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1. WO2015138992 - MITOCHONDRIAL DELIVERY OF 3-BROMOPYRUVATE

Publication Number WO/2015/138992
Publication Date 17.09.2015
International Application No. PCT/US2015/020591
International Filing Date 13.03.2015
IPC
A61K 31/66 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
66Phosphorus compounds
CPC
A61K 31/19
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
19Carboxylic acids, e.g. valproic acid
A61K 31/194
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
19Carboxylic acids, e.g. valproic acid
194having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
A61K 31/416
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
41having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
4151,2-Diazoles
416condensed with carbocyclic ring systems, e.g. indazole
A61K 31/7004
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
70Carbohydrates; Sugars; Derivatives thereof
7004Monosaccharides having only carbon, hydrogen and oxygen atoms
A61K 41/0042
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
41Medicinal preparations obtained by treating materials with wave energy or particle radiation ; ; Therapies using these preparations
0042Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
A61K 41/0057
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
41Medicinal preparations obtained by treating materials with wave energy or particle radiation ; ; Therapies using these preparations
0057Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
Applicants
  • UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC. [US]/[US]
Inventors
  • MARRACHE, Sean
  • DHAR, Shanta
Agents
  • CAMPBELL, Keith, M.
Priority Data
61/953,15914.03.2014US
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) MITOCHONDRIAL DELIVERY OF 3-BROMOPYRUVATE
(FR) ADMINISTRATION DE 3-BROMOPYRUVATE DANS LES MITOCHONDRIES
Abstract
(EN)
A mitochondria targeted gold nanoparticle (T-3-BP-AuNP) decorated with 3- bromopyruvate (3 -BP) and delocalized lipophilic triphenylphosphonium (TPP) cations to target the mitochondrial membrane potential (Δψm) was developed for delivery of 3 -BP to cancer cell mitochondria by taking advantage of higher Δψm in cancer cell compared to normal cells. This construct showed remarkable anticancer activity in prostate cancer cells compared to non-targeted construct NT-3-BP-AuNP and free 3- BP. Anticancer activity of T-3-BP-AuNP was further enhanced upon laser irradiation by exciting the surface plasmon resonance band of AuNP and thereby utilizing a combination of 3 -BP chemotherapeutic and AuNP photothermal effects. T-3-BP- AuNPs showed markedly enhanced ability to alter cancer cell metabolism by inhibiting glycolysis and demolishing mitochondrial oxidative phosphorylation in prostate cancer cells. Our findings demonstrated that mitochondria targeted and concerted chemo-photothermal treatment of glycolytic cancer cells with a single NP may have promise as a new anticancer therapy.
(FR)
L'invention concerne une nanoparticule d'or ciblant les mitochondries (T-3-BP-AuNP) décorée avec du 3-bromopyruvate (3-BP) et des cations de triphénylphosphonium (TPP) lipophiles délocalisés pour cibler le potentiel de la membrane mitochondriale (Δψm), ladite nanoparticule étant mise au point pour administrer du 3-BP dans les mitochondries de cellules cancéreuses grâce à une valeur de Δψm plus élevée dans une cellule cancéreuse que dans une cellule normale. Ce produit de construction montre une activité anticancéreuse remarquable dans le cancer de la prostate par rapport à une construction non ciblée NT-3-BP-AuNP et 3-BP libre. L'activité anticancéreuse de T-3-BP-AuNP est encore renforcée après irradiation laser en excitant la bande de résonance plasmonique de surface d'AuNP et en utilisant donc une association des effets chimiothérapeutiques de 3-BP et des effets photothermiques d'AuNP. Les T-3-BP-AuNP présentent une capacité remarquablement supérieure à modifier le métabolisme des cellules cancéreuses en inhibant la glycolyse et en démolissant la phosphorylation oxydative mitochondriale dans les cellules du cancer de la prostate. Les données montrent que les mitochondries ciblées et le traitement chimio-photothermique concerté des cellules cancéreuses glycolitiques avec une seule NP unique peuvent être prometteuses en tant que nouveau traitement anticancéreux.
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