with 50 μg/mL and 5 % mass gain at maximum relative humidity. The synthesis and crystallization of some crystal modifications were upscaled to >10 g. Single crystal X-ray diffraction was performed which resulted in the first crystal structure determination and absolute configuration of a cyclic guanosine monophosphorothioate, confirming the RP- conformation at the phosphorus atom. 

Place, publisher, year, edition, pages
John Wiley and Sons Inc, 2023
National Category
Medical Engineering
Identifiers
urn:nbn:se:ri:diva-68032 (URN)10.1002/open.202300141 (DOI)2-s2.0-85174819785 (Scopus ID)
Note

This research was funded by grants from the European Union (transMed: H2020‐MSCA‐765441, and TreatRP: EJP RD JTC 2020).

Available from: 2023-11-23 Created: 2023-11-23 Last updated: 2024-06-11Bibliographically approved
Christensen, G., Urimi, D., Lorenzo‐Soler, L., Schipper, N. & Paquet-Durand, F. (2023). Ocular permeability, intraocular biodistribution of lipid nanocapsule formulation intended for retinal drug delivery. European journal of pharmaceutics and biopharmaceutics, 187, 175-183
Open this publication in new window or tab >>Ocular permeability, intraocular biodistribution of lipid nanocapsule formulation intended for retinal drug delivery
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2023 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 187, p. 175-183Article in journal (Refereed) Published
Abstract [en]

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. © 2023 The Author(s)

Place, publisher, year, edition, pages
Elsevier B.V., 2023
Keywords
Drug delivery, Explant cultures, Inherited retinal degenerations, Intravitreal injections, Lipid nanocapsules, Liposomes
National Category
Ophthalmology Pharmaceutical Sciences
Identifiers
urn:nbn:se:ri:diva-64844 (URN)10.1016/j.ejpb.2023.04.012 (DOI)2-s2.0-85156267023 (Scopus ID)
Funder
EU, Horizon 2020, H2020-MSCA-ITN-2017-765441German Research Foundation (DFG), PA1751/10-1
Note

Funding details: European Commission, EC, H2020-MSCA-ITN-2017-765441; Funding details: Deutsche Forschungsgemeinschaft, DFG, PA1751/10-1; Funding text 1: This work was financially supported by the German Research Council (DFG; PA1751/10-1), and the European Union (transMed, H2020-MSCA-ITN-2017-765441), European Joint Programme on Rare Diseases - Joint Transnational Call 2020 (TreatRP).; 

Available from: 2023-05-15 Created: 2023-05-15 Last updated: 2023-05-26Bibliographically approved
Christensen, G., Chen, Y., Urimi, D., Zizmare, L., Trautwein, C., Schipper, N. & Paquet-Durand, F. (2023). Pyruvate-conjugation of PEGylated liposomes for targeted drug delivery to retinal photoreceptors. Biomedicine and Pharmacotherapy, 163, Article ID 114717.
Open this publication in new window or tab >>Pyruvate-conjugation of PEGylated liposomes for targeted drug delivery to retinal photoreceptors
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2023 (English)In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 163, article id 114717Article in journal (Refereed) Published
Abstract [en]

Despite several promising candidates, there is a paucity of drug treatments available for patients suffering from retinal diseases. An important reason for this is the lack of suitable delivery systems that can achieve sufficiently high drug uptake in the retina and its photoreceptors. A promising and versatile method for drug delivery to specific cell types involves transporter-targeted liposomes, i.e., liposomes surface-coated with substrates for transporter proteins highly expressed on the target cell. We identified strong lactate transporter (monocarboxylate transporter, MCT) expression on photoreceptors as a potential target for drug delivery vehicles. To evaluate MCT suitability for drug targeting, we used PEG-coated liposomes and conjugated these with different monocarboxylates, including lactate, pyruvate, and cysteine. Monocarboxylate-conjugated and dye-loaded liposomes were tested on both human-derived cell-lines and murine retinal explant cultures. We found that liposomes conjugated with pyruvate consistently displayed higher cell uptake than unconjugated liposomes or liposomes conjugated with lactate or cysteine. Pharmacological inhibition of MCT1 and MCT2 reduced internalization, suggesting an MCT-dependent uptake mechanism. Notably, pyruvate-conjugated liposomes loaded with the drug candidate CN04 reduced photoreceptor cell death in the murine rd1 retinal degeneration model while free drug solutions could not achieve the same therapeutic effect. Our study thus highlights pyruvate-conjugated liposomes as a promising system for drug delivery to retinal photoreceptors, as well as other neuronal cell types displaying high expression of MCT-type proteins. © 2023 The Authors

Place, publisher, year, edition, pages
Elsevier Masson s.r.l., 2023
Keywords
Liposomes, Monocarboxylate transporter, Neurodegenerative therapy, Ocular drug delivery, Retinal degeneration, Retinal explant culture
National Category
Neurosciences
Identifiers
urn:nbn:se:ri:diva-64389 (URN)10.1016/j.biopha.2023.114717 (DOI)2-s2.0-85153080882 (Scopus ID)
Note

Funding details: Deutsche Forschungsgemeinschaft, DFG, PA1751/10–1; Funding details: Eberhard Karls Universität Tübingen; Funding details: Tistou and Charlotte Kerstan Stiftung; Funding text 1: This work was financially supported by the Deutsche Forschungsgemeinschaft ( DFG ; grant no. PA1751/10–1 ), the Tistou and Charlotte Kerstan Foundation , and the Zinke Heritage Foundation . 

