Sadekar S, Linares O, Noh Gj, Hubbard D, Ray A, Janát-Amsbury M, Peterson C M, Facelli J, Ghandehari H
Department 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.
Drug Deliv Transl Res. 2013 Jun 1;3(3):260-271. doi: 10.1007/s13346-012-0119-6.
The purpose of this study was to model data from a head to head comparison of the 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 (AUC). Renal clearance (CL) 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 (K, K) and elimination (K) rate constants using multivariable constrained optimization solver in Matlab®. Tumor exposures (AUC) 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.
本研究的目的是对超支化聚酰胺-胺（PAMAM）树枝状大分子与线性聚（N-（2-羟丙基）甲基丙烯酰胺）（HPMA）共聚物的命运进行直接比较的数据进行建模，以便使用房室药代动力学分析来了解分子量（MW）、流体力学尺寸（Rh）和聚合物结构对荷瘤小鼠生物分布的影响。使用Winnonlin®通过二室分析对血浆浓度数据进行建模，以获得消除清除率（E.CL）和血浆暴露量（AUC）。根据1周内收集的尿液数据计算肾清除率（CL）。通过在Matlab®中使用多变量约束优化求解器改变肿瘤外渗（K、K）和消除（K）速率常数，将血浆-肿瘤连接模型拟合到实验性血浆和肿瘤数据。通过线性梯形法从肿瘤浓度-时间曲线下的面积计算肿瘤暴露量（AUC）。与MW和Rh一样，聚合物结构对影响PAMAM-OH树枝状大分子和HPMA共聚物的血液和肿瘤药代动力学至关重要。与HPMA共聚物相比，PAMAM-OH树枝状大分子的消除清除率随流体力学尺寸的增加下降得更快。HPMA共聚物经肾脏消除的程度高于PAMAM-OH树枝状大分子。这些结果表明，不同结构的聚合物通过肾小球基底膜的外渗存在差异。虽然线性HPMA共聚物在无规卷曲构象中可能通过尺寸小于其流体力学半径的孔进行蠕动，但PAMAM树枝状大分子必须变形才能穿过这些孔。已知随着分子量或代数的增加，PAMAM-OH树枝状大分子的变形能力会降低，与具有可比分子量的HPMA共聚物相比，更高代数的PAMAM-OH树枝状大分子更难通过肾小球筛选。与具有可比分子量的HPMA共聚物相比，PAMAM-OH树枝状大分子具有更高的肿瘤外渗速率常数和更高的肿瘤与血浆暴露比，这表明在所研究的尺寸范围内，在循环时，PAMAM-OH树枝状大分子比HPMA共聚物具有更高的肿瘤积累亲和力。
