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.
Highlights
Dendrimers represent highly branched macromolecules that have a well-defined structure with precisely controlled size and shape as well as terminal group functionality [1]
In a study in which diethylene glycol was used as a linker between naproxen, a poorly water-soluble drug, and G3 PAMAM dendrimer (Figure 1)
G3 dendrimer and Naproxen-diethylene glycol (NAP-deg)-(4-nitrophenyl carbonate) were reacted in appropriate molar ratios to form a carbamate bond between the diethylene glycol linker and the G3 dendrimer
Summary
Dendrimers represent highly branched macromolecules that have a well-defined structure with precisely controlled size and shape as well as terminal group functionality [1]. The high degree of branching allows drug encapsulation and the formation of dendrimer-drug conjugates [5], in addition, the ability to modify terminal functional groups allows for the surface engineering of dendrimers for different applications such as the enhancement of drug solubility [6,7,8] and permeability [9]. Using diethylene glycol as a linker/spacer between the drug and dendrimer resulted in ester prodrugs that showed high chemical stability at pH 1.2, 7.4 and 8.5 (37 ◦ C), but that readily released the drug in human plasma (in vitro). Such conjugates have potential as carriers for low solubility drugs, such as naproxen.
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