Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1999-06-03
2001-09-04
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001730, C424S001110, C424S001650, C424S001690, C435S006120, C435S007100, C435S320100, C435S005000, C530S350000, C530S224000, C530S307000, C534S010000, C534S014000, C534S015000, C534S551000, C514S455000, C514S016700, C514S017400, C514S018700, C514S012200, C514S04400A, C536S023100, C536S024500, C549S280000
Reexamination Certificate
active
06284220
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is chemistry, molecular biology, gene therapy, radiology and medical imaging.
BACKGROUND OF THE INVENTION
Many diseases and disorders result from a genetic defect. In gene transfer therapy (often called simply “gene therapy”), an exogenous gene is introduced into somatic cells (as opposed to germ line cells) of an animal or human to substitute for, or compensate for, a defective gene.
Various methods for delivering exogenous genes into somatic cells of mammalian tissues have been developed. Examples of gene delivery methods include: injection of naked plasmid DNA (Wolff et al., 1990,
Science
247:1465-68), cationic liposome-mediated DNA transfer (Felgner et al., 1989
Nature
337:387-388), retroviral vectors (Boris-Lawrie et al., 1994,
Ann. NY Acad. Sci.
176:59-71), adenoviral vectors (Curiel, 1994,
Ann. NY Acad. Sci.
176:36-58); microprojectiles, electroporation, and receptor-targeted co-transport of DNA and magnetic resonance contrast agents (Kayyem et al., 1995,
Chemistry & Biology
2:615-620).
Regardless of the gene transfer method used, it is generally desirable for the researcher or clinician to be able to determine, noninvasively, where in the body the transferred gene went, and in what amount. Such information has been difficult to obtain. There is a need for methods of imaging the biodistribution of circular, double-stranded DNA by radioactivity or magnetic resonance.
SUMMARY OF THE INVENTION
DNA-imaging compositions and methods have been developed for noninvasive imaging of nucleic acid vectors, e.g., double-stranded, circular DNA vectors introduced into somatic tissues of an animal or human. The noninvasive imaging enables quantitative assessment of the biodistribution of the introduced nucleic acid.
The invention features a nucleic acid imaging compound that includes a base-binding moiety, a phosphate-binding moiety, and a metal-binding moiety. In some embodiments, the base-binding moiety intercalates between adjacent bases in double-stranded DNA. In some embodiments, the base-binding moiety forms a covalent bond with a base, e.g., upon irradiation with UV light.
Examples of base-binding moieties include psoralen, 8-methoxypsoralen, daunomycin, hycanthone, ethidium, methidium, acridine, acridine yellow, proflavin and propapyrroleindole. A preferred base-binding moiety is psoralen. Preferably, the phosphate-binding moiety bears a net positive charge, at physiological pH. Preferably, the phosphate-binding moiety contains one to six amino groups. Preferred types of phosphate-binding moieties are polyamines, polyimines and cationic polypeptides. Spermine is an example of a suitable polyamine. Pentalysine is an example of a suitable cationic polypeptide. Preferably, the metal-binding moiety forms a complex, e.g., a coordination complex or an ionic complex, with a metal or metal oxide. Examples of suitable metals and metal oxides are:
99m
Tc(V)O
3+
,
99m
Tc(IV)O
2+
, 111In
3+
, Ga
2+
, Re, Fe
3+
, Gd
3+
, D
3+
, Mn
2+
, and lanthanides. Examples of metal binding moieties include: mercaptoacetyl-triglycyl; N-acetyl-glycyl-cysteinyl(S-acetamidomethyl)-glycyl-cysteinyl(S-acetamidomethyl)-glycyl; and glycyl-cysteinyl(S-acetamidomethyl)-glycyl; and glycyl-cysteinyl(S-acetamidomethyl)-glycyl-cysteinyl(S-acetamido-methyl)-glycyl.
