Radiolabeled liposomes and methods of use for treatment of soft meningeal metastasis

Abstract

Radiolabeled liposomes can be used to treat cancer. These topical therapies may be used to treat cancers, including but not limited to hemametriometastases. In an embodiment, a radiolabelled liposome obisbemeda, including (186Re), may be administered to a patient through an Oma reservoir. Therapy may include imaging the radiolabelled liposomes simultaneously with or after administration.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 302,953, filed on January 25, 2022; U.S. Provisional Application No. 63 / 333,050, filed on April 20, 2022; and U.S. Provisional Application No. 63 / 343,034, filed on May 17, 2022, all of which are incorporated herein by reference. Background Art

[0003] Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor in adults. Over the past decade, the standard treatment for GBM has been surgery followed by chemoradiation with temozolomide, with radiation therapy being the main factor for survival in this regimen. Although external beam radiation therapy (EBRT) remains a mainstay of primary brain tumor treatment, it is limited by the tolerance of surrounding normal brain tissue. Since most recurrences occur within two centimeters of the resection margin, there is still an urgent need to develop local therapies, such as brachytherapy.

[0004] Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis, is a rare but typical fatal complication of advanced cancers in which many cancer cells metastasize. Although any solid tumor may develop into LM, the most common LM originates from four common primary cancers, i.e. breast cancer, lung cancer, melanoma and gastrointestinal cancer, which metastasize to the central nervous system (CNS) and are found in the leptomeninges (membranes surrounding the brain and spinal cord) or cerebrospinal fluid (CSF) (circulating nutrients and chemicals to the brain and spinal cord). Due to the lack of symptoms, it is often undiagnosed and causes neurological complications such as difficulty thinking, diplopia and headache. 5% of patients with metastatic cancer are diagnosed with LM. LM occurs in 5-8% of patients with solid tumors. There is no good treatment in the recognized standard of care, and patients often have to choose between toxic treatments and very short life expectancy.

[0005] Most solid tumors are known to cause LM, but the most common solid tumors that cause LM are breast cancer, lung cancer, melanoma, gastrointestinal tumors, and primary central nervous system tumors. Other LM categories include hematological malignancies (leukemias and lymphomas) and primary CNS tumors (especially medulloblastomas). Standard treatment includes radiotherapy (RT) to the affected site, followed by chemotherapy delivered to the cerebrospinal fluid (CSF) or systemic treatment of the underlying malignant tumor. Most intrathecal and systemic chemotherapy have unfriendly side effects. The median survival depends on the source of the primary tumor and is usually 2-4 months. If untreated, the survival period is usually about 6-8 weeks. Neurological symptoms are usually fixed and rarely improve with treatment. LM patients are in great need of new treatment methods that can prolong survival and maintain quality of life by delaying further neurological deterioration. Treatment of LM with external beam radiation must travel through and therefore damage surrounding normal tissue to reach the tumor. In this relatively radioresistant tumor, the risk of significant side effects of whole neuroaxial radiotherapy usually outweighs the benefits. Focal radiation therapy relieves neurological symptoms but has no significant effect on survival. Other radiotherapeutic agents are usually unable to reach and destroy tumors via systemic administration because of the blood-brain barrier.

[0006] Thalamic tumors account for about 5% of brain tumors. Thalamic tumors are difficult to remove surgically due to their location. Selected examples of thalamic tumors are gliomas such as astrocytomas and glioblastomas.

[0007] Brainstem tumors are difficult to remove surgically due to their location and can affect basic functions such as breathing and heartbeat. Selected examples of brainstem tumors are diffuse intrinsic brainstem gliomas (DIPGs) and focal brainstem gliomas.

[0008] There remains a need to develop localized therapies for cancers, such as lung cancer, breast cancer, colorectal cancer, prostate cancer, skin cancer, stomach cancer, bladder cancer, liver cancer, leukemia, lymphoma, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, melanoma, sarcoma, head and neck cancer, thalamic tumors, brain stem tumors, gliomas, glioblastomas, medulloblastomas, ependymomas, diffuse intrinsic pontine gliomas, leptomeningeal metastases, and high-grade gliomas in children. Summary of the invention

[0009] In one aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a radiolabeled liposome comprising a liposome and a compound of Formula I:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] M is99m Tc, 186 Re, 188 Re or a combination thereof;

[0013] X is NR 1 ;

[0014] R 1 is CH2CH2NEt2 or CH2CH2CH2CH3; and

[0015] R 2 It is CH2CH2N(CH2CH2SH)(CH2CH2NEt2) or CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3).

[0016] In some embodiments, R 1 is CH2CH2NEt2 and R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2). In some embodiments, R 1 is CH2CH2CH2CH3 and R 2 is CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3). In some embodiments, M is 186 Re.

[0017] In some embodiments, the compound is incorporated into or attached to the liposome.

[0018] In some embodiments, the liposome further comprises a drug incorporated into the liposome.

[0019] In some embodiments, the drug is a compound comprising at least one thiol group. In some embodiments, the drug reacts with the compound. In some embodiments, the drug comprises glutathione, cysteine, N-acetylcysteine, 2-mercaptosuccinic acid, 2,3-dimercaptosuccinic acid, captopril, or a combination thereof.

[0020] In some embodiments, the liposomes comprise lipids. In some embodiments, the liposomes comprise phospholipids.

[0021] In some embodiments, the liposomes comprise cholesterol or a cholesterol analog. In some embodiments, the liposomes comprise distearoylphosphatidylcholine.

[0022] In some embodiments, the radiolabeled liposomes include about 0.01 mCi to about 400 mCi of the compound per 50 mg of lipid used to prepare the liposomes.

[0023] In some embodiments, the liposome further comprises a chemotherapeutic agent, an antibiotic agent, or a therapeutic molecule, wherein the chemotherapeutic agent, the antibiotic agent, or the therapeutic molecule is incorporated into or attached to the liposome.

[0024] In some embodiments, the disease or illness is cancer. In some embodiments, the cancer is selected from lung cancer, breast cancer, colorectal cancer, prostate cancer, skin cancer, gastric cancer, bladder cancer, liver cancer, leukemia, lymphoma, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, melanoma, sarcoma, head and neck cancer, glioma, glioblastoma, medulloblastoma, ependymoma, diffuse intrinsic pontine glioma, leptomeningeal metastasis and high-grade glioma in children. In some embodiments, the cancer is glioma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is recurrent glioblastoma. In some embodiments, the cancer is leptomeningeal metastasis.

[0025] In some embodiments, the subject has not previously received a therapy comprising bevacizumab.

[0026] In some embodiments, the radiolabeled liposomes are administered by infusion of an infusion comprising the radiolabeled liposomes.

[0027] In some embodiments, the radiolabeled liposomes are administered by convection enhanced delivery. In some embodiments, the convection enhanced delivery comprises administering the radiolabeled liposomes through one or more catheters. In some embodiments, the convection enhanced delivery comprises administering the radiolabeled liposomes through one catheter. In some embodiments, the convection enhanced delivery comprises administering the radiolabeled liposomes through two catheters. In some embodiments, the convection enhanced delivery comprises administering the radiolabeled liposomes through three catheters. In some embodiments, the convection enhanced delivery comprises administering the radiolabeled liposomes through four catheters. In some embodiments, convection enhanced delivery comprises

[0028] In some embodiments, the concentration of the mixture is about 1 μL min -1 About 50 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 5 μL min -1 About 20 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 5 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 10 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 15 μL min-1 In some embodiments, the infusion is administered at a maximum flow rate of about 20 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 25 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 30 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 35 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 40 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 45 μL min -1 The infusate is administered at a maximum flow rate of .

[0029] In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 0.1 mCi to about 50 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 1 mCi to about 20 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 1 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 2 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 4 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 8 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 13.4 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 22.3 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 31.2 mCi.

