Oral and pulmonary delivery of thioether-bridged angiotensin-(1-7).
Instability and proteolytic degradation limit the delivery options and in vivo efficacy of many therapeutic peptides. We previously generated a thioether stabilized angiotensin-(1-7) analog, cAng-(1-7), which is resistant against proteolytic degradation in the circulation. We here investigated oral and pulmonary delivery of this compound. In a first step we investigated the in vitro stability of the peptide under conditions that mimic those that will be met after oral administration. We demonstrated that cAng-(1-7) is stable at pH 2.0, a pH value close to that of the stomach, has enhanced resistance to breakdown by proteases from pancreas at pH 7.4, and is resistant to breakdown by proteases from liver at the lysosomal pH 5.0. We subsequently demonstrated that, in the absence of any delivery system or formulation, cAng-(1-7) can be delivered orally and via the lung, with bioavailabilities of 0.28+/-0.05% and 28+/-5%, whereas drug uptake was maximal after subcutaneous administration (bioavailability of 98+/-6%). Therapeutic concentrations could be reached via all three routes of administration. The data prove that introduction of a thioether bridge in peptides opens novel delivery options for medically important peptides.
de Vries
Louwe
L
BiOMaDe Technology Foundation, Nijenborgh 4, 9747 AG Groningen, The Netherlands. de.vries@biomade.nl
Reitzema-Klein
Christina E
CE
Meter-Arkema
Anita
A
van Dam
Annie
A
Rink
Rick
R
Moll
Gert N
GN
Akanbi
Marijke Haas Jimoh
MH
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000803:Angiotensin I / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004333:Drug Administration Routes; D008297:Male; D013058:Mass Spectrometry; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014132:Trachea / Q000378:metabolism
D010446:Peptide Fragments; D000803:Angiotensin I; C118790:angiotensin I (1-7)