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Molecules 2017, 22(10), 1661; doi:10.3390/molecules22101661

In Vitro Evaluation of Third Generation PAMAM Dendrimer Conjugates

1
Faculty of Medical Science, Anglia Ruskin University, Bishops Hall Lane, Chelmsford CM1 1SQ, UK
2
Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, UK
3
School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston upon Thames KT1 2EE, UK
4
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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Abstract

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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MDPI and ACS Style

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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