[0030] In some embodiments, the volume of the infusion is about 0.1mL to about 25mL. In some embodiments, the volume of the infusion is about 0.5mL to about 10mL. In some embodiments, the volume of the infusion is about 1mL to about 5mL. In some embodiments, the volume of the infusion is about 2mL to about 15mL. In some embodiments, the volume of the infusion is about 5mL to about 10mL. In some embodiments, the volume of the infusion is about 10mL to about 15mL. In some embodiments, the volume of the infusion is about 15mL to about 20mL. In some embodiments, the volume of the infusion is about 0.66mL. In some embodiments, the volume of the infusion is about 1mL. In some embodiments, the volume of the infusion is about 1.32mL. In some embodiments, the volume of the infusion is about 2mL. In some embodiments, the volume of the infusion is about 2.64mL. In some embodiments, the volume of the infusion is about 3mL. In some embodiments, the volume of the infusion is about 4mL. In some embodiments, the volume of the infusion is about 5mL. In some embodiments, the volume of the infusion is about 5.28 mL. In some embodiments, the volume of the infusion is about 6 mL. In some embodiments, the volume of the infusion is about 7 mL. In some embodiments, the volume of the infusion is about 8 mL. In some embodiments, the volume of the infusion is about 8.8 mL. In some embodiments, the volume of the infusion is about 9 mL. In some embodiments, the volume of the infusion is about 10 mL. In some embodiments, the volume of the infusion is about 11 mL. In some embodiments, the volume of the infusion is about 12 mL. In some embodiments, the volume of the infusion is about 12.3 mL. In some embodiments, the volume of the infusion is about 13 mL. In some embodiments, the volume of the infusion is about 14 mL. In some embodiments, the volume of the infusion is about 15 mL. In some embodiments, the volume of the infusion is about 16 mL. In some embodiments, the volume of the infusion is about 16.35 mL. In some embodiments, the volume of the infusion is about 17 mL. In some embodiments, the volume of the infusion is about 18 mL. In some embodiments, the volume of the infusate is about 18.5 mL. In some embodiments, the volume of the infusate is greater than about 18.5 mL. In some embodiments, a volume of the infusate is delivered to a single hemisphere of the brain (e.g., including a glioblastoma). In some embodiments, a volume of the infusate is delivered to both hemispheres of the brain (e.g., including a glioblastoma).

[0031] In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 0.1 mCi mL -1 to about 50 mCi mL -1In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 0.5 mCi mL -1 About 10mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 1 mCimL -1 to about 5mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 1 mCi mL -1 to about 10mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 2 mCi mL -1 to about 10mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 4 mCi mL -1 to about 10mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 5 mCi mL -1 to about 10mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 1 mCi mL -1 About 3mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 1 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 1.5 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 2 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 2.5 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 3 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 4 mCi mL -1In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 5 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 6 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 7 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 8 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 9 mCimL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 10 mCi mL -1 .

[0032] In some embodiments, the method further comprises imaging the radiolabeled liposomes while administering. In some embodiments, the method further comprises imaging the radiolabeled liposomes after administering.

[0033] Incorporation by reference

[0034] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The novel features of the present invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by referring to the following detailed description and the accompanying drawings, which set forth exemplary embodiments utilizing the principles of the present invention, wherein:

[0036] Figure 1 Figure 2 shows the tumor volume of patients previously treated with bevacizumab and patients who had not received bevacizumab. 186 Absorbed dose of Re nanoliposomes.

[0037] Figure 2 Shown 186 Tumor volume per patient treated with Re nanoliposomes.

[0038] Figure 3 Shows the 186Ratio of volume treated to volume infused vs. volume infused after Re nanoliposome treatment.

[0039] Figure 4 The difference between patients previously treated with bevacizumab and those who had not received bevacizumab was shown. 186 Differences in survival after Re nanoliposome treatment.

[0040] Figure 5 The results for each dose level are shown. 186 Re nanoliposomes, mean absorbed doses to brain, whole body, and tumor volume.

[0041] Figure 6 Shows the 186 Baseline magnetic resonance images (MRI) and single-photon emission computed tomography (SPECT) images after Re nanoliposome treatment.

[0042] Figure 7 Shows the baseline and current 186 Magnetic resonance images (MRI) and perfusion scan images 56 days after Re nanoliposome treatment.

[0043] Figure 8 shows a 3D image showing the 186 Range of radiation delivered (measured as absorbed dose) within 8 days after Re nanoliposome treatment.

[0044] Fig. 9 A graph showing the overall survival of the subjects, including the varying mean absorbed dose and TuV / TrV percentages is shown.

[0045] Fig.10 Images including baseline MRI, and SPECT images at the end of infusion, 24 hours post-infusion, 120 hours post-infusion, and 192 hours post-infusion are shown.

[0046] Fig.11 Images including baseline MRI, and SPECT images after 20% infusion, at the end of infusion, 24 hours after infusion, 120 hours after infusion, and 192 hours after infusion are shown.

[0047] Fig.12 Kaplan Meier curves comparing overall survival of patients who received greater than 100 Gy to those who received less than 100 Gy are shown.

[0048] Fig.13 Baseline MRI and multiple SPECT images taken at various time points are shown.

[0049] Fig.14A Shows 186 Re nanoliposomes (e.g. 186 3D dose distribution in RNL brachytherapy.

[0050] Fig. 14B A dose volume histogram including percentage of coverage on the Y-axis and absorbed dose (in Gy) on the X-axis for a number of patients is shown.

[0051] Fig. 14C Iso-dose distributions of stereotactic body radiation therapy (SBRT) doses are shown for comparison.

[0052] Fig.15 Baseline magnetic resonance images (MRI) and single photon emission computed tomography (SPECT) images after treatment with 186Re nanoliposomes are shown.

[0053] Fig.16 MRI scans of tumor responses observed through day 362 are shown.

[0054] Fig.17 A process for convection-enhanced delivery for treating GBM is shown.

[0055] Fig.18 Efficacy and survival data for ReSPECT-GBM are shown.

[0056] Fig.19 Shown are SPECT CT, planar imaging, and CSF liquid biopsy results for patients after 186RNL treatment.

[0057] 20A and 20B show methods of producing Re-188 nanoliposomes and Re-188 nanoliposome biodegradable alginate microspheres.

[0058] Fig.21 An approach to nonsurgical locoregional treatment options for solid organ tumors is presented.

[0059] Fig. 22 A graph of radiation density and a table of density versus infusion volume are shown.

[0060] Fig.23 A table of patients versus infusion volumes is shown.

[0061] Fig.24 RNL Kaplan-Meier plots are shown comparing overall survival of patients who received greater than 100 Gy to those who received less than 100 Gy up to 40 months.

[0062] Fig.25 Shown is an RNL Kaplan-Meier plot comparing overall survival of GBM patients receiving greater than 100 Gy to those receiving less than 100 Gy up to 42 months.

[0063] Fig.26 Plots of mortality as a function of dose and tumor coverage are shown.

[0064] Fig. 27 Radiotherapeutic formulations of rhenium (186Re)obisbemeda and rhenium-188 nanoliposomal biodegradable alginate microspheres are shown.

[0065] Fig.28 Shown are graphs of tumor retention over time based on percent injected activity for 186Re-nanoliposomes, 186Re-BMEDA, and 186Re-perrhenate (intratumoral administration of CED in head / neck SCC xenografts in nude rats).

[0066] Fig.29 Shown are graphs of tumor response based on tumor volume over time for 186Re-nanoliposomes, 186Re-BMEDA, 186Re-perrhenate, and nanoliposome control (intratumoral administration of CED in head / neck SCC xenografts in nude rats).

[0067] Fig.30 The proportion alive as a percentage of treated tumor volume versus number of months (overall survival) is shown.

[0068] Fig.31 The proportion alive with mean absorbed dose in tumor versus number of months (overall survival) is shown.

[0069] Fig.32 Pial administration and rapid diffusion of rhenium (186Re)obisbemeda targeting CSF are shown.

[0070] Fig.33 Shows the latest information about the ReSPECT-LM clinical trial. DETAILED DESCRIPTION

[0071] definition

[0072] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0073] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0074] As used herein, the term "radionuclide" refers to any element that emits radiation. Examples of radiation that can be emitted from a radionuclide include, but are not limited to, α-emission, β-emission, γ-emission, x-ray-emission, conversion electron emission, or Auger electron emission. Radiation emitted from a radionuclide can be detected and measured using techniques known in the art (see, Goins and Phillips "The use of scintigraphic imaging as a tool in the development of liposome formulations," Progress in Lipid Research, 40, pp. 95-123, 2001, which is incorporated herein by reference in its entirety). Examples of radionuclides useful in embodiments provided herein are disclosed in "Srivastava et al. in "Recent Advances in Radionuclide Therapy," Seminars in Nuclear Medicine, Vol. XXXI, No. 4, pp. 330-341, (October), 2001, which is incorporated by reference in its entirety.

