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Dendrimer-based Uneven Nanopatterns to Locally Control Surface Adhesiveness: A Method to Direct Chondrogenic Differentiation
Published on: January 20, 2018
Engineering of dendrimer surfaces to enhance transepithelial transport and reduce cytotoxicity
Rachaneekorn Jevprasesphant1, Jeffrey Penny, David Attwood
1School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
Purpose:
To evaluate the cytotoxicity, permeation, and transport mechanisms of PAMAM dendrimers and surface-modified cationic PAMAM dendrimers using monolayers of the human colon adenocarcinoma cell line, Caco-2.
Methods:
Cytotoxicity was determined using the MTT assay. The effect of dendrimers on monolayer integrity was determined from measurements of transepithelial electrical resistance (TEER) and [14C]mannitol apparent permeability coefficient (Papp). The Papp of dendrimers through monolayers was measured in both the apical (A)-to-basolateral (B) and B --> A directions at 4 degrees C and 37 degrees C and also in the presence and absence of ethylenediamine tetraacetic acid (EDTA) and colchicine.
Results:
The cytotoxicity and permeation of dendrimers increased with both concentration and generation. The cytotoxicity of cationic dendrimers (G2, G3, G4) was greater than that of anionic dendrimers (G2.5, G3.5) but was reduced by conjugation with lauroyl chloride: the least cytotoxic conjugates were those with six attached lauroyl chains. At 37 degrees C the Papp of cationic dendrimers was higher than that of anionic dendrimers and, in general, increased with the number of attached lipid chains. Cationic dendrimers decreased TEER and significantly increased the Papp of mannitol. Modified dendrimers also reduced TEER and caused a more marked increase in the Papp of mannitol. The Papp values of dendrimers and modified dendrimers were higher in the presence of EDTA, lower in the presence of colchicine, and lower at 4 degrees C than at 37 degrees C.
Conclusions:
The properties of dendrimers may be significantly modified by surface engineering. Conjugation of cationic PAMAM dendrimers with lauroyl chloride decreased their cytotoxicity and increased their permeation through Caco-2 cell monolayers. Both PAMAM dendrimers and lauroyl-PAMAM dendrimer conjugates can cross epithelial monolayers by paracellular and transcellular pathways.
Insights
Surface modification of polyamidoamine (PAMAM) dendrimers with lauroyl chloride reduced cytotoxicity and enhanced permeation through Caco-2 cell monolayers. These modified dendrimers can traverse epithelial barriers via paracellular and transcellular routes.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Cell Biology
Background:
- Dendrimers, a class of hyperbranched polymers, are explored for drug delivery and biomedical applications.
- Understanding their interaction with biological barriers like the intestinal epithelium is crucial for in vivo efficacy.
Purpose of the Study:
- To assess the cytotoxicity and permeation of polyamidoamine (PAMAM) dendrimers and their surface-modified variants.
- To elucidate the transport mechanisms of these dendrimers across Caco-2 cell monolayers.
Main Methods:
- Cytotoxicity evaluated using MTT assay.
- Monolayer integrity assessed via transepithelial electrical resistance (TEER) and [14C]mannitol permeability.
- Dendrimer apparent permeability (Papp) measured under various conditions (temperature, chemical modifiers).
Main Results:
- Dendrimer cytotoxicity and permeation increased with concentration and generation.
- Cationic dendrimers exhibited higher cytotoxicity and Papp than anionic ones.
- Lauroyl chloride conjugation reduced cytotoxicity and enhanced permeation, with effects varying by the number of lauroyl chains.
Conclusions:
- Surface engineering significantly alters PAMAM dendrimer properties.
- Lauroyl-PAMAM dendrimer conjugates demonstrate reduced cytotoxicity and improved Caco-2 cell monolayer permeation.
- Both unmodified and modified PAMAM dendrimers can cross epithelial monolayers via paracellular and transcellular pathways.
