METHODS FOR IMAGE-GUIDED RADIOTHERAPY
The disclosure relates to methods for treating tumors. In particular, the disclosure relates to a method of treating a tumor by magnetic resonance image-guided radiation therapy in a subject in need thereof, said method comprising the steps of: (i) administering an efficient amount of high-Z element containing nanoparticles having, contrast enhancement for magnetic resonance imaging and/or radiosensitizing properties for radiation therapy, in a subject in need thereof, and, (ii) exposing said subject to magnetic resonance image-guided radiation therapy by means of a Magnetic Resonance Imaging Guided Linear Accelerator (MR-Linac), wherein said high-Z element containing nanoparticles are nanoparticles containing an element with an atomic Z number higher than 40, preferably higher than 50, and said nanoparticles have a mean hydrodynamic diameter below 20 nm, for example between 1 and 10 nm, preferably between 2 and 8 nm.
1 . A method of treating a tumor in a subject in need thereof, the method comprising
(i) administering an efficient amount of high-Z element containing nanoparticles having contrast enhancement for magnetic resonance imaging and/or radiosensitizing properties for radiation therapy, in a subject in need thereof, and,
(ii) exposing said subject to magnetic resonance image-guided radiation therapy by means of a Magnetic Resonance Imaging Guided Linear Accelerator (MR-Linac),
wherein said high-Z element containing nanoparticles are nanoparticles containing an element with an atomic Z number higher than 40, preferably higher than 50,
wherein said nanoparticles have a mean hydrodynamic diameter 20 nm or less, for example between 1 and 10 nm, preferably between 2 and 8 nm, and
wherein said subject is exposed to 2 or more sessions of magnetic resonance image-guided radiation therapy after a single administration of an efficient amount of said high-Z containing nanoparticles, for example between 2 and 7 sessions.
2 . The method of claim 1 , wherein said MR-Linac is preferably selected among MR-Linac with magnetic strength field of 0.5 T or lower strength field, for example 0.35 T.
3 . The method of claim 1 , wherein said nanoparticles comprise, as high-Z element, a rare earth metal, or a mixture of rare earth metals.
4 . The method of claim 1 , wherein said nanoparticles comprise, as high-Z element, gadolinium, bismuth, or a mixture thereof.
5 . The method of claim 1 , wherein said nanoparticles comprise chelates of high-Z element, for example chelates of rare earth elements.
6 . The method of claim 1 , wherein said nanoparticles comprise
polyorganosiloxane,
chelates covalently bound to said polyorganosiloxane,
high-Z elements complexed by the chelates.
7 . The method of claim 1 , wherein said nanoparticles comprise
polyorganosiloxane with a silicon weight ratio of at least 8% of the total weight of the nanoparticle, preferably between 8% and 50%,
chelates covalently bound to said polyorganosiloxane, in a proportion comprising between 5 and 100, preferably between 5 and 20 per nanoparticle, and,
high-Z elements complexed to the chelates.
8 . The method of claim 1 , wherein said nanoparticles comprise chelates for complexing the high-Z elements, obtained by grafting one or more of the following chelating agents on said nanoparticles: DOTA, DTPA, EDTA, EGTA, BAPTA, NOTA, DOTAGA, and DTPABA, or their mixtures.
9 . The method of claim 1 , wherein said nanoparticles are gadolinium-chelated polysiloxane nanoparticles of the following formula
wherein PS is a matrix of polysiloxane, and,
n is comprised between 5 and 50, preferably 5 and 20, and wherein the hydrodynamic diameter is comprised between 1 and 10 nm, for example between 2 and 8 nm.
10 . The method of claim 1 , wherein said method comprises a first tumor pre-filling step comprising administering an effective amount of high-Z element containing nanoparticles as radiosensitizing agents in said subject in need thereof within a period between 2 and 10 days, preferably 2 and 7 days, prior to the first exposure to radiation therapy.
11 . The method of claim 1 , wherein said subject is exposed to at least one or more additional session of magnetic resonance image-guided radiation therapy, without further administration of a contrast agent for magnetic resonance imaging.
12 . The method of claim 1 , wherein said subject is exposed to 2 or more sessions of magnetic resonance image-guided radiation therapy within 5-7 days, typically with a minimum timeline of 2 or 3 days between each session.
13 . The method of claim 1 , wherein the subject is exposed to a dose of ionizing radiations per session of magnetic resonance image-guided radiation therapy of about 3 Gy to about 20 Gy, and the total dose is administered preferably in a maximum of 10 fractions, for example in 1 to 10 fractions, typically in 4 to 10 fractions.
14 . The method of claim 1 , wherein said tumor is a solid tumor, preferably selected from
(i) primary tumors of uterine cervix, rectum, lung, head and neck, prostate, colorectal, liver, and pancreas cancers and
(ii) bone metastases, typically undergoing intrafraction movements, such as sternal bones.
15 . The method of claim 1 , wherein said nanoparticles are administered as an injectable solution at a concentration between 50 and 150 mg/mL, and preferably between 80 and 120 mg/mL, for example 100 mg/mL, preferably by intravenous injection.
16 . The method of claim 15 , wherein a therapeutically effective amount administered for magnetic resonance image-guided radiation therapy is comprised between 50 mg/kg and 150 mg/kg, typically, between 80 and 120 mg/kg, for example 100 mg/kg.