Biological evaluation of polyester dendrimer: poly(ethylene oxide) "bow-tie" hybrids with tunable molecular weight and architecture.
High molecular weight (MW) polymers have shown promise in terms of improving the properties and the efficacy of low MW therapeutics. However, new systems that are highly biocompatible, are biodegradable, have well-defined MW, and have multiple functional groups for drug attachment are still needed. The biological evaluation of a library of eight polyester dendrimer-poly(ethylene oxide) (PEO) bow-tie hybrids is described here. The group of evaluated polymers was designed to include a range of MWs (from 20000 to 160000) and architectures with the number of PEO arms ranging from two to eight. In vitro experiments revealed that the polymers were nontoxic to cells and were degraded to lower MW species at pH 7.4 and pH 5.0. Biodistribution studies with (125)I-radiolabeled polymers showed that the high MW carriers (>40000) exhibited long circulation half-lives. Comparison of the renal clearances for the four-arm versus eight-arm polymers indicated that the more branched polymers were excreted more slowly into the urine, a result attributed to their decreased flexibility. Due to their essentially linear architecture that does not provide for good isolation of the iodinated phenolic moieties, the polymers with "two arms" were rapidly taken up by the liver. The biodistributions of two long-circulating high MW polymers in mice bearing subcutaneous B16F10 tumors were evaluated, and high levels of tumor accumulation were observed. These new carriers are therefore promising for applications in drug delivery and are also useful for improving our understanding of the effect of polymer architecture on pharmacokinetic properties.
Gillies
Elizabeth R
ER
Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720-1460, USA.
Dy
Edward
E
Fréchet
Jean M J
JM
Szoka
Francis C
FC
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001672:Biocompatible Materials / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005069:Evaluation Studies as Topic; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D008958:Models, Molecular; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D011091:Polyesters / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D011108:Polymers / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors; D014018:Tissue Distribution; D014439:Tyramine / Q000737:chemistry
D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D004337:Drug Carriers; D011091:Polyesters; D011108:Polymers; D011092:Polyethylene Glycols; D014439:Tyramine