Combination therapy of nanoparticles and radiopharmaceuticals

Abstract

The present invention relates to a nanoparticle comprising a high atomic number element for use in a method of treating a tumor by radiopharmaceutical therapy in a subject in need thereof; the method comprises the step of jointly administering an effective amount of the nanoparticles containing the high atomic number elements and an effective amount of the therapeutic radiopharmaceutical containing the radionuclide, wherein the effective amount of the nanoparticles containing the high atomic number elements and the effective amount of the therapeutic radiopharmaceutical containing the radionuclide are combined; wherein the nanoparticles containing high atomic number elements comprise elements with atomic numbers greater than 40, preferably greater than 50; and wherein the nanoparticles have an average hydrodynamic diameter of 20 nm or less, for example between 1 nm and 10 nm, preferably between 2 nm and 8 nm.

Description

Background Art

[0001] The principle of radiotherapy is to induce irreparable DNA damage in tumor cells, which in turn leads to cell death. Half of cancer patients receive conventional external radiotherapy (X-RT), i.e., irradiating the tumor from outside the body. This method is suitable for treating local tumors or oligometastases, but usually cannot be used for the treatment of diffuse or metastatic diseases due to unacceptable irradiation of healthy tissues. With the recent approval of several compounds by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), radiopharmaceutical therapy (also known as targeted radionuclide therapy, TRT) has become a safe and effective systemic treatment for irradiating all tumor sites (Sgouros et al., 2020).

[0002] In targeted radionuclide therapy (TRT), radiolabeled cancer-binding molecules (such as antibodies, peptides) are injected into the patient's body. After circulating in the blood, they can recognize, bind to, and locally irradiate tumor cells. TRT can use β-particles, or powerful α-particles or Auger electron emitters (AEEs). Like the X-rays used in X-RT, β-particles are low linear energy transfer (LET) particles that produce "simple DNA damage", such as single-strand breaks and double-strand breaks (SSBs, DSBs) or base damage (e.g., thymidine glycol). In contrast, α-particles and to a lesser extent Auger electron emitters are high linear energy transfer (LET) particles that produce irreparable complex or clustered DNA damage, making them an attractive option for overcoming radioresistance. Different from X-RT, the irradiation of TRT is continuous and carried out at a low dose and low dose rate, thus reducing the side effects on the bone marrow and circulating blood cells. For these reasons, the radiobiology of X-RT cannot be directly extrapolated to TRT (Pouget et al., 2011; Pouget et al., 2021).

[0003] Ovarian cancer (OC) is the most lethal gynecological malignancy today and the eighth most common cause of cancer-related death in women globally. From a histological perspective, 90% of ovarian cancers originate from the malignant transformation of epithelial cells. In this context, the most aggressive form of ovarian cancer comes from the fallopian tube epithelium and is called high-grade serous ovarian cancer (HGSOC). In most cases, the disease progresses without clinical signs or symptoms, and when it spreads to the peritoneal cavity in the form of peritoneal carcinomatosis (PC), it leads to a late diagnosis (stage III / IV). The treatment of peritoneal carcinomatosis (PC) includes cytoreductive surgery aimed at removing visible lesions, followed by intraperitoneal adjuvant platinum-based chemotherapy. Although many women respond to this treatment method, 70%-90% of cases still experience disease recurrence, and the recurrence is still limited to the peritoneal cavity.

[0004] In the 1980s, Sugarbaker proposed combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for treating residual disease in some patients with peritoneal cancer (Sugarbaker, 2009). Hyperthermic intraperitoneal chemotherapy has improved the survival rate of patients with primary recurrent disease and is now used as first- or second-line treatment. However, because its morbidity is one of the major drawbacks of hyperthermic intraperitoneal chemotherapy, it is not recommended in non-clinical trials (Goodman et al., 2016). Therefore, there is an urgent need to inhibit residual disease as it is the cause of patient relapse. For such metastatic and diffuse diseases, conventional radiotherapy cannot be applied due to the high risk of damage to surrounding healthy tissues. The strategy of targeted radionuclide therapy (TRT) using radioactively labeled antibodies specific to tumor nodules has brought new treatment opportunities for treating high-grade serous ovarian cancer (HGSOC) (Pouget et al., 2015).

[0005] Multiple studies in rodents have shown that radioimmunotherapy (RIT) is an effective adjuvant treatment after cytoreductive surgery for peritoneal cancer cells (Koppe et al., 2005; Aarts et al., 2007; Aarts et al., 2008; Müller et al., 2012; Seidl et al., 2011; Milenic et al., 2004; Andersson et al., 2003; Elgqvist et al., 2005). Several antibodies (against mucin 1 (MUC1), cancer antigen 125 (CA-125), tumor-associated glycoprotein 72 (TAG72), and glycoprotein 38 (gp38)) have been conjugated with four β-emitting radionuclides for intraperitoneal radioimmunotherapy in ovarian cancer patients (Pouget et al., 2011). Based on previous encouraging results (Meredith et al., 2007; Alvarez et al., 2002; Epenetos et al., 2002; Hird et al., 1993), a phase III randomized multicenter study was conducted (Verheijen et al., 2006) in which the efficacy of conventional chemotherapy was compared with that of intraperitoneal injection of yttrium-90-labeled murine monoclonal antibody HMGF1 (anti-MUC1). However, although peritoneal recurrence was significantly delayed, no improvement in survival was observed after radioimmunotherapy (RIT).

[0006] Although the strategy of targeted radionuclide therapy (TRT) is promising, the therapeutic index still needs to be improved. In particular, adverse side effects on healthy tissues (such as bone marrow) limit dose escalation. This need is more prominent in cases where tumors (such as ovarian cancer) are radioresistant.

[0007] Accordingly, there is still a need to overcome the deficiencies of the prior art and to provide improved treatment regimens based on targeted radionuclide therapy (TRT).

[0008] Part of the present disclosure follows from the inventors' unexpected discovery that nanoparticles according to the present disclosure, when used in combination with a therapeutic radiopharmaceutical compound in a treatment regimen of targeted radionuclide therapy (TRT), result in increased efficacy of the targeted radionuclide therapy (TRT). Surprisingly, this combination therapy enables tumor co-localization of the nanoparticles and the therapeutic radiopharmaceutical compound sufficient to enhance the efficacy of the therapeutic radiopharmaceutical compound.

[0009] Accordingly, such nanoparticles can be used in combination with a therapeutic radiopharmaceutical to increase the effectiveness of targeted radiotherapy or to maintain its efficacy while reducing the dose of the therapeutic radiopharmaceutical to be administered. SUMMARY OF THE INVENTION

[0010] Accordingly, an embodiment E1 of the present disclosure relates to the use of a nanoparticle containing a high atomic number element in a method for treating a tumor in a subject in need thereof by radiopharmaceutical therapy; the method comprising co-administering an effective amount of the nanoparticle containing a high atomic number element and an effective amount of a therapeutic radiopharmaceutical containing a radionuclide; wherein the nanoparticle containing a high atomic number element contains an element having an atomic number greater than 40, preferably greater than 50; and wherein the nanoparticle has an average hydrodynamic diameter of 20 nm or less, such as between 1 nm and 10 nm, preferably between 2 nm and 8 nm.

[0011] An embodiment E2 of the present disclosure relates to the nanoparticle for use in the method according to embodiment E1, wherein the nanoparticle enhances the therapeutic effect of the radiopharmaceutical.

[0012] An embodiment E3 of the present disclosure relates to the nanoparticle for use according to any one of embodiments E1 or E2, wherein the high atomic number element is selected from heavy metals, more preferably from Au, Ag, Pt, Pd, Sn, Ta, Zr, Tb, Tm, Ce, Dy, Er, Eu, La, Nd, Pr, Lu, Yb, Bi, Hf, Ho, Pm, Sm, In, and Gd, and mixtures thereof.

[0013] An embodiment E4 of the present disclosure relates to the nanoparticle for use according to any one of embodiments E1 to E3, wherein the radionuclide is selected from 177 Lu, 161 Tb, 186 Re, 131 I, 90 Y, 225 Ac / 213 Bi, 223 Ra, 212 Pb / 212 Bi, 227 Th, 211 At, 97 Ru, 103 Pd, 67 Ga, 195m Pt, 193m Pt, 125 I, 111 In, and mixtures thereof.

[0014] Embodiment E5 of the present disclosure relates to nanoparticles for use according to any one of Embodiments E1 to E3, wherein an effective amount of the radiopharmaceutical is between 0.5 MBq and 100 GBq, preferably between 1 MBq and 100 GBq.

[0015] Embodiment E6 of the present disclosure relates to nanoparticles for use according to any one of Embodiments E1 to E4, wherein the radionuclide is linked to a cancer targeting moiety.

[0016] Embodiment E7 of the present disclosure relates to nanoparticles for use according to Embodiment E5, wherein the cancer targeting moiety is an antibody, a peptide or a small molecule ligand.

[0017] Embodiment E8 of the present disclosure relates to nanoparticles for use according to any one of Embodiments E6 or E7, wherein the cancer targeting moiety is selected from:

[0018] Anti-HER2 antibodies, such as trastuzumab, pertuzumab or ibritumomab tiuxetan (also known as ibritumomab tiuxetan octreotide, sold under the trademark commercially);

[0019] Anti-EGFR antibodies, such as cetuximab or panitumumab;

[0020] Anti-CD20 antibodies, such as rituximab or Zevalin;

[0021] Anti-CD33 antibodies, such as lintuzumab;

[0022] Anti-CD37 antibodies, such as olaratumab (TRU-016), monoclonal antibody 37.1 (BI 836826) or IMGN529 (K7153A-DM1);

[0023] Anti-AMHRII antibodies, such as mulranumab; or

[0024] Anti-TYRP1 / gp75 antibodies, such as IMC-20D7S;

[0025] Somatostatin analogs, such as octreotide (DOTATOC) or octreotide acid (DOTATATE); or

[0026] PSMA small molecule ligands, such as 617 ligand, I&T ligand, R2 ligand or MIP-1095 ligand).

[0027] Embodiment E9 of the present disclosure relates to nanoparticles for use according to any one of Embodiments E1 to E8, wherein the therapeutic radiopharmaceutical is selected from: 177 Lu-anti-HER2 antibody, such as 177 Lu-trastuzumab; 177 Lu-somatostatin analogs, such as 177 Lu-octreotide acid; 177 Lu-PSMA ligand; 90 Y-anti-CD20 antibody, such as 90 Y-rituximab or 90 Y-ibritumomab tiuxetan; 212 Pb-anti-HER2 antibody; 177 Lu-anti-CD37 antibody.

[0028] Embodiment E10 of the present disclosure relates to nanoparticles for use according to any one of Embodiments E1 to E4, wherein the therapeutic radiopharmaceutical consists of 131 I or 223 Ra.

[0029] Embodiment E11 of the present disclosure relates to nanoparticles for use according to any one of Embodiments E1 to E10, wherein the nanoparticles are administered to a subject in a fractionated dose regimen.

[0030] Embodiment E12 of the present disclosure relates to nanoparticles for use according to any one of Embodiments E1 to E11, wherein for a single dose of therapeutic radiopharmaceutical administered to a subject, the fractionated dose regimen of the nanoparticles comprises 2 to 10 fractionated doses of nanoparticles.

[0031] Embodiment E13 of the present disclosure relates to nanoparticles for use according to any one of Embodiments E1 to E12, wherein the subject is a subject who cannot receive a standard effective dose of radiopharmaceutical therapy.

[0032] Embodiment E14 of the present disclosure relates to nanoparticles for use according to any one of Embodiments E1 to E13, wherein the tumor is a radioresistant tumor.

