Methods and compositions for detection of bacteria and treatment of diseases and disorders
Described herein are methods for detecting a bacteria in a subject and methods for detecting, imaging or diagnosing a site, disease, disorder or condition in a subject using bacteria. The methods can be used in conjunction with methods for treating a disease, disorder or condition. Such sites, diseases and disorders include sites of cellular proliferation, such as tumors, tumor tissues, metastases, areas of inflammation, immunoprivileged sites or tissues, wounds and infections. Further described are bacteria for use in the methods and compositions, combinations and kits, including diagnostic and pharmaceutical compositions, containing a bacterium. Bacteria described herein include those that bind, sequester or accumulate radiolabeled compounds by expression of an endogenous gene product that binds to the radiolabeled compound. Additional imaging and therapeutic agents and methods also are described.
1. A method for detecting or imaging a site of proliferation in a subject, comprising:
(a) administering an Escherichia coli Nissle strain bacterium that expresses its endogenous thymidine kinase, and a radiolabeled nucleoside analog compound to a subject; and
(b) after a sufficient time for the Nissle bacterium to accumulate in proliferating tissues and the radiolabeled nucleoside compound to be phosphorylated by the endogenous thymidine kinase to result in accumulation of the resulting radiolabeled nucleotide within the Nissle bacterium, imaging the subject to detect the site of accumulation of the radiolabeled nucleotide in the subject, thereby detecting or imaging the site of proliferation.
2. The method of claim 1 , wherein the bacteria strain is Nissle 1917.
3. The method of claim 1 , wherein the bacterium and the radiolabeled compound are administered to the subject sequentially, simultaneously or intermittently.
4. The method of claim 1 , wherein the bacterium is administered systemically.
5. The method of claim 1 , wherein the bacterium is administered intravenously, intraperitoneally or orally.
6. The method of claim 1 , wherein the radiolabeled compound comprises a radioisotope selected from among 123 I, 124 I, 125 I, 131 I, 18 F, 19 F, 11 C, 13 C, 14 C, 75 Br, 76 Br and 3 H.
7. The method of claim 1 , wherein the nucleoside analog is selected from among 1-(2′deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodouracil (FIAU), 1-(2′deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-ethyluracil (FEAU), 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-methyluracil (FMAU), 3′-deoxy-3′-fluorothymidine (FLT), 9-[4′-fluoro-3′-(hydroxymethyl)butyl]guanine (FHBG) and 9-[(3′-fluoro-1′-hydroxy-2′-propoxy)methyl]guanine (FHPG).
8. The method of claim 1 , wherein the radiolabeled compound is selected from among [ 125 I]-1-(2′deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodouracil ([ 125 I]-FIAU), [ 124 I]-1-(2′deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodouracil ([ 124 I]-FIAU), [ 18 F]-1-(2′detoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodouracil ([ 18 F]-FIAU), [ 18 F]-1-(2′deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-ethyluracil ([ 18 F]-FEAU), [ 18 F]-1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-methyluracil ([ 18 F]-FMAU), [ 18 F]-3′-deoxy-3′-fluorothymidine ([ 18 F]-FLT), [ 18 F]-9-[4′-fluoro-3′-(hydroxymethyl)butyl]guanine ([ 18 F]-FHBG) and [ 18 F]-9-[(3′-fluoro-1′-hydroxy-2′-propoxy)methyl]guanine ([ 18 F]-FHPG).
9. The method of claim 1 , wherein the site of proliferation is selected from among a tumor, tumor tissue, wound, wound tissue, site of inflammation and inflamed tissue.
10. The method of claim 1 , wherein the site of proliferation comprises cancerous tissue.
11. The method of claim 1 , wherein the radiolabeled compound and bacterium are formulated and administered separately.
12. The method of claim 1 , wherein the bacterium and the radiolabeled compound are administered in a single composition.
13. The method of claim 1 , wherein detection of the radiolabeled compound is effected by positron emission tomography, planar gamma imaging or single photon emission computed tomography.
14. The method of claim 10 , wherein the cancerous tissue comprises a solid tumor.
15. The method of claim 1 , further comprising administering an anti-tumor or anti-cancer agent to the subject.
16. The method of claim 15 , wherein the anti-tumor or anti-cancer agent is selected from among a cytokine, a growth factor, a photosensitizing agent, a radionuclide, a toxin, an anti-metabolite, a signaling mothilator, an anti-cancer antibiotic, an anti-cancer antibody, an angiogenesis inhibitor, radiation therapy and a chemotherapeutic compound.
17. The method of claim 1 , wherein the bacterium encodes a product for therapy of a tumor, tumor tissue, wound, wounded tissue, site of inflammation or inflamed tissue.
18. The method of claim 17 , wherein the therapeutic product is selected from among a cell-surface receptor, a cytokine, a chemokine, an apoptotic protein, an antimitotic oligopeptide, a toxin, a tumor antigen, a prodrug converting enzyme and an RNA.