Abstract
Prior studies suggested that nanoparticle drug delivery might improve the therapeutic response to anticancer drugs and allow the simultaneous monitoring of drug uptake by tumors. We employed modified PAMAM dendritic polymers <5 nm in diameter as carriers. Acetylated dendrimers were conjugated to folic acid as a targeting agent and then coupled to either methotrexate or tritium and either fluorescein or 6-carboxytetramethylrhodamine. These conjugates were injected i.v. into immunodeficient mice bearing human KB tumors that overexpress the folic acid receptor. In contrast to nontargeted polymer, folate-conjugated nanoparticles concentrated in the tumor and liver tissue over 4 days after administration. The tumor tissue localization of the folate-targeted polymer could be attenuated by prior i.v. injection of free folic acid. Confocal microscopy confirmed the internalization of the drug conjugates into the tumor cells. Targeting methotrexate increased its antitumor activity and markedly decreased its toxicity, allowing therapeutic responses not possible with a free drug.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / pharmacokinetics
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Carrier Proteins / metabolism
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Dendrimers
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Disease Models, Animal
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Drug Carriers / administration & dosage*
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Drug Carriers / pharmacokinetics
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Female
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Fluorescent Dyes / administration & dosage*
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Fluorescent Dyes / pharmacokinetics
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Folate Receptors, GPI-Anchored
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Humans
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KB Cells
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Methotrexate / administration & dosage*
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Methotrexate / pharmacokinetics
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Mice
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Mice, Nude
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Mice, SCID
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Nanostructures*
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Polyamines / administration & dosage*
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Polyamines / pharmacokinetics
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Radiopharmaceuticals / administration & dosage*
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Radiopharmaceuticals / pharmacokinetics
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Receptors, Cell Surface / metabolism
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Tissue Distribution
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Tritium / pharmacokinetics
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Carrier Proteins
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Dendrimers
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Drug Carriers
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Fluorescent Dyes
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Folate Receptors, GPI-Anchored
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PAMAM Starburst
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Polyamines
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Radiopharmaceuticals
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Receptors, Cell Surface
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Tritium
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Methotrexate