[0075] As used herein, "radiolabeled liposomes" refers to liposomes that include a radiolabeled compound provided herein, which is incorporated into or attached to the liposomes. The term "liposome" refers to any vesicle that includes a bilayer membrane. "Liposomes" include unilamellar and multilamellar liposomes.

[0076] As used herein, the term "incorporated" means that the compound of Formula I is embedded in the bilayer membrane of the liposome. Since the bilayer membrane of the liposome is lipophilic, a compound with high lipophilicity can be trapped within the bilayer membrane of the liposome.

[0077] "Pharmaceutically acceptable carrier" refers to ingredients in a pharmaceutical composition other than the active ingredient that are non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives, such as those known in the art, for example, as described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0078] As used herein, "treatment" or "treating" is a method of obtaining beneficial or desired results, including and preferably clinical results. For example, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dosage of other drugs required to treat the disease, delaying the progression of the disease, and / or prolonging the survival of the individual.

[0079] As used herein, an "effective dose" or "effective amount" of a drug, compound or pharmaceutical composition is an amount sufficient to produce a beneficial or desired result. For preventive use, beneficial or desired results include results such as eliminating or reducing risk, reducing severity or delaying the onset of disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes that occur during the development of the disease. For therapeutic use, beneficial or desired results include clinical results such as reducing one or more symptoms caused by the disease, improving the quality of life of patients with the disease, reducing the dose of other drugs required to treat the disease, enhancing the effect of other drugs (such as by targeting), delaying disease progression and / or prolonging survival. In the case of cancer or tumors, an effective amount of the drug can have the following effects: reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing down and preferably preventing to some extent) the infiltration of cancer cells into peripheral organs; inhibiting (i.e., slowing down and preferably preventing to some extent) tumor metastasis; inhibiting tumor growth to some extent; and / or alleviating one or more symptoms associated with the disease to some extent. The effective dose can be administered in one or more administrations. For purposes of the present invention, the effective dose of a medicine, compound or pharmaceutical composition is the amount that is enough to directly or indirectly complete preventive or therapeutic treatment. As understood in clinical context, the effective dose of a medicine, compound or pharmaceutical composition may or may not be combined with other medicines, compounds or pharmaceutical compositions to achieve. Therefore, "effective dose" can be considered in the case of one or more therapeutic agents of administration, and if combined with one or more other agents, it is possible or has reached desirable results, then it is possible to consider giving a single agent with an effective amount.

[0080] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate the administration of active agents and absorption by subjects, and can be included in the compositions of the present invention without causing significant adverse toxicological effects on patients. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine and pigments, etc. Such preparations can be sterilized and, if necessary, can be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants and / or aromatic substances, etc., which do not react harmfully with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0081] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without other carriers, is surrounded by a carrier and thereby combined with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration. The term is intended to encompass radiolabels.

[0082] As used herein, the term "administration" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, convection (e.g., by convection enhancement delivery) or subcutaneous administration, or implanting a sustained release device, such as a micro-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., oral, sublingual, palate, gums, nose, vagina, rectum or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other delivery methods include, but are not limited to, use liposome compositions, intravenous infusion, transdermal patches, etc.

[0083] As used herein, the term "delivered" and variations thereof (eg, "delivering") are used interchangeably with the term "administered" and variations thereof (eg, "administering").

[0084] "Co-administration" means administering a compound as described herein at the same time, just before, or just after administration of one or more other therapies (e.g., anticancer agents described herein). The compounds described herein may be administered to a patient alone, or the compounds described herein may be co-administered. Co-administration is meant to include administration of compounds (more than one compound or agent) separately or in combination, either simultaneously or sequentially. Thus, the formulation may also be combined with other active substances (e.g., anticancer agents) when desired.

[0085] Co-administration includes administration of one active agent (e.g., a radiolabeled nanoliposome described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent (e.g., an anticancer agent). Embodiments are also contemplated herein in which co-administration includes administration of one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes simultaneous, approximately simultaneous (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other) or sequential administration of two active agents in any order. Co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition comprising two active agents. In other embodiments, the active agents can be formulated separately. In some embodiments, the active agents and / or adjuvants are linked or conjugated to each other. In some embodiments, the compounds described herein are combined with cancer treatments such as chemotherapy or radiotherapy.

[0086] "Patient," "subject," "patient in need thereof," and "subject in need thereof" are used interchangeably herein and refer to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human. A "cancer patient" is a patient suffering from or susceptible to developing cancer.

[0087] Unless otherwise expressly stated, the term "subject" as used herein refers to a mammal, including but not limited to cattle, horses, cats, rabbits, dogs, rodents, or primates (e.g., humans). In some embodiments, the subject is a human. In some embodiments, the subject is a non-human primate, such as a chimpanzee and other ape and monkey species. In some embodiments, the subject is a farm animal, such as cattle, horses, sheep, goats, and pigs; a pet, such as a rabbit, dog, and cat; a laboratory animal, including rodents, such as rats, mice, and guinea pigs; and the like. In some embodiments, the present invention has applications in both human medicine and veterinary settings.

[0088] "Disease" or "disorder" refers to a living state or health condition of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, the disease as used herein refers to cancer.

[0089] "Chemotherapeutic" or "chemotherapeutic agent" are used in their plain ordinary sense and refer to a chemical composition or compound that has anti-tumor properties or the ability to inhibit cell growth or proliferation.

[0090] As used herein, "cancer model organism" is an organism that exhibits a phenotype indicating the activity of cancer or carcinogenic elements in an organism. The term cancer is defined above. Various organisms can serve as cancer model organisms, and include, for example, cancer cells and mammalian organisms, such as rodents (e.g., mice or rats) and primates (such as humans). Cancer cell lines are widely understood by those skilled in the art to be cells that exhibit a phenotype or genotype similar to cancer in vivo. Cancer cell lines as used herein include cell lines from animals (e.g., mice) and from humans.

[0091] Radiolabeled nanoliposomes

[0092] Brachytherapy can be used to treat cancer selected from the group consisting of lung cancer, breast cancer, colorectal cancer, prostate cancer, skin cancer, stomach cancer, bladder cancer, liver cancer, leukemia, lymphoma, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, melanoma, sarcoma, head and neck cancer, glioma, glioblastoma, medulloblastoma, ependymoma, diffuse intrinsic pontine glioma, thalamic tumor, brain stem tumor, leptomeningeal metastasis, and high-grade glioma in children. In some embodiments, the cancer is a thalamic tumor. In some embodiments, the cancer is a brain stem tumor. In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a recurrent glioblastoma. In some embodiments, the cancer is a leptomeningeal metastasis.

[0093] Liposomes including phospholipids and / or sphingolipids can be used to deliver hydrophilic (water-soluble) or precipitated therapeutic compounds encapsulated in the internal liposome volume and / or deliver hydrophobic therapeutic agents dispersed in the hydrophobic bilayer membrane. In some aspects, liposomes include lipids selected from sphingolipids, ether lipids, sterols, phospholipids, phosphoglycerides and glycolipids. In some aspects, lipids include, for example, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine).

[0094] Liposomes are of considerable interest due to their value as carriers of diagnostic agents, particularly radiopharmaceuticals for tracer and imaging studies. There are many advantages to using liposomes as carriers of therapeutic radionuclides. Some of the advantages include: (1) the biocompatibility of liposomes; (2) liposome particles of varying sizes with a uniform population size range can be easily obtained by using extrusion techniques; (3) the surface of liposomes can be modified with different kinds of functional groups; (4) the distribution of liposomes can be functionalized and microtargeted; and (5) the mechanism of diffusion of radioisotopes from liposomes can be monitored, which helps to deliver uniform dose distribution in tumor tissue.

[0095] Radionuclides have been widely used as a non-invasive method to study the distribution of drugs in vivo. However, attempts to label liposomes with radionuclides as imaging agents have produced variable results. Many radionuclides bind weakly to liposomes, resulting in leaching of the radionuclide from the liposomes and inaccurate biodistribution data. In addition, trapping water-soluble radionuclides within liposomes during manufacturing is relatively inefficient.

