Extravasation of poly(amidoamine) (PAMAM) dendrimers across microvascular network endothelium

Purpose. To study the influence of a controlled incremental increase in size and molecular weight of a series of poly(amidoamine) (PAMAM) dendrimers on their extravasation across the microvascular network endothelium. Methods. A series of PAMAM dendrimers (generations 0-4) were fluorescently labeled using fluorescein isothiocyanate (FITC). Purification and fractionation of the fluorescently labeled polymers were done using size exclusion chromatography. The hamster cremaster muscle preparation was used as an in vivo model to study the extravasation process of the fluorescently labeled polymers. The extravasation process was visualized and recorded using intravital microscopy techniques. Analysis of the recorded experiments was done using Metamorph Imaging System. Extravasation of the fluorescently labeled polymers is reported in terms of their extravasation time (tau), i.e., the time needed for the fluorescence intensity in the interstitial tissue to reach 90% of the fluorescence intensity in the neighboring microvessels. Results. Extravasation time (tau) describes the rate of microvascular extravasation of polymeric drug carriers across the microvascular endothelium into the interstitial tissue. Extravasation time (tau) of the studied PAMAM dendrimers showed size and molecular weight dependence. An increase in size and/or molecular weight of PAMAM dendrimers resulted in a corresponding exponential increase in the extravasation time (tau). Conclusions. Extravasation of PAMAM dendrimers across the microvascular endothelium showed size and molecular weight dependence. Results suggest that in addition to size and molecular weight other physicochemical properties of polymeric drug carriers such as molecular geometry and charge may influence their microvascular extravasation. Systematic studies of the influence of the physicochemical properties of polymeric drug carriers on their microvascular extravasation will aid in the design of novel macromolecular drug carriers with controlled extravasation profiles.