Synthesis and functional evaluation of DNA-assembled polyamidoamine dendrimer clusters for cancer cell-specific targeting.
We sought to produce dendrimers conjugated to different biofunctional moieties (fluorescein [FITC] and folic acid [FA]), and then link them together using complementary DNA oligonucleotides to produce clustered molecules that target cancer cells that overexpress the high-affinity folate receptor. Amine-terminated, generation 5 polyamidoamine (G5 PAMAM) dendrimers are first partially acetylated and then conjugated with FITC or FA, followed by the covalent attachment of complementary, 5'-phosphate-modified 34-base-long oligonucleotides. Hybridization of these oligonucleotide conjugates led to the self-assembly of the FITC- and FA-conjugated dendrimers. In vitro studies of the DNA-linked dendrimer clusters indicated specific binding to KB cells expressing the folate receptor. Confocal microscopy also showed the internalization of the dendrimer cluster. These results demonstrate the ability to design and produce supramolecular arrays of dendrimers using oligonucleotide bridges. This will also allow for further development of DNA-linked dendrimer clusters as imaging agents and therapeutics.
Choi
Youngseon
Y
Department of Biomedical Engineering, School of Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
Thomas
Thommey
T
Kotlyar
Alina
A
Islam
Mohammad T
MT
Baker
James R
JR
D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000737:chemistry* / Q000493:pharmacokinetics; D015195:Drug Design; D005069:Evaluation Studies as Topic; D019793:Fluorescein / Q000737:chemistry / Q000493:pharmacokinetics; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D008970:Molecular Weight; D009841:Oligonucleotides / Q000737:chemistry / Q000493:pharmacokinetics; D010710:Phosphates / Q000737:chemistry; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013499:Surface Properties
D002352:Carrier Proteins; D018076:DNA, Complementary; D058973:Folate Receptors, GPI-Anchored; D009841:Oligonucleotides; D010710:Phosphates; D011073:Polyamines; D011956:Receptors, Cell Surface; D005492:Folic Acid; D019793:Fluorescein