[0096] In embodiments, occult tumor cells are responsible for tumor recurrence.In embodiments, targeted killing of both tumor and specific margins of abnormal tissue is performed while sparing normal neuronal tissue and cells.

[0097] Embodiments of the present disclosure are methods of delivering a significant increment of a composition to a patient receiving a previous maximum dose of radiation therapy to treat a primary disease, a secondary disease, or both of the patient. Embodiments of the present disclosure are methods of delivering a significant increment of a composition to a patient receiving a previous maximum dose of radiation therapy to treat a primary disease, a secondary disease, or both of the patient. In embodiments, radiation is selected from beta radiation or alpha particle therapy including isotopes Ac225, Pb212, or Cu67. In embodiments, radiolabeled liposome formulations deliver radiation plus residence time sufficient to eradicate cancer cells in cerebrospinal fluid, pia mater lining, or both but without damaging the surrounding brain or other systemic organs and tissues. In embodiments, the composition includes simultaneous delivery and visualization of radioactive therapeutic material delivery, with the goal of ensuring successful delivery or changing key delivery parameters for administration. In some embodiments, the subject receiving the radiation increment has previously received the maximum dose of radiation. In some embodiments, the subject receiving the radiation increment has previously received the maximum dose of radiation for treating one or more of its primary and / or secondary diseases. In some embodiments, the subject has previously received the maximum dose of radiation to treat cancer (e.g., glioblastoma). In some cases, the maximum radiation dose comprises a maximum permissible dose (eg, an upper limit of permissible radiation that a subject can receive without risk of significant side effects).

[0098] In embodiments, radiolabeled nanoliposomes (RNL) may be used to treat cancer. In embodiments, RNL may be used to treat cancer by brachytherapy. In embodiments, RNL may be used to treat glioblastoma, leptomeningeal metastases, thalamic tumors, and brainstem tumors.

[0099] In some embodiments, provided herein is a method for delivering and visualizing (e.g., imaging) radioactive therapeutic material delivery. In some embodiments, the radioactive therapeutic material includes a pharmaceutical composition disclosed herein. In some embodiments, provided herein is a method for delivering and visualizing (e.g., imaging) a pharmaceutical composition (e.g., a radiolabeled liposome (e.g., 186Re nanoliposome)). In some embodiments, the method includes ensuring delivery to a target. In some embodiments, the target is cancer. In some embodiments, the target is a tumor. In some embodiments, the tumor is a primary tumor. In some embodiments, the tumor is a secondary tumor. In some embodiments, the method includes modifying (e.g., changing) one or more delivery parameters during delivery. In some embodiments, a radioactive therapeutic material (e.g., a pharmaceutical composition) is delivered. In some embodiments, the method includes modifying one or more delivery parameters during delivery and ensuring that the pharmaceutical composition is delivered to the target during delivery.

[0100] In some embodiments, visualization (e.g., imaging) comprises any imaging method disclosed herein (e.g., SPECT, SPECT-CT, MRI, etc.). In some embodiments, visualization (e.g., delivery of radioactive therapeutic substances (radiolabeled liposomes (e.g., mRe))) comprises imaging the whole body. In some embodiments, visualization comprises imaging a region (e.g., a local region) of the body (e.g., the head). In some embodiments, visualization comprises imaging a target (e.g., a tumor). In some embodiments, visualization comprises imaging a primary tumor. In some embodiments, visualization comprises imaging a secondary tumor. In some embodiments, visualization comprises imaging a primary tumor and a secondary tumor. In some embodiments, visualization comprises imaging a tumor and a surrounding area of ​​the tumor (e.g., an area where the tumor is located and / or within 6 inches of the tumor). In some embodiments, visualization comprises imaging one or more organs (e.g., including the tumor and / or within the area of ​​the tumor). In some embodiments, visualization comprises imaging a primary tumor or a disease area. In some embodiments, a surrogate marker is measured in conjunction with visualization of a disease area.

[0101] Rhenium-186 isotope

[0102] Dual energy emitter: β (cytotoxicity) & γ (imaging)

[0103] Short average path length (1.8mm): high precision

[0104] Low dose rate: safer for normal tissues

[0105] High radiation density: overwhelms the innate DNA repair mechanism

[0106] Rhenium-188

[0107] Dual energy emitter: β (cytotoxicity) & γ (imaging)

[0108] Short average path length (3.1mm): provides higher accuracy

[0109] Low dose rate: safer for normal tissues

[0110] High radiation density: overwhelms the innate DNA repair mechanism

[0111] Generator-generated for fast availability

[0112] The therapeutic agent can be a chemotherapeutic agent or a radiotherapeutic agent. In some aspects, the chemotherapeutic agent is a taxane, an epothilone, or a vinca alkaloid. In some aspects, the radiotherapeutic agent is 131 I. 90 Y. 99 mTc, 177 Lu, 186 Re, 188 Re, 125 I. 123 I or any combination thereof. In other aspects, the radioactive therapeutic agent can be one or more of the following: bismuth-213, cesium-131, chromium-51, cobalt-60, dysprosium-165, erbium-169, holmium-166, iodine-125, iodine-131, iridium-192, iron-59, lead-212, lutetium-177, molybdenum-99, palladium-103, phosphorus-32, potassium-42, radium-223, rhenium-186, rhenium-188, samarium-153, scandium-47, selenium-75, Sodium-24, strontium-89, technetium-99m, thorium-227, xenon-133, ytterbium-169, ytterbium-177, yttrium-90, actinium-225, astatine-211, bismuth-212, carbon-11, fluorine-18, nitrogen-13, oxygen-15, cobalt-57, copper-64, copper-67, gallium-67, gallium-68, germanium-68, indium-111, iodine-123, iodine-124, krypton-81m, rubidium-82, strontium-82, and / or thallium-201.

[0113] In embodiments, the liposomes encapsulate a therapeutic agent complexed with a loading agent, a diagnostic agent complexed with a loading agent, or a combination thereof, wherein the loading efficiency of the therapeutic agent is 10, 20, 30, 40, 50, 60, 70, 80, 90 to 100%, including all ranges and values ​​therebetween. In certain aspects, the therapeutic agent or diagnostic agent is one or more of the following: bismuth-213, cesium-131, chromium-51, cobalt-60, dysprosium-165, erbium-169, holmium-166, iodine-125, iodine-131, iridium-192, iron-59, lead-212, lutetium-177, molybdenum-99, palladium-103, phosphorus-32, potassium-42, radium-223, rhenium-186, rhenium-188, samarium-153, scandium-47, selenium-75, Sodium-24, strontium-89, technetium-99m, thorium-227, xenon-133, ytterbium-169, ytterbium-177, yttrium-90, actinium-225, astatine-211, bismuth-212, carbon-11, fluorine-18, nitrogen-13, oxygen-15, cobalt-57, copper-64, copper-67, gallium-67, gallium-68, germanium-68, indium-111, iodine-123, iodine-124, krypton-81m, rubidium-82, strontium-82, and / or thallium-201.

[0114] Notable materials that can be encapsulated include radiotherapeutic materials (e.g., rhenium-188), radiolabels (e.g., technetium-99m), chemotherapeutic materials (doxorubicin), magnetic particles (e.g., 10 μm iron nanoparticles), and radiopaque materials (e.g., iodine contrast agents). In certain aspects, rhenium-188 liposomes can be used to treat liver tumors, particularly hepatocellular carcinoma (HCC). In more specific aspects, HCC treatment can be by radioembolization, in which the microspheres block the blood supply from the artery to the tumor while rhenium-188 also delivers high-dose radiation that primarily targets cancer cells.

[0115] In an embodiment, the radiotherapeutic agent is 209Bi, 211Bi, 212Bi, 213Bi, 210Po, 211Po, 212Po, 214Po, 215Po, 216Po, 218Po, 215At, 217At, 218At, 218Rn, 219Rn, 220Rn, 222Rn, 226Rn, 221Fr, 223Ra, 224Ra, 226 Ra, 225Ac, 227Ac, ​​227Th, 228Th, 229Th, 230Th, 232Th, 231Pa, 233U, 234U, 235U, 236U, 238U, 237Np, 238Pu, 239Pu, 240Pu, 244Pu, 241Am, 244Cm, 245Cm, 248Cm, 249Cf, 252Cf, or alpha decay isotopes.

