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  • 1.
    Christensen, Gustav
    et al.
    University of Tübingen, Germany.
    Chen, Yiyi
    University of Tübingen, Germany.
    Urimi, Dileep
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Zizmare, Laimdota
    University Hospital Tübingen, Germany.
    Trautwein, Christoph
    University Hospital Tübingen, Germany.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Paquet-Durand, Francois
    University of Tübingen, Germany.
    Pyruvate-conjugation of PEGylated liposomes for targeted drug delivery to retinal photoreceptors2023In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 163, article id 114717Article in journal (Refereed)
    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

  • 2.
    Christensen, Gustav
    et al.
    University of Tübingen, Germany.
    Urimi, Dileep
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. University of Iceland, Iceland.
    Lorenzo‐Soler, Laura
    University of Iceland, Iceland.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Paquet-Durand, François
    University of Tübingen, Germany.
    Ocular permeability, intraocular biodistribution of lipid nanocapsule formulation intended for retinal drug delivery2023In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 187, p. 175-183Article in journal (Refereed)
    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)

  • 3.
    Perez, Oswaldo
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Leandri, Valentina
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Svensson, Per H.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. KTH Royal Institute of Technology, Sweden.
    Bohlin, Martin
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Loftsson, Thorsteinn
    University of Iceland, Iceland.
    Bollmark, Martin
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Crystal Modifications of a Cyclic Guanosine Phosphorothioate Analogue, a Drug Candidate for Retinal Neurodegenerations2023In: ChemistryOpen, ISSN 2191-1363Article in journal (Refereed)
    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. 

  • 4.
    Urimi, Dileep
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. University of Iceland, Iceland.
    Hellsing, Maja
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. Swedish Research Council, Sweden.
    Mahmoudi, Najet
    Rutherford Appleton Laboratory, Uk.
    Söderberg, Christopher
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Widenbring, Ronja
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Gedda, Lars
    Uppsala University, Sweden.
    Edwards, Katarina
    Uppsala University, Sweden.
    Loftsson, Thorsteinn
    University of Iceland, Iceland.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Structural Characterization Study of a Lipid Nanocapsule Formulation Intended for Drug Delivery Applications Using Small-Angle Scattering Techniques2022In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 19, no 4, p. 1068-1077Article in journal (Refereed)
    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.

  • 5. Christensen, Gustav
    et al.
    Urimi, Dileep
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Novel treatments for retinal degeneration: Ocular bio-distribution and treatment efficacy of lipid nanocapsules and liposomes2022Conference paper (Other academic)
  • 6.
    Huang, Li
    et al.
    University of Modena and Reggio Emilia, Italy.
    Himawan, Erico
    InoCure sro, Czech Republic.
    Belhadj, Soumaya
    University of Tuebingen, Germany.
    Perez, Oswaldo
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Paquet Durand, François
    University of Tuebingen, Germany.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Buzgo, Matej
    InoCure sro, Czech Republic.
    Simaite, Aiva
    InoCure sro, Czech Republic.
    Marigo, Valeria
    University of Modena and Reggio Emilia, Italy; Center for Neuroscience and Neurotechnology, Italy.
    Efficient Delivery of Hydrophilic Small Molecules to Retinal Cell Lines Using Gel Core-Containing Solid Lipid Nanoparticles2022In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 14, no 1, p. 74-74Article in journal (Refereed)
    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.

  • 7.
    Christensen, Gustav
    et al.
    University of Tübingen, Germany.
    Barut, Leon
    University of Tübingen, Germany.
    Urimi, Dileep
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Paquet-Durand, François
    University of Tübingen, Germany.
    Investigating Ex Vivo Animal Models to Test the Performance of Intravitreal Liposomal Drug Delivery Systems2021In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 13, no 7, article id 1013Article in journal (Refereed)
    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.

  • 8.
    Schaffler, K
    et al.
    HPR Dr. Schaffler GmbH, Germany.
    Popescu, T
    HPR Dr. Schaffler GmbH, Germany.
    Hellgren, M
    Alzecure Pharma AB, Sweden.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Gripenhall, Annika
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Sandin, J
    Alzecure Pharma AB, Sweden.
    Forsell, P
    Alzecure Pharma AB, Sweden.
    Segerdahl, M
    Alzecure Pharma AB, Sweden.
    Rother, M
    Alzecure Pharma AB, Sweden.
    ACD440 – A Novel TRPV1 Antagonist for the Topical Treatment of Pain2021In: Scientific presentation at the IASP conference on pain, June 2021, 2021Conference paper (Other academic)
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  • 9.
    Perez, Oswaldo
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. University of Iceland, Iceland.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Bollmark, Martin
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations2021In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 25, no 11, p. 2453-Article in journal (Refereed)
    Abstract [en]

    Cyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and sulfurization of the nucleoside 5′-H-phosphonate monoester, which affords the desired RP-3′,5′-cyclic phosphorothioate in 9:1 ratio to the undesired SP-diastereomer. This route was made viable as a result of the silyl protection sequence used, which achieved >80% selectivity for 2′,5′-hydroxyls over 3′,5′-hydroxyls. Finally, the chromatography-free process allowed for a scale-up, as intermediates and the final product were isolated by crystallization to give 125 g of 1a (13.8% total yield) with over 99.9% HPLC purity. © 2021 The Authors.