[0033] Embodiment E15 of the present disclosure relates to nanoparticles for use according to any one of embodiments E1 to E14, wherein the tumor is selected from peritoneal tumors, neuroendocrine tumors, prostate tumors, neuroblastomas, meningiomas, lymphomas, Merkel cell carcinomas, breast tumors, renal cell tumors, and salivary gland carcinomas;

[0034] The peritoneal tumors include primary peritoneal tumors and secondary peritoneal tumors;

[0035] The neuroendocrine tumors include gastroenteropancreatic neuroendocrine tumors and pheochromocytomas or paragangliomas (PPGL). BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Shows the fractionated dose regimens tested in Example 1 Regimen 1 (5×4 mg): Mice received a single injection of 4 mg AGuIX in 200 μl of physiological saline for 5 consecutive days. Regimen 2 (10×2 mg): Mice received two injections per day of 2 mg AGuIX in 200 μl of physiological saline (separated by a 6-hour time interval) for 5 consecutive days. Regimen 3 (4×5 mg): Mice received two injections per day of 5 mg AGuIX in 200 μl of physiological saline (separated by a 6-hour time interval) 24 hours and 72 hours after targeted radionuclide therapy (TRT).

[0037] Figure 2 Presents the total tumor mass (mg) of SK-OV-3-luc xenograft tumors 4 weeks after treatment with 10 MBq with or without treatment. The results show that an activity of 10 MBq is very effective for evaluating radiosensitization. TZ: Trastuzumab. 10 MBq: 10 MBq of 177 Lu-trastuzumab.

[0038] Figure 3 Presents the total tumor mass (mg) of SK-OV-3-luc xenograft tumors 4 weeks after treatment with 2.5 MBq or 5 MBq with or without treatment. The results indicate that an activity of 5 MBq of 177 Lu-trastuzumab in combination with 10 mg showed a radiosensitization trend. TZ: Trastuzumab. 2.5 MBq: 2.5 MBq of 177 Lu-trastuzumab. 5 MBq: 5 MBq of 177 Lu-trastuzumab.

[0039] Figure 4Shows the quantitative analysis results of gadolinium (Gd) in tumor nodules, heart, blood, liver and kidney of mice treated with 5 MBq of 177 Lu-trastuzumab and 10 mg of in combination therapy.

[0040] Figure 5 shows the total tumor mass (mg) of SK-OV-3-luc xenograft tumors 4 weeks after treatment with 5 MBq of according to Protocol 1, Protocol 2 or Protocol 3. The results showed a significant difference between targeted radionuclide therapy (TRT) (5 MBq) and Protocol 3 with fractionated administration ( Figure 5A ), and a significant difference in the standard assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST) between 5 MBq and 5 MBq + Protocol 3 ( Figure 5B ).

[0041] Figure 6 shows: A) The clonogenic cell survival rate of SK-OV-3 cells and A431 cells exposed to 177 Lu-trastuzumab at concentrations of 0.5, 1 MBq / mL, 2 MBq / mL and 4 MBq / mL ± 10 mg / mL of . B) The clonogenic cell survival rate of B16F10 cells exposed to 125 I-TA99 at a concentration of 4 MBq / mL ± 1 mg / mL of . C) The clonogenic cell survival rate of MiaPaca2 cells exposed to at concentrations of 0.8 MBq / mL, 2 MBq / mL and 4 MBq / mL ± 1 mg / mL, 5 mg / mL and 10 mg / mL of .

[0042] Figure 7 Shows the 177 biological distribution of Lu-labeled trastuzumab. 3 × 10 6 SK-OV-3-luc cells were xenografted intraperitoneally (IP) into athymic female Swiss nude mice. After 14 days, the mice were injected intraperitoneally with 177 Lu-labeled trastuzumab. Tumors and various organs were collected, weighed, and the radioactivity uptake was measured by gamma counting. For each organ or tumor, the percentage of injected activity per gram of tissue (%IA / g) was plotted.

[0043] Figure 8 Shows the Kaplan-Meier survival curves and the mean tumor absorbed dose of mice with intraperitoneal transplantation of SK-OV-3-luc tumor cells, which received single intraperitoneal injections of sodium chloride, 25 μg of trastuzumab + (2×5 mg per day, 24 and 72 h after trastuzumab injection), 5 MBq of 177 Lu-trastuzumab, or 5 MBq of 177 Lu-trastuzumab + (2×5 mg per day, 24 and 72 h after TRT).

[0044] Figure 9 Shows the clonogenic survival of SK-OV-3-luc, A-431, and OVCAR-3 cells after 18 h of incubation with or without deferiprone (DFP) in the presence or absence of of 177 Lu-trastuzumab (0 - 4 MBq / mL). Results are the mean ± standard deviation (SD) of three independent experiments (performed in triplicate for each experiment); *p < 0.05, **p < 0.01, ***p < 0.001, ns: not significantly different compared to cells treated with 177 Lu-trastuzumab (Mann-Whitney t test). These data suggest that ferroptosis may be associated with the radiosensitizing effect of high atomic number nanoparticles according to the present invention (such as ).

[0045] Figure 10 Shows transmission electron microscopy (TEM) micrographs of SKOV3 cells 48 h after treatment with 1 MBq / mL of 177 Lu-trastuzumab + 10 mg / mL of in the presence of the iron chelator deferiprone (DFP). Cytoplasmic lysis / necrosis-like features are indicated by the arrows.

[0046] The left panel shows the results of targeted radionuclide therapy (TRT) + nanoparticle (NP) therapy 48 h after incubation, and the right panel shows the results of the same therapy in the presence of deferiprone (DFP). In the presence of the iron chelator, cytoplasmic vacuolization (arrows) disappears. Overall, the combination of targeted radionuclide therapy (TRT) + results in significant ultrastructural changes observed by transmission electron microscopy (TEM), characterized by extensive cytoplasmic vacuolization, followed by marked cytoplasmic lysis and the accumulation of autophagosomes and damaged undigested cell components. Iron chelation was shown to increase the survival of cells treated with targeted radionuclide therapy (TRT) + nanoparticles (NP), restore lysosomal integrity, and reverse the ultrastructural changes. Detailed Description of the Invention

[0047] This disclosure is partly based on the unexpected discovery shown by the inventors that certain nanoparticles with radiosensitizing properties co-localize with therapeutic radiopharmaceutical compounds and substantially enhance the efficacy of targeted radionuclide therapy (TRT).

[0048] Without wishing to be bound by any particular theory, it is believed that the beneficial effects of the therapeutic methods of the present disclosure are at least related to the following two characteristics of these nanoparticles:

[0049] (i) They contain high atomic number elements, typically complexes of high atomic number cations with radiosensitizing properties;

[0050] (ii) They have a small average hydrodynamic diameter and are capable of passive targeting of cancer cells.

[0051] In the present disclosure, "passive targeting of cancer cells" and "passive targeting" refer to the phenomenon that the nanoparticles of the present invention, although not functionalized for this purpose (in particular not linked to any cancer targeting moiety), accumulate in tumor tissue.

[0052] Without wishing to be bound by any theory, the inventors believe that the phenomenon of passive targeting of cancer cells by the high atomic number element-containing nanoparticles according to the present invention can be explained at least in part by the enhanced permeability and retention (EPR) effect. The EPR effect refers to the phenomenon that certain molecules, macromolecular compounds or nanoparticles tend to accumulate in tumor tissue. This may be at least partly attributed to the relatively loose endothelial cells of the blood vessels supplying the tumor, which makes circulating substances more diffusible, and / or the fact that the drainage of the tumor is poor.

[0053] The inventors have shown that, surprisingly, the nanoparticles of the present invention, although not functionalized to target specific tissues, reach the tumor tissue only due to passive targeting, resulting in enhanced effects of therapeutic radiopharmaceuticals.

[0054] Without wishing to be bound by any theory, the inventors believe that the efficacy of the combination administration is attributed to the tumor co-localization with the therapeutic radiopharmaceutical compound and the radiosensitization of the therapeutic radiopharmaceutical containing a radionuclide by the high atomic number element-containing nanoparticles, and this radiosensitization is mediated by ferroptosis. This aspect will be described in more detail below.

[0055] In the present disclosure, the term "radiosensitizing" is readily understood by those of ordinary skill in the art and generally refers to the process of increasing the sensitivity of cancer cells to radiotherapy (such as photon radiation, electron radiation, proton radiation, α radiation, heavy ion radiation). The high atomic number elements used herein refer to elements with an atomic number greater than 40, for example greater than 50.

[0056] In certain embodiments, the high atomic number elements are selected from heavy metals, and more preferably, selected from Au, Ag, Pt, Pd, Sn, Ta, Zr, Tb, Tm, Ce, Dy, Er, Eu, La, Nd, Pr, Lu, Yb, Bi, Hf, Ho, Pm, Sm, In, and Gd, and mixtures thereof.

[0057] The high atomic number elements described above are preferably cationic elements, and they are included in the nanoparticles in the form of oxides and / or chalcogenides or halides, or included in the nanoparticles as complexes formed with chelating agents (such as organic chelating agents).

[0058] For example, the size distribution of the above-mentioned nanoparticles can be measured using a commercially available particle size analyzer, such as the Malvern Zetasizer Nano-S particle size analyzer based on PCS (Photon Correlation Spectroscopy).

[0059] For the purposes of the present disclosure, the term "average hydrodynamic diameter" or "average diameter" is intended to represent the harmonic mean of the particle diameters. The method for measuring this parameter is also described in standard ISO 13321:1996.

[0060] Nanoparticles having an average hydrodynamic diameter, for example, less than 20 nm, particularly between 1 nm and 10 nm, even more preferably between 1 nm and 8 nm or, for example, between 2 nm and 8 nm, or typically about 5 nm are suitable for the methods disclosed herein. In particular, they have been shown to provide excellent passive targeting in tumors and rapid renal elimination (and thus lower toxicity) after intravenous injection.

[0061] In one embodiment, the above-mentioned nanoparticles contain more than 10% by weight of high atomic number elements and preferably less than 50% by weight of high atomic number elements, and this percentage is relative to the total weight of the nanoparticles.

[0062] In a specific embodiment, the nanoparticles contain between 10% and 50%, preferably between 10% and 20%, of Gd, for example, about 15% by weight ± 1% of Gd, and this percentage is relative to the total weight of the nanoparticles.

[0063] In one embodiment, the nanoparticles contain at least 50% by weight of gadolinium (Gd), dysprosium (Dy), lutetium (Lu), bismuth (Bi), or holmium (Ho), or mixtures thereof (relative to the total weight of the high atomic number elements in the nanoparticles), for example, at least 50% by weight of the high atomic number elements in the nanoparticles are gadolinium.

[0064] In a particularly preferred embodiment, the nanoparticles used in the methods of the present disclosure are gadolinium-based nanoparticles.

[0065] In certain embodiments, the high atomic number element is a cationic element complexed with an organic chelator, and the organic chelator is selected, for example, from chelators having carboxylic acid, amine, thiol or phosphonic acid groups.

[0066] In preferred embodiments, in addition to the high atomic number element and optionally the chelator, the nanoparticles further comprise a biocompatible coating. Reagents suitable for such biocompatibility include, but are not limited to, biocompatible polymers such as polyethylene glycol, poly(ethylene oxide), polyacrylamide, biopolymers, polysaccharides or polysiloxanes.

[0067] In certain embodiments, the nanoparticles are selected to have a relaxation rate r1 of 10 mM−1·s−1 to 5000 mM−1·s−1 (at 37° C. and 1.4 T) and / or a gadolinium weight ratio of at least 5%, such as between 5% and 30%.

[0068] In one particular embodiment, the nanoparticles having a very small hydrodynamic diameter (e.g., between 1 nm and 10 nm, preferably between 2 nm and 8 nm) are nanoparticles comprising a chelate of a high atomic number element (e.g., a chelate of a rare earth element). In certain embodiments, the nanoparticles comprise a chelate of gadolinium or bismuth.