In an exemplary embodiment of the invention, the base-binding moiety is psoralen, the phosphate-binding moiety is spermine, and the metal-binding moiety is mercaptoacetyltriglycine. In another exemplary embodiment, the base binding moiety is psoralen, the phosphate-binding moiety is spermine, and the metal-binding moiety is N-acetyl-glycyl-cysteinyl(S-acetamidomethyl)-glycyl-cysteinyl(S-acetamidomethyl)-glycine. In another exemplary embodiment, the base intercalation moiety is psoralen, the phosphate-binding moiety is pentalysine, and the metal-binding moiety is glycyl-cysteinyl(S-acetamidomethyl)-glycyl-cysteinyl(S-acetamidomethyl)-glycine.
The invention also features a nucleic acid imaging composition, which includes a nucleic acid; and an imaging compound, as described above. In the nucleic acid imaging composition, the nucleic acid can be single-stranded or double-stranded, and it can be linear or circular.
The invention also features a method for non-invasive imaging of a nucleic acid. The method includes the following steps: providing a nucleic acid; providing an imaging compound (described above); combining the nucleic acid and the imaging compound to form a nucleic acid-imaging composition; combining the nucleic acid-imaging composition with a metal or metal oxide detectable by a noninvasive detector, thereby forming a labeled imaging composition; introducing the labeled imaging composition into a tissue; and imaging the nucleic acid with the noninvasive detector. The the nucleic acid can be single-stranded or a double-stranded, and it can be linear or circular. In some embodiments, the method includes the step of covalently binding the imaging compound to the nucleic acid, e.g., by irradiation with UV light. The detector may detect radioactivity or nuclear magnetic resonance, depending on whether the metal is paramagnetic or radioactive. The cell can be in an in vivo tissue, e.g., a somatic tissue in a mammal or human.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present application, including definitions will control. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference.
Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the detailed description, and from the claims.
REFERENCES:
patent: 5356929 (1994-10-01), Heindel et al.
patent: 5473083 (1995-12-01), Heindel et al.
patent: 5714328 (1998-02-01), Magda et al.
patent: 187332 (1986-07-01), None
Boris-Lawrie et al., “The Retroviral Vector”, Ann. NY Acad. Sci., 716:59-71, 1994.
Curiel; “High-Efficiency Gene Transfer Mediated by Adenovirus-Polylysine-DNA Complexes”, Ann. NY Acad. Sci. 716:36-58, 1994.
de Marco et al., “MR Imaging of Gene Delivery to the Central Nervous System With an Artificial Vector,” Radiology, 208:65-71, Jul. 1998.
Dervan, Peter B., “Design of Sequence-Specific DNA-Binding Molecules”, Science, 232:464-471, Apr. 25, 1986.
Felgner et al., “Cationic Liposome-Mediated DNA Transfection”, Nature, 337:387-388, 1989.
Kayyem et al., “Receptor Targeted Co-Transport of DNA and Magnetic Resonance Contrast Agents,” Chemistry & Biology, 2:615-620, 1995.
Mallinckrodt Technical Product Data sheet for Technescan® Gluceptate Kit (undated).
Palmer et al., “Instrumentation and Radiopharmaceuticals”, in Practical Nuclear Medicine, W.B. Saunders Co., Philadephia, p. 27-69, 1992.
Schellingerhout et al., “Mapping the In Vivo Distribution of Herpes Simplex Virions”, Human Gene Therapy, 9:1543-1549, Jul. 20, 1998.
Wiebe et al., “Radiopharmaceuticals to Monitor Gene Transfer”, Nuclear Medicine, 41:79-89, 1997.
Wolff et al., “Injection of Naked Plasmid DNA”, Science, 247:1465-68, 1990.
Bogdanov Alexei
Tung Ching-Hsuan
Weissleder Ralph
Carlson Karen Cochrane
Fish & Richardson P.C.
Robinson Hope A.
The General Hospital Corporation
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