Design of (Gd-DO3A)n-polydiamidopropanoyl-peptide nucleic acid-D(Cys-Ser-Lys-Cys) magnetic resonance contrast agents

We hypothesized that chelating Gd(III) to 1,4,7‐tris(carboxymethylaza)cyclododecane‐10‐azaacetylamide (DO3A) on peptide nucleic acid (PNA) hybridization probes would provide a magnetic resonance genetic imaging agent capable of hybridization to a specific mRNA. Because of the low sensitivity of Gd(I...

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Published in:Biopolymers 2008-12, Vol.89 (12), p.1061-1076
Main Authors: Amirkhanov, Nariman V., Dimitrov, Ivan, Opitz, Armin W., Zhang, Kaijun, Lackey, John P., Cardi, Christopher A., Lai, Song, Wagner, Norman J., Thakur, Mathew L., Wickstrom, Eric
Format: Article
Language:English
Subjects:
Anthracenes - chemistry
Base Sequence
Chelating Agents - chemistry
chelator
Computer Simulation
Cysteine
dendrimer
Gadolinium - chemistry
Gadolinium DTPA - chemistry
hybridization
Lysine
Magnetic Resonance Imaging - methods
Models, Molecular
Molecular Conformation
molecular imaging
noninvasive
Oligonucleotides - chemistry
Oligopeptides - chemistry
oncogene
Peptide Nucleic Acids - chemistry
receptor
Serine
solid phase synthesis
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Summary:We hypothesized that chelating Gd(III) to 1,4,7‐tris(carboxymethylaza)cyclododecane‐10‐azaacetylamide (DO3A) on peptide nucleic acid (PNA) hybridization probes would provide a magnetic resonance genetic imaging agent capable of hybridization to a specific mRNA. Because of the low sensitivity of Gd(III) as an magnetic resonance imaging (MRI) contrast agent, a single Gd‐DO3A complex per PNA hybridization agent could not provide enough contrast for detection of cancer gene mRNAs, even at thousands of mRNA copies per cell. To increase the Gd(III) shift intensity of MRI genetic imaging agents, we extended a novel DO3An‐polydiamidopropanoyl (PDAPm) dendrimer, up to n = 16, from the N‐terminus of KRAS PNA hybridization agents by solid phase synthesis. A C‐terminal D(Cys‐Ser‐Lys‐Cys) cyclized peptide analog of insulin‐like growth factor 1 (IGF1) was included to enable receptor‐mediated cellular uptake. Molecular dynamic simulation of the (Gd‐DO3A‐AEEA)16‐PDAP4‐AEEA2‐KRAS PNA‐AEEA‐D(Cys‐Ser‐Lys‐Cys) genetic imaging nanoparticles in explicit water yielded a pair correlation function similar to that of PAMAM dendrimers, and a predicted structure in which the PDAP dendron did not sequester the PNA. Thermal melting measurements indicated that the size of the PDAP dendron included in the (DO3A‐AEEA)n‐PDAPm‐AEEA2‐KRAS PNA‐AEEA‐D(Cys‐Ser‐Lys‐Cys) probes (up to 16 Gd(III) cations per PNA) did not depress the melting temperatures (Tm) of the complementary PNA/RNA hybrid duplexes. The Gd(III) dendrimer PNA genetic imaging agents in phantom solutions displayed significantly greater T1 relaxivity per probe (r1 = 30.64 ± 2.68 mM−1 s−1 for n = 2, r1 = 153.84 ± 11.28 mM−1 s−1 for n = 8) than Gd‐DTPA (r1 = 10.35 ± 0.37 mM−1 s−1), but less than that of (Gd‐DO3A)32‐PAMAM dendrimer (r1 = 771.84 ± 20.48 mM−1 s−1) (P < 0.05). Higher generations of PDAP dendrimers with 32 or more Gd‐DO3A residues attached to PNA‐D(Cys‐Ser‐Lys‐Cys) genetic imaging agents might provide greater contrast for more sensitive detection. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 1061–1076, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
ISSN:0006-3525
1097-0282
DOI:10.1002/bip.21059