title: Efficacy, safety and mechanism of HP-β-CD-PEI polymers as absorption enhancers on the intestinal absorption of poorly absorbable drugs in rats.
abstract: BACKGROUND
  Oral bioavailability of some hydrophilic therapeutic macromolecules was very poor, thus leading to their limited application in clinic.
  
  
  OBJECTIVE
  To investigate the efficacy, safety and mechanism of HP-β-CD-PEI polymers on the intestinal absorption of some poorly absorbable drugs in rats.
  
  
  METHODS
  Effects of HP-β-CD-PEI polymers on the intestinal absorptions of drugs were investigated by an in situ closed loop method in rats. The safety of HP-β-CD-PEI polymer was evaluated by measurement of lactate dehydrogenase (LDH) activity and amount of protein released from rat intestinal perfusate. The absorption enhancing mechanisms were explored by the measurement of zeta potential, transepithelial electrical resistance (TEER) and in vitro transport of FD4 (a paracellular marker) across rat intestinal membranes, respectively.
  
  
  RESULTS
  HP-β-CD-PEI polymers, especially HP-β-CD-PEI1800, demonstrated excellent absorption enhancing effects on drug absorption in a concentration-dependent manner and the enhancing effect was more efficient in the small intestine than that in the large intestine. Five percent (w/v) HP-β-CD-PEI1800obviously decreased the TEER, accompanied with increase in the intestinal transport of FD4, indicating that absorption enhancing actions of HP-β-CD-PEI polymers were possibly performed by loosening tight junctions of intestinal epithelium cells, thereby increasing drug permeation via a paracellular pathway. A good liner relationship between absorption enhancing effects of HP-β-CD-PEI polymers and their zeta potentials suggested the contribution of positive charge on the surface of these polymers to their absorption enhancing effects.
  
  
  CONCLUSIONS
  HP-β-CD-PEI polymers might be potential and safe absorption enhancers for improving oral delivery of poorly absorbable macromolecules including peptides and proteins.
authors.affiliation: a Department of Pharmacy, School of Pharmacy , Xi'an Jiaotong University , Xi'an , China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: a Department of Pharmacy, School of Pharmacy , Xi'an Jiaotong University , Xi'an , China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Huang
authors.affiliation: a Department of Pharmacy, School of Pharmacy , Xi'an Jiaotong University , Xi'an , China.
authors.forename: Yongjing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: a Department of Pharmacy, School of Pharmacy , Xi'an Jiaotong University , Xi'an , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008297:Male; D009924:Organ Culture Techniques; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000378:metabolism*; D011108:Polymers / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D011108:Polymers; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011094:Polyethyleneimine
keywords: HP-β-CD-PEI polymers; Intestinal absorption; absorption enhancement; absorption enhancing mechanism; membrane damage