Available from: 2023-05-05 Created: 2023-05-05 Last updated: 2023-05-26Bibliographically approved
Huang, L., Himawan, E., Belhadj, S., Perez, O., Paquet Durand, F., Schipper, N., . . . Marigo, V. (2022). Efficient Delivery of Hydrophilic Small Molecules to Retinal Cell Lines Using Gel Core-Containing Solid Lipid Nanoparticles. Pharmaceutics, 14(1), 74-74
Open this publication in new window or tab >>Efficient Delivery of Hydrophilic Small Molecules to Retinal Cell Lines Using Gel Core-Containing Solid Lipid Nanoparticles
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2022 (English)In: Pharmaceutics, E-ISSN 1999-4923, Vol. 14, no 1, p. 74-74Article in journal (Refereed) Published
Abstract [en]

In this study, we developed a novel solid lipid nanoparticle (SLN) formulation for drug delivery of small hydrophilic cargos to the retina. The new formulation, based on a gel core and composite shell, allowed up to two-fold increase in the encapsulation efficiency. The type of hydrophobic polyester used in the composite shell mixture affected the particle surface charge, colloidal stability, and cell internalization profile. We validated SLNs as a drug delivery system by performing the encapsulation of a hydrophilic neuroprotective cyclic guanosine monophosphate analog, previously demonstrated to hold retinoprotective properties, and the best formulation resulted in particles with a size of ±250 nm, anionic charge > −20 mV, and an encapsulation efficiency of ±60%, criteria that are suitable for retinal delivery. In vitro studies using the ARPE-19 and 661W retinal cell lines revealed the relatively low toxicity of SLNs, even when a high particle concentration was used. More importantly, SLN could be taken up by the cells and the release of the hydrophilic cargo in the cytoplasm was visually demonstrated. These findings suggest that the newly developed SLN with a gel core and composite polymer/lipid shell holds all the characteristics suitable for the drug delivery of small hydrophilic active molecules into retinal cells.

Keywords
drug delivery system; thermoresponsive polymer; rod photoreceptor; retinal pigment epithelium
National Category
Physical Chemistry
Identifiers
urn:nbn:se:ri:diva-58475 (URN)10.3390/pharmaceutics14010074 (DOI)
Funder
European Commission, H2020-MSCA-ITN-765441
Available from: 2022-02-01 Created: 2022-02-01 Last updated: 2024-07-04Bibliographically approved
Christensen, G., Urimi, D. & Schipper, N. (2022). Novel treatments for retinal degeneration: Ocular bio-distribution and treatment efficacy of lipid nanocapsules and liposomes. In: : . Paper presented at Controlled Release Society 2022 Annual Meeting and Expo. , Article ID 3724611.
Open this publication in new window or tab >>Novel treatments for retinal degeneration: Ocular bio-distribution and treatment efficacy of lipid nanocapsules and liposomes
2022 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Natural Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:ri:diva-58476 (URN)
Conference
Controlled Release Society 2022 Annual Meeting and Expo
Funder
EU, Horizon 2020
Available from: 2022-02-01 Created: 2022-02-01 Last updated: 2023-05-26Bibliographically approved
Urimi, D., Hellsing, M., Mahmoudi, N., Söderberg, C., Widenbring, R., Gedda, L., . . . Schipper, N. (2022). Structural Characterization Study of a Lipid Nanocapsule Formulation Intended for Drug Delivery Applications Using Small-Angle Scattering Techniques. Molecular Pharmaceutics, 19(4), 1068-1077
Open this publication in new window or tab >>Structural Characterization Study of a Lipid Nanocapsule Formulation Intended for Drug Delivery Applications Using Small-Angle Scattering Techniques
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2022 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 19, no 4, p. 1068-1077Article in journal (Refereed) Published
Abstract [en]

Lipid nanocapsules (LNCs) are increasingly being used for various drug delivery applications due to their versatile nature and ability to carry a wide variety of therapeutic drug molecules. In the present investigation, small-angle X-ray (SAXS) and neutron scattering (SANS) techniques were used to elucidate the structure of LNCs. Overall, size measurements obtained from SAXS and SANS techniques were complemented with dynamic light scattering, zeta potential, and cryogenic transmission electron microscopy measurements. The structural aspects of LNCs can be affected by drug loading and the properties of the drug. Here, the impact of drug loading on the overall structure was evaluated using DF003 as a model drug molecule. LNCs with varying compositions were prepared using a phase inversion method. Combined analysis of SAXS and SANS measurements indicated the presence of a core–shell structure in the LNCs. Further, the drug loading did not alter the overall core–shell structure of the LNCs. SANS data revealed that the core size remained unchanged with a radius of 20.0 ± 0.9 nm for unloaded LNCs and 20.2 ± 0.6 nm for drug-loaded LNCs. Furthermore, interestingly, the shell becomes thicker in an order of ∼1 nm in presence of the drug compared to the shell thickness of unloaded LNCs as demonstrated by SAXS data. This can be correlated with the strong association of hydrophilic DF003 with Kolliphor HS 15, a polyethylene glycol-based surfactant that predominantly makes up the shell, resulting in a drug-rich hydrated shell.