  • 10.
    Urimi, Dileep
    et al.
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. University of Iceland, Iceland.
    Widenbring, Ronja
    RISE Research Institutes of Sweden.
    Perez, Oswaldo
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. University of Iceland, Iceland.
    Gedda, Lars
    Uppsala University, Uppsala.
    Edwards, Katarina
    Uppsala University, Uppsala.
    Loftsson, Thorsteinn
    University of Iceland, Iceland.
    Schipper, Nicolaas
    RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
    Formulation development and upscaling of lipid nanocapsules as a drug delivery system for a novel cyclic GMP analogue intended for retinal drug delivery2021In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 602, article id 120640Article in journal (Refereed)
    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.

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  • 11.
    Urimi, Dileep
    et al.
    RISE Res Inst Sweden, SE-15136 Södertälje, Sweden.;Univ Iceland, Fac Pharmaceut Sci, Sch Hlth Sci, Hofsvallagata 53, IS-107 Reykjavilc, Iceland..
    Widenbring, Ronja
    RISE Res Inst Sweden, SE-15136 Södertälje, Sweden..
    Garcia, Raul Oswaldo Perez
    RISE Res Inst Sweden, SE-15136 Södertälje, Sweden.;Univ Iceland, Fac Pharmaceut Sci, Sch Hlth Sci, Hofsvallagata 53, IS-107 Reykjavilc, Iceland..
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Loftsson, Thorsteinn
    Univ Iceland, Fac Pharmaceut Sci, Sch Hlth Sci, Hofsvallagata 53, IS-107 Reykjavilc, Iceland..
    Schipper, Nicolaas
    RISE Res Inst Sweden, SE-15136 Södertälje, Sweden..
    Formulation development and upscaling of lipid nanocapsules as a drug delivery system for a novel cyclic GMP analogue intended for retinal drug delivery2021In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 602, p. 120640-, article id 120640Article in journal (Refereed)
    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.

    Download full text (pdf)
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  • 12.
    Paquet-Durand, F.
    et al.
    Institute for Ophthalmic Research, Germany.
    Peters, T.
    University Hospital Tuebingen, Germany.
    Gaillard, P.
    2-BBB medicines BV, Netherlands.
    Schipper, Nicolaas
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Strasser, T.
    Institute for Ophthalmic Research, Germany.
    Schwede, F.
    Biolog Life science Institute, Germany.
    Marigo, V.
    University of Modena and Reggio Emilia, Italy.
    Ekstrom, P. A. R.
    Lund University, Sweden.
    Safholm, C.
    Karolinska Institute, Sweden.
    Systemic and intraocular administration of the liposomal formulation of the cyclic GMP analogue CN03: An exploratory safety and tolerability study in non-human primates2019In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 60, no 9Article in journal (Refereed)
    Abstract [en]

    Purpose : The cGMP analogue CN03 targets cGMP signalling, a disease driver common to different types of retinal degeneration. For efficient targeting to the neuroretina CN03 was combined with a liposomal (LP) drug delivery system. In rodents, LP-CN03 has shown significant photoreceptor protection and preservation of in vivo retinal function, without major adverse events. The objective of the study was to determine the toxicity of CN03 and LP-CN03, following intravitreal (IVT) or intravenous (IV) administration. IVT administration is the intended human therapeutic route, IV injection was tested to investigate systemic toxicity.

    Methods : Cynomolgus monkeys were assigned to five different groups, consisting of one male and one female (n=2). Group 1 served as saline control for IVT and IV dosing, group 2 served as liposome (LP) control. Groups 3 and 4 received IVT injections of either 1X or 10X of the intended therapeutic dose, of either LP-CN03 (left eye) or CN03 (right). Group 5 received 100X IV bolus injections of LP-CN03 (Day 1) and CN03 (Day 25). Toxicity was assessed based on clinical observations, body weights, ophthalmology, intraocular pressure (IOP), electroretinography (ERG), and clinical and anatomic pathology.

    Results : IVT administration of LP caused transient white opacity in the vitreous body of all treated eyes, related to the milky consistency of LP. IVT injection of 1X and 10X CN03 was well-tolerated and only showed temporary pupil dilation in one male. IVT injection of 1X and 10X LP-CN03 was additionally associated with particles in the anterior chamber and vitreous body. At 10X, pigmented dots were also noted in the anterior lens capsule. IV injection of 100X LP-CN03 and CN03 was well tolerated and did not cause systemic toxicity. Comparison of pre- and post-dosing ERG did not reveal significant differences (p>0.05) in any of the groups, nor were there any indications of pathological changes in retinal morphology.

    Conclusions : IVT injection of CN03 and LP-CN03 at the intended therapeutic dose was not associated with any changes in ophthalmoscopy, electroretinography or histopathology, and only revealed slight pupil dilation in one animal. IV slow bolus injection at 100X the intended therapeutic dose was well tolerated.

