Fabrication Principles and Their Contribution to the Superior In Vivo Therapeutic Efficacy of Nano-Liposomes Remote Loaded with Glucocorticoids

Avnir, Yuval; Turjeman, Keren; Tulchinsky, Deborah; Sigal, Alex; Kizelsztein, Pablo; Tzemach, Dina; Gabizón, Alberto; Barenholz, Yechezkel

doi:10.1371/journal.pone.0025721

Cited by 65 publications

(78 citation statements)

References 58 publications

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“…This exchange process can continue until the liposome will lose all its acetate. However, in practice this exchange process is stopped much earlier as the retained trans-membrane calcium acetate gradient stabilizes the drug remote loading (31). The scheme on right shows loading of mupirocin into nano-liposomes exhibiting a tansmembrane gradient of calcium acetate which also contain HPCD (present in the figure in its toroid structure).…”

Section: Introductionmentioning

confidence: 99%

Nano-mupirocin: enabling the parenteral activity of mupirocin

Cern¹,

Michael-Gayego

Bavli

et al. 2016

European Journal of Nanomedicine

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Mupirocin is an antibiotic having a unique mode of action, not shared by any other therapeutically available antibiotic. However, due to its rapid elimination following injection and high protein binding, current therapeutic use is limited to topical administration. Computational methods have identified mupirocin as a good candidate for delivery via long-circulating nano-liposomes. Formulating mupirocin in such liposomes to form Nano-mupirocin protects the drug in the circulation, enabling therapeutic efficacy. This was demonstrated using two different animal models that served as a proof of concept: the mice necrotizing fasciitis and rabbit endocarditis models. In both animal models, mupirocin administered intravenously (IV) lacked therapeutic efficacy, while the Nano-mupirocin administered IV was efficacious. In both mice and rabbits the pharmacokinetic (PK) profile following IV injection of Nano-mupirocin showed significantly greater AUC and elimination half-life of Nano-mupirocin compared to the free drug. In addition, in mice we also demonstrated significant drug distribution into the disease site. These PK profiles may explain Nano-mupirocin's superior therapeutic efficacy. To the best of our knowledge, this is the first study demonstrating that systemic activity of mupirocin is feasible. Therefore, Nano-mupirocin can be considered a novel and unique parenteral antibiotic candidate drug.

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Section: Introductionmentioning

confidence: 99%

Nano-mupirocin: enabling the parenteral activity of mupirocin

Cern¹,

Michael-Gayego

Bavli

et al. 2016

European Journal of Nanomedicine

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“…It has been shown that using a calcium acetate ion gradient can lead to high loading efficiencies of corticosteroid succinates, with 80% encapsulation efficiency (EE) for betamethasone hemisuccinate, 100% EE for hydrocortisone hemisuccinate, and 95% EE for methylprednisolone hemisuccinate. 25,52 In our case, we achieved a 70% EE for PH that is lower compared to the other corticosteroids, and this could likely be improved by optimizing the loading parameters. Furthermore, palmitate corticosteroid derivatives have also been studied since the late 1970s, with cortisol palmitate, prednisolone palmitate, and dexamethasone palmitate having been loaded into liposomes.…”

Section: Discussionmentioning

confidence: 69%

“…The passive loading of hydrophilic corticosteroids in liposomes initially resulted in very low encapsulation efficiencies (<5%). [50][51][52] Low loading can be overcome by choosing amphipathic weak acid corticosteroids and using a remote-loading approach. It has been shown that using a calcium acetate ion gradient can lead to high loading efficiencies of corticosteroid succinates, with 80% encapsulation efficiency (EE) for betamethasone hemisuccinate, 100% EE for hydrocortisone hemisuccinate, and 95% EE for methylprednisolone hemisuccinate.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Protein C–Targeting Liposomes Show Enhanced Uptake and Improved Therapeutic Efficacy in Human Retinal Endothelial Cells

