title: Preclinical antitumor efficacy evaluation of dendrimer-based methotrexate conjugates.
abstract: Our previous studies have demonstrated the in-vitro and in-vivo targeting of a generation-5 (G5) dendrimer-based multifunctional conjugate, which used folic acid (FA) as the targeting agent and methotrexate (MTX) as the chemotherapeutic drug. For the synthesized G5-FA-MTX nanodevice conjugate to be clinically applicable as a cancer therapeutic drug, it is important that the compound elicits cytotoxicity specifically and consistently. The aim of this work was to evaluate four independently synthesized batches of G5-FA-MTX conjugates for their cytotoxic potential and specificity. For determination of specificity, we have used a unique 'coculture' assay in which FA receptor-positive and FA receptor-negative cells were cultured together and have examined the preferential killing of the former. The results of our study show the batch-to-batch consistency and specificity of the G5-FA-MTX nanodevice in the preferential killing of FA receptor-positive cells. The coculture assay shows the consistency of the four different G5-FA-MTX conjugate lots in the specific killing of targeted cells. Further in-vivo studies are, however, necessary to prove the clinical potential of this targeted therapeutic nanodevice.
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, BSRB, Ann Arbor, Michigan 48109, USA. myca@umich.edu
authors.forename: Andrzej
authors.initials: A
authors.lastname: Myc
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Douce
authors.forename: Niharika
authors.initials: N
authors.lastname: Ahuja
authors.forename: Alina
authors.initials: A
authors.lastname: Kotlyar
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kukowska-Latallo
authors.forename: Thommey P
authors.initials: TP
authors.lastname: Thomas
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D050091:Dendrimers; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005434:Flow Cytometry; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007624:KB Cells; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D011073:Polyamines / Q000737:chemistry* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014410:Tumor Stem Cell Assay / Q000379:methods; D000097573:Red Fluorescent Protein
chemical_list: D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D050091:Dendrimers; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D008727:Methotrexate; D011073:Polyamines; D011956:Receptors, Cell Surface; D000097573:Red Fluorescent Protein; C104700:PAMAM Starburst