EL-AWADY MAHMOUD EL-SHAHAT (EG)
EL-AWADY MAHMOUD EL-SHAHAT (EG)
| WO2006102307A2 | 2006-09-28 | |||
| WO2009120702A2 | 2009-10-01 | |||
| WO2011156296A1 | 2011-12-15 |
| US20110105825A1 | 2011-05-05 |
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YUHONG REN ET AL: "Overcoming Multidrug Resistance in Human Carcinoma Cells by an Antisense Oligodeoxynucleotide-Doxorubicin Conjugate in Vitro and in Vivo", MOLECULAR PHARMACEUTICS, vol. 5, no. 4, 1 August 2008 (2008-08-01), pages 579 - 587, XP055035223, ISSN: 1543-8384, DOI: 10.1021/mp800001j
| CLAIMS 1. TARGETING CYCLIN Bl mRNA WITH MAGNETIC NANOP ARTICLES, RELATES TO A THERAPEUTIC STRATEGY THAT AIMS TO FIGHT CANCER BY SELECTIVE DISPOSITION OF MAGNETIC NANOP ARTICLES INSIDE CANCER CELLS AND SUBSEQUENT MAGNETIC FIELD HYPERTHERMIA. 2. CHANGING TARGET MENTIONED IN CLAIM 1, MAKE THE STRATEGY SUITABLE FOR MANY OTHER DISEASES, LIKE TARGRTING MESSENGER RNA OF VIRAL OR MICROBIAL PROTEINS. 3. MODIFIED APTAMERS THAT COULD PERFORM STRATEGY DESCRIBED IN CLAIMS 1 AND 2, ENABLE TARGETING OF PROTEIN PRODUCT WHICH IS MORE STABLE THAN MESSENGER RNA. 4. USING TARGET SPECIFIC PEPTIDE OR PEPTIDOMIMICS THAT COULD BE LIPIDATED INSIDE CELL, COULD PERFORM STRATEGY MENTIONED IN CLAIMS 1 AND 2. 5. THE DIRECT USE OF A LIPIDATED LIGAND LIKE ANTISENSE RNA, SMALL INTERFERING RNA, APTAMERS, PEPTIDES, PEPTIDOMIMICS OR ANY OTHER LIGAND INSTEAD OF LIPIDATION INDIDE CELL, COULD PERFORM STRATEGY DESCRIBED IN CLAIMS 1 AND 2. 6. REPLACING MAGNETIC NANOP ARTICLES MENTIONED IN CLAIMS 1 AND 2 BY A DRUG, PRODRUG OR IMAGING AGENT, COULD INCREASE EFFECIENCY OR ENABLE OTHER USES. |
NANOP ARTICLES TECHNICAL FIELD
THIS INVENTION COULD BE APPLIED IN MEDICINE AS IT AIMS TO FIGHT CANCER BY MAGNETIC FIELD HYPERTHERMIA.
BACKGROUND ART THE INVENTION RELATES TO A THERAPEUTIC STRATEGY IN WHICH A TRAP IS BUILT FOR SELECTIVE DESPOSITION OF MAGNETIC NANOP ARTICLES INSIDE CANCER CELLS. THIS TRAP IS ACHIEVED BY USING ONE OR MORE MODIFIED ANTISENSE RNA STRAND (SPECIFIC FOR CYCLIN Bl MESSENGER RNA) THAT IS ABLE TO BE LIPIDATED INSIDE CELLS. THIS LIPIDATION INSURES ASSOCIATION OF THE ANTISENSE STRAND TO CELLULAR MEMBRANES. THE ABILITY OF ANTISENSE STRAND TO BE LIPIDATED THANKS TO A 3' END MODIFICATION WITH A TETRAPEPTIDE DERIVED FROM THE C-TERMINUS OF MEMBRANE ANCHORED PROTEINS (CAAX MOTIF). THIS PEPTIDE IS RECOGNIZED BY CERTAIN ENZYMES THAT ADDS A LIPID RESIDUE TO THE CYSTEINE AMINO ACID. SO, CYCLIN Bl MESSENGER RNA COULD BE KEPT IN ASSOCIATION WITH CELLULAR MEMBRANES AFTER COMPLEXING WITH THE MODIFIED ANTISENSE RNA STRAND. AFTER ADMINISTRATION OF MAGNETIC NANOP ARTICLES THAT IS FUNCTIONALIZED WITH AN ANTISENSE RNA STRND SPECIFIC FOR ANOTHER REGION OF THE TARGETED MESSENGER RNA COULD RESULT IN THE SELECTIVE FIXATION OF THESE NANOP ARTICLES INSIDE CELLS CONTAINING THE PREVIOUSLY FIXED MESSENGER RNA.
THERMAL ABLATION COULD BE ACHIEVED AFTER EXPOSURING MAGNETIC NANOP ARTICLES TO AN ALTERNATIVE MAGNETIC FIELD. IN ADDITION, THE ANTISENSE STRANDS DOWNREGULATE CYCLIN B l WHICH IS ESSENTIAL KEY FOR CELL DIVISION RESULTING IN GROWTH ARREST. ALSO, ALTERNATION IN CELL MORPHOLOGY AND EXPRESSION OF HEAT SHOCK PROTEINS COULD RESULT IN RECOGNITION BY IMMUNE SYSTEM.
MAGNETIC NANOP ARTICLES COULD BE ALSO USED AS IMAGING AGENT TO DETERMINE LOCALIZATION OF METASTIZED TUMORS TO BE EXPOSED TO THE MAGNETIC FIELD.
DICLOSURE OF THE INVENTION
IN CANCER CELLS, PRESENCE OF CYCLIN Bl MESSENGER RNA ENSURES TRAPPING OF MAGNETIC NANOP ARTICLES INSIDE IT. MAGNETIC NANOP ARTICLES WILL BE ALSO DEPOSITED INSIDE NORMAL DIVIDIND CELLS ALSO. TO PROTECT THESE CELLS, IT COULD BE PREVENTED FROM EXPOSURE TO THE MAGNETIC FIELD. SO, MAGNETIC NANOP ARTICLES ARE KEPT INACTIVE INSIDE THESE CELLS. IN NORMAL RESTING CELLS, THERE IS NO CYCLIN B l . CONSEQUENTLY, MAGNETIC NANOP ARTICLES AND ANTSENSE RNA STRANDS WILL BE ELEMINATED.
ADVANTAGES
1. THE INVENTED STRATEGY ENHANCES TARGET SELECTION AND REDUCE TOXICITY BY TARETING CYCLIN B 1 WHICH IS A MITOTIC MARKER.
2. FIGHTING CANCER FROM THREE AXES:
a. GROWTH ARREST BY DOWN REGLATING CYCLIN B 1. b. THERMAL ABLATION BY MAGNETIC NANOP ARTICLES, c. IMMUNE ATTACK BY RECOGNIZING HEAT SHOCK
PROTEINS ON SURFACE ON SURFACE OF CANCER
CELLS.
3. ALL COMPONENTS ARE BIODEGRADABLE.
4. NO NEED FOR SURGERY.
5. NO NEED FOR LONG TERM EXPOSURE.
6. COULD BE USED FOR ALL TYPES OF CANCER. 7. COULD BE USED AT ANY GRADE AND ANY STAGE.
BREIF DESCRIPTION OF DRAWINGS
FIGURE (1) SHOWS THE INVENTED STRATEGY IN ITS COMPLETE FORM, PRESENCE OF TARGET (CYCLIN B l
MESSENGER RNA) RESULTS IN THE INDIRECT ASSOCIATION OF MAGNETIC NANOP ARTICLES WITH PLASMA MEMBRANE, a, LIPID RESIDUE; b, CYCLIN Bl MESSENGER RNA; c, AN
ANTISENSE RNA STRAND; d, MAGNETIC NANOP ARTICLES ; e, LINKER BETWEEN MAGNETIC NANOP ARTICLES AND AN ANTISENSE RNA STRAND; f , LINKER BETWEEN THE ANTISENSE RNA STRAND AND A LIPID RESIDUE; g, CELL MEMBRANE.
FIGURE (2) SHOWS INABILITY OF MAGNETIC
NANOP ARTICLES TO BE FIXED INSIDE THE CELL IN THE ABSENSE OF TARGET (CYCLIN Bl MESSENGER RNA). a, AN ANTISENSE RNA STRAND; b, MAGNETIC NANOP ARTICLES; c, LINKER BETWEEN MAGNETIC NANOP ARTICLES AND AN ANTISENSE RNA STRAND; d, LINKER BETWEEN THE
ANTISENSE RNA STRAND AND A LIPID RESIDUE; e: LIPID
RESIDUE; f: CELL MEMBRANE.
MODES FOR CARRYING OUT THE INVENTION
TARGETED MESSENGER RNA COULD CONTAIN ONE OR MORE GENETIC MUTATION THAT CHANGES ITS SEQUENCE. TO SOLVE THIS PROBLEM, MULTISEQUENCES OF ANTISENSE RNA (SPECIFIC FOR DIFFERENT REGIONS OF TARGETED MESSENGER RNA) COULD BE SYNTHESIZED AND FUNCTIONALIZED INTO TWO GROUPS; ONE GROUP FOR ANCHORING IN CELLULAR MEMBRANES AND THE OTHER GROUP TO BE LINKED TO MAGNETIC NANOP ARTICLES.
TO FIX THE PROBLEM OF RNA INSTABILITY, PROTEIN PRODUCT COULD BE TARGETED BY AN APTAMER THAT IS MODIFIED FOR BOTH PERFORMING THE DESCRIBED STRATEGY AND RESISITING THE ACTION OF NUCLEASES.
ANY SPECIFIC LIGAND (APTAMER, PEPTIDE, ANTISENSE RNA OR SMALL INTERFERING RNA) FOR A GIVEN TARGET COULD BE USED BY MODIFYING IT DIRECTLY WITH A LIPID RESIDUE BUT IT MAY NOT INSURE THE DESIRED ORIENTATION (i.e. ANCHORING IN THE OUTER SURFACE OF CELL INSTEAD OF THE INNER ONE) SO, MODIFYING THE LIGAND WITH A CAAX PEPTIDE RESULT IN THE ADDITION OF THE LIPID RESIDUE INTERACELLULARLY AND IN TURN ANCHORING INSIDE CELL CHANGING TARGET ENABLES THIS STRATEGY TO BE
APPLIED FOR MANY OTHER DISEASES LIKE VIRAL DISEASES THAT COULD ESCAPE IMMUNE DETECTION (e.g. HIV, HCV,... etc.) ANY CELL CONTAIN ONE OF THESE VIRUSES COULD BE TARGETED BY USING THE DESCRIBED METHOD OR BY REPLACING MAGNETIC NANOP ARTICLES BY ANY OTHER PRODRUG.
INDUSTRIAL APPLICABILITY
SUCH INVENTION COULD BE USED IN PRODUCING A THERAPEUTIC OR IMAGING AGNET FOR CANCER. ALSO, IT COULD BE APPLIED FOR MANY VIRAL DISEASES BY CHANGING THE TARGET FROM CYCLIN B l MESSENGER RNA TO OTHER RNA ENCODED BY THOSE VIRUSES .