[0116] In certain aspects, the radioactive therapeutic agent includes a radiolabel or radioactive therapeutic substance such as a beta emitter ( 131 I. 90 Y. 177 Lu, 186 Re, 188 Re, any of which may be specifically excluded) or gamma emitters ( 125 I. 123 I. 99m Tc) or any combination thereof. In certain aspects, the radioactive therapeutic agent is 188Re. In addition, the term "radiotherapeutic substance" may more broadly encompass any radiolabeled moiety and may include any liposome that is bound to or includes a radionuclide. Nuclear reactors are the source of many radioisotopes, while radioisotopes also come from cyclotrons. In general, nuclear fission [reactors] produce neutron-rich isotopes, while neutron-poor isotopes, such as PET radionuclides, are produced by cyclotrons [common PET positron isotopes have cyclotron energies of ~10-20 MeV, while single-photon products generally require higher cyclotron energies [~30 MeV]. In certain embodiments, the radiotherapeutic substance may be a reactor radioisotope or a cyclotron radioisotope. Reactor radioisotopes may include (1) therapeutic [Rx], beta and alpha and low energy x-rays [for brachytherapy] and / or (2) diagnostic [Dx], positrons and single photons. The Rx or Dx listed here are exemplary embodiments of how radioisotopes may be used. The scope of the present invention includes the use of the radioisotopes listed herein in other Rx or Dx.Reactor radioisotopes include, but are not limited to: Bismuth-213 (alpha), Cesium-131 ​​(x-ray brachytherapy Rx), Chromium-51 (Dx), Cobalt-60 (formerly EBRT, now commonly used for sterilization; historically HSACo-60 for brain cancer Rx), Dysprosium-165 (beta Rx), Erbium-169 (beta Rx), Holmium-166 (beta Rx), Iodine-125 (low energy x-ray Rx brachytherapy and RIA applications), Iodine-131 (beta Rx [fission product]; has imaging gamma, albeit at high energy), Iridium-192 (beta Rx; commonly used for Often used in the form of wires for brachytherapy, e.g., prostate), iron-59 (Dx used to study iron metabolism), lead-212 (αRx), lutetium-177 (Rxβ; with gamma emission for imaging), molybdenum-99 (precursor of Dx-Tc99m [fission products]), palladium-103 (an example of a low-energy x-ray Rx for permanent implant brachytherapy), phosphorus-32 (βRx; a past Rx for polycythemia vera), potassium-42 (Dx, used to measure exchangeable K+ for coronary blood flow), radium-223 (Rxα; with a low-energy x-rays (past brachytherapy Rx), rhenium-186 (beta Rx with imaging photons; past Rx bone pain), rhenium-188 (beta Rx; past coronary arteries via stents), samarium-153 (beta Rx; past product for bone pain / metastasis [Quadramet]), scandium-47 (beta Rx with imaging capabilities; ~Lu-177; produced by irradiating Ca-46 to produce Ca-47, which decays to Sc-47), selenium-75 (Dx; past selenomethionine for GI studies), sodium-24 (Dx, past electrolytes research), strontium-89 (Rx bone pain and metastasis [fission product]), technetium-99m (Dx; the workhorse Dx isotope in nuclear medicine; produced in generators from Mo-99), thorium-227 (Rx alpha; decays to Ra-223 (another alpha Rx)), xenon-133 (Dx [a gaseous fission product]), ytterbium-169 (Dx; used before In-111, for CSF flow studies), ytterbium-177 (Rx precursor to Lu-177 via neutron irradiation of Yb-176), and yttrium-90 (Rx pure beta emitter [fission product]).Cyclotron radioisotopes include, but are not limited to: Actinium-225 (Rxα), Astatine-211 (Rxα), Bismuth-212 (Rxα), Carbon-11 (Dx positron / PET), Fluorine-18 (Dx positron / PET), Nitrogen-13 (Dx positron / PET), Oxygen-15 (Dx positron / PET), Cobalt-57 (Dx in vitro Dx kit), Copper-64 (Dx positron; used to study copper metabolism), Copper-67 (Rxβ), Gallium-67 (Dx single photon), Gallium-68 (Dx positron), germanium-68 (Dx—precursor of Ga-68 generator), indium-111 (Dx), iodine-123 (Dx, no beta emission), iodine-124 (Dx positron), krypton-81m (Dx [gas generator generated from Rb-81 at clinical T1 / 2 = 13 seconds]), rubidium-82 (Dx positron potassium analog for perfusion imaging; generator generated at patient T1 / 2 = 75 seconds), strontium-82 (Dx—precursor of Rb-82 generator), and thallium-201 (Dx). Liposomes can be bound to the radionuclide by chelating agents, direct chemical bonding, or some other means such as linker proteins.

[0117] In embodiments, the chelating agent may form a chelate complex with a transition metal or a radiolabeled agent such as a radionuclide.

[0118] In an embodiment, the chelating agent may be selected from the group consisting of: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives; 1,4,8,11-tetraazacyclotetradecane (cyclam) and its derivatives; 1,4,7,10-tetraazacyclododecane (cyclen) and its derivatives; 1,4-ethylidene-1,4,8,11-tetraazacyclotetradecane (et-cyclam) and its derivatives; 1,4,7,11-tetraazacyclotetradecane (isocyclam) and its derivatives; 1,4,7,10-tetraazacyclotridecane (

[13] alkane N4) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A) and its derivatives ; 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphonic acid) (DO2P) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanephosphonic acid) (DOTP) and its derivatives; ethylenediaminetetraacetic acid (EDTA) and its derivatives; diethylenetriaminepentaacetic acid (DTPA) and its derivatives; 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) and its derivatives or other adamanzane and its derivatives.

[0119] In an embodiment, the chelating agent is selected from the group consisting of: macrocyclic compounds including adamanzane; 1,4,7,10-tetraazacyclododecane (

[12] alkane N4) or its derivatives; 1,4,7,10-tetraazacyclotridecane (

[13] alkane N4) or its derivatives; 1,4,8,11-tetraazacyclotetradecane (

[14] alkane N4) or its derivatives; 1,4,8,12-tetraazacyclopentadecane (

[15] alkane N4) or its derivatives; 1,5,9,13-tetraazacyclohexadecane (

[16] alkane N4) or its derivatives; and other chelating agents capable of binding metal ions such as ethylenediaminetetraacetic acid (EDTA) or its derivatives, diethylenetriaminepentaacetic acid (DTPA) or its derivatives.

[0120] In an embodiment, the chelating agent is selected from the group consisting of: 1,4-ethano-1,4,8,11-tetraazacyclotetradecane (et-cyclam) or a derivative thereof; 1,4,7,11-tetraazacyclotetradecane (iso-cyclam) or a derivative thereof; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a derivative thereof; 2-(1,4,7,10-tetraazacyclododecane-1-yl) acetate (DO1A) or a derivative thereof; 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetic acid (DO2A) or a derivative thereof; 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DO3A) or a derivative thereof; 1 ,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanephosphonic acid) (DOTP) or its derivatives; 1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphonic acid) (DO2P) or its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P) or its derivatives; 1,4,8,11-15-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) or its derivatives; 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A) or its derivatives; 2,2′-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A) or its derivatives; and other adamanzane or its derivatives.

[0121] Rhenium-186( 186 Re) is a beta-emitting therapeutic radionuclide with a half-life of approximately 90 hours, a 1.8-mm radiation pathlength, and a high beta / gamma energy ratio suitable for cancer brachytherapy. In addition, 186 Re has gamma ray energy sufficient to allow imaging of drug behavior in vivo with standard SPECT / CT. Therapeutic radionuclides require carriers to ensure their sequestration within the tumor and slow redistribution. Liposomal nanoparticles (nanoliposomes) offer a way to encapsulate radionuclides and aid sustained intratumoral accumulation. We have successfully developed a method to deliver 186 A method for loading Re into nanoliposomes with high efficiency and specific activity. This method produces significantly higher levels of specific activity than previously described and has the potential to provide significantly higher delivered therapeutic radiation doses with reduced toxicity.