  • 13.
    Rinwa, Vihbu
    et al.
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Schipper, Nicolaas
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Bohlin, Martin
    RISE - Research Institutes of Sweden, Bioscience and Materials, Surface, Process and Formulation.
    Warpman Berglund, Ulrika
    KI Karolinska Institute, Sweden.
    Scobie, Martin
    KI Karolinska Institute, Sweden.
    Helleday, Thomas
    KI Karolinska Institute, Sweden.
    Effect of chloride ion on solubility and dissolution of a basic drug and salt form for oral delivery2018Conference paper (Other academic)
    Abstract [en]

    Introduction:

    Chloride ions are the predominant anionic counter-ion present in vivo (intestine/ jejunum: 0.13M and stomach: 0.10M), significantly effecting solubility and dissolution of drugs for oral absorption1. Our group has recently discovered a novel small molecule, with good permeability but low aqueous solubility potentially limiting exposure after oral administration. It is a basic compound (pKa- 6-7) and provides opportunities to develop salt exploiting different counter-ions. Solubility is not only dependent on the ionization of the weak acid or weak base itself but also on the solubility of the counter ion pairs. Counter ion exchanges between salt forms or formation of hydrates is well known to occur in the gastrointestinal environment. If this happens, then formation of less soluble species can lead to in vivo precipitation of the drug.

  • 14.
    Warpman Berglund, U.
    et al.
    Science for Life Laboratory, Sweden.
    Sanjiv, K.
    Science for Life Laboratory, Sweden.
    Gad, H.
    Science for Life Laboratory, Sweden.
    Kalderén, C.
    Science for Life Laboratory, Sweden.
    Koolmeister, T.
    Science for Life Laboratory, Sweden.
    Pham, T.
    Science for Life Laboratory, Sweden.
    Gokturk, C.
    Science for Life Laboratory, Sweden.
    Jafari, R.
    Science for Life Laboratory, Sweden.
    G., Maddalo
    Science for Life Laboratory, Sweden.
    Seashore-Ludlow, B.
    Science for Life Laboratory, Sweden.
    Chernobrovkin, A.
    Karolinska Institute, Sweden.
    Manoilov, A.
    Karolinska Institute, Sweden.
    Pateras, I. S.
    National and Kapodistrian University of Athens, Greece.
    Rasti, A.
    Science for Life Laboratory, Sweden.
    Jemth, A.-S.
    Science for Life Laboratory, Sweden.
    Almlöf, I.
    Science for Life Laboratory, Sweden.
    Loseva, O.
    Science for Life Laboratory, Sweden.
    Visnes, T.
    Science for Life Laboratory, Sweden.
    Einarsdottir, B. O.
    University of Gothenburg, Sweden.
    Gaugaz, F. Z.
    Science for Life Laboratory, Sweden; Uppsala University, Sweden.
    Saleh, A.
    Science for Life Laboratory, Sweden; Uppsala University, Sweden.
    Platzack, B.
    Swedish Toxicology Sciences Research Center, Sweden.
    Wallner, O. A.
    Science for Life Laboratory, Sweden.
    Vallin, Karl
    Science for Life Laboratory, Sweden.
    Henriksson, M.
    Science for Life Laboratory, Sweden.
    Wakchaure, P.
    Science for Life Laboratory, Sweden.
    Borhade, S.
    Science for Life Laboratory, Sweden.
    Herr, P.
    Science for Life Laboratory, Sweden.
    Kallberg, Y.
    Science for Life Laboratory, Sweden; Karolinska Institute, Sweden.
    Baranczewski, P.
    Science for Life Laboratory, Sweden; Uppsala University, Sweden.
    Homan, E. J.
    Science for Life Laboratory, Sweden.
    Wiita, E.
    Science for Life Laboratory, Sweden.
    Nagpal, V.
    RISE, SP – Sveriges Tekniska Forskningsinstitut. Science for Life Laboratory, Sweden.
    Meijer, T.
    RISE, SP – Sveriges Tekniska Forskningsinstitut.
    Schipper, Nicolaas
    RISE, SP – Sveriges Tekniska Forskningsinstitut.
    Rudd, S. D.
    Science for Life Laboratory, Sweden.
    Bräutigam, L.
    Science for Life Laboratory, Sweden.
    Lindqvist, A.
    Science for Life Laboratory, Sweden; Uppsala University, Sweden.
    Filppula, A.
    Uppsala University, Sweden.
    Lee, T-C.
    Academia Sinica, Taiwan.
    Artursson, P.
    Science for Life Laboratory, Sweden; Uppsala University, Sweden.
    Nilsson, J. A.
    University of Gothenburg, Sweden.
    Gorgoulis, V. G.
    Academy of Athens, Greece; University of Manchester, UK.
    Lehtiö, J.
    Science for Life Laboratory, Sweden.
    Zubarev, R. A.
    Karolinska Institute, Sweden.
    Scobie, M.
    Science for Life Laboratory, Sweden.
    Helleday, T.
    Science for Life Laboratory, Sweden.
    Validation and development of MTH1 inhibitors for treatment of cancer2016In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27, no 12, p. 2275-2283Article in journal (Refereed)
    Abstract [en]

    Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment.

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