Nanovectors and uses

Patent metadata

Field	Value
Publication number	US-11857604-B2
Application number	US-201816755866-A
Country	US
Kind code	B2
Filing date	Oct 12, 2018
Priority date	Oct 13, 2017
Publication date	Jan 2, 2024
Grant date	Jan 2, 2024

Abstract

The present invention relates to the field of nanovectors for the delivery of active substances in the body, in particular for the treatment of tumours. In particular, the use of these nanovectors makes it possible to improve the pharmacokinetics of the active substances with a more selective delivery, for example in the tumour tissues.

First claim

The invention claimed is:

1. A nanovector for the delivery of an active substance in a human being, wherein said nanovector comprises a nanoparticle on the surface of which the active substance is bonded by physisorption, said nanoparticle is a polysiloxane-based nanoparticle with a mean diameter of less than 10 nm, the active substance is chosen from organic molecules which have a molar mass of between 2% and 40% of the total molar mass of said nanoparticle, and said nanoparticle comprises:
a. polysiloxanes, with a weight ratio of silicon of at least 8% of the total weight of the nanoparticle,
b. a chelating agent grafted onto the nanoparticle, wherein the chelating agent which is grafted onto the nanoparticle is selected from DOTA, DTPA, EDTA, EGTA, BAPTA, NOTA, DOTAGA and DTPABA or a mixture thereof, and
c. optionally, a metal element, said metal element being complexed to the chelating agent.

2. The nanovector according to claim 1 , wherein the load content, expressed in milligrams of active substance per gram of nanovector, is greater than 0.5 mg/g.

3. The nanovector according to claim 1 , wherein the nanoparticle is of formula (I) below:
Si n [O] m [OH] o [Ch 1 ] a [Ch 2 ] b [Ch 3 ] c [M y+ ] d [D z+ ] e [Gf] f   (I)

in which:
n is between 20 and 5000,
m is greater than n and less than 4 n,
o is between 0 and 2 n,
Ch 1 , Ch 2 and Ch 3 are chelating agents, which may be identical or different, bonded to the Si atoms of the polysiloxanes by an Si—C covalent bond; a, b and c are integers between 0 and n and a+b+c is less than or equal to n,
M y+ and D z+ are metal cations, which may be identical to or different from one another, with y and z=1 to 6; d and e are integers between 0 and a+b+c, and d+e is less than or equal to a+b+c,
Gf is a targeting graft, which may be identical to or different from one another, each bonded to the Si by an Si—C bond and resulting from the grafting of a targeting molecule allowing the targeting of the nanoparticle to biological tissues of interest, and f is an integer between 0 and n.

4. The nanovector according to claim 1 , wherein the nanovector comprises a metal element chosen from elements with a high atomic number Z.

5. The nanovector according to claim 1 , wherein said nanoparticle is a polysiloxane-based nanoparticle with a mean diameter of between 1 and 5 nm, comprising gadolinium complexed to the chelating agent obtained by grafting of DOTAGA onto the nanoparticle.

6. The nanovector according to claim 1 , wherein the active substance is chosen from small organic molecules having a molar mass of less than 5000.

7. The nanovector according to claim 1 , wherein said nanoparticle comprises a targeting agent covalently grafted to the polysiloxanes and allowing active targeting of biological zones of interest.

8. The nanovector according to claim 1 , wherein said active substance is chosen from anti-cancer substances.

9. The nanovector according to claim 8 , wherein said anti-cancer substance is chosen from the following substances: actinomycin, all-trans retinoic acid, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabin, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, tioguanine, topotecan, valrubicin, vemurafenib, vinblastine, vincristine, vindesine, lenalidomide, ibrutinib, abiraterone, erlotinib, everolimus, nilotinib, sunitinib, sorafenib, goserelin, nedaplatin, laboplatin, TATE peptide and heptaplatin, or a mixture thereof.