[0122] In certain aspects, contrast agents or imaging agents include, but are not limited to, transition metals, carbon nanomaterials such as carbon nanotubes, fullerenes and graphene, near infrared (NIR) dyes such as indocyanine green (ICG) and gold nanoparticles. Transition metals refer to metals of Groups 3 to 12 in the periodic table, such as titanium (Ti), vanadium (V), niobium (Nb), tantalum (Ta), chromium (Cr), molybdenum (Mo), tungsten (W), manganese (Mn), iron (Fe), ruthenium (Ru), osmium (Os), iridium (Ir), nickel (Ni), copper (Cu), technetium (Tc), rhenium (Re), cobalt (Co), rhodium (Rh), iridium (Ir), palladium (Pd), platinum (Pt), silver (Ag), gold (Au), lanthanides such as europium (Eu), gadolinium (Gd), lanthanum (La), ytterbium (Yb) and erbium (Er), or post-transition metals such as gallium (Ga) and indium (In). In one aspect, the imaging modality is selected from the group comprising: positron emission tomography (PET), single photon emission tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), ultrasound imaging (US), and optical imaging. In another aspect of the invention, the imaging modality is positron emission tomography (PET). Imaging agents include, but are not limited to, radioactive labels, fluorophores, fluorochromes, optical reporters, magnetic reporters, X-ray reporters, ultrasound imaging reporters, or nanoparticle reporters. In another aspect of the invention, the imaging agent is a radioactive label selected from the group comprising radioisotope elements, the radioisotope elements being selected from the group consisting of: astatine, bismuth, carbon, copper, fluorine, gallium, indium, iodine, lutetium, nitrogen, oxygen, phosphorus, rhenium, rubidium, samarium, technetium, thallium, yttrium, and zirconium. In another aspect, the radioactive label is selected from the group comprising: zirconium-89 ( 89 Zr), iodine-124 ( 124 I), iodine-131( 131 I), iodine-125( 125 I), iodine-123( 123 I), bismuth-212( 212 Bi), bismuth-213( 213 Bi), astatine-211( 211 At), copper-67( 67 Cu), copper-64( 64 Cu), rhenium-186 ( 186 Re), rhenium-188 ( 188 Re), phosphorus-32 ( 32 P), Samarium-153 ( 153 Sm), Lutetium-177( 177 Lu), technetium-99m ( 99m Tc), Gallium-67( 67 Ga), indium-111( 111 In), Thallium-201( 201Tl), carbon-11, nitrogen-13 ( 13 N), oxygen-15( 15 O), fluorine-18 ( 18 F) and rubidium-82( 82 Like).

[0123] In one aspect, provided herein is a radiolabeled liposome comprising a liposome and a compound of formula I:

[0124]

[0125] or a pharmaceutically acceptable salt thereof, wherein:

[0126] M is 99m Tc, 186 Re, 188 Re or a combination thereof;

[0127] X is NR 1 ;

[0128] R 1 is CH2CH2NEt2 or CH2CH2CH2CH3; and

[0129] R 2 It is CH2CH2N(CH2CH2SH)(CH2CH2NEt2) or CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3).

[0130] In some embodiments, R 1 is CH2CH2NEt2. In some embodiments, R 1 is CH2CH2CH2CH3. In some embodiments, R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2). In some embodiments, R 2 is CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3). In some embodiments, R 1 is CH2CH2NEt2 and R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2). In some embodiments, R 1 is CH2CH2CH2CH3 and R 2 It is CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3).

[0131] In some embodiments, M is 99m In some embodiments, M is 186 Re. In some embodiments, M is188 In some embodiments, when M is 186 When the liposomes include nanoliposomes, the radiolabeled liposomes are referred to as 186 Re nanoliposomes.

[0132] In some embodiments, the compound is incorporated into or attached to the liposome (eg, nanoliposome).

[0133] In some embodiments, the liposome further comprises a drug incorporated into the liposome.

[0134] In some embodiments, the drug is a compound comprising at least one thiol group. In some embodiments, the drug reacts with the compound. In some embodiments, the drug comprises glutathione, cysteine, N-acetylcysteine, 2-mercaptosuccinic acid, 2,3-dimercaptosuccinic acid, captopril, or a combination thereof. In some embodiments, the drug comprises glutathione. In some embodiments, the drug comprises cysteine. In some embodiments, the drug comprises N-acetylcysteine. In some embodiments, the drug comprises 2-mercaptosuccinic acid. In some embodiments, the drug comprises 2,3-dimercaptosuccinic acid. In some embodiments, the drug comprises captopril. In some embodiments, the drug comprises a combination.

[0135] In some embodiments, the liposome comprises a lipid. In one embodiment, the liposome is a nanoliposome. In some embodiments, the liposome comprises a phospholipid.

[0136] In some embodiments, the liposomes include cholesterol or a cholesterol analog. In some embodiments, the liposomes include cholesterol. In some embodiments, the liposomes include a cholesterol analog. In some embodiments, the liposomes include distearoylphosphatidylcholine.

[0137] In some embodiments, the liposomes include cholesterol or a cholesterol analog. In some embodiments, the liposomes include cholesterol. In embodiments, the liposomes include cholesterol. In embodiments, the liposomes include distearoylphosphatidylcholine. In embodiments, the composition delivers gamma and beta radiation. In embodiments, the drug releases beta rays, gamma rays, or a combination thereof.

[0138] Pharmaceutical composition

[0139] The pharmaceutical compositions of the present disclosure may be formulated into any suitable pharmaceutical preparation. The pharmaceutical compositions of the present disclosure generally comprise an active ingredient and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants. The compositions of the present disclosure may be formulated into any suitable pharmaceutical preparation. Including 186 The pharmaceutical composition of Re nanoliposomes can be referred to as 186 Rhenium-lipid nanoparticles ( 186 RNL). In some embodiments, the pharmaceutical composition comprises 186 Re nanoliposomes. In some embodiments, the pharmaceutical composition comprises 186 Re nanoliposomes, 188 Re nanoliposomes, 99m Tc nanoliposomes or any combination thereof. In some embodiments, the pharmaceutical composition results in sustained intratumoral accumulation.

[0140] The pharmaceutical composition can be provided in any suitable form, which can depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated into a dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, oral, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhaled, intraventricular, into the pia mater space (e.g., for the treatment of pia mater metastases) and / or intraperitoneal administration. In some embodiments, the pharmaceutical composition is formulated for administration by convection enhanced delivery (CED). In some embodiments, the pharmaceutical composition is suitable for infusion by a ventricular reservoir.

[0141] Radiolabeled nanoliposomes (e.g. 186 The amount of Re nanoliposomes) will depend on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician.

[0142] In some embodiments, the radiolabeled nanoliposomes can be administered as part of a treatment regimen that includes administering one or more second agents (e.g., 1, 2, 3, 4, 5, or more second agents) simultaneously or sequentially with the radiolabeled nanoliposomes. When administered sequentially, the radiolabeled nanoliposomes can be administered before or after the one or more second agents. When administered simultaneously, the radiolabeled nanoliposomes and the one or more second agents can be administered by the same route (e.g., convection enhanced delivery to the same location), by different routes (e.g., oral tablets while receiving convection enhanced delivery), or as part of the same combination (e.g., a solution comprising radiolabeled nanoliposomes and one or more second agents). In some embodiments, the radiolabeled nanoliposomes (e.g., 186 Re nanoliposomes) are delivered in a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 186 Re nanoliposomes.

[0143] The combination therapy according to the invention can be effective within a wide dosage range. The exact dosage will depend on the agent selected, the route of administration, the form of the compound administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0144] In some embodiments, the pharmaceutical composition includes one or more surfactants. Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0145] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic or zwitterionic compounds for which the HLB range is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is generally used to enable the formulation of industrial, pharmaceutical and cosmetic emulsions.

[0146] The hydrophilic surfactant may be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysolecithin and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acylactylates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0147] In the above group, ionic surfactants include, by way of example: lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0148] The ionic surfactant can be in the form of an ion of lecithin, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactate, stearoyl lactylate, succinylated monoglycerides, monoglycerides / glycerol Mono / diacetylated tartaric acid esters of oleyl diesters, citrates of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine and salts and mixtures thereof.

[0149] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkylthio glucosides; lauryl polyethylene glycol glycerides; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols with at least one member of the group of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols and derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of polyols with at least one member of the group of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a sugar.

