METHOD FOR TREATING TUMOURS BY CAPTURING COPPER AND/OR IRON
The present disclosure relates to nanoparticles and the uses thereof in medicine, in particular for the treatment of tumours.
1 . A nanoparticle of the following formula:
[Ch1] n —PS—[Ch2] m ,
wherein:
PS is an organic or inorganic polymer matrix,
Ch1 is a chelating group which is uncomplexed or is complexed with a metal cation M1,
M1 is absent, or selected from metal cations for which the constant for complex formation with Ch1 is less than that of copper,
Ch2 is a chelating group, identical to or different from the chelating group Ch1, and complexed with a metal cation M2 having a high atomic number Z, greater than 40
wherein,
(i) the chelating agents Ch1 and Ch2 are grafted to the polymer matrix,
(ii) the n/(n+m) ratio is between 10% and 100%, and
(iii) the mean hydrodynamic diameter of the nanoparticle is between 1 and 50 nm.
2 . The nanoparticle as claimed in claim 1 , wherein at least 50% of the Ch1 is complexed with zinc, calcium or magnesium.
3 . The nanoparticle as claimed in claim 1 , wherein the chelating group Ch1, and where appropriate Ch2, is selected from macrocyclic agents.
4 . The nanoparticle as claimed in claim 1 , wherein the metal cation M2 is selected from radiosensitizers and/or magnetic resonance imaging contrast agents.
5 . The nanoparticle as claimed in claim 1 , wherein
(i) PS is a polysiloxane matrix,
(ii) Ch1 and Ch2 are DOTAGA chelating groups of the following formula (I)
and grafted to the polysiloxane matrix by Si—C bonding,
(iii) M1 is absent, and M2 is the gadolinium cation Gd 3+ ,
(iv) n+m is between 5 and 50, and
(iv) the mean hydrodynamic diameter is between 2 and 8 nm.
6 . A colloidal solution of nanoparticles, wherein the colloidal solution of nanoparticles comprises the nanoparticle as claimed in claim 1 .
7 . A pharmaceutical compositiong, wherein the pharmaceutical composition comprises a colloidal solution of nanoparticles comprising the nanoparticle as claimed in claim 1 and wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
8 . The pharmaceutical composition as claimed in claim 7 , wherein the pharmaceutical composition is an injectable composition for intravenous, intratumoral or intrapulmonary administration in a subject.
9 . A method for treatment of cancer in a subject, in particular for the in vivo capture of copper and/or iron in a tumor, wherein the method comprises administering the pharmaceutical composition as claimed in claim 7 .
10 . The method as claimed in claim 9 , wherein the subject is treated by radiotherapy after administering said pharmaceutical composition comprising an effective amount of metal cation M2, preferably gadolinium, for use as a radiosensitizer.
11 . The nanoparticle as claimed in claim 1 , wherein M1 is selected from metal cations for which the constant for complex formation with Ch1 is at least ten times less than that of copper.
12 . The nanoparticle as claimed in claim 1 , wherein M1 is selected from zinc or alkaline-earth metals.
13 . The nanoparticle as claimed in claim 1 , wherein M1 is calcium or magnesium.
14 . The nanoparticle as claimed in claim 1 , wherein M2 has an atomic number Z greater than 50.
15 . The nanoparticle as claimed in claim 1 , wherein the mean hydrodynamic diameter of the nanoparticle is between 2 and 20 nm.
16 . The nanoparticle as claimed in claim 1 , wherein the mean hydrodynamic diameter of the nanoparticle is between 2 and 8 nm.
17 . The nanoparticle as claimed in claim 1 , wherein the chelating group Ch1, and where appropriate Ch2, is selected from 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1-glutaric-4,7-diacetic acid (NODAGA), 1,4,7,10-tetraazacyclododecane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), 2,2′,2″, 2″′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide (DOTAM), 1,4,8,11-tetraazacyclotetradecane (Cyclam), 1,4,7,10-tetraazacyclododecane (Cyclen), and deferoxamine (DFO).
18 . The nanoparticle as claimed in claim 1 , wherein the metal cation M2 is gadolinium or bismuth.
19 . The nanoparticle as claimed in claim 5 , wherein n+m is between 10 and 30.
20 . The pharmaceutical composition as claimed in claim 8 , wherein the pharmaceutical composition comprises an effective amount of chelating group Ch1 for the in vivo capture of copper in a tumor, for example wherein the free chelator is at a concentration of at least 10 mM in the composition.