title: In vitro evaluation of dendrimer prodrugs for oral drug delivery.
abstract: Dendrimer-based prodrugs were used to enhance the transepithelial permeability of naproxen, a low solubility model drug. The stability of the dendrimer-naproxen link was assessed. Naproxen was conjugated to G0 polyamidoamine (PAMAM) dendrimers either by an amide bond or an ester bond. The stability of G0 prodrugs was evaluated in 80% human plasma and 50% rat liver homogenate. The cytotoxicity of conjugates towards Caco-2 cells was determined and the transport of the conjugates across Caco-2 monolayers (37 degrees C) was reported. In addition, one lauroyl chain (L) was attached to the surface group of G0 PAMAM dendrimer of the diethylene glycol ester conjugate (G0-deg-NAP) to enhance permeability. The lactic ester conjugate, G0-lact-NAP, hydrolyzed slowly in 80% human plasma and in 50% rat liver homogenate (t(1/2)=180 min). G0-deg-NAP was hydrolyzed more rapidly in 80% human plasma (t(1/2)=51 min) and was rapidly cleaved in 50% liver homogenate (t(1/2)=4.7 min). The conjugates were non-toxic when exposed to Caco-2 cells for 3h. Permeability studies showed a significant enhancement in the transport of naproxen when conjugated to dendrimers; L-G0-deg-NAP yielding the highest permeability. Dendrimer-based prodrugs with appropriate linkers have potential as carriers for the oral delivery of low solubility drugs such as naproxen.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Najlah
authors.forename: Sally
authors.initials: S
authors.lastname: Freeman
authors.forename: David
authors.initials: D
authors.lastname: Attwood
authors.forename: Antony
authors.initials: A
authors.lastname: D'Emanuele
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers; D007851:Dodecanol / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D004355:Drug Stability; D017097:Electric Impedance; D004952:Esters / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D009288:Naproxen / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D010949:Plasma / Q000378:metabolism; D011073:Polyamines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000577:Amides; D050091:Dendrimers; D004952:Esters; C104700:PAMAM Starburst; D011073:Polyamines; D011355:Prodrugs; D007851:Dodecanol; D009288:Naproxen