[0150] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 triolein, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 capric / caprylic glycerides, PEG-8 capric / caprylic glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 plant sterols, PEG-30 soybean sterols, PEG-20 trioleate, PEG-40 deoxycholate Sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series and poloxamer.

[0151] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and diglycerides; hydrophobic transesterification products of polyols with at least one member of the group of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0152] In one embodiment, the composition may include a solubilizing agent to ensure good solubilization and / or dissolution of the radiolabeled nanoliposomes of the present disclosure and to minimize precipitation of the radiolabeled nanoliposomes of the present disclosure. This may be particularly important for injection. A solubilizing agent may also be added to increase the solubility of a hydrophilic drug and / or other components (such as a surfactant), or to maintain the composition as a stable or uniform solution or dispersion.

[0153] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (tetrahydrofuran polyglycol ether) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidones, N-hydroxyalkylpyrrolidones, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether and water.

[0154] Mixtures of solubilizing agents can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methyl pyrrolidone, N-hydroxyethyl pyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, carbitol, propylene glycol and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycofurol and propylene glycol.

[0155] The amount of the solubilizing agent that can be included is not particularly limited.The amount of a given solubilizing agent can be limited to biologically acceptable amount, which can be easily determined by those skilled in the art.In some cases, it may be advantageous to include the amount of the solubilizing agent that far exceeds biologically acceptable amount, for example, in order to maximize the concentration of the medicine, before compositions is provided to the patient, conventional techniques (such as distillation or evaporation) are used to remove excessive solubilizing agent.If present, the weight ratio of the solubilizing agent can be 10%, 25%, 50%, 100% or up to about 200% by weight based on the combined weight of medicine and other excipients.If desired, a very small amount of solubilizing agent can also be used, such as 5%, 2%, 1% or even less.Usually, the solubilizing agent can exist with an amount of about 1% to about 100% by weight, more generally about 5% to about 25%.

[0156] The composition may further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adherents, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavoring agents, colorants, flavoring agents, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants and mixtures thereof.

[0157] In addition, acids or bases can be incorporated into the composition to facilitate processing, enhance stability or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. In addition, suitable bases are pharmaceutically acceptable acids, such as salts of acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Salts of polyacids can also be used, such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate. When the base is a salt, the cation can be any suitable and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[0158] Suitable acid is a pharmaceutically acceptable organic acid or inorganic acid. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0159] Pharmaceutical compositions for infusion

[0160] In some embodiments, the present disclosure provides a pharmaceutical composition for infusion (such as convection enhanced delivery) comprising a radiolabeled nanoliposome (e.g. 186 Re nanoliposomes) and pharmaceutical excipients suitable for injection. The components and amounts of the agents in the composition are as described herein. In some embodiments, the pharmaceutical composition is suitable for infusion through a ventricular reservoir.

[0161] The radiolabeled nanoliposomes of the present disclosure may be incorporated into forms for administration by infusion including aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar drug carriers.

[0162] Aqueous solutions in saline are also commonly used for infusion. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Suitable fluidity may be maintained, for example, by the use of coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action may be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0163] Sterile infusible solutions are prepared by mixing the radiolabeled nanoliposomes of the present disclosure in the required amount with various other ingredients listed above (as needed) in an appropriate solvent, followed by filtration sterilization. Generally speaking, dispersions are prepared by mixing various sterilized active ingredients into a sterile carrier, which contains an alkaline dispersion medium and other ingredients from those listed above as required. In the case of sterile powders for the preparation of sterile infusible solutions, certain desirable preparation methods are vacuum drying and freeze drying techniques, which produce powders of the active ingredient and any additional desired ingredients from its previous sterile filtered solution.

[0164] In some embodiments, the pharmaceutical composition is administered for about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, or about 2 hours.

[0165] Convection Enhanced Delivery

[0166] Convection enhanced delivery (CED) involves the stereotactic placement of one or more catheters, which are directly accessed through a skull burr hole into the brain tissue. The therapeutic agent can be continuously administered through the catheter through a microinfusion delivery system to create a positive pressure gradient at the catheter tip. When the pressure is maintained, it produces fluid convection or flow to supplement the diffusion through the extracellular space and enhance the distribution of the therapeutic agent to the targeted area. The purpose of CED can be to provide uniform distribution of therapeutic agents to a larger volume of brain tissue, provide higher drug concentrations directly to the tissue, and use therapeutic agents in treatments that may not cross the blood-brain barrier (BBB).

[0167] Convection-enhanced delivery can be chronic delivery, acute delivery, or a combination thereof. For example, a therapeutic method can include chronic delivery of radiolabeled nanoliposomes to a brain region, wherein the radiolabeled nanoliposomes are delivered at a sustained infusion rate over a period of days, weeks, months, or years. The therapeutic method can include acute delivery of radiolabeled nanoliposomes, wherein the radiolabeled nanoliposomes are delivered with discrete boluses over a process of minutes or hours. The therapeutic method can include a combination of chronic and acute delivery, wherein radiolabeled nanoliposomes are delivered at a continuous first infusion rate interspersed with intervals of regular or irregular limited duration infusions at a second faster rate over a period of days, weeks, months, or years. Infusion rate and infusion time can be important factors for achieving adequate delivery. In addition, infusion rate and infusion time can be alternatives to infusion pressure. Methods for assessing delivery adequacy include, but are not limited to, dosimetry, imaging, brain biopsy, therapeutic response assessment map (TRAM), and cerebral blood volume (CBV).

[0168] CED of the pharmaceutical composition or formulation comprising radiolabeled nanoliposomes, other therapeutic agents, or a combination thereof may comprise an infusion rate of about 0.1 μL / min to about 20 μL / min.

[0169] The CED of a pharmaceutical composition or formulation comprising radiolabeled nanoliposomes, other therapeutic agents, or a combination thereof can include an infusion rate greater than about 0.1 μL / min, 0.5 μL / min, 0.7 μL / min, 1 μL / min, 1.2 μL / min, 1.5 μL / min, 1.7 μL / min, 2 μL / min, 2.2 μL / min, 2.5 μL / min, 2.7 μL / min, 3 μL / min, 3.5 μL / min, 4 μL / min, 5 μL / min, 6 μL / min, 7 μL / min, 7.5 μL / min, 10 μL / min, 15 μL / min, 20 μL / min, 25 μL / min, 30 μL / min, 35 μL / min, 40 μL / min, 45 μL / min, 50 μL / min, or greater than 50 μL / min.

[0170] The CED of the pharmaceutical composition or formulation comprising radiolabeled nanoliposomes, other therapeutic agents, or a combination thereof may include or further include an infusion rate of less than about: 50 μL / min, 45 μL / min, 40 μL / min, 35 μL / min, 30 μL / min, 25 μL / min, 20 μL / min, 15 μL / min, 12 μL / min, 10 μL / min, 7.5 μL / min, or 5 μL / min.

[0171] The CED of a pharmaceutical composition or formulation comprising radiolabeled nanoliposomes, other therapeutic agents, or a combination thereof may include or further include incremental increases in flow rate during delivery, referred to as "steps". Steps may include an infusion rate of about 0.1 μL / min to about 20 μL / min. At periodic intervals, a step CED may include an increase in the infusion rate of one or more of the following steps: about 0.1 μL / min, 0.2 μL / min, 0.3 μL / min, 0.4 μL / min, 0.5 μL / min, 0.6 μL / min, 0.7 μL / min, 0.8 μL / min, 0.9 μL / min, 1 μL / min, 1.25 μL / min, 1.5 μL / min, 2 μL / min, 2.5 μL / min, 3 μL / min or greater.

