In Vitro and In Vivo Studies on the Pharmacokinetics and Metabolism of PNA Constructs in Rodents

Kristensen, Edward

doi:10.1385/1-59259-290-2:259

Cited by 9 publications

(4 citation statements)

References 1 publication

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“…As a special class of oligonucleotide analogues, the biological behavior of PNAs has been extensively studied in vitro and in vivo since they were first proposed ( 14 , 28 , 32 , − . In contrast, the utilization of PNAs as imaging probes of cancer for PET and SPECT is very limited, probably because the accumulation of the PNA imaging probes in the tumors could barely reach a detectable level.…”

Section: Discussionmentioning

confidence: 99%

“…It is self-evident that unmodified or minimally modified oligonucleotides should be studied in-depth before they could be applied to the gene transfection or drug delivery systems for various proposes. As a special class of oligonucleotide analogues, the biological behavior of PNAs has been extensively studied in vitro and in vivo since they were first proposed (14,28,32,(64)(65)(66)(67)(68)(69)(70)(71)(72). In contrast, the utilization of PNAs as imaging probes of cancer for PET and SPECT is very limited, probably because the accumulation of the PNA imaging probes in the tumors could barely reach a detectable level.…”

Section: Discussionmentioning

confidence: 99%

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MicroPET Imaging of MCF-7 Tumors in Mice via unr mRNA-Targeted Peptide Nucleic Acids

Sun

Fang

et al. 2005

Bioconjugate Chem.

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As more becomes known about the expression profiles of normal and cancerous cells, it should become possible to design antisense-based imaging agents for the early detection of cancer noninvasively. In this report, we rationally designed and synthesized three antisense and one sense hybrid PNA (peptide nucleic acid) to the unr mRNA that is highly overexpressed in a breast cancer cell line (MCF-7). The conjugates had a four-lysine tail at the carboxy terminus for cell permeation and a DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) chelating moiety at the amino terminal end for chelating (64)Cu for biodistribution and microPET imaging studies. Biodistribution of two (64)Cu-labeled conjugates with antisense and sense sequences (PNA50 and PNA50S) showed high uptake and long retention in kidney and low uptake and efficient clearance in blood and muscle in normal balb/c mice when administered intravenously or intraperitoneally. Intraperitoneal administration, however, gave a much slower release rate. MCF-7 tumors (100-320 mg) in CB-17 SCID mice were imaged with all four (64)Cu-labeled PNA conjugates by microPET, but the image contrast varied with different time points and different conjugates. Of the conjugates studied, (64)Cu-DOTA-Y-PNA50-K4 showed the best tumor image quality at all time points with a tumor/muscle ratio of 6.6 +/- 1.1 at 24 h postinjection, which is among the highest reported for radiolabeled oligonucleotides. Our work further strengthens the potential of antigene and antisense PNAs to be utilized as specific molecular probes for early detection of cancer and ultimately for patient specific radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MicroPET Imaging of MCF-7 Tumors in Mice via unr mRNA-Targeted Peptide Nucleic Acids

Sun

Fang

et al. 2005

Bioconjugate Chem.

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“…In one in vivo analysis, metabolites of PNA ODN were not detected in mice plasma and urine samples for up to 6 h [136]. Incubation of PNA in human serum and with nucleases and proteases did not result in significant degradation [120].…”

Section: Stabilitymentioning

confidence: 93%

Radiolabelled Oligonucleotides for Imaging of Gene Expression with PET

Lendvai¹,

Estrada²,

Bergström³

2009

CMC

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Our understanding of altered patterns of gene expression being responsible for many diseases has been growing thanks to modern molecular biological methods. Today, these changes can only be identified when tissue samples are available. Therefore, a noninvasive method allowing us to monitor gene expression in vivo would be valuable, not only as a research tool, but also for patient stratification before treatment and for treatment follow-up. Antisense oligonucleotides (ODN) have been considered to be suitable molecules to trace active genes in vivo, as well as to treat diseases by hybridising to its complementary messenger RNA (mRNA) sequence in the cells thereby preventing the synthesis of the peptide. However, the use of ODNs in the organisms are endangered by many hurdles such as physical barriers to pass and enzyme attack to be avoided. Positron emission tomography (PET) provides a most advanced in vivo imaging technology that allows the exploration of the fate of radionuclide-labelled antisense ODNs in the body; thereby providing information about biodistribution and quantitative accumulation in tissues to assess pharmacokinetic properties of ODNs. This kind of evaluation is important as part of the characterisation of antisense therapeutics but also as part of the development of antisense imaging agents. This review provides a general summary about the antisense concept and displays the present status of the antisense imaging field with the major achievements and remaining challenges on the long journey towards accomplishing in vivo monitoring of gene expression using PET.

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“…Previous studies evaluated key pharmacokinetic parameters in vivo to explore the use of PNA (Kristensen, 2000;Jansen and Richelson, 2000;McMahon et al, 2002a,b) or vector-mediated PNA (Pardridge et al, 1995;Shi et al, 2000;Lee et al, 2002;Paroo and Corey, 2003) as an antisense reagent. We believed that this issue should be further investigated and expanded, with the aim of determining the pharmacokinetics of PNAE-NLS in SCID mice where the growth of BL-derived human tumor can be xenotransplanted.…”

Section: Introductionmentioning

confidence: 99%

Therapeutically Promising PNA Complementary to a Regulatory Sequence for c-myc:Pharmacokinetics in an Animal Model of Human Burkitt's Lymphoma

et al. 2005

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In Burkitt's lymphoma (BL) cells c-myc is often translocated in proximity to the Emu enhancer of the Ig gene locus. This translocation causes c-myc hyperexpression and an increase in the cells' proliferative capacity. A peptide nucleic acid (PNA) complementary to enhancer Emu intronic sequence (PNAEmu), linked to a nuclear localization signal (NLS), selectively and specifically blocks the expression of the c-myc oncogene under Emu control in vitro, suggesting potential therapeutic use. To explore this issue further, we have determined the pharmacokinetics of (14)C-labeled PNAEmu in SCID mice where a human tumor is established by inoculation of cells from a BL cell line. The data demonstrate that the compound has a relatively long life in vivo in tissues and, in particular, in BL tumor mass. Furthermore, in this animal model, PNAEmu shows low or no toxicity. All these results are in favor of a successful preclinical application in a BL human tumor animal model of a PNA targeting a regulatory, nontranscribed DNA sequence that can selectively inhibit the hyperexpression of a translocated gene linked to neoplastic cell expansion.

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In Vitro and In Vivo Studies on the Pharmacokinetics and Metabolism of PNA Constructs in Rodents

Cited by 9 publications

References 1 publication

MicroPET Imaging of MCF-7 Tumors in Mice via unr mRNA-Targeted Peptide Nucleic Acids

MicroPET Imaging of MCF-7 Tumors in Mice via unr mRNA-Targeted Peptide Nucleic Acids

Radiolabelled Oligonucleotides for Imaging of Gene Expression with PET

Therapeutically Promising PNA Complementary to a Regulatory Sequence for c-myc:Pharmacokinetics in an Animal Model of Human Burkitt's Lymphoma

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