# US 11,998,615 B2 · Functionalized nanoparticles and their use in treating bacterial infections > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,998,615 B2 - Document ID: US11998615B2 - Status: Granted - Kind: B2 - Application number: 17/719,727 - Filed: 2022-04-13 - Published: 2022-10-27 - Granted: 2024-06-04 - Earliest claimed: 2021-04-14 - Assignees: The Board of Trustees of the Leland Stanford Junior University - Applicants: The Board of Trustees of the Leland Stanford Junior University - Inventors: Peter Luke Santa Maria; Laurent Bekale - Web page: https://patentgrep.com/patent/US11998615B2 ## CPC - A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle} - A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol - A61K 47/6923: {the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb} - A61P 31/04: Antibacterial agents - 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 Compositions, methods, and kits are provided for treating bacterial infections with nanoparticles comprising a thiol-binding metallic core conjugated to a fluoroquinolone antibiotic. Recalcitrant infections are often difficult to treat because of the presence of persister cells, a subpopulation of bacterial cells that is highly tolerant of traditional antibiotics. Persister cells are dormant, which makes them less susceptible to many antibiotics, which are designed to kill growing cells. Administration of nanoparticles comprising a thiol-binding metallic core conjugated to fluoroquinolone antibiotics was found to be highly efficacious in eradicating persister cells and for treating infections for a broad range of bacterial species, including Gram-positive and Gram-negative bacteria. Such treatment was effective not only in eradicating planktonic bacteria but also bacteria in biofilms. ## Claims ### Claim 1 A method of treating an infection in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a nanoparticle comprising a thiol-binding metallic core conjugated to a fluoroquinolone antibiotic, wherein the diameter of the nanoparticle is in a range from about 1 nm to about 5 nm. ### Claim 2 (depends on 1) The method of claim 1, further comprising administering a therapeutically effective amount of at least one antibiotic in combination with the composition. ### Claim 3 (depends on 1) The method of claim 1, wherein the subject has a chronic infection. ### Claim 4 (depends on 3) The method of claim 3, wherein the infection is an ear infection, a cutaneous infection, a lung infection, a catheter-associated urinary tract infection, or a gastrointestinal infection. ### Claim 5 (depends on 1) The method of claim 1, wherein the subject has chronic suppurative otitis media (CSOM), cystic fibrosis, or tuberculosis. ### Claim 6 (depends on 1) The method of claim 1, wherein the composition is administered intravenously, subcutaneously, by inhalation, or topically. ### Claim 7 (depends on 1) The method of claim 1, wherein the infection is an ear infection, and the composition is administered locally into the ear canal. ### Claim 8 A method of eradicating bacteria in a biofilm or dormant bacteria comprising persister cells, the method comprising contacting the biofilm or the dormant bacteria with an effective amount of a nanoparticle comprising a thiol-binding metallic core conjugated to a fluoroquinolone antibiotic, wherein the diameter of the nanoparticle is in a range from about 1 nm to about 5 nm. ### Claim 9 (depends on 8) The method of claim 8, wherein the biofilm is on a medical device, a personal hygiene article, toiletry, cosmetic, disinfectant, cleaning solution, or in a water treatment or distribution system. ### Claim 10 (depends on 1) The method of claim 1, wherein the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, ofloxacin, moxifloxacin, gemifloxacin, levofloxacin, and finafloxacin. ### Claim 11 (depends on 10) The method of claim 10, wherein the thiol-binding metallic core is conjugated to 47 ciprofloxacin molecules. ### Claim 12 (depends on 10) The method of claim 10, wherein the ciprofloxacin is conjugated to the thiol-binding metallic core through a bond between an amino group of the ciprofloxacin and a metal atom of the metallic core. ### Claim 13 (depends on 1) The method of claim 1, wherein the thiol-binding metallic core comprises one or more of gold, silver, nickel, copper, aluminum, or cobalt, or an oxide, carbide, nitride, or alloy thereof. ### Claim 14 (depends on 1) The method of claim 1, wherein the metallic core has a diameter of about 4 nm. ### Claim 15 (depends on 1) The method of claim 1, wherein the nanoparticle further comprises a cell penetrating peptide, an anionic moiety, or a polyethylene glycol (PEG) polymer attached to the outer surface of the nanoparticle. ### Claim 16 (depends on 15) The method of claim 15, wherein the anionic moiety comprises a carboxylate functional group, a phosphate functional group, or a sulfate functional group. ### Claim 17 (depends on 15) The method of claim 15, wherein the PEG polymer is functionalized with the anionic moiety. ### Claim 18 (depends on 1) The method of claim 1, wherein the nanoparticle further comprises an antimicrobial agent having bactericidal activity against persister cells or bacteria residing in biofilms, wherein the antimicrobial agent is attached to the outer surface of the nanoparticle. ### Claim 19 (depends on 18) The method of claim 18, wherein the antimicrobial agent is a D-carbohydrate, a D-amino acid, or a nucleic acid comprising a CrcZ RNA sequence or a CrcZ A-rich motif sequence. ### Claim 20 (depends on 1) The method of claim 1, wherein the nanoparticle further comprises a nucleotide, wherein the nucleotide is conjugated to the thiol-binding metallic core. ### Claim 21 (depends on 20) The method of claim 20, wherein the nucleotide is adenosine triphosphate (ATP), adenosine monophosphate (AMP), adenosine diphosphate (ADP), or a phosphorothioate analog, deoxyribonucleotide analog, a 7-deaza purine nucleotide analog, or a phosphomethylphosphonic acid adenylate ester thereof. ### Claim 22 (depends on 1) The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable excipient or carrier. ### Claim 23 A method of eradicating intra-macrophage bacteria in a subject, the method comprising administering to the subject a therapeutically effective of a nanoparticle comprising a thiol-binding metallic core conjugated to a fluoroquinolone antibiotic, wherein the diameter of the nanoparticle is in a range from about 1 nm to about 5 nm.