Enabling Noninvasive Systemic Delivery of the Kv1.3-Blocking Peptide HsTX1[R14A] via the Buccal Mucosa

Jin, Liang; Boyd, Ben J.; Larson, Ian; Pennington, Michael W.; Norton, Raymond S.; Nicolazzo, Joseph A.

doi:10.1016/j.xphs.2016.05.008

Cited by 20 publications

(9 citation statements)

References 29 publications

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“…Selectivity of Kv1.3 over Kv1.1 and other related channels is considered a benchmark standard for potential Kv1.3 blocker-based therapeutics for the treatment of autoimmunity [13; 15] and the high selectivity of HsTX1[R14A] for Kv1.3 makes it a potential therapeutic for chronic inflammatory diseases. HsTX1[R14A] has also been shown to be systemically deliverable through the pulmonary and buccal mucosal routes [36; 37], making this peptide attractive in a clinical setting.…”

Section: Introductionmentioning

confidence: 99%

Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog

Tanner

Tajhya

Huq

et al. 2017

Clinical Immunology

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Effector memory T lymphocytes (TEM cells) that lack expression of CCR7 are major drivers of inflammation in a number of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis. The Kv1.3 potassium channel is a key regulator of CCR7− TEM cell activation. Blocking Kv1.3 inhibits TEM cell activation and attenuates inflammation in autoimmunity, and as such, Kv1.3 has emerged as a promising target for the treatment of TEM cell-mediated autoimmune diseases. The scorpion venom-derived peptide HsTX1 and its analog HsTX1[R14A] are potent Kv1.3 blockers and HsTX1[R14A] is selective for Kv1.3 over closely-related Kv1 channels. PEGylation of HsTX1[R14A] to create a Kv1.3 blocker with a long circulating half-life reduced its affinity but not its selectivity for Kv1.3, dramatically reduced its adsorption to inert surfaces, and enhanced its circulating half-life in rats. PEG-HsTX1[R14A] is equipotent to HsTX1[R14A] in preferential inhibition of human and rat CCR7− TEM cell proliferation, leaving CCR7+ naïve and central memory T cells able to proliferate. It reduced inflammation in an active delayed-type hypersensitivity model and in the pristane-induced arthritis (PIA) model of rheumatoid arthritis (RA). Importantly, a single subcutaneous dose of PEG-HsTX1[R14A] reduced inflammation in PIA for a longer period of time than the non-PEGylated HsTX1[R14A]. Together, these data indicate that HsTX1[R14A] and PEG-HsTX1[R14A] are effective in a model of RA and are therefore potential therapeutics for TEM cell-mediated autoimmune diseases. PEG-HsTX1[R14A] has the additional advantages of reduced non-specific adsorption to inert surfaces and enhanced circulating half-life.

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Section: Introductionmentioning

confidence: 99%

Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog

Tanner

Tajhya

Huq

et al. 2017

Clinical Immunology

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“…We have therefore explored buccal 15–17 and pulmonary 18 delivery of this peptide, both of which proved to be effective. We are also exploring slow-release formulations (unpublished).…”

Section: Introductionmentioning

confidence: 99%

Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats

Bergmann

Kubeil

Zarschler

et al. 2017

Sci Rep

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The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, which is a highly promising target for the treatment of autoimmune diseases and other conditions. In order to assess the biodistribution of this peptide, it was conjugated with NOTA and radiolabelled with copper-64. [64Cu]Cu-NOTA-HsTX1[R14A] was synthesised in high radiochemical purity and yield. The radiotracer was evaluated in vitro and in vivo. The biodistribution and PET studies after intravenous and subcutaneous injections showed similar patterns and kinetics. The hydrophilic peptide was rapidly distributed, showed low accumulation in most of the organs and tissues, and demonstrated high molecular stability in vitro and in vivo. The most prominent accumulation occurred in the epiphyseal plates of trabecular bones. The high stability and bioavailability, low normal-tissue uptake of [64Cu]Cu-NOTA-HsTX1[R14A], and accumulation in regions of up-regulated Kv channels both in vitro and in vivo demonstrate that HsTX1[R14A] represents a valuable lead for conditions treatable by blockade of the voltage-gated potassium channel Kv1.3. The pharmacokinetics shows that both intravenous and subcutaneous applications are viable routes for the delivery of this potent peptide.

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“…Then, this peptide in solution or formulated in chitosan gel with or without cetrimide was administered in Swiss mice. After buccal administration in mice, the peptide was detected in plasma, with the presence of cetrimide in the gel further enhancing plasma exposure, with area under the plasma concentration-time curve values of 77.9 ± 9.7 and 31.0 ± 2.3 nM•h − 1 , respectively [39]. This study enforces the buccal mucosa is a promising alternative administration route for the peptides for non-invasive routes.…”

Section: Hydrogelsmentioning

confidence: 64%

An overview of polymeric dosage forms in buccal drug delivery: State of art, design of formulations and their in vivo performance evaluation

Fonseca-Santos

2018

Materials Science and Engineering: C

109

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Owing to the ease of the administration, the oral cavity is an attractive site for the delivery of drugs. The main difficulty for administration via the buccal route is an effective physiological removal mechanism of the oral cavity that takes way the formulation from the buccal site and decreases the bioavailability of drugs. The use of mucoadhesive polymers in buccal drug delivery shows assessing buccal drug permeation and absorption, however some studies bring an in vivo performance. This review points to the use of polymers in the manufacture of drug delivery systems (hydrogels, films and tablets) and shows the results of their in vivo performance tests.

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Enabling Noninvasive Systemic Delivery of the Kv1.3-Blocking Peptide HsTX1[R14A] via the Buccal Mucosa

Cited by 20 publications

References 29 publications

Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog

Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog

Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats

An overview of polymeric dosage forms in buccal drug delivery: State of art, design of formulations and their in vivo performance evaluation

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