[0069] In certain embodiments combinable with any of the above embodiments, the high atomic number element-containing nanoparticles comprise:

[0070] Polysiloxane;

[0071] A chelator covalently bound to the polysiloxane;

[0072] A high atomic number element complexed with the chelator.

[0073] As used herein, the term “chelator” refers to one or more chemical moieties capable of complexing one or more metal ions.

[0074] Exemplary chelating agents include, but are not limited to, 1,4,7-triazacyclononane triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1-pentanedioic acid-4,7-diacetic acid (NODAGA), ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), ethylene glycol-0,0′-bis(2-aminoethyl)-N,N,N′,N′-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)ethylenediamine-N,N′-diacetic acid (HBED), triethylenetetraminehexaacetic acid (TTHA), hydroxyethylethylenediaminetriacetic acid (HEDTA), 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N″′-tetraacetic acid (TETA), 1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC), and 1,4,7,10-tetraazacyclododecane-1-(pentanedioic acid)-4,7,10-triacetic acid (DOTAGA), deferoxamine (DFO).

[0075] In a preferred embodiment, the chelating agent is selected from the following substances:

[0076]

[0077] Wherein, the wavy bond represents the bond of the chelating agent to the linking group forming the biocompatible coating of the nanoparticle.

[0078] In a specific embodiment that can be preferably combined with the above embodiments, the rare earth element chelate is a chelate of gadolinium and / or bismuth, preferably a chelate of Gd 3 + and / or Bi 3 + DOTA or DOTAGA.

[0079] In a specific and preferred embodiment, the proportion of the high atomic number element in each nanoparticle, for example, the proportion of the rare earth element (such as gadolinium, optionally chelated with DOTAGA) in each nanoparticle is between 3 and 100, preferably between 5 and 50, for example between 5 and 20, and usually about 10. With such a proportion, the nanoparticle has excellent relaxivity and contrast enhancement characteristics in magnetic resonance (MR) imaging, even when used in conjunction with a magnetic resonance linear accelerator (MR-Linac) with a low magnetic field strength (such as an MR-Linac of 0.35T or 0.5T).

[0080] In certain embodiments, the hybrid nanoparticles are core-shell type. Core-shell nanoparticles are known based on a core consisting of a rare earth oxide and an optionally functionalized polyorganosiloxane matrix (see in particular WO 2005 / 088314, WO2009 / 053644).

[0081] The above nanoparticles can be further functionalized with molecules capable of targeting the nanoparticles to specific tissues. The reagent can be coupled to the nanoparticles by covalent coupling or captured by the nanoparticles by non-covalent binding (e.g., by encapsulation, hydrophilic / hydrophobic interactions or using chelating agents).

[0082] In a particular embodiment, hybrid nanoparticles are used, which comprise:

[0083] A polyorganosiloxane (POS or PS) matrix comprising rare earth cations M n+ (n is an integer between 2 and 4), and the cations are optionally partially present in the form of metal oxides and / or hydroxyoxides, and optionally combined with doping cations D m+ (m is an integer between 2 and 6, and D is preferably a rare earth metal other than M, an actinide element and / or a transition element);

[0084] A chelate covalently bonded to the polyorganosiloxane (POS) via a covalent bond -Si-C-;

[0085] M n+ Cations and, where appropriate, D m+ Cations complexed by the chelate.

[0086] In a preferred embodiment, the above nanoparticles are not functionalized with molecules capable of targeting the nanoparticles to specific tissues (especially tumors).

[0087] In this embodiment, the above nanoparticles reach the tumor only by passive targeting, as follows. In the case of a core-shell structure, the polyorganosiloxane (POS) matrix forms a surface layer around the core based on metal cations. Its thickness can be in the range of 0.5 nm to 10 nm and can account for 25% to 75% of the total volume.

[0088] The POS matrix protects the core against the external medium (especially hydrolysis) and can optimize the performance of the contrast agent (e.g., luminescence performance). It can also enable the functionalization of the nanoparticles by grafting chelating agents and targeting molecules.

[0089] Ultra-fine nanoparticles for the treatment methods of the present disclosure

[0090] In a particularly preferred embodiment, the nanoparticles are gadolinium-chelated polysiloxane nanoparticles having the following general formula.

[0091]

[0092] Wherein, PS is a polysiloxane matrix, and wherein n ranges from 5 to 50, typically from 5 to 20, and wherein the hydrodynamic diameter ranges from 1 nm to 10 nm, such as from 2 nm to 8 nm, and typically about 5 nm.

[0093] More specifically, the gadolinium chelated polysiloxane nanoparticles described by the above general formula are the AGuIX ultrafine nanoparticles described in the next section.

[0094] Such ultrafine nanoparticles that can be used according to the method described in the present disclosure may be obtained or obtainable by a top-down synthetic route, which includes the steps of:

[0095] a. Obtaining a metal (M) oxide core, wherein M is the high atomic number element described above, preferably gadolinium;

[0096] b. Adding a polysiloxane shell around the M oxide core, for example, by a sol-gel process;

[0097] c. Grafting a chelating agent onto the polyorganosiloxane (POS) shell such that the chelating agent binds to the polyorganosiloxane (POS) shell through a -Si-C- covalent bond, thereby obtaining core-shell precursor nanoparticles; and,

[0098] d. Transferring the core-shell precursor nanoparticles to an aqueous solution for dissolution and purification of the metal oxide core;

[0099] Wherein, the amount of the grafting agent is sufficient to complex the cationic form of (M), and wherein the average hydrodynamic diameter of the resulting ultrafine nanoparticles after core dissolution is less than 10 nm, such as from 1 nm to 10 nm, typically less than 8 nm, such as from 2 nm to 8 nm.

[0100] In a preferred embodiment where the metal oxide core is completely dissolved, these nanoparticles obtained according to the above method do not include a metal oxide core encapsulated by at least one layer of coating. More details regarding the synthesis of these nanoparticles will be given below.

[0101] The nanoparticles obtained by this top-down synthesis method typically range in size from 1 nm to 8 nm, more specifically from 2 nm to 8 nm. The term used here is ultrafine nanoparticles.

[0102] Alternatively, another "one-pot" synthesis method will be described below for preparing the ultrafine nanoparticles having an average diameter less than 10 nm (such as from 1 nm to 8 nm, typically from 2 nm to 6 nm).

[0103] More detailed information about these ultra - fine nanoparticles or non - nucleated nanoparticles, the processes for synthesizing them, and their uses is described in patent applications WO2011 / 135101, WO2018 / 224684, or WO2019 / 008040, which are incorporated herein by reference.

[0104] Process for obtaining a preferred embodiment of the nanoparticles for use in the treatment methods of the present disclosure

[0105] Generally, those skilled in the art can easily prepare the nanoparticles used according to the present disclosure. More specifically, the following elements should be noted:

[0106] For core - shell nanoparticles based on lanthanide oxide or hydroxide cores, a production process using alcohol as a solvent can be employed, as described in, for example, P. Perriat et al., J. Coll. Int. Sci, 2004, 273, 191; O. Tillement et al., J. Am. Chem. Soc., 2007, 129, 5076, and P. Perriat et al., J. Phys. Chem. C, 2009, 113, 4038.

[0107] For polyorganosiloxane (POS) matrices, several techniques can be used, which are derived from Stoeber (Stoeber, W; J. Colloid Interf Sci 1968, 26, 62). Processes for coating as described by Louis et al. (Louis et al., 2005, Chemistry of Materials, 17, 1673 - 1682) or in international application WO 2005 / 088314 can also be used.

[0108] In fact, for example, the synthesis of ultra - fine nanoparticles is described in Mignot et al., Chem. Eur. J. 2013, 19, 6122 - 6136: Generally, core / shell - type precursor nanoparticles are formed by a lanthanide oxide core (by a modified polyol route) and a polysiloxane shell (by sol / gel); the object has a hydrodynamic diameter of, for example, about 5 nm to 10 nm. Thus, lanthanide element oxide cores with very small sizes (adjustable to less than 10 nm) can be prepared in alcohol by one of the processes described in the following publications: P. Perriat et al., J. Coll. Int. Sci, 2004, 273, 191; O. Tillement et al., J. Am. Chem. Soc., 2007, 129, 5076, and P. Perriat et al., J. Phys. Chem. C, 2009, 113, 4038.

[0109] These nuclei can be coated with a layer of polysiloxane according to a protocol described, for example, in the following publications: C. Louis et al., Chem. Mat., 2005, 17, 1673 and O. Tillement et al., J. Am. Chem. Soc., 2007, 129, 5076.

[0110] A chelating agent specific for the metal cation (e.g., DOTAGA for Gd 3 +) is grafted onto the polysiloxane surface; it is also possible to insert a part of it inside the layer, but the control of polysiloxane formation is more complex, and at these very small sizes, a simple external grafting can achieve a sufficient grafting ratio.

[0111] The above nanoparticles can be separated from the synthetic residues by methods such as dialysis or tangential flow filtration (e.g., on a membrane with a suitable pore size).

[0112] The above nuclei are destroyed by dissolution (e.g., by adjusting the pH value or introducing complexing molecules into the solution). This destruction of the nuclei then enables the polysiloxane layer to diffuse and rearrange (according to a slow corrosion or collapse mechanism), and ultimately a polysiloxane object with a complex morphology can be obtained, whose characteristic size is on the order of the polysiloxane layer thickness, i.e., much smaller than the objects prepared so far.

[0113] Therefore, removing the nuclei can reduce the particle size from a diameter of about 5 nm to 10 nm to less than 8 nm, for example, a size between 2 nm - 8 nm. The number of M at the nanoparticle size can be evaluated by the M / Si atomic ratio measured by energy-dispersive X-ray spectroscopy (EDX). Generally, the number of M in each ultrafine nanoparticle can be between 5 and 50.

[0114] In a specific embodiment, the nanoparticles according to the present disclosure contain a chelating agent with acid functional groups, such as DOTA or DOTAGA. The acid functional groups of the nanoparticles can be activated in the presence of an appropriate amount of targeting molecules, for example, using EDC / NHS (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / N-hydroxysuccinimide). The nanoparticles grafted in this way can then be purified, for example, by tangential flow filtration.

[0115] Alternatively, the nanoparticles according to the present disclosure can be or are obtained by a synthetic method ("one-pot synthesis method"), which includes mixing at least one hydroxy silane or alkoxysilane that is negatively charged at physiological pH and at least one chelating agent selected from polyaminopolycarboxylic acids with:

[0116] at least one hydroxy silane or alkoxysilane that is neutral at physiological pH; and / or

[0117] At least one hydroxy silane or alkoxy silane that is positively charged at physiological pH and contains an amino functional group;

[0118] Wherein:

[0119] The molar ratio A of neutral silane to negatively charged silane is defined as follows: 0 ≤ A ≤ 6, preferably 0.5 ≤ A ≤ 2;

[0120] The molar ratio B of positively charged silane to negatively charged silane is defined as follows: 0 ≤ B ≤ 5, preferably 0.25 ≤ B ≤ 3;

[0121] The molar ratio C of neutral and positively charged silanes to negatively charged silane is defined as follows: 0 < C ≤ 8, preferably 1 ≤ C ≤ 4.

[0122] According to a more specific embodiment of this one-pot synthesis method, the method comprises mixing at least one alkoxy silane that is negatively charged at physiological pH (the alkoxy silane is selected from APTES-DOTAGA (aminopropyltriethoxysilane-1,4,7,10-tetraazacyclododecane-1-(pentanedioic acid)-4,7,10-triacetic acid), TANED (ethyl naphthyridine dicarboxylate), chemical exchange saturation transfer (CEST), and mixtures thereof) with the following substances:

[0123] At least one alkoxy silane that is neutral at physiological pH (the alkoxy silane is selected from TMOS (tetramethoxysilane), TEOS (tetraethyl orthosilicate), and mixtures thereof); and / or

[0124] APTES that is positively charged at physiological pH,

[0125] Wherein:

[0126] The molar ratio A of neutral silane to negatively charged silane is defined as follows: 0 ≤ A ≤ 6, preferably 0.5 ≤ A ≤ 2;

[0127] The molar ratio B of positively charged silane to negatively charged silane is defined as follows: 0 ≤ B ≤ 5, preferably 0.25 ≤ B ≤ 3;

[0128] The molar ratio C of neutral and positively charged silanes to negatively charged silane is defined as follows: 0 < C ≤ 8, preferably 1 ≤ C ≤ 4.