10. The nanovector according to claim 1 , wherein the nanoparticle comprises a chelate of an element with an atomic number greater than 40, having a radiosensitizing effect.

11. The nanovector according to claim 1 , wherein the nanoparticle comprises a metal element chelate, said metal element being chosen for use in imaging by magnetic resonance imaging, scans or scintigraphy.

12. The nanovector according to claim 1 wherein said nanoparticle comprises:
a. polysiloxanes, with a weight ratio of silicon between 8% and 50% of the total weight of the nanoparticle,
b. the chelating agent in a proportion of between 5 and 100 per nanoparticle, and
c. optionally, the metal element in a proportion of between 5 and 100 per nanoparticle, said metal element being complexed to the chelating agent.

13. The nanovector according to claim 1 , wherein the load content, expressed in milligrams of active substance per gram of nanovector, is between 1 mg/g and 100 mg/g.

14. The nanovector according to claim 1 , wherein the nanovector comprises a metal element chosen from elements with a high atomic number Z chosen from gadolinium, bismuth or a mixture thereof.

15. The nanovector according to claim 3 , wherein the nanovector comprises a metal element chosen from elements with a high atomic number Z chosen from gadolinium, bismuth or a mixture thereof.

16. An injectable pharmaceutical solution comprising a nanovector according to claim 1 , and at least one pharmaceutically acceptable excipient.

17. The injectable pharmaceutical solution according to claim 16 , wherein the nanovector comprises an element with a high atomic number Z greater than 40, and wherein said high-Z element is at a concentration between 10 and 200 mM in said solution.

18. The injectable pharmaceutical solution according to claim 16 , wherein the active substance of the nanovector is chosen from doxorubicin, cisplatin and the TATE peptide.

19. The injectable pharmaceutical solution according to claim 16 , wherein the injectable pharmaceutical solution is directly obtained by means of a method for preparing a nanovector for the delivery of an active substance in a human being, said method comprising mixing two solutions that can be administered in a human being:
a. a first solution comprising a nanoparticle, said nanoparticle being a polysiloxane-based nanoparticle having a mean diameter of less than 10 nm, and
b. a second solution comprising an active substance or a mixture of active substances chosen from organic molecules,

under concentration ratio, pH and temperature conditions which allow an interaction by physisorption of the active substance or mixture of active substances at the surface of said nanoparticle.

20. A method for preparing a nanovector according to claim 1 , said method comprising mixing two solutions:
a. a first solution comprising a nanoparticle, said nanoparticle being a polysiloxane-based nanoparticle having a mean diameter of less than 10 nm, wherein said nanoparticle comprises polysiloxanes with a weight ratio of silicon of at least 8% of the total weight of the nanoparticle and a chelating agent grafted onto the nanoparticle, wherein the chelating agent which is grafted onto the nanoparticle is selected from DOTA, DTPA, EDTA, EGTA, BAPTA, NOTA, DOTAGA and DTPABA or a mixture thereof, and
b. a second solution comprising an active substance chosen from organic molecules having a molecular weight of between 2% and 40% of the molecular weight of said nanoparticle, under concentration ratio, pH and temperature conditions which allow an interaction by physisorption of the active substance at the surface of said nanoparticle.

21. The method according to claim 20 , wherein the [active substance in the second solution]:[nanoparticle in the fir

Assignees

• Nh Theraguix
• Univ Claude Bernard Lyon
• Centre National De La Rech Scientifique—Cnrs—

Inventors

• Tillement Olivier
• Lux François
• Rossetti Fabien
• Tran Vu-Long
• Mathieu Clélia
• Dahan Myleva

Classifications

• A61K38/31 Primary

  Somatostatins · CPC title

• A61K9/146

  with organic macromolecular compounds · CPC title

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · CPC title

• A61K33/243

  Platinum; Compounds thereof · CPC title

• A61K33/244

  Lanthanides; Compounds thereof (medicinal preparations containing radioactive lanthanides for use in therapy or testing in vivo A61K51/00) · CPC title