COMPARATIVE PHARMACOKINETICS OF PAMAM-OH DENDRIMERS AND HPMA COPOLYMERS IN OVARIAN-TUMOR-BEARING MICE
1Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, 84108, USA ; Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, Utah, 84108, USA.
Abstract:
The purpose of this study was to model data from a head to head comparison of the in vivo fate of hyper-branched PAMAM dendrimers with linear HPMA copolymers in order to understand the influence of molecular weight (MW), hydrodynamic size (Rh) and polymer architecture on biodistribution in tumor-bearing mice using compartmental pharmacokinetic analysis. Plasma concentration data was modeled by two-compartment analysis using Winnonlin® to obtain elimination clearance (E.CL) and plasma exposure (AUCplasma). Renal clearance (CLR) was calculated from urine data collected over 1 week. A plasma-tumor link model was fitted to experimental plasma and tumor data by varying the tumor extravasation (K4, K6) and elimination (K5) rate constants using multivariable constrained optimization solver in Matlab®. Tumor exposures (AUCtumor) were computed from area under the tumor concentration time profile curve by the linear trapezoidal method. Along with MW and Rh, polymer architecture was critical in affecting the blood and tumor pharmacokinetics of the PAMAM-OH dendrimers and HPMA copolymers. Elimination clearance decreased more rapidly with increase in hydrodynamic size for PAMAM-OH dendrimers as compared to HPMA copolymers. HPMA copolymers were eliminated renally to a higher extent than PAMAM-OH dendrimers. These results are suggestive of a difference in extravasation of polymers of varying architecture through the glomerular basement membrane. While the linear HPMA copolymers can potentially reptate through a pore smaller in size than their hydrodynamic radii in a random coil conformation, PAMAM dendrimers have to deform in order to permeate across the pores. With increase in molecular weight or generation, the deforming capacity of PAMAM-OH dendrimers is known to decrease, making it harder for higher generation PAMAM-OH dendrimers to sieve through the glomerulus as compared to HPMA copolymers of comparable molecular weights. PAMAM-OH dendrimer had greater tumor extravsation rate constants and higher tumor to plasma exposure ratios than HPMA copolymers of comparable molecular weights which indicated that in the size range studied, when in circulation, PAMAM-OH dendrimers had a higher affinity to accumulate in the tumor than the HPMA copolymers.
