title: Cellular mechanism of oral absorption of solidified polymer micelles.
abstract: Oral delivery of poorly soluble and permeable drugs represents a significant challenge in drug development. The oral delivery of drugs remains to be the ultimate route of any drugs. However, in many cases, drugs are not absorbed well in the gastrointestinal tract, or they lose their activity. Polymer micelles were recognized as an effective carrier system for drug encapsulation, and are now studied as a vehicle for oral delivery of insoluble compounds. We characterized the properties of monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles, and visualized their internalization in mouse small intestine. Using Caco-2 cells as a cellular model, we studied the kinetics of particle uptake, their transport, and the molecular mechanism of their intestinal absorption. Moreover, by inhibiting specific endocytosis pathways, pharmacologically and genetically, we found that mPEG-PLA nanoparticle endocytosis is mediated by clathrin in an energy-dependent manner, and that the low-density lipoprotein receptor is involved.
  
  
  BACKGROUND
  Many current drugs used are non-water soluble and indeed, the ability to deliver these drugs via the gastrointestinal tract remains the holy grail for many researchers. The authors in this paper developed monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles as a drug nanocarrier, and studied the mechanism of uptake across intestinal cells. The findings should improve our current understanding and point to the development of more nanocarriers.
authors.affiliation: School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Eva
authors.initials: E
authors.lastname: Abramov
authors.affiliation: Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: Flavia
authors.initials: F
authors.lastname: Cassiola
authors.affiliation: School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Ouri
authors.initials: O
authors.lastname: Schwob
authors.affiliation: School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Karsh-Bluman
authors.affiliation: School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Mara
authors.initials: M
authors.lastname: Shapero
authors.affiliation: Ocular Repair and Regeneration Biology, UCL Institute of Ophthalmology, University College London Institute of Ophthalmology.
authors.forename: James
authors.initials: J
authors.lastname: Ellis
authors.affiliation: Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: Dema
authors.initials: D
authors.lastname: Luyindula
authors.affiliation: Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: Irit
authors.initials: I
authors.lastname: Adini
authors.affiliation: Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: D'Amato
authors.affiliation: School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: ofrab@huji.ekmd.ac.il.
authors.forename: Ofra
authors.initials: O
authors.lastname: Benny
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D004705:Endocytosis; D006801:Humans; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D019344:Lactic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D008810:Mice, Inbred C57BL; D008823:Micelles; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics*; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); C028210:monomethoxypolyethylene glycol
keywords: Caco-2; Nanomedicine; Oral delivery; Polymer micelles; mPEG-PLA