[0129] According to a specific embodiment, the one-pot synthesis method comprises mixing APTES-DOTAGA that is negatively charged at physiological pH with the following substances:

[0130] At least one alkoxy silane that is neutral at physiological pH (the alkoxy silane is selected from tetra-TMOS, TEOS, and mixtures thereof); and / or

[0131] APTES, which is positively charged at physiological pH,

[0132] wherein:

[0133] The molar ratio A of neutral silane to negatively charged silane is defined as follows: 0 ≤ A ≤ 6, preferably 0.5 ≤ A ≤ 2;

[0134] The molar ratio B of positively charged silane to negatively charged silane is defined as follows: 0 ≤ B ≤ 5, preferably 0.25 ≤ B ≤ 3;

[0135] The molar ratio C of neutral and positively charged silanes to negatively charged silane is defined as follows: 0 < C ≤ 8, preferably 1 ≤ C ≤ 4.

[0136] AGuIX nanoparticles

[0137] In a more particularly preferred embodiment, the gadolinium chelate-based polysiloxane nanoparticles are ultrafine AGuIX nanoparticles having the following general formula:

[0138]

[0139] wherein PS is polysiloxane, n is on average about 10, the hydrodynamic diameter is 5 ± 2 nanometers, the mass is between 2 and 200 kDa, preferably between 5 and 30 kDa, more preferably between 8 and 12 kDa, for example about 10 ± 1 kDa.

[0140] The AGuIX nanoparticles can also be described by the average chemical formula:

[0141] (GdSi 3-8 C 24-34 N 5-8 O 15-30 H 40-60 ,5-15H2O) x , or preferably

[0142] (GdSi 4-7 C 24-30 N 5-8 O 15-25 H 40-60 ,5-10H2O) x .

[0143] In the present disclosure, the terms "AGuIX" and are used interchangeably.

[0144] The pharmaceutical formulation of the nanoparticles for use according to the method of the present disclosure

[0145] When used as a medicine, a composition comprising nanoparticles containing the high atomic number elements for use as provided herein can be administered in the form of a pharmaceutical formulation of a nanoparticle suspension. These formulations can be prepared as described herein or elsewhere and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated.

[0146] In a particular embodiment, the pharmaceutical formulation for use as described herein comprises a suspension of nanoparticles containing a high atomic number element (as provided herein) as the active ingredient, in combination with one or more pharmaceutically acceptable carriers (excipients). In preparing the pharmaceutical formulations provided herein, the nanoparticle composition can, for example, be mixed with or diluted by an excipient. When an adjuvant is used as a diluent, it can be a solid, semi-solid or liquid material that acts as a carrier, vehicle or medium for the nanoparticle composition.

[0147] Accordingly, the above pharmaceutical formulations can be in the form of powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), sterile injectable solutions, sterile packaged powders, etc.

[0148] In a particular embodiment, the pharmaceutical formulation for use as described herein is a sterile lyophilized powder, packaged in a pre-filled vial, for example reconstituted in an aqueous solution for intravenous injection. In a particular embodiment, the lyophilized powder contains an effective amount of the nanoparticles containing a high atomic number element as the active ingredient, typically nanoparticles based on gadolinium chelated polysiloxanes, and more particularly AGuIX nanoparticles as described herein. In certain particular embodiments, the lyophilized powder contains from about 200 mg to 15 g per vial, for example 280 mg to 320 mg of AGuIX per vial, typically 300 mg of AGuIX per vial, or about 800 mg to 1200 mg per vial, for example 1 g of AGuIX per vial.

[0149] Such a powder can further comprise one or more additional excipients, and in particular CaCl2, for example between 2 mg and 5 mg of CaCl2, typically 4.4 mg of CaCl2 per gram of AGuIX.

[0150] The lyophilized powder can be reconstituted in an aqueous solution (usually water for injection). Thus, in certain embodiments, the pharmaceutical solution for use according to the present disclosure is an injectable solution that contains an effective amount of the high atomic number element-containing nanoparticles as the active ingredient, typically gadolinium chelated polysiloxane-based nanoparticles, and more particularly AGuIX nanoparticles as described herein. For example, the injectable solution for use according to the method of the present disclosure is a solution of gadolinium chelated polysiloxane-based nanoparticles (usually AGuIX nanoparticles) at a concentration between 50 mg / mL and 150 mg / mL, such as between 80 mg / mL and 120 mg / mL, and typically 100 mg / mL, optionally containing one or more additional pharmaceutically acceptable excipients, such as CaCl2 at a concentration between 0.2 mg / mL and 0.6 mg / mL, and typically 0.44 mg / mL.

[0151] In certain embodiments, the pharmaceutical formulation for use as described herein is an aqueous solution contained in a vial that contains an effective amount of the high atomic number element-containing nanoparticles as the active ingredient, typically gadolinium chelated polysiloxane-based nanoparticles, and more particularly AGuIX nanoparticles as described herein. In certain specific embodiments, the vial contains about 1 g to 5 g of AGuIX, typically about 2 g to 3 g of AGuIX, such as 2.5 g of AGuIX. In certain embodiments, the above aqueous solution can be used to prepare the above injectable solution, or it is itself the above injectable solution.

[0152] The treatment method of the present disclosure

[0153] The present disclosure relates to the use of high atomic number element-containing nanoparticles in a method for treating tumors by radiopharmaceutical therapy in a subject in need thereof; the method includes co-administering an effective amount of the high atomic number element-containing nanoparticles and an effective amount of a therapeutic radiopharmaceutical containing a radionuclide. As used herein, the term "high atomic number element-containing nanoparticles" refers to the nanoparticles described in the previous section.

[0154] The present disclosure also relates to a method for treating tumors by radiopharmaceutical therapy in a subject in need thereof, including co-administering (particularly according to the dosing regimen described in the present disclosure) an effective amount of the high atomic number element-containing nanoparticles and an effective amount of a therapeutic radiopharmaceutical containing a radionuclide as described in the present disclosure.

[0155] The present disclosure also relates to the use of the nanoparticles containing high atomic number elements as described in the present disclosure and therapeutic radiopharmaceuticals containing radionuclides in the preparation of a medicament for treating tumors by radiopharmaceutical therapy in a subject in need thereof, wherein an effective amount of the nanoparticles containing high atomic number elements and an effective amount of the therapeutic radiopharmaceutical are administered in combination, particularly according to the dosing regimens described in the present disclosure.

[0156] According to the present disclosure, the term "radiopharmaceutical therapy", also referred to as "targeted radionuclide therapy" (abbreviated as TRT), "targeted radiopharmaceutical therapy", "molecular radiotherapy", "radioimmunotherapy" or "targeted radiotherapy", refers to the treatment of neoplastic diseases using therapeutic radiopharmaceuticals containing radionuclides. In radiopharmaceutical therapy, a therapeutic radiopharmaceutical containing a radionuclide capable of delivering ionizing radiation directly to tumor cells is used to deliver radiation systemically or locally to the tumor. The ionizing radiation deposits energy, damaging or destroying the cells within the treated area (target tissue and so-called "targeting effect") by disrupting the genetic material of the cells, rendering these cells unable to continue growing. Generally, the ionizing radiation is α-particles, β-particles and Auger electrons. Radiation can also disrupt non-irradiated cells through intercellular communication at short distances (bystander effect) or long distances (systemic or immune effect).

[0157] According to the present disclosure, the term "treating" or "treatment" refers to one or more of the following: (1) inhibiting a disease; for example, inhibiting a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, disorder or condition (i.e., preventing the further development of the pathology and / or symptomatology); and (2) ameliorating a disease; for example, ameliorating a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, disorder or condition (i.e., reversing the pathology and / or symptomatology), such as reducing the severity of the disease or reducing or alleviating one or more symptoms of the disease. In particular, with respect to the treatment of tumors, the term "treatment" may refer to the inhibition of tumor growth, the reduction in tumor size or the complete destruction of the tumor.

[0158] According to the present disclosure, the "effective amount" or "therapeutically effective amount" of the main active ingredient (e.g., a therapeutic radiopharmaceutical) refers to the amount of the main active ingredient that can elicit a biological or medical response in a subject, such as improving symptoms, alleviating the condition, slowing or delaying the progression of the disease or preventing the disease, and the active ingredient can be used alone or in combination with other main active ingredients (e.g., in combination with the nanoparticles containing high atomic number elements).

[0159] According to the present disclosure, an effective amount of a therapeutic radiopharmaceutical refers to the amount of the therapeutic radiopharmaceutical administered to a patient in the context of radiopharmaceutical therapy to treat a tumor, e.g., an amount that induces tumor regression or elimination by disrupting the tumor structure and / or killing tumor cells. Such an effective amount of the therapeutic radiopharmaceutical is typically expressed in terms of activity (megabecquerels, MBq or gigabecquerels, GBq), and may also be referred to as the "total injected activity". Such an effective amount typically delivers an appropriate radiation dose (in grays, Gy) to the tumor.

[0160] According to the present disclosure, an effective amount of the therapeutic radiopharmaceutical can be administered in a fractionated dose regimen, i.e., a regimen in which the total dose (i.e., total injected activity) of the therapeutic radiopharmaceutical is divided into several smaller doses, where each dose is referred to as a "fractionated dose of the therapeutic radiopharmaceutical", and is administered to the patient over multiple dosing cycles, e.g., over a period of several days or months. Alternatively, the above-mentioned therapeutic radiopharmaceutical can be administered as a single dose. The effective amount of the therapeutic radiopharmaceutical depends on multiple factors, such as the dosing regimen, the therapeutic radiopharmaceutical itself, the patient's body weight, the location and severity of the tumor.

[0161] In one embodiment, the effective amount of the therapeutic radiopharmaceutical administered to a subject is between 0.5 MBq and 100 GBq, preferably between 10 MBq and 50 GBq.

[0162] In one embodiment, the above-mentioned therapeutic radiopharmaceutical is administered in a fractionated dose regimen having 4 to 20 dosing cycles, and each fractionated dose has an activity between 0.5 MBq and 100 GBq, preferably between 1 MBq and 10 GBq, more preferably between 2 MBq and 8 GBq.

[0163] In a particular embodiment, the above-mentioned therapeutic radiopharmaceutical is 177 Lu-DOTATATE (octreotate), and the effective amount of the therapeutic radiopharmaceutical is administered in a fractionated dose regimen having 2 to 6 dosing cycles, preferably 4 dosing cycles, and each fractionated dose has an activity between 1 GBq and 10 GBq, preferably between 5 GBq and 10 GBq, more preferably between 7 GBq and 9 GBq, e.g., 7.4 GBq. For example, 177 Lu-DOTATATE (octreotate) can be administered in a fractionated dose regimen having 4 dosing cycles, and each dose has an activity between 7 GBq and 8 GBq, typically 7.4 GBq.

[0164] In one embodiment, an effective amount of a therapeutic radiopharmaceutical is designed to deliver a radiation dose of at least 50 mGy (in gray, Gy) to the tumor, preferably at least 500 mGy, more preferably at least 1 Gy. It should be noted that radionuclide imaging techniques result in a radiation exposure of less than 50 mGy, while treatment with radionuclides can achieve gray (Gy) levels.

[0165] According to the present disclosure, an effective amount of nanoparticles refers to the amount of nanoparticles that can enhance the therapeutic efficacy of a therapeutic radiopharmaceutical administered to a patient for treating a tumor. The effective amount of nanoparticles may depend on multiple factors, such as the type, effective amount, and dosing regimen of the therapeutic radiopharmaceutical administered to the patient.

[0166] According to the present disclosure, the effective amount of nanoparticles is preferably administered in a fractionated dose regimen, i.e., for a single dose of the therapeutic radiopharmaceutical administered to the patient, the total dose of nanoparticles is divided into several smaller nanoparticle doses, where each smaller nanoparticle dose is referred to as a "nanoparticle fractionated dose" and is administered to the patient over multiple dosing cycles, e.g., within a time period of 4 to 72 hours before or after each dose of the therapeutic radiopharmaceutical.

[0167] According to the present disclosure, the terms "patient" and "subject" used interchangeably herein refer to any member of the animal kingdom, including mammals and invertebrates. For example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, fish, and humans. Preferably, the subject is a mammal, more preferably a human, including, for example, a subject suffering from a tumor.

[0168] According to the present disclosure, the terms "co - administration", "concomitant administration", or "adjuvant administration" refer to the co - administration of at least two therapeutic agents, where the first agent (usually a therapeutic radiopharmaceutical compound) and the second agent (usually nanoparticles containing high - atomic - number elements, preferably AGuIX) are administered to a subject in need thereof either simultaneously or at separate time intervals, particularly in accordance with the dosing regimens according to the present disclosure, and these time intervals enable the combined components to exhibit a cooperative or synergistic effect in treating the tumor. This does not mean that the therapeutic agents must be administered simultaneously and / or formulated to be administered together, although these administration methods are within the scope described herein. As used herein, the terms "co - administration", "concomitant administration", and "adjuvant administration" are relative to single - therapy that includes the administration of only a single therapeutic agent. The therapeutic radiopharmaceutical can be administered simultaneously with, before, or after one or more other additional therapies or therapeutic agents. These terms also are intended to include treatment regimens in which at least one or both therapeutic agents are administered in a fractionated dose regimen. These terms also are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration.

[0169] In one embodiment, the combination administration for use according to the present invention can induce oxidative cell death in tumor cells.

[0170] In one embodiment, the combination administration for use according to the present invention can reduce the antioxidant capacity of tumor cells and / or increase the accumulation of reactive oxygen species (ROS) in tumor cells, thereby resulting in oxidative cell death in tumor cells.

[0171] Therapeutic radiopharmaceutical

[0172] According to the present disclosure, radiopharmaceutical therapy can be implemented using any kind of therapeutic radiopharmaceutical.

[0173] In the present disclosure, the terms "therapeutic radiopharmaceutical containing a radionuclide", "therapeutic radiopharmaceutical", "targeted radiopharmaceutical", "radiopharmaceutical compound" or "radiopharmaceutical" are used interchangeably herein, and they refer to a pharmaceutical compound intended to be administered to a subject in need, which contains a radionuclide capable of emitting ionizing radiation, particularly a radionuclide capable of directly and specifically delivering ionizing radiation to tumor cells, the microenvironment of tumor cells, and / or the organ containing tumor cells.

[0174] According to the present disclosure, the term "radionuclide" refers to any radioactive isotope of an element that emits one or more types of ionizing radiation, and these ionizing radiations are selected from β-particles, α-particles, and Auger electrons.

[0175] In one embodiment, the above radionuclides are selected from 177 Lu, 161 Tb, 186 Re, 131 I, 90 Y, 225 Ac / 213 Bi, 223 Ra, 212 Pb / 212 Bi, 227 Th, 211 At, 97 Ru, 103 Pd, 67 Ga, 195m Pt, 193m Pt, 125 I, 111 In, and mixtures thereof.

[0176] In one embodiment, the above radionuclides are selected from 177 Lu, 161 Tb, 186 Re,131 I, 90 β-particle emitters of Y and their mixtures.

[0177] In one embodiment, the above radionuclides are selected from 225 Ac / 213 Bi, 223 Ra, 212 Pb / 212 Bi, 227 Th, 211 α-particle emitters of At and their mixtures.

[0178] In one embodiment, the above radionuclides are selected from 97 Ru, 103 Pd, 67 Ga, 195m Pt, 193m Pt, 125 I, 111 Auger electron emitters of In and their mixtures.

[0179] Some of the radionuclides described herein, such as 177 Lu, 131 I, 111 In, in addition to the above ionizing radiation, also emit γ / X-rays or β+ particles, and thus can be monitored by SPECT imaging (single photon emission computed tomography).

[0180] The targeting effect of radionuclides on tumors can be provided by cancer targeting moieties or can be inherent in the radionuclides, as described in detail below.

[0181] In the present disclosure, therapeutic radiopharmaceuticals containing radionuclides are different from nanoparticles containing high atomic number elements.

[0182] Radionuclides linked to cancer targeting moieties

[0183] In one embodiment, the above radionuclides are linked to cancer targeting moieties.

[0184] According to the present disclosure, the term "linked" means that the cancer targeting moiety and the radionuclide are chemically linked by a covalent bond (optionally through a linker), or the cancer targeting moiety includes a chelating moiety and the radionuclide complexes with the chelating moiety of the cancer targeting moiety.

[0185] In one embodiment, the above-mentioned therapeutic radiopharmaceutical has the formula N-(X-)M, where N is a radionuclide, M is a cancer-targeting moiety, and X is an optional chelating moiety (Ch) or a linking moiety (L). In one embodiment, the radionuclide N is complexed with the cancer-targeting moiety through the chelating moiety (Ch). In another embodiment, the radionuclide is covalently linked to the cancer-targeting moiety M through the linking moiety (L).

[0186] According to the present disclosure, the term "cancer-targeting moiety" refers to a moiety that provides targeting to tumor cells.

[0187] In one embodiment, the above-mentioned cancer-targeting moiety exhibits the ability to recognize and bind to one or more sites or antigens (such as cell surface receptors specific to tumor cells, the tumor microenvironment, or organs containing tumor cells).

[0188] The above-mentioned cancer-targeting moiety can be an antibody, a peptide, or preferably a small molecule ligand that specifically binds to a tumor antigen or a tumor-associated antigen, which can be a binding fragment thereof.

[0189] According to the present disclosure, "specifically bind to" or "bind specifically to" or "target" means that a cancer-targeting moiety (such as an antibody) binds to an antigen with a stronger affinity than it binds to an irrelevant antigen. Preferably, this affinity is at least 10 times stronger than the affinity of the cancer-targeting fragment for an irrelevant antigen, more preferably at least 100 times stronger, and most preferably at least 1000 times stronger. In a specific embodiment, "specifically bind" means that the cancer-targeting moiety binds only to the target and not to other antigens.

[0190] As used herein, the term "tumor antigen" or "cancer antigen" refers to any protein that is produced in tumor cells and has an abnormal sequence or structure due to mutation and can serve as a tumor antigen. Mutations in proto-oncogenes and tumor suppressor genes that result in the production of abnormal proteins are the cause of tumor formation, and thus such abnormal proteins are called tumor-specific antigens. Examples of tumor antigens include abnormal products of the ras and p53 genes. "Tumor antigen" also refers to "tumor-associated antigen", that is, a protein with other gene mutations unrelated to tumor formation that can lead to abnormal protein synthesis. The term also includes other cellular antigens, which may be naturally occurring but may be targeted by anti-cancer drugs to eliminate cells expressing such antigens.

[0191] In a particular embodiment, the cancer targeting moiety is an antibody that specifically binds to a tumor antigen or tumor-associated antigen.

[0192] According to the present disclosure, the term "antibody" refers to any intact antibody molecule, such as an antibody molecule of any isotype (IgG, IgA, IgM, IgE, etc.) that contains an immunoglobulin binding domain that specifically binds an antigen (such as a tumor antigen or tumor-associated antigen). The term "antibody" includes polyclonal antibodies, monoclonal antibodies, or other purified preparation antibodies and recombinant antibodies. The term "antibody binding fragment" refers to a fragment of an intact antibody that retains the property of specifically binding an antigen. Antibodies can be fragmented using conventional techniques, and the fragments can be screened for their interaction with the target antigen. Thus, the term "fragment" includes proteolytically cleaved or recombinantly prepared portions of an antibody molecule that are capable of specifically binding an antigen. Non-limiting examples of such proteolytic and / or recombinant fragments include Fab, F(ab’)2, Fab’, Fv, and single-chain antibodies (scFv) containing V[L] and / or V[H] domains linked by a peptide linker. The scFv can be covalently or non-covalently linked to form an antibody with two or more binding sites.

[0193] In one embodiment, the cancer targeting moiety specifically binds to one or more cancer cell antigens selected from the following: HER2 (human epidermal growth factor receptor 2), EGFR (epidermal growth factor receptor), GRBR (gastrin-releasing peptide receptor), CD20, CD33, CD37, somatostatin receptor, prostate-specific membrane antigen (PSMA), AMHRII (anti-Müllerian hormone type II receptor), and TYRP1 / gp75 (tyrosinase-related protein 1).

[0194] In one embodiment, the cancer targeting moiety specifically binds to at least one antigen of the tumor microenvironment, such as a cancer-associated fibroblast (CAF) antigen, such as fibroblast activation protein α (FAP), or an immune checkpoint antigen, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death 1 receptor (PD-1), or its ligand programmed death ligand 1 (PD-L1).

[0195] In one embodiment, the cancer targeting moiety is an anti-HER2 antibody, such as trastuzumab, pertuzumab, or iodine 131 tositumomab (also known as tositumomab octreotide, under the trademark Commercially available); anti-EGFR antibodies such as cetuximab or panitumumab; anti-CD20 antibodies such as rituximab or Zevalin; anti-CD33 antibodies such as lintuzumab; anti-CD37 antibodies such as olaratumab (TRU-016), monoclonal antibody 37.1 (BI 836826) or IMGN529 (K7153A-DM1); anti-AMHRII antibodies such as mulranumab; or anti-TYRP1 / gp75 antibodies such as IMC-20D7S.

[0196] In one embodiment, the cancer targeting moiety is a somatostatin analogue such as octreotide (DOTATOC) or octreotate (DOTATATE), which targets somatostatin receptor 2 (SSTR2).

[0197] In one embodiment, the cancer targeting moiety is a PSMA small molecule ligand such as the 617 ligand, the I&T ligand, the R2 ligand or the MIP-1095 ligand).

[0198] In one embodiment, the therapeutic radiopharmaceutical is selected from 177 Lu-anti-HER2 antibody such as 177 Lu-trastuzumab; 177 Lu-somatostatin analogue such as 177 Lu-octreotate; 177 Lu-PSMA ligand; 90 Y-anti-CD20 antibody such as 90 Y-rituximab or 90 Y-ibritumomab tiuxetan; 212 Pb-anti-HER2 antibody; 177 Lu-anti-CD37 antibody.

[0199] Radionuclides with intrinsic targeting

[0200] In another embodiment, the therapeutic radiopharmaceutical consists of a radionuclide with intrinsic targeting, i.e., the radionuclide has an intrinsic affinity for tumor cells, the microenvironment of tumor cells, or organs containing tumor cells. In this embodiment, the therapeutic radiopharmaceutical does not have the above-mentioned cancer targeting moiety.

[0201] Such therapeutic radiopharmaceuticals may be selected from iodine-131 ( 131 I) or radium-223 ( 223 Ra).

[0202] Iodine-131 naturally accumulates in the thyroid gland and can be used as a therapeutic radiopharmaceutical for treating thyroid tumors.

[0203] Radium-223 naturally accumulates in the bones and can be used as a therapeutic radiopharmaceutical for the treatment of bone metastases of prostate cancer or breast cancer.

[0204] Nanoparticle

[0205] In one embodiment, the therapeutic radiopharmaceutical containing a radionuclide and the nanoparticle do not have the same targeting properties.

[0206] In one embodiment, the nanoparticle is not functionalized with molecules that can target specific tissues (especially tumors).

[0207] In one embodiment, the nanoparticle is not linked to the cancer targeting moieties described herein.

[0208] In one embodiment, the nanoparticle reaches the tumor, especially tumor cells, only through passive targeting. In one embodiment, the nanoparticle is sufficiently co-localized with the therapeutic radiopharmaceutical containing a radionuclide such that the nanoparticle has a radiosensitizing effect on the radiopharmaceutical, preferably specifically at the tumor site.

[0209] In one embodiment, the nanoparticle has a radiosensitizing effect on the therapeutic radiopharmaceutical containing a radionuclide, preferably specifically at the tumor site.

[0210] In one embodiment, the nanoparticle has a radiosensitizing effect on the lysosomes of tumor cells.

[0211] In one embodiment, the radiosensitizing effect is sufficient to trigger one or more of the following in tumor cells: (i) enhanced destruction of lysosomes within tumor cells; (ii) enhanced release of iron within tumor cells; (iii) enhanced production of reactive oxygen species (ROS) within tumor cells; (iv) enhanced lipid peroxidation within tumor cells; and / or (v) oxidative cell death of tumor cells.

[0212] In one embodiment, the radiosensitizing effect is at least partially mediated by ferroptosis.

[0213] In one embodiment, the radiosensitizing effect is sufficient to induce oxidative cell death in tumor cells.

[0214] In one embodiment, the nanoparticle is the AGuIX nanoparticle described in the foregoing sections.

[0215] Dosing regimen

[0216] The present disclosure relates to nanoparticles comprising a high atomic number element, for use in a method of treating tumors by radiopharmaceutical therapy in a subject in need thereof, said method comprising the combined administration of nanoparticles comprising a high atomic number element and a therapeutic radiopharmaceutical comprising a radionuclide.

[0217] The inventors have shown that such combined administration (especially when the nanoparticles are administered to the subject in a fractionated dose regimen) increases the degree of tumor regression compared to the administration of the therapeutic radiopharmaceutical comprising a radionuclide alone. The beneficial effects of the combined administration in the treatment method according to the present disclosure are believed to be as follows:

[0218] (i) improving the therapeutic efficacy of administering a given dose of a therapeutic radiopharmaceutical to a patient to treat a tumor;

[0219] (ii) reducing the effective amount of the therapeutic radiopharmaceutical required to be administered to a patient to treat a tumor, thereby enabling the reduction of the toxicity caused by radiation to the patient.

[0220] In one embodiment, the nanoparticles comprising a high atomic number element and the therapeutic radiopharmaceutical are administered simultaneously, separately or sequentially. In a particular embodiment, the therapeutic radiopharmaceutical is administered before or after the nanoparticles.

[0221] In one embodiment, the nanoparticles are administered to the subject in a fractionated dose regimen.

[0222] In one embodiment, the therapeutic radiopharmaceutical is administered to the subject in a fractionated dose regimen.

[0223] In one embodiment, both the nanoparticles and the therapeutic radiopharmaceutical are administered to the subject in a fractionated dose regimen, i.e., the therapeutic radiopharmaceutical is administered to the subject in a fractionated dose regimen, and for a single dose of the therapeutic radiopharmaceutical, the nanoparticles are administered in a fractionated dose regimen.

[0224] In one embodiment, the fractionated dose regimen of the nanoparticles is intended to enhance the therapeutic activity of the dose of the therapeutic radiopharmaceutical for at least the effective half-life of the dose of the therapeutic radiopharmaceutical. In the present disclosure, the effective half-life (T eff ) of the dose of the therapeutic radiopharmaceutical can be calculated by considering the radioactive half-life (T Phys ) of the radionuclide and the biological half-life (T biol ) of the radiopharmaceutical, using the formula 1 / T eff =(1 / T phys )+(1 / T biol ). In French, the term "effective half-life (T eff) is referred to as “période effective”.

[0225] In one embodiment, for a single dose of a therapeutic radiopharmaceutical administered to a subject, the fractionated dose regimen of the nanoparticles comprises 2 to 10 fractionated doses of nanoparticles.

[0226] In one example, the nanoparticles are administered in fractions between 24 hours and 72 hours after administration of a single dose of the therapeutic radiopharmaceutical.

[0227] In one embodiment, the fractionated dose regimen of the nanoparticles is administered on days 1, 2, 3, 4, and / or 5 after administration of a single dose of the therapeutic radiopharmaceutical.

[0228] In one embodiment, the fractionated dose regimen of the nanoparticles is administered on days 1, 2, 3, 4, and / or 5 after administration of a single dose of the therapeutic radiopharmaceutical.

[0229] In a preferred embodiment, the fractionated dose regimen of the nanoparticles is administered once a day or once every two days.

[0230] The first fractionated dose of the nanoparticles can be administered before or after the first administration of the therapeutic radiopharmaceutical to a subject in need thereof.

[0231] In one embodiment, the first fractionated dose of the nanoparticles is administered 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, or 72 hours after administration of a single dose of the therapeutic radiopharmaceutical, preferably between 24 hours and 72 hours.

[0232] In one embodiment, the first fractionated dose of the nanoparticles is administered 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, or 72 hours after the first administration of a single dose of the therapeutic radiopharmaceutical to a subject in need thereof, preferably between 24 hours and 72 hours.

[0233] In one embodiment, the time interval between the fractionated doses of the nanoparticles is between 4 hours and 48 hours, preferably between 4 hours and 12 hours, more preferably between 4 hours and 10 hours, such as a 6-hour dosing interval.

[0234] In one embodiment, the fractionated dosing regimen of the nanoparticles is designed based on the following factors:

[0235] (i) the tumor elimination and / or renal retention of the nanoparticles to avoid excessive toxicity; and

[0236] (ii) The residence time of the therapeutic radiopharmaceutical at the tumor site.

[0237] Without wishing to be bound by any theory, the inventors believe that when the therapeutic radiopharmaceutical is a radionuclide conjugated to an antibody, a dose of the therapeutic radiopharmaceutical will localize to the tumor within 24 to 168 hours after administration to a patient, reaching a maximum between 24 and 72 hours. In this case, the inventors believe that the nanoparticle administration is preferably administered in divided doses between 24 and 72 hours after administration of a dose of the therapeutic radiopharmaceutical to maximize the potential of that dose of the therapeutic radiopharmaceutical.

[0238] Patient selection

[0239] In one embodiment, the present disclosure relates to a method of treating a tumor in a subject in need thereof by radiopharmaceutical therapy, the method comprising co-administering a nanoparticle comprising a high atomic number element and a dose of a therapeutic radiopharmaceutical, wherein the nanoparticle is capable of reducing the dose of the therapeutic radiopharmaceutical to be administered to a subject in need thereof as compared to the dose to be administered to a subject treated only by radiopharmaceutical therapy.

[0240] In one embodiment, the method of the present disclosure is applicable to subjects who cannot receive a standard effective dose of targeted radionuclide therapy.

[0241] In a preferred embodiment, the method of the present disclosure is applicable to subjects suffering from radiation-resistant tumors. Radiation-resistant tumors include, but are not limited to, renal tumors, melanoma, thyroid tumors, colorectal tumors.

[0242] In one practice of the radiation, the therapeutic activity of the therapeutic radiopharmaceutical is due to the biological action of the cancer-targeting moiety and the ionizing radiation effect of the radionuclide.

[0243] Tumor to be treated

[0244] According to the present disclosure, the term "tumor" refers to an abnormal mass of tissue, where the growth rate of the mass exceeds that of normal tissue and is not as coordinated as the growth of normal tissue. Tumors can be "benign" or "malignant", depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. "Benign tumors" are usually well-differentiated, have a significantly slower growth rate than malignant tumors, and are confined to the primary site. In addition, benign tumors do not have the ability to infiltrate, invade, or metastasize to distant sites. In some cases, some "benign" tumors may later develop into malignant tumors, which may be due to additional genetic changes in subsets of the tumor's tumor cells. Such tumors are called "precancerous tumors". A typical precancerous tumor is a teratoma. In contrast, "malignant tumors" are usually poorly differentiated (anaplastic), have a significantly faster growth rate, and gradually infiltrate, invade, and destroy surrounding tissues. In addition, malignant tumors usually have the ability to metastasize to distant sites. The terms "malignant tumor" and "cancer" are used interchangeably herein.

[0245] In certain embodiments, the tumor to be treated expresses tumor antigens that can be specifically targeted by the radiopharmaceutical compounds for use in the methods described in the present disclosure.

[0246] Exemplary cancers include, but are not limited to: acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangioendotheliosarcoma, lymphangiosarcoma, angiosarcoma); appendiceal cancer; benign monoclonal propionibacterium; biliary tract cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast carcinoma, breast medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal carcinoma, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma)); hematopoietic system cancers (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma, and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-associated T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma));The above-described mixed states of one or more leukemias / lymphomas; and multiple myeloma (MM), heavy chain disease (such as alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immunocyte amyloidosis; kidney cancer (such as nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (such as hepatocellular carcinoma (HCC), malignant liver cancer); lung cancer (such as bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (such as systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative diseases (MPDs) (such as polycythemia vera (PV), essential thrombocythemia (ET), agnogenic myeloid metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromatosis (such as neurofibromatosis type 1 or type 2, schwannomatosis); neuroendocrine tumors (such as gastroenteropancreatic neuroendocrine tumors (GEP-NET), carcinoid); osteosarcoma (such as bone cancer); ovarian cancer (such as cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (such as pancreatic adenocarcinoma (pancreatic adenocarcinoma), intraductal papillary mucinous neoplasm (IPMN), islet cell carcinoma); penile cancer (such as Paget's disease of the penis and scrotum); peritoneal cancer (such as primary peritoneal cancer or peritoneal cancer metastasis, i.e., a secondary peritoneal cancer that spreads to the peritoneal cavity after developing in other parts of the body (such as the gastrointestinal tract, pancreas, melanoma, breast, lung, and ovary)); pinealoma; primitive neuroectodermal tumor (PNT); plasmacytoma; paraneoplastic syndrome; intraepithelial neoplasia; prostate cancer (such as prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (such as squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (such as appendiceal cancer); soft tissue sarcoma (such as malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland cancer; synovial tumor; testicular cancer (such as seminoma, testicular embryonal carcinoma); thyroid cancer (such as papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (such as Paget's disease of the vulva).;

[0247] In one embodiment, the tumor to be treated is a metastatic tumor.

[0248] According to the present disclosure, the term "metastatic tumor" refers to a tumor formed by tumor cells from other parts of the body (other than the location of the metastatic tumor). The term "metastatic" refers to the spread or metastasis of tumor cells from a primary or original tumor to another organ or tissue. During metastasis, tumor cells detach from the original (primary) tumor, spread through the blood or lymphatic system, and form new tumors in other organs or tissues of the body. The new metastatic tumor is of the same cancer type as the primary tumor. In the organ or tissue where the secondary (metastatic) tumor is located, there is a "secondary tumor" of the primary or original tumor tissue type, rather than the tumor type of that organ or tissue itself. For example, prostate cancer that has metastasized to the bone is called metastatic prostate cancer, which includes cancerous prostate cells growing in bone tissue. In some embodiments, the metastatic tumor may be a diffuse tumor, i.e., widely spread, rather than a local or confined tumor.

[0249] In one embodiment, the tumor is a HER2-positive tumor, such as a HER2-positive breast, bladder, pancreas, ovary, or stomach tumor.

[0250] In a preferred embodiment, the tumor is selected from peritoneal tumors (including primary peritoneal tumors and secondary peritoneal tumors), neuroendocrine tumors (including gastroenteropancreatic neuroendocrine tumors and pheochromocytomas or paragangliomas (PPGLs)), prostate tumors, neuroblastomas, meningiomas, lymphomas, Merkel cell carcinomas, breast tumors, renal cell tumors, and salivary gland carcinomas.

[0251] In a particular embodiment, the secondary peritoneal carcinoma tumor is a peritoneal carcinomatosis metastatic tumor, i.e., a tumor that develops in other parts of the body (such as the gastrointestinal tract, pancreas, melanoma, breast, lung, and ovary) and then spreads to the peritoneal cavity.

[0252] In one embodiment, the present disclosure relates to the use of nanoparticles containing high atomic number elements in a method for treating tumors by radiopharmaceutical therapy in a subject in need thereof, wherein the tumor is a HER-2 positive tumor, more specifically a HER-2 breast tumor, and the method comprises co-administering:

[0253] An effective amount of nanoparticles containing high atomic number elements as described herein, more specifically the AGuIX nanoparticles as described herein; and

[0254] An effective amount of 177 Lu-anti-HER2 antibody, more specifically 177 Lu-trastuzumab.

[0255] In one embodiment, the present disclosure relates to the use of nanoparticles comprising a high atomic number element in a method for treating a tumor by radiopharmaceutical therapy in a subject in need thereof, wherein the tumor is a somatostatin receptor 2 (SSTR2)-positive tumor, such as a midgut neuroendocrine tumor of somatostatin receptor 2 (SSTR2), and the method comprises co-administering:

[0256] An effective amount of the nanoparticles comprising a high atomic number element as described herein, more particularly the AGuIX nanoparticles as described herein; and

[0257] An effective amount of a somatostatin analogue, such as octreotide (DOTATOC) or octreotide acid (DOTATATE) (which targets the somatostatin receptor 2 (SSTR2) receptor), more particularly 177 Lu-DOTATATE.

[0258] Route of administration

[0259] In one embodiment, the nanoparticles and / or the therapeutic radiopharmaceuticals are administered to the subject using a route selected from local (intratumoral (IT), intraarterial (IA), subcutaneous, intravenous (IV), intradermal, airway (inhalation), intraperitoneal, intramuscular, intrathecal, intraocular or oral routes).

[0260] Brief intraperitoneal radioimmunotherapy (BIP-RIT) or brief intraperitoneal targeted radionuclide therapy (TRT)

[0261] In one embodiment, the present disclosure relates to the use of nanoparticles comprising a high atomic number element in a method for treating a tumor in a subject in need thereof by radiopharmaceutical therapy, the method comprising:

[0262] (i) Performing cytoreductive surgery on a tumor (such as an appendiceal tumor, a colon tumor, a gastric tumor, an ovarian tumor and peritoneal mesothelioma) originating from or having spread to the abdominal cavity;

[0263] (ii) Co-administering intraperitoneally the nanoparticles comprising a high atomic number element and a therapeutic radiopharmaceutical comprising a radionuclide according to the method described herein, more particularly the AGuIX nanoparticles as described herein; and

[0264] (iii) Optionally, flushing the abdominal cavity, for example using a peristaltic pump with physiological saline, to remove the therapeutic radiopharmaceutical not bound to the tumor.

[0265] In the present disclosure, the term "cytoreductive surgery" (also referred to as "CRS") refers to a surgical procedure aimed at reducing the number of tumor cells in the abdominal cavity and is applicable to patients in whom the tumor has spread within the abdominal cavity (peritoneal carcinomatosis). It is commonly used to treat ovarian cancer but can also be used for other abdominal malignancies.

[0266] Examples

[0267] The present invention is further illustrated by the following examples.

[0268] Example 1

[0269] Materials and Methods

[0270] Cell Lines

[0271] The SK-OV-3-luc cell line, derived from human ovarian serous cystadenocarcinoma, was obtained from the American Type Culture Collection (ATCC) and transfected to express the luciferase gene, which enabled us to track the growth of intraperitoneal (IP) tumors by bioluminescence imaging. The cells were cultured in DMEM / F12 medium supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin at 37 °C in an atmosphere of 5% carbon dioxide. Hygromycin was added to the medium at a concentration of 0.1 mg / ml to select for cells expressing the luciferase gene. The SK-OV-3-luc cells express human epidermal growth factor receptor 2 (HER2) of the epidermal growth factor receptor (EGFR) family, which can be targeted by trastuzumab ( Roche). In addition, this cell line exhibits two main characteristics of high-grade serous ovarian cancer (HGSOC): platinum resistance and p53 mutation. In vitro radiosensitization and cytotoxicity have been determined in other cancer models: A431 (human vulvar epidermoid carcinoma), B16F10 (mouse melanoma), and MiaPaca2 (human pancreatic cancer, expressing somatostatin sst2), all of which were obtained from the American Type Culture Collection (ATCC).

[0272] Animals

[0273] Female athymic Swiss nude mice (6 - 8 weeks old) (Charles River) were housed in the animal facility for 1 week before use. They were kept in an environment of 22°C and 55% humidity, with a 12 - hour light - dark cycle, and had free access to food and water. Body weight was monitored weekly, and the mice were examined throughout the study. Mice were xenografted with 3×106 SK - OV - 3 - luc cells by intraperitoneal injection (IP) in 200 μl of DMEM - F12 serum - free medium. Tumor growth was monitored by bioluminescence imaging. The health status of the mice was monitored throughout the study, and no clinical signs of pain or distress were observed. Four weeks after treatment, tumor nodules were removed and measured. Results were presented as the mean tumor mass (mg) corresponding to different treatment groups.

[0274] Treatment

[0275] In vitro

[0276] Trastuzumab (Herceptin, Roche) conjugated with p - SCN - benzyl - DOTA (Macrocyclics, Plano, Tx, USA) was labeled with 177 Lu ([[]] 177 Lu - trastuzumab), with a specific activity of 200 MBq / mg. was directly dissolved in 1 mL of water for injection (WFI) for injection preparation and stirred at 25°C for 10 minutes, then diluted in DMEM / F12 medium to a concentration range of 1 mg / mL - 10 mg / mL. 177 Lu - trastuzumab was used to treat SK - OV - 3 and A431 cells. In addition, ( 177 Lu - octreotide acid, targeting sst2) was used to treat MiaPaca2 cells, and 125 I - TA99 monoclonal antibody was used to treat B16F10 cells, targeting the TYRP1 / gp75 receptor. Notably, is routinely used in the treatment of patients with midgut neuroendocrine tumors (Strosberg et al., 2017; Strosberg et al., 2021).

[0277] In vivo

[0278] Fourteen days after xenografting, the mice were divided into different groups (n = 8) and received intraperitoneal (IP) injections summarized in Table 1 below:

[0279] Table 1

[0280]

[0281] Inductively coupled plasma mass spectrometry (ICP-MS)

[0282] SK-OV-3-luc xenografts received 10 mg (7200 nmol of gadolinium) of At 30 minutes, 6 hours, 24 hours, and 48 hours after injection (n = 3 mice per time point), the tumors and organs of interest were harvested ex vivo. Gadolinium quantification of the samples was performed by inductively coupled plasma mass spectrometry (ICP-MS).

[0283] Biodistribution of radiolabeled antibodies

[0284] Three million SK-OV-3-luc cells were xenografted intraperitoneally (IP) into athymic female Swiss nude mice. Fourteen days later, the mice received an intraperitoneal injection of 177 Lu-labeled trastuzumab. Tumors and various organs were collected, weighed, and radioactivity uptake was measured by gamma counting. For each organ or tumor, the percentage of injected activity per gram of tissue (%IA / g) was plotted.

[0285] Results

[0286] The activity of 10 MBq was too strong to demonstrate The radiosensitizing effect.

[0287] Figure 2 The results shown indicate that when targeted radionuclide therapy (TRT) is combined with co-administered:[[]]

[0288] Compared with the NaCl control, the total tumor mass was reduced by 97% (***p = 0.0006).

[0289] Compared with trastuzumab + the total tumor mass was reduced by 89% (**p = 0.006).

[0290] No significant difference was found compared with targeted radionuclide therapy (TRT) alone.

[0291] 177 The maximum tolerated activity (MTA) of Lu-trastuzumab (10 MBq) showed a strong therapeutic effect such that the potential radiosensitizing effect of AGuIX nanoparticles could not be demonstrated. In subsequent experiments, the 177 activity of Lu-trastuzumab was reduced to 5 MBq and 2.5 MBq.

[0292] 5 MBq of 177 Lu-trastuzumab in combination with 10 mg showed a trend of radiosensitization

[0293] Figure 3 The results showed that:

[0294] Of 2.5 MBq 177 Lu-trastuzumab + / − Compared with trastuzumab + control, no significant efficacy was shown.

[0295] Of 5 MBq 177 Lu-trastuzumab + Compared with NaCl control and trastuzumab + control, the total tumor mass was reduced by 97% (***p = 0.0003) and 94% (**p = 0.001), respectively.

[0296] Of 5 MBq 177 Lu-trastuzumab + Compared with using targeted radionuclide therapy (TRT) alone, no significant difference was found.

[0297] Of 5 MBq 177 The injected activity of Lu-trastuzumab was determined as the working activity for subsequent experiments. In addition to the high efficacy of using targeted radionuclide therapy (TRT) alone, the lack of significant radiosensitization may also be related to the uptake and retention duration of nanoparticles (NPs) in tumors. Further biological distribution studies were performed on tumor-bearing animals to evaluate their uptake / elimination kinetics.

[0298] showed rapid clearance and insufficient long-term retention in tumors.

[0299] Figure 4 The results showed that within 30 minutes to 6 hours after injection, the nanoparticles in the tumors were rapidly cleared. When combined with external radiation beam, this elimination kinetics was appropriate, where the irradiation reached a high dose rate in a flash manner. For the targeted radionuclide therapy (TRT) protocol, the irradiation was performed at a low dose rate but for a period of time. Therefore, it was expected that the nanoparticles would have a longer residence time in the tumors. In summary, these observations led to the design of 3 fractionated dosing regimens in combination with targeted radionuclide therapy (TRT).

[0300] Compared with using targeted radionuclide therapy (TRT) alone, the fractionated dosing regimen significantly increased the degree of tumor regression.

[0301] Figure 5AThe results showed a significant difference between targeted radionuclide therapy (5 MBq) and fractionated dosing regimen 3 (4 × 5 mg).

[0302] To compare the responses to the two treatments, the Response Evaluation Criteria in Solid Tumors (RECIST) (Gengenbacher et al., 2017) were used for assessment ( Figure 5B ). Briefly, the RECIST-based trichotomy classifies drug responses into three categories: complete response (CR), stable disease (SD), and progressive disease (PD), which is based on the relative tumor volume (RTV) relative to a certain day after the start of treatment (complete response: RTV ≤ 0.65, progressive disease: RTV ≥ 1.35, stable disease: 0.65 < RTV < 1.35). The results are as follows Figure 5B and shown in Table 2:

[0303] Table 2

[0304]

[0305] In in vitro experiments, cancer cells were made more sensitive to β-particle and Auger electron targeted radionuclide therapy (TRT).

[0306] The results in Figure 6 showed:

[0307] Figure 6A : The clonogenic cell survival rates of SK-OV-3 cells and A431 cells exposed to 177 Lu-trastuzumab at 0.5 MBq / mL, 1 MBq / mL, 2 MBq / mL, and 4 MBq / mL ± 10 mg / mL at the time of.

[0308] Figure 6B : The clonogenic cell survival rates of B16F10 cells exposed to 125 I-TA99 at 4 MBq / mL ± 1 mg / mL at the time of.

[0309] Figure 6C : The clonogenic cell survival rates of MiaPaca2 cells exposed to LUTATHERA at concentrations of 0.8 MBq / mL, 2 MBq / mL, and 4 MBq / mL ± 1 mg / mL, 5 mg / mL, and 10 mg / mL at the time of.

[0310] Alone treatment did not have a significant cytotoxic effect on any of the tested cell lines. When 177 Lu-trastuzumab was combined with 10 mg / mL When incubating the gynecological cancer cell lines SK-OV-3 and A431, a significant radiosensitizing effect was found ( Figure 6A ). Similarly, when B16F10 murine melanoma cells were exposed to 4 MBq / mL in the presence of 1 mg / mL 125 I-TA99, a radiosensitizing effect was found ( Figure 6B ). Similarly, when MiaPaca2 pancreatic cancer cells were treated with in the presence of 10 mg / mL , a significant radiosensitizing effect was shown ( Figure 6C ).

[0311] Conclusion

[0312] The in vitro and in vivo experimental results indicate that when co-administered with , the therapeutic radiopharmaceutical has a radiosensitizing effect and enhanced therapeutic efficacy, while reducing the total injected activity. This result may have a significant impact on patients by reducing radiation-induced toxicity.

[0313] In addition, the inventors have generated biodistribution data to track the dynamics of radiolabeled antibodies 177 Lu-trastuzumab ( Figure 7 ) and nanoparticles in tumors. The monitoring of nanoparticles in tumors is ensured by ICPMS measurement, while the monitoring of radiolabeled antibodies is ensured by measuring the radioactivity in tumors. The results show that:

[0314] The incorporation of radiolabeled antibodies in tumors increased between 0 and 48 hours and then decreased.

[0315] The incorporation of nanoparticles (NP) in tumors was faster. It increased within 30 minutes and then decreased.

[0316] By injecting NP at t24h, t30h, t72h, t78h after antibody injection, within a given time, NP and antibody co-existed in tumors, i.e., co-localized.

[0317] Therefore, by injecting nanoparticles (NP) between 24 hours, 30 hours, 72 hours and 78 hours after antibody injection, at a specific time, nanoparticles and antibodies co-existed in tumors, i.e., co-localized.

[0318] Example 2: Animal survival rate of Protocol 3

[0319] The animal survival rate after administration according to Protocol 3 described in Example 1 was determined.

[0320] Materials and methods

[0321] In the second set of experiments, mice received two injections daily, each injection being 5 mg AGuIX in 200 μl of physiological saline (separated by a 6-hour time interval), 24 hours and 72 hours after targeted radionuclide therapy (TRT).

[0322] The survival of the mice was monitored by bioluminescence measurement within 130 days after treatment. Kaplan-Meier survival estimates were calculated from the date of xenografting to the date of the target event (i.e., a bioluminescence flux of 4×1010 photons / second) and compared by the log-rank test.

[0323] Results

[0324] The results are as Figure 8 shown.

[0325] The established Kaplan Meyer survival curves demonstrated that regimen 3 (R3) resulted in the most significant improvement in median survival ([[]] Figure 8 ). Specifically, compared to NaCl (median survival = 30 days; ****p<0.0001), trastuzumab +[[[]] (median survival = 33 days; ****p<0.0001), and 5 MBq[[[]] 177 Lu-trastuzumab alone (median survival = 69 days; *p = 0.016), [[[]] 177 Lu-trastuzumab + R3] significantly improved survival (median survival = 97 days; 2 mice cured for over 11).

[0326] Example 3: Colocalization of nanoparticles containing high atomic number elements with lysosomes according to the present invention Materials and methods

[0327] To evaluate the localization of the nanoparticles relative to mitochondria and lysosomes, SK-OV-3-luc cells were incubated with [[[]] -AF488 (i.e., [[[]] functionalized with Alexa Fluor dye) for 18 hours, followed by incubation with the mitochondrial tracer Mitotracker[[[]] TM Red CM-H2Xros (M7513, Thermofisher) or the lysosomal tracer Lysotracker[[[]] TM Red DND-99 (L7528, Thermofisher) for 45 minutes.

[0328] Results

[0329] Using the latter method, the results showed that [[[]] Colocalizes with lysosomes but not with mitochondria (data not shown). These results were demonstrated by transmission electron microscopy (TEM) imaging.

[0330] Example 4: Role of iron in the radiosensitization of nanoparticles containing high atomic number elements according to the present invention

[0331] Materials and methods

[0332] Cells were seeded in 6-well plates at a density of 100 - 300 cells / well. The next day, the cells were incubated with increasing activities (0 - 4 MBq / mL) of 177 Lu-trastuzumab in the presence of 100 μM deferoxamine (DFP) (Selleck Chemicals), with or without 10 mg / mL of for 18 hours. Then, the medium was removed, the cells were washed twice with 1X phosphate-buffered saline (PBS), fresh medium was added, and the clonogenic survival assay of the cells was performed as described above. Three independent experiments were conducted with three replicates for each experiment.

[0333] Results

[0334] The results are as Figure 9 and Figure 10 shown.

[0335] Figure 9 The results of showed that in the presence of deferoxamine (an iron chelator), the sensitization effect on targeted radionuclide therapy (TRT) disappeared, as measured by the clonogenic survival rate of the treated cells. Lysosomes contain iron, which participates in the formation of reactive oxygen species (ROS) through the Fenton reaction. When nanoparticles were co-administered with targeted radionuclide therapy (TRT), this process was exacerbated and led to lysosomal rupture. The oxidative process caused lysosomal rupture, manifested as a decrease in the number of lysosomes and a decrease in cytoplasmic pH (data not shown). The iron released from the ruptured lysosomes also generated a wave of reactive oxygen species (ROS) in the cytoplasm, resulting in DNA damage, manifested as an increase in micronucleus formation (data not shown). The role of reactive oxygen species (ROS) in the sensitization effect on targeted radionuclide therapy (TRT) was demonstrated by the use of ROS scavengers (dimethyl sulfoxide (DMSO), N-acetylcysteine (NAC)) and antioxidant enzymes (catalase). Therefore, severe lipid peroxidation was observed, indicating the potential role of ferroptosis in the mediated toxicity.

[0336] In summary, these results indicate that targeted radionuclide therapy (TRT) + The efficacy of combination therapy is mediated by ferroptosis.

[0337] These results were confirmed by transmission electron microscopy (TEM) images of cells treated with targeted radionuclide therapy (TRT) in the presence or absence of deferiprone and treatment ( Figure 10 ).

[0338] Figure 10 The shown transmission electron microscopy (TEM) micrographs depict SKOV3 cells treated with 1 MBq / mL 177 Lu-trastuzumab + 10 mg / mL for 48 hours in the presence of the iron chelator deferiprone (DFP). Yellow arrows indicate cytoplasmic lysis / necrosis-like features. Figure 10 The left panel of shows the results of targeted radionuclide therapy (TRT) + Figure 10 treatment after 48 hours of incubation, and the right panel of

[0339] shows the same treatment results in the presence of deferiprone (DFP). In the presence of the iron chelator, cytoplasmic vacuolization (indicated by arrows) disappears. In summary, Figure 10 the transmission electron microscopy (TEM) micrographs of show that the combination of targeted radionuclide therapy (TRT) + results in significant observed ultrastructural changes characterized by extensive cytoplasmic vacuolization, followed by marked cytoplasmic lysis and accumulation of autophagosomes and undigested damaged cellular components. Thus, iron chelation increases the survival rate of cells treated with targeted radionuclide therapy (TRT) + , restores lysosomal integrity, and reverses the above-mentioned ultrastructural changes.

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Claims

1. Use of nanoparticles containing high atomic number elements in a method for treating tumors by radiopharmaceutical therapy in a subject in need thereof; The method comprises co-administering an effective amount of the nanoparticles containing high atomic number elements and an effective amount of a therapeutic radiopharmaceutical containing a radionuclide; Among them, The nanoparticles containing high atomic number elements comprise elements with an atomic number greater than 40, preferably greater than 50; and Wherein, the nanoparticles have an average hydrodynamic diameter of 20 nanometers or less, for example, between 1 nanometer and 10 nanometers, preferably between 2 nanometers and 8 nanometers.

2. The nanoparticles for use in a method according to claim 1, wherein, The nanoparticles enhance the therapeutic effect of the radiopharmaceutical.

3. The nanoparticle for use according to any one of claims 1 or 2, wherein, The high atomic number elements are selected from heavy metals, more preferably selected from Au, Ag, Pt, Pd, Sn, Ta, Zr, Tb, Tm, Ce, Dy, Er, Eu, La, Nd, Pr, Lu, Yb, Bi, Hf, Ho, Pm, Sm, In, and Gd, and mixtures thereof.

4. The nanoparticle for use according to any one of claims 1 to 3, wherein, The radioactive nuclide is selected from 177 Lu, 161 Tb, 186 Re, 131 I, 90 Y, 225 Ac / 213 Bi, 223 Ra, 212 Pb / 212 Bi, 227 Th, 211 At, 97 Ru, 103 Pd, 67 Ga, 195m Pt, 193m Pt, 125 I, 111 In, and mixtures thereof.

5. The nanoparticles for use according to any one of claims 1 to 3, wherein, The effective amount of the radiopharmaceutical is between 0.5 MBq and 100 GBq.

6. The nanoparticles for use according to any one of claims 1 to 4, wherein, The radionuclide is linked to a cancer targeting moiety.

7. The nanoparticle for use according to claim 5, wherein, The cancer targeting moiety is an antibody, a peptide, or a small molecule ligand.

8. The nanoparticles for use according to any one of claims 6 or 7, wherein, The cancer targeting moiety is selected from: Anti-HER2 antibodies, such as trastuzumab, pertuzumab or ibritumomab (also known as ibritumomab tiuxetan, sold under the trademark commercially available); Anti-EGFR antibodies, such as cetuximab or panitumumab; Anti-CD20 antibodies, such as rituximab or Zevalin; Anti-CD33 antibodies, such as lintuzumab; Anti-CD37 antibodies, such as olaratumab (TRU-016), monoclonal antibody 37.1 (BI 836826), or IMGN529 (K7153A-DM1); Anti-AMHRII antibodies, such as mulranumab; or Anti-TYRP1 / gp75 antibodies, such as IMC-20D7S; Somatostatin analogs, such as octreotide (DOTATOC) or octreotate (DOTATATE); or PSMA small molecule ligands, such as 617 ligand, I&T ligand, R2 ligand, or MIP-1095 ligand).

9. The nanoparticle for use according to any one of claims 1 to 8, wherein, The therapeutic radiopharmaceutical is selected from: 177 Lu-anti-HER2 antibody, such as 177 Lu-trastuzumab; 177 Lu-somatostatin analog, such as 177 Lu-octreotide acid; 177 Lu-PSMA ligand; 90 Y-anti-CD20 antibody, such as 90 Y-rituximab or 90 Y-ibritumomab tiuxetan; 212 Pb-anti-HER2 antibody; 177 Lu-anti-CD37 antibody.

10. The nanoparticle for use according to any one of claims 1 to 4, wherein, The therapeutic radiopharmaceutical consists of 131 I or 223 Ra.

11. The nanoparticles for use according to any one of claims 1 to 10, wherein, The nanoparticles are administered to the subject in a fractionated dose regimen.

12. The nanoparticle for use according to any one of claims 1 to 11, wherein, For a single dose of the therapeutic radiopharmaceutical administered to the subject, the fractionated dose regimen of the nanoparticles comprises 2 to 10 fractionated doses of the nanoparticles.

13. The nanoparticles for use according to any one of claims 1 to 12, wherein, The subject is a subject who cannot receive a standard effective dose of radiopharmaceutical therapy.

14. The nanoparticles for use according to any one of claims 1 to 13, wherein, The tumor is a radioresistant tumor.

15. The nanoparticle for use according to any one of claims 1 to 14, wherein, The tumors are selected from peritoneal tumors, neuroendocrine tumors, prostate tumors, neuroblastomas, meningiomas, lymphomas, Merkel cell carcinomas, breast tumors, renal cell tumors, and salivary gland carcinomas; The peritoneal tumors include primary peritoneal tumors and secondary peritoneal tumors; The neuroendocrine tumors include gastroenteropancreatic neuroendocrine tumors and pheochromocytomas or paragangliomas (PPGL).

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