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

Purpose. To study the influence of a controlled incremental increase in siz e and molecular weight of a series of poly(amidoamine) (PAMAM) dendrimers o n 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 fractiona tion of the fluorescently labeled polymers were done using size exclusion c hromatography. The hamster cremaster muscle preparation was used as an in v ivo model to study the extravasation process of the fluorescently labeled p olymers. The extravasation process was visualized and recorded using intrav ital microscopy techniques. Analysis of the recorded experiments was done u sing Metamorph Imaging System. Extravasation of the fluorescently labeled p olymers is reported in terms of their extravasation time (tau), i.e., the t ime needed for the fluorescence intensity in the interstitial tissue to rea ch 90% of the fluorescence intensity in the neighboring microvessels. Results. Extravasation time (tau) describes the rate of microvascular extra vasation of polymeric drug carriers across the microvascular endothelium in to the interstitial tissue. Extravasation time (tau) of the studied PAMAM d endrimers showed size and molecular weight dependence. An increase in size and/or molecular weight of PAMAM dendrimers resulted in a corresponding exp onential increase in the extravasation time (tau). Conclusions. Extravasation of PAMAM dendrimers across the microvascular end othelium showed size and molecular weight dependence. Results suggest that in addition to size and molecular weight other physicochemical properties o f polymeric drug carriers such as molecular geometry and charge may influen ce their microvascular extravasation. Systematic studies of the influence o f the physicochemical properties of polymeric drug carriers on their microv ascular extravasation will aid in the design of novel macromolecular drug c arriers with controlled extravasation profiles.