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Nanocarriers' repartitioning of drugs between blood subcompartments as a mechanism of improving pharmacokinetics, safety, and efficacy.
Zaleski, Michael H; Omo-Lamai, Serena; Nong, Jia; Chase, Liam S; Myerson, Jacob W; Glassman, Patrick M; Lee, Florence; Reyes-Esteves, Sahily; Wang, Zhicheng; Patel, Manthan N; Peshkova, Alina D; Komatsu, Hiroaki; Axelsen, Paul H; Muzykantov, Vladimir R; Marcos-Contreras, Oscar A; Brenner, Jacob S.
Afiliación
  • Zaleski MH; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Omo-Lamai S; Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
  • Nong J; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Chase LS; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Myerson JW; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Glassman PM; Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, USA.
  • Lee F; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Reyes-Esteves S; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
  • Wang Z; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Patel MN; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Peshkova AD; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Komatsu H; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Axelsen PH; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Muzykantov VR; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Marcos-Contreras OA; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
  • Brenner JS; Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: jacob.brenner@pennmedicine.upenn.edu.
J Control Release ; 374: 425-440, 2024 Oct.
Article en En | MEDLINE | ID: mdl-39103056
ABSTRACT
For medical emergencies, such as acute ischemic stroke, rapid drug delivery to the target site is essential. For many small molecule drugs, this goal is unachievable due to poor solubility that prevents intravenous administration, and less obviously, by extensive partitioning to plasma proteins and red blood cells (RBCs), which greatly slows delivery to the target. Here we study these effects and how they can be solved by loading into nanoscale drug carriers. We focus on fingolimod, a small molecule drug that is FDA-approved for treatment of multiple sclerosis, which has also shown promise in the treatment of stroke. Unfortunately, fingolimod has poor solubility and very extensive partitioning to plasma proteins and RBCs (in whole blood, 86% partitions to RBCs, 13.96% to plasma proteins, and 0.04% is free). We develop a liposomal formulation that slows the partitioning of fingolimod to RBCs and plasma proteins, enables intravenous delivery, and additionally prevents fingolimod toxicity to RBCs. The liposomal formulation nearly completely prevented fingolimod adsorption to plasma proteins (association with plasma proteins was 98.4 ± 0.4% for the free drug vs. 5.6 ± 0.4% for liposome-loaded drug). When incubated with whole blood in vitro, the liposomal formulation greatly slowed partitioning of fingolimod to RBCs and also eliminated deleterious effects of fingolimod on RBC rigidity, morphology, and hemolysis. In vivo, the liposomal formulation delayed fingolimod partitioning to RBCs for over 30 min, a critical time window for stroke. Fingolimod-loaded liposomes showed improved efficacy in a mouse model of post-stroke neuroinflammation, completely sealing the leaky blood-brain barrier (114 ± 11.5% reduction in albumin leak into the brain for targeted liposomes vs. 38 ± 16.5% reduction for free drug). This effect was only seen for liposomes modified with antibodies to enable targeted delivery to the site of action, and not in unmodified, long-circulating liposomes. Thus, loading fingolimod into liposomes prevented partitioning to RBCs and associated toxicities and enabled targeted delivery. This paradigm can be used for tuning the blood distribution of small molecule drugs for the treatment of acute illnesses requiring rapid pharmacologic intervention.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Portadores de Fármacos / Proteínas Sanguíneas / Eritrocitos / Clorhidrato de Fingolimod / Liposomas Límite: Animals / Humans / Male Idioma: En Revista: J Control Release Asunto de la revista: FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Portadores de Fármacos / Proteínas Sanguíneas / Eritrocitos / Clorhidrato de Fingolimod / Liposomas Límite: Animals / Humans / Male Idioma: En Revista: J Control Release Asunto de la revista: FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos