# US 9,517,272 B2 · Temperature dependent activation of catalytic nucleic acids for controlled active substance release > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,517,272 B2 - Document ID: US9517272B2 - Status: Granted - Kind: B2 - Application number: 13/515,173 - Filed: 2010-12-16 - Published: 2013-04-25 - Granted: 2016-12-13 - Earliest claimed: 2009-12-16 - Assignees: Magforce AG - Applicants: Jiang Gao; Monika Fischler; Volker A. Erdmann - Inventors: Jiang Gao; Monika Fischler; Volker A. Erdmann - Web page: https://patentgrep.com/patent/US9517272B2 ## CPC - A61K 47/556: {enzyme catalyzed therapeutic agent [ECTA]} - A61K 9/0009: {involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis} - A61K 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)} - A61K 9/513: {Organic macromolecular compounds; Dendrimers} - A61K 41/0028: {Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds} - A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids} - A61K 47/6923: {the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb} - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics - A61P 31/04: Antibacterial agents - A61P 35/00: Antineoplastic agents - A61P 37/02: Immunomodulators - A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to an active substance release system containing two compounds. The first compound comprises a nanoparticle, combined with an oligonucleotide inhibition strand that is hybridized with a catalytically active nucleic acid. The second compound comprises a carrier, combined with a substrate molecule that is coupled to a therapeutic active substance. By means of external stimulation, the catalytically active nucleic acid of the first compound is released and specifically binds to the substrate molecule of the second compound. This leads to cleavage of the substrate molecule, whereby the active substance bound thereto is released. ## Claims ### Claim 1 An active substance release system, containing i) a Compound 1, containing at least one nanoparticle bonded to an oligonucleotide inhibitor strand, wherein said oligonucleotide inhibitor strand is hybridized with a catalytically active nucleic acid which upon dehybridization and release is catalytically active for specifically cleaving a substrate molecule in a Compound 2 which is also part of the active substance release system, and ii) the Compound 2, containing a carrier bonded to at least one substrate molecule which is specifically cleaved by the catalytically active nucleic acid from Compound 1, wherein the substrate molecule is bonded to at least one therapeutically active substance, wherein the therapeutically active substance can be released by the specific cleavage of the substrate molecule, with the substrate molecules being specifically cleaved by the catalytically active nucleic acid. ### Claim 2 (depends on 1) The active substance release system as claimed in claim 1, wherein the oligonucleotide inhibitor strand is covalently bonded to the nanoparticle. ### Claim 3 (depends on 1) The active substance release system as claimed in claim 1, wherein the catalytically active nucleic acid and the oligonucleotide inhibitor strand are selected from the group consisting of RNA, DNA, L-RNA, L-DNA, and a modified nucleic acid. ### Claim 4 (depends on 2) The active substance release system as claimed in claim 2, wherein the oligonucleotide inhibitor strand is covalently bonded via a Linker 1 to the nanoparticle; wherein Linker 1 is formed on the 5′-terminal of the oligonucleotide inhibitor strand. ### Claim 5 (depends on 1) The active substance release system as claimed in claim 1, wherein in Compound 1, the ratio of the oligonucleotide inhibitor strands to the catalytically active nucleic acid is ≧1. ### Claim 6 (depends on 3) The active substance release system as claimed in claim 3, wherein in Compound 1, the ratio of the oligonucleotide inhibitor strands to the catalytically active nucleic acid is 1.0 to 1.3. ### Claim 7 (depends on 1) The active substance release system as claimed in claim 1, wherein the catalytically active nucleic acid is completely hybridized with the oligonucleotide inhibitor strand under physiological conditions, and in which at 43° C., at least one catalytically active nucleic acid is dehybridized. ### Claim 8 (depends on 1) The active substance release system as claimed in claim 1, wherein the nanoparticle possesses a core containing at least a paramagnetic or superparamagnetic iron oxide. ### Claim 9 (depends on 8) The active substance release system as claimed in claim 8, wherein the therapeutically active substance is released by cleavage of the substrate molecule, with the substrate molecules being cleaved by the catalytically active nucleic acid, when the paramagnetic or superparamagnetic nanoparticles are heated in an alternating magnetic field. ### Claim 10 (depends on 1) The active substance release system as claimed in claim 1, wherein the nanoparticle has at least one covering. ### Claim 11 (depends on 1) The active substance release system as claimed in claim 1, wherein the substrate molecule is an oligonucleotide. ### Claim 12 (depends on 1) The active substance release system as claimed in claim 1, wherein the carrier is a polymer, an SiO2 particle, or a metallic particle, which is present in the form of a gel, microparticles, microspheres, or nanoparticles. ### Claim 13 (depends on 1) The active substance release system as claimed in claim 1, wherein the substrate molecule is bonded covalently. ### Claim 14 (depends on 11) The active substance release system as claimed in claim 11, wherein the substrate molecule oligonucleotide is selected from the group consisting of DNA, RNA, L-DNA, L-RNA, and a modified nucleic acid. ### Claim 15 (depends on 14) The active substance release system as claimed in claim 14, wherein the substrate molecule oligonucleotide has a length of 10 to 100 nucleotides. ### Claim 16 (depends on 1) The active substance release system as claimed in claim 1, wherein the therapeutically active substance is selected from the group consisting of nucleic acids, siRNAs, antisense RNAs, amino acids, aptamers, peptides, proteins, glycoproteins, carbohydrates, glycans, lipids, and lipoproteins. ### Claim 17 (depends on 1) The active substance release system as claimed in claim 1, wherein the therapeutically active substance is covalently bonded to the substrate molecule. ### Claim 18 (depends on 17) The active substance release system as claimed in claim 17, wherein the therapeutically active substance is covalently bonded to the substrate molecule via a Linker 3, wherein Linker 3 is selected from the group consisting of an amino group and hydrazone. ### Claim 19 (depends on 17) The active substance release system as claimed in claim 17, wherein the therapeutically active substance is inactive as long as it is bonded to the substrate molecule, and it is activated when the therapeutically active substance is released from the substrate molecule, or after subsequent intake into a cell. ### Claim 20 (depends on 1) The active substance release system as claimed in claim 1, wherein the catalytically active nucleic acid can cleave the substrate molecule, provided that the catalytically active nucleic acid is dissociated from the oligonucleotide inhibitor strand, wherein the following applies in the cleavage reaction of the substrate molecules via the catalytically active nucleic acid: the concentration of the substrate molecules is ≧KM. ### Claim 21 (depends on 1) The active substance release system as claimed in claim 1, wherein the ratio of Compound 1 to Compound 2 is ≦2. ### Claim 22 (depends on 11) The active substance release system as claimed in claim 11, wherein the oligonucleotide inhibitor strand, the catalytically active nucleic acid, and the substrate oligonucleotide are all mirror-image nucleic acids. ### Claim 23 (depends on 1) A medicine containing an active substance release system as claimed in claim 1. ### Claim 24 (depends on 1) A medicine containing an active substance release system as claimed in claim 1 for the treatment and/or prevention of proliferative diseases, cancer, inflammatory diseases, autoimmune diseases, and bacterial infections. ### Claim 25 (depends on 24) The medicine as claimed in claim 24, wherein Compounds 1 and 2 are adapted in the release system to be administered to the patient simultaneously or sequentially. ### Claim 26 (depends on 24) The medicine as claimed in claim 24, wherein Compounds 1 and 2 are adapted in the release system to be placed in the tumor bed when a tumor is removed. ### Claim 27 (depends on 1) A process for the release of an active substance from Compound 2 as claimed in claim 1, comprising the following steps: i) placement of Compound 1 as described in claim 1 in the vicinity of Compound 2 under conditions that allow diffusion of the released, catalytically active nucleic acid to the substrate oligonucleotide, as well as cleavage thereof, and (ii) active or passive heating of Compound 1 so that the catalytically active nucleic acid is released. ### Claim 28 (depends on 1) The active substance release system as claimed in claim 1, wherein the therapeutically active substance is a substance having an antiproliferative, cytostatic, cytotoxic, antimigrative, anti-angiogenic, antithrombotic, anti-inflammatory, anti-phlogistic, anticoagulant, antibacterial, antiviral and/or antimycotic action. ### Claim 29 (depends on 20) The active substance release system as claimed in claim 20, wherein kcat is ≧0.05min. ### Claim 30 (depends on 1) The active substance release system as claimed in claim 1, wherein the therapeutically active substance is a low-molecular-weight therapeutically active substance.