title: PEGylation of HPMA-based block copolymers enhances tumor accumulation in vivo: a quantitative study using radiolabeling and positron emission tomography.
abstract: This paper reports the body distribution of block copolymers (made by controlled radical polymerization) with N-(2-hydroxypropyl)methacrylamide (HPMA) as hydrophilic block and lauryl methacrylate (LMA) as hydrophobic block. They form micellar aggregates in aqueous solution. For this study the hydrophilic/hydrophobic balance was varied by incorporation of differing amounts of poly(ethylene glycol) (PEG) side chains into the hydrophilic block, while keeping the degree of polymerization of both blocks constant. PEGylation reduced the size of the micellar aggregates (Rh=113 to 38 nm) and led to a minimum size of 7% PEG side chains. Polymers were labeled with the positron emitter (18)F, which enables to monitor their biodistribution pattern for up to 4h with high spatial resolution. These block copolymers were investigated in Sprague-Dawley rats bearing the Walker 256 mammary carcinoma in vivo. Organ/tumor uptake was quantified by ex vivo biodistribution as well as small animal positron emission tomography (PET). All polymers showed renal clearance with time. Their uptake in liver and spleen decreased with size of the aggregates. This made PEGylated polymers--which form smaller aggregates--attractive as they show a higher blood pool concentration. Within the studied polymers, the block copolymer of 7% PEGylation exhibited the most favorable organ distribution pattern, showing highest blood-circulation level as well as lowest hepatic and splenic uptake. Most remarkably, the in vivo results revealed a continuous increase in tumor accumulation with PEGylation (independent of the blood pool concentration)--starting from lowest tumor uptake for the pure block copolymer to highest enrichment with 11% PEG side chains. These findings emphasize the need for reliable (non-invasive) in vivo techniques revealing overall polymer distribution and helping to identify drug carrier systems for efficient therapy.
authors: Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099 Mainz, Germany.
authors: Mareli
authors: M
authors: Allmeroth
authors: Institute of Nuclear Chemistry, Johannes Gutenberg University, Fritz-Strassmann-Weg 2, 55128 Mainz, Germany.
authors: Dorothea
authors: D
authors: Moderegger
authors: Institute of Physiology, University Halle, Magdeburger Str. 6, 06097 Halle (Saale), Germany.
authors: Daniel
authors: D
authors: Gündel
authors: Department of Nuclear Medicine, University Medicine Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
authors: Hans-Georg
authors: HG
authors: Buchholz
authors: Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099 Mainz, Germany.
authors: Nicole
authors: N
authors: Mohr
authors: Max-Planck-Institute for Polymer Research, Ackermannweg 10, D-55128 Mainz, Germany.
authors: Kaloian
authors: K
authors: Koynov
authors: Institute of Nuclear Chemistry, Johannes Gutenberg University, Fritz-Strassmann-Weg 2, 55128 Mainz, Germany. Electronic address: frank.roesch@uni-mainz.de.
authors: Frank
authors: F
authors: Rösch
authors: Institute of Physiology, University Halle, Magdeburger Str. 6, 06097 Halle (Saale), Germany. Electronic address: oliver.thews@medizin.uni-halle.de.
authors: Oliver
authors: O
authors: Thews
authors: Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55099 Mainz, Germany. Electronic address: zentel@uni-mainz.de.
authors: Rudolf
authors: R
authors: Zentel
mesh_terms: D000818:Animals; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000175:diagnosis / Q000000981:diagnostic imaging; D008689:Methacrylates / Q000737:chemistry* / Q000493:pharmacokinetics*; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D008689:Methacrylates; D008823:Micelles; D011092:Polyethylene Glycols; C032802:hydroxypropyl methacrylate
keywords: Fluorine-18 labeling; HPMA; PEG; PET; Structure–property relationships; Walker 256 mammary carcinoma