The influence of polymer topology on pharmacokinetics: differences between cyclic and linear PEGylated poly(acrylic acid) comb polymers.
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.
Chen
Bo
B
Department of Bioengineering Therapeutic Sciences and Pharmaceutical Chemistry, University of California, San Francisco, California 94143-0912, United States.
Jerger
Katherine
K
Fréchet
Jean M J
JM
Szoka
Francis C
FC
D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000378:metabolism; D005079:Excipients; D005260:Female; D006207:Half-Life; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D010599:Pharmacokinetics; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility; D014018:Tissue Distribution; D000099166:Polyacrylamides
D000178:Acrylamides; D000970:Antineoplastic Agents; D005079:Excipients; D011092:Polyethylene Glycols; D011108:Polymers; C113798:polyethyleneglycol-polyacrylamide copolymer; D000099166:Polyacrylamides