Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer.
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.
Kukowska-Latallo
Jolanta F
JF
University of Michigan Center for Biologic Nanotechnology, Ann Arbor, Michigan, USA.
Candido
Kimberly A
KA
Cao
Zhengyi
Z
Nigavekar
Shraddha S
SS
Majoros
Istvan J
IJ
Thomas
Thommey P
TP
Balogh
Lajos P
LP
Khan
Mohamed K
MK
Baker
James R
JR
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism; D050091:Dendrimers; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D007624:KB Cells; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D049329:Nanostructures; D011073:Polyamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D050091:Dendrimers; D004337:Drug Carriers; D005456:Fluorescent Dyes; D058973:Folate Receptors, GPI-Anchored; C104700:PAMAM Starburst; D011073:Polyamines; D019275:Radiopharmaceuticals; D011956:Receptors, Cell Surface; D014316:Tritium; D008727:Methotrexate