Place, publisher, year, edition, pages
American Chemical Society, 2022
National Category
Physical Chemistry
Identifiers
urn:nbn:se:ri:diva-58789 (URN)10.1021/acs.molpharmaceut.1c00648 (DOI)2-s2.0-85126139711 (Scopus ID)
Note

This work was financially supported by the grant from the European Union (transMed, H2020-MSCA-ITN-2017-765441) and VINNOVA (2019-03616). The authors acknowledge the ISIS facility for the award of beam time on Sans2d (doi:10.5286/ISIS.E.RB2010513). This work benefited from the use of the SasView application, originally developed under NSF Award DMR-0520547. SasView also contains code developed with funding from the EU Horizon 2020 programme under the SINE2020 project Grant No 654000.

Available from: 2022-03-04 Created: 2022-03-04 Last updated: 2024-05-14Bibliographically approved
Schaffler, K., Popescu, T., Hellgren, M., Schipper, N., Gripenhall, A., Sandin, J., . . . Rother, M. (2021). ACD440 – A Novel TRPV1 Antagonist for the Topical Treatment of Pain. In: Scientific presentation at the IASP conference on pain, June 2021: . Paper presented at IASP. June, 2021.
Open this publication in new window or tab >>ACD440 – A Novel TRPV1 Antagonist for the Topical Treatment of Pain
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2021 (English)In: Scientific presentation at the IASP conference on pain, June 2021, 2021Conference paper, Oral presentation with published abstract (Other academic)
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:ri:diva-58140 (URN)
Conference
IASP. June, 2021
Available from: 2022-01-10 Created: 2022-01-10 Last updated: 2023-05-26Bibliographically approved
Urimi, D., Widenbring, R., Perez, O., Gedda, L., Edwards, K., Loftsson, T. & Schipper, N. (2021). Formulation development and upscaling of lipid nanocapsules as a drug delivery system for a novel cyclic GMP analogue intended for retinal drug delivery. International Journal of Pharmaceutics, 602, Article ID 120640.
Open this publication in new window or tab >>Formulation development and upscaling of lipid nanocapsules as a drug delivery system for a novel cyclic GMP analogue intended for retinal drug delivery
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2021 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 602, article id 120640Article in journal (Refereed) Published
Abstract [en]

Lipid nanocapsules (LNCs) were prepared with a novel cyclic GMP analogue, DF003, intended for the treatment of neurodegenerative retinal degenerations. LNCs loaded with DF003 were prepared by a phase inversion method and characterized for particle size, polydispersity index, drug loading, entrapment efficiency, stability, and in vitro drug release. Particle size, PdI and zeta potential of selected optimized formulation were 76 ± 1.2 nm, 0.16 ± 0.02, and −11.6 ± 0.4 mV, respectively, with an entrapment efficiency of 69 ± 0.5%. The selected formulation showed a sustained drug release for up to 6 days in phosphate buffer as well as in vitreous components. Stability evaluation of LNCs in presence of vitreous components demonstrated structural stability and compatibility. Further, the nanoparticle preparation process was upscaled to 1000 times (10 L) of the typical lab scale (0.01 L). Product parameters were observed to be unaffected by the upscaling, demonstrating that the LNCs were of the same quality as those prepared at lab scale. Additionally, the manufacturing process was adapted and assessed for a continuous production of LNCs to leverage it for industrial viability. Overall, these findings reveal the remarkable potential of LNCs as drug delivery vehicles and their possibility for clinical translation.

Keywords
Lipid nanocapsules, Retinal degenerations, Drug Release, Upscaling, Continuous manufacture, Clinical translation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:ri:diva-53129 (URN)10.1016/j.ijpharm.2021.120640 (DOI)
Available from: 2021-05-21 Created: 2021-05-21 Last updated: 2023-12-06Bibliographically approved
Christensen, G., Barut, L., Urimi, D., Schipper, N. & Paquet-Durand, F. (2021). Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems. Pharmaceutics, 13(7), Article ID 1013.
Open this publication in new window or tab >>Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems
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2021 (English)In: Pharmaceutics, E-ISSN 1999-4923, Vol. 13, no 7, article id 1013Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
liposomes, intravitreal, ocular drug delivery, retinal explants
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:ri:diva-55204 (URN)10.3390/pharmaceutics13071013 (DOI)
Available from: 2021-07-05 Created: 2021-07-05 Last updated: 2024-07-04Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-3401-0728

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