title: Design considerations for PAMAM dendrimer therapeutics.
abstract: We have previously shown that methotrexate (MTX) conjugated to a cancer-specific poly amido amine (PAMAM) dendrimer has a higher therapeutic index than MTX alone. Unfortunately, these therapeutics have been difficult to advance because of the complicated syntheses and an incomplete understanding of the dendrimer properties. We wished to address these obstacles by using copper-free click chemistry to functionalize the dendrimer scaffolds and to exploring the effects of two dendrimer properties (the targeting ligand and drug linkage) on cytotoxicity. We conjugated either ester or amide-linker modified MTX to dendrimer scaffolds with or without folic acid (FA). Because of multivalency, the FA and MTX functionalized dendrimers had similar capacities to target the folate receptor on cancer cells. Additionally, we found that the ester- and amide-linker modified MTX compounds had similar cytotoxicity but the dendrimer-ester MTX conjugates were much more cytotoxic than the dendrimer-amide MTX conjugates. These results clarify the impact of these properties on therapeutic efficacy and will allow us to design more effective polymer therapeutics.
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, Ann Arbor, MI 48109, USA. sngoonew@med.umich.edu
authors.forename: Sascha N
authors.initials: SN
authors.lastname: Goonewardena
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Kratz
authors.forename: Hong
authors.initials: H
authors.lastname: Zong
authors.forename: Ankur M
authors.initials: AM
authors.lastname: Desai
authors.forename: Shengzhuang
authors.initials: S
authors.lastname: Tang
authors.forename: Sarah
authors.initials: S
authors.lastname: Emery
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
authors.forename: Baohua
authors.initials: B
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004705:Endocytosis; D006801:Humans; D007624:KB Cells; D008727:Methotrexate / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; C104700:PAMAM Starburst; D008727:Methotrexate