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 30 kDa had a significantly longer elimination time (between 10 and 33% longer) than did the comparable linear polymer (for the 66 kDa cyclic polymer, t(1/2,beta)=35+/-2 h) and a greater area under the serum concentration versus 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.

Figure 1

Synthesis of PEGylated cyclic and linear PAA comb polymers. (n ≈ 45, q ≈ 1, p+q+i=45) (i) CuBr, PMDETA, t-BA (ii)DMF, NaN₃ (iii) CuBr, PMDETA, 120°C, 72h (iv) DCM, TFA (v) HATU, HOAT, mPEG amine, tyramine, DMF, 120°C, 48h

Figure 2

Characterization of cyclic and linear polymers. (A) ¹HNMR spectra of linear APtBA-Br (2), linear APtBA-N₃ (3) and cyclic PtBA (5). The hydrogens a – e and numbers 2, 3 and 5 are corresponding to the hydrogens and polymers in scheme 1, respectively. (B) The retention volume of linear (3, black) and cyclic (5, green) PtBA measured by GPC in THF. Numbers 2, 3 and 5 are corresponding to the polymers in Figure 1. (C) Linear polyacrylic acid (APAA-N₃) and cyclic PAA characterized by matrix assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS)

Figure 3

Blood circulation profile of radiolabeled cyclic and linear polymers given as the average percent injected dose of polymer in the blood over time (n = 3 mice per time point).

Figure 4

T _1/2,β (A) and AUC_{0→ ∞} (B) of cyclic and linear polymers as function of molecular weight. (n = 3 mice per time point)

Figure 5

Polymer amount in organs at 24 h postinjection (A) as the percent of injected dose per gram tissue (B) as percent of the injected dose per organ. (n = 3 mice per time point)

Figure 6

Polymer concentration as the percent injected dose per gram of tissue in tumor bearing mice at 48 h. (n = 3 mice per time point)

Figure 7

Polymer concentration variations for 66 kDa cyclic and 65 kDa linear polymers as the average percent injected dose in per gram of tumor. (n = 3 mice per time point)

Scheme 1

Schematic diagram depicting the PEGylated cyclic and linear polyacrylic acid comb structures with MWs larger than pores in the kidney. The hypothetical repation for the linear comb polymer through the pore is easier than for the cyclic comb polymer with same MWs.