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Molecules 2017, 22(10), 1661;

In Vitro Evaluation of Third Generation PAMAM Dendrimer Conjugates

Faculty of Medical Science, Anglia Ruskin University, Bishops Hall Lane, Chelmsford CM1 1SQ, UK
Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, UK
School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston upon Thames KT1 2EE, UK
Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK
Author to whom correspondence should be addressed.
Received: 26 September 2017 / Revised: 29 September 2017 / Accepted: 30 September 2017 / Published: 4 October 2017
(This article belongs to the Special Issue Dendrimers in Medicine)
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The present study compares the use of high generation G3 and low generation G0 Polyamidoamine (PAMAM) dendrimers as drug carriers of naproxen (NAP), a poorly water soluble drug. Naproxen was conjugated to G3 in different ratios and to G0 in a 1:1 ratio via a diethylene glycol linker. A lauroyl chain (L), a lipophilic permeability enhancer, was attached to G3 and G0 prodrugs. The G3 and G0 conjugates were more hydrophilic than naproxen as evaluated by the measurement of partitioning between 1-octanol and a phosphate buffer at pH 7.4 and pH 1.2. The unmodified surface PAMAM-NAP conjugates showed significant solubility enhancements of NAP at pH 1.2; however, with the number of NAP conjugated to G3, this was limited to 10 molecules. The lactate dehydrogenase (LDH) assay indicated that the G3 dendrimer conjugates had a concentration dependent toxicity towards Caco-2 cells. Attaching naproxen to the surface of the dendrimer increased the IC50 of the resulting prodrugs towards Caco-2 cells. The lauroyl G3 conjugates showed the highest toxicity amongst the PAMAM dendrimer conjugates investigated and were significantly more toxic than the lauroyl-G0-naproxen conjugates. The permeability of naproxen across monolayers of Caco-2 cells was significantly increased by its conjugation to either G3 or G0 PAMAM dendrimers. Lauroyl-G0 conjugates displayed considerably lower cytotoxicity than G3 conjugates and may be preferable for use as a drug carrier for low soluble drugs such as naproxen. View Full-Text
Keywords: PAMAM dendrimers; transepithelial transport; Caco-2 cells; dendrimer prodrugs; oral drug delivery PAMAM dendrimers; transepithelial transport; Caco-2 cells; dendrimer prodrugs; oral drug delivery

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Najlah, M.; Freeman, S.; Khoder, M.; Attwood, D.; D’Emanuele, A. In Vitro Evaluation of Third Generation PAMAM Dendrimer Conjugates. Molecules 2017, 22, 1661.

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