Arta

Eriksen

Melander

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine whether human retinal endothelial cells (HRECs) express the endothelial cell protein C receptor (EPCR) and to realize its potential as a targeting moiety by developing novel single and dual corticosteroid-loaded functionalized liposomes that exhibit both enhanced uptake by HRECs and superior biologic activity compared to nontargeting liposomes and free drug.METHODS. EPCR expression of HRECs was investigated through flow cytometry and Western blot assays. EPCR-targeting liposomes were developed by functionalizing EPCR-specific antibodies onto liposomes, and the uptake of liposomes was assessed with flow cytometry and confocal laser scanning microscopy. The therapeutic potential of EPCR-targeting liposomes was determined by loading them with prednisolone either through bilayer insertion and/or by remote loading into the aqueous core. The carrier efficacy was assessed in two ways through its ability to inhibit secretion of interleukins in cells stimulated with high glucose and angiogenesis in vitro by using an endothelial cell tube formation assay. RESULTS.HRECs express EPCR at a similar level in both human aortic and umbilic vein endothelial cells. The EPCR-targeting liposomes displayed at least a 3-fold higher uptake compared to nontargeting liposomes. This enhanced uptake was translated into superior antiinflammatory efficacy, as the corticosteroid-loaded EPCR-targeting liposomes significantly reduced the secretion of IL-8 and IL-6 and inhibited the development of cell tube formations in contrast to nontargeting liposomes. CONCLUSIONS.We show that HRECs express EPCR and this receptor could be a promising nanomedicine target in ocular diseases where the endothelial barrier of the retina is compromised.

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“…Methylprednisolone hemisuccinate sodium salt was incorporated in nanoliposomes using the strategy of transmembrane ion gradient-driven remote loading of amphipathic weak acid or base drugs into PEGylated nanoliposomes. Overall, the features of the optimized nano-sterically stabilized liposomes methylprednisolone hemisuccinate gave a high drug payload, high encapsulation efficacy, good storage stability at 4°C storage and superior pharmacokinetic and biodistribution properties, as well as a slow zero-order drug release [75]. This formulation showed superior therapeutic efficacy in mouse and rat models of diseases with inflammatory components like rheumatoid arthritis [73][74], in murine models of experimental autoimmune encephalomyelitis and cerebral malaria and in two types of mouse tumor models (the methylprednisolone hemisuccinate sodium salt-sensitive BCL-1 B-cell leukemia and the methylprednisolone hemisuccinate sodium salt-insensitive J6456 T-cell lymphoma) [75].…”

Section: Liposomal Carriersmentioning

confidence: 97%

Innovative Formulations for the Controlled and Site-specific Delivery of Antiinflammatory Drugs

Serpe¹,

Canaparo²,

Foglietta³

et al. 2013

CPD

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Pharmaceutical technology has introduced a promising pathway in the future of medicinein particular nanotechnological innovations have provided the opportunity to design and develop efficient drug delivery systems able to target and treat several diseases, including those mediated by inflammation. The engineering of drug delivery systems can be used to target tissues involved in the pathology under treatment, to avoid early drug biological environmental degradation and to modulate drug pharmacokinetics. Glucocorticoids and non-steroidal anti-inflammatory drugs are the most commonly prescribed drug categories worldwide for the treatment of disorders associated with inflammation.Although glucocorticoids can be highly effective in treating inflammation, their systemic application is limited due to the high incidence of serious adverse effects, mainly in long-term treatment. Non-steroidal anti-inflammatory drugs are a heterogeneous group of compounds and most of them have unfavorable pharmacokinetics and pharmacodynamics, leading to adverse effects, such as gastrointestinal disorders. Therefore, the need for drug delivery systems for long term administration of anti-inflammatory drugs witha well-controlled release profile is evident. The aim of this review is to assess innovative colloidal drugs carriers, in particular liposomes and nanoparticles, with special focus on site-specific delivery for particularly problematic tissues such as the gastrointestinal tract, joints and eyes.3

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Fabrication Principles and Their Contribution to the Superior In Vivo Therapeutic Efficacy of Nano-Liposomes Remote Loaded with Glucocorticoids

Cited by 65 publications

References 58 publications

Nano-mupirocin: enabling the parenteral activity of mupirocin

Nano-mupirocin: enabling the parenteral activity of mupirocin

Endothelial Protein C–Targeting Liposomes Show Enhanced Uptake and Improved Therapeutic Efficacy in Human Retinal Endothelial Cells

Innovative Formulations for the Controlled and Site-specific Delivery of Antiinflammatory Drugs

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