The influence of polymer topology on pharmacokinetics: Differences between cyclic and linear PEGylated poly(acrylic acid) comb polymers

Abstract

Water-soluble polymers for the delivery of chemotherapeutic drugs passively target solid tumors as a consequence of reduced renal clearance and the enhanced permeation and retention (EPR) effect. Elimination of the polymers in the kidney occurs due to filtration through biological nanopores with a hydrodynamic diameter comparable to the polymer. Therefore we have investigated chemical features that may broadly be grouped as "molecular architecture" such as: molecular weight, chain flexibility, number of chain ends and branching, to learn how they impact polymer elimination. In this report we describe the synthesis of four pairs of similar molecular weight cyclic and linear polyacrylic acid polymers grafted with polyethylene glycol (23, 32, 65, 114 kDa) with low polydispersities using ATRP and "click" chemistry. The polymers were radiolabeled with 125 I and their pharmacokinetics and tissue distribution after intravenous injection were determined in normal and C26 adenocarcinoma tumored BALB/c mice. Cyclic polymers above the renal threshold of 30kDa had a significantly longer elimination time (between 10 to 33 % longer) than did the comparable linear polymer (for the 66 kDa cyclic polymer, t 1/2, β = 35 ± 2 h) and a greater area under the serum concentration time curve. This resulted in a greater tumor accumulation of the cyclic polymer than the linear polymer counterpart. Thus water-soluble cyclic comb polymers join a growing list of polymer topologies that show greatly extended circulation times compared to their linear counterparts and provide alternative polymer architecture for use as drug carriers.

Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism

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“…Easily quantifiable analytic methods such as inductively coupled plasma mass spectroscopy are not applicable to organic nanoparticles. Hence, we turned to radiolabeling techniques based on the introduction of 14 C, 3 H, or 125 I radionuclides in polymer backbones (10)(11)(12), liposomes (13)(14)(15), or lipid nanoparticles (16)(17)(18). We triply labeled lipidots with 2 radiotracers and a fluorescent dye with close physicochemical properties favoring their colocalization in the particle's core, that is, a slightly polar head (cyanine or cholesterol moiety) and long hydrophobic chain or chains.…”

Smart polymers in drug delivery systems on crossroads: Which way deserves following?

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