[0172] In a pharmaceutical composition or formulation administered by CED, the effective amount of radioactivity delivered by the radiolabeled liposomes may be 1 mCi to 1000 mCi. For example, the effective amount may be 1-1000 mCi, 1-500 mCi, 1-250 mCi, 1-150 mCi, 1-100 mCi, 1-75 mCi, 1-50 mCi, 1-25 mCi, 1-10 mCi, 1-5 mCi, 5-1000 mCi, 5-500 mCi, 5-250 mCi, 5-150 mCi, 5-100 mCi, 5-75mCi, 5-50mCi, 5-25mCi, 5-10mCi, 10-1000mCi, 10-500mCi, 10-250mCi, 1 0-150mCi, 10-100mCi, 10-75mCi, 10-50mCi, 10-25mCi, 25-1000mCi, 25-500mCi, 2 5-250mCi, 25-150mCi, 25-100mCi, 25-75mCi, 25-50mCi, 50-1000mCi, 50-500mCi, 50-250mCi, 50-150mCi, 50-100mCi, 50-75mCi, 75-1000mCi, 75-500mCi, 75-250mC In some embodiments, the effective amount is 10mCi to 250mCi. In some embodiments, the effective amount of the radioactivity delivered by radiolabeled liposomes is 50mCi to 150mCi. In some embodiments, the effective amount of the radioactivity delivered by radiolabeled liposomes is 10mCi to 500mCi.

[0173] The volume of an effective amount of radioactivity delivered by radiolabeled liposomes administered by CED can be 1-2000 μL, 1-1500 μL, 1-1000 μL, 1-750 μL, 1-500 μL, 1-250 μL, 1-100 μL, 1-50 μL, 1-10 μL, 10-2000 μL, 10-1500 μL, 10-1000 μL, 10-750 μL, 10-500 μL, 10-250 μL, 10-100 μL, 10-50 μL, 50-2000 μL, 50-1500 μL, 50-1000 μL, 50-750 μL, 50-500 μL, 50-250 μL. , 50-100μL, 100-2000μL, 100-1500μL, 100-1000μL, 100-750μL, 100-50 0μL, 100-250μL, 250-2000μL, 250-1500μL, 250-1000μL, 250-750μL, 250 -500μL, 500-2000μL, 500-1500μL, 500-1000μL, 500-750μL, 750-2000μ L, 750-1500μL, 750-1000μL, 1000-2000μL, 1000-1500μL or 1500-2000μL.

[0174] The concentration of an effective amount of radioactivity delivered by radiolabeled liposomes administered by CED (e.g., in a pharmaceutical composition) can be about 0.5 mCi / ml, about 1 mCi / ml, about 1.5 mCi / ml, about 1.52 mCi / ml, about 2 mCi / ml, about 2.24 mCi / ml, about 2.36 mCi / ml, about 2.5 mCi / ml, about 2.53 mCi / ml, about 2.54 mCi / ml, about 3 mCi / ml, or about 3.5 mCi / ml.

[0175] For further teachings on CED methods, see, e.g., Saito et al., Exp. Neurol., 196:381-389, 2005; Krauze et al., Exp. Neurol., 196:104-111, 2005; Krauze et al., Brain Res. Brain Res. Protocol., 16:20-26, 2005; U.S. Patent Application Publication No. 2006 / 0073101; and U.S. Patent No. 5,720,720, each of which is incorporated herein by reference in its entirety. See also Noble et al., Cancer Res. 2006 Mar. 1; 66(5):2801-6; Saito et al., J Neurosci Methods. 2006 Jun. 30; 154(1-2):225-32; Hadaczek et al., Hum Gene Ther. 2006 March; 17(3):291-302; and Hadaczek et al., Mol Ther. 2006 July; 14(1):69-78, each of which is incorporated herein by reference in its entirety.

[0176] Convection Enhanced Delivery and Imaging

[0177] The advantage of convection-enhanced delivery can be the ability to use imaging techniques to allow observation of drug distribution during infusion. Gadolinium-based and iodine-based imaging compounds can be used as tracers, using, for example, magnetic resonance imaging or computed tomography imaging to safely and accurately track the distribution of active ingredients in real time. These tracers can show the distribution of both small molecular weight and large molecular weight compounds with similar convection characteristics during infusion. In addition, radiolabeled nanoliposomes may be able to image without the use of tracers (e.g., by the gamma-ray emission of radiolabeled nanoliposomes). In some embodiments, methods and compositions provided herein do not include tracers.

[0178] In the method of the pharmaceutical composition including radiolabeled nanoliposomes, other therapeutic agents or combinations thereof delivered by CED, the pharmaceutical composition may include a tracer. The tracer may be able to monitor the distribution of the tracer when the tracer moves through the CNS, and stop the delivery of the pharmaceutical composition when the radiolabeled nanoliposomes, other therapeutic agents or combinations thereof are distributed in the CNS with a predetermined volume. The movement of the tracer through solid tissues can be monitored by imaging techniques such as magnetic resonance imaging (MRI), computed tomography imaging, X-ray computed tomography (CT) or single photon emission computed tomography. The tracer may have a substantially similar fluidity to the therapeutic agent (e.g., radiolabeled nanoliposomes) in CNS tissues, and delivery may be stopped when the tracer is observed to arrive at the desired area or reach the desired distribution volume, or arrive or approach to reach or exceed the boundary of the target tissue. In some embodiments, the radiolabeled nanoparticles of the present disclosure can provide the same function (e.g., monitoring distribution) as the composition including the tracer.

[0179] The desired volume may correspond to a specific area of ​​the brain that is targeted for treatment. The desired volume of distribution may be "substantially similar" to the volume of distribution of the tracer observed by monitoring after infusion. "Substantially similar" means that the volume difference is less than 20%. More preferably, the volume difference is less than 15%, more preferably less than 10%, and more preferably less than 5%. By monitoring the distribution of the tracer, the infusion may be stopped when the predetermined volume of distribution is reached.

[0180] For example, this can be accomplished by using imaging software standard in the art, such as iFLOW TM to determine the expected volume of distribution. See also, for example, Krautze et al., Brain Res. Protocols, 16:20-26, 2005; and Saito et al., Exp. Neurol., 196:3891-389, 2005, each of which is incorporated herein by reference in its entirety.

[0181] Tracers may include paramagnetic ions for use with MRI. Suitable metal ions include those having atomic numbers of 22-29 (inclusive), 42, 44, and 58-70 (inclusive) and having an oxidation state of +2 or +3. Examples of such metal ions are chromium (III), manganese (II), iron (II), iron (III), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), and ytterbium (III).

[0182] In embodiments where X-ray imaging (such as CT) is used to monitor CED, the tracer may include a radiopaque material. Suitable radiopaque materials include, but are not limited to, iodine compounds, barium compounds, gallium compounds, thallium compounds, and the like. Specific examples of radiopaque materials include barium, diatrizoate, ethiodized oil, gallium citrate, iocarmic acid, iocetamic acid, iodamide, iodipamide, iodoxamic acid, iogulamide, iohexol, iopamidol, iopanoic acid, ioprocemic acid, iosefamic acid, ioseric acid, iosulamide meglumine, iosumetic acid, iotasul, iotetric acid, iothalamic acid, iotroxic acid, ioxaglic acid, ioxotriroic acid, acid, ipodate, meglumine, metrizamide, metrizoate, propyliodone, and thallium chloride.

[0183] Device for convection enhanced delivery (CED)

[0184] It is contemplated that any suitable device may be used in the methods disclosed herein, wherein a pharmaceutical composition or formulation comprising radiolabeled nanoliposomes, other therapeutic agents, or a combination thereof is administered to a brain region via CED.

[0185] The delivery device can include a pump capable of delivering a pharmaceutical composition or formulation comprising radiolabeled nanoliposomes, other therapeutic agents or a combination thereof by CED. The pump can be an osmotic pump or an infusion pump. These pumps can be used to prevent the undesirable problems associated with pump failure, such as problems associated with back pressure and / or obstruction, because these pumps can include a back pressure sensor for forcing closure when the back pressure rises above a threshold. The device can include a catheter or cannula that contributes to local delivery to a subject's brain region, or can be used in combination with a catheter or cannula. The catheter or cannula can include multiple outlet ports. The catheter or cannula can include an outer tube to provide structural rigidity to the catheter or cannula. The catheter or cannula can be a cannula of a reflux-free step-design.

[0186] One or more catheters or cannulas can be inserted into or near one or more brain regions of the subject. Stereotactic maps and positioning devices are available, such as ASI Instruments from Warren, Michigan. Positioning can be performed by using anatomical maps obtained by CT and / or MRI imaging of the subject's brain to help guide the injection device to the selected target.

[0187] No-return stepped design casing

[0188] CED can be performed using a CED-compatible, no-reflux stepped design cannula, such as the cannula disclosed in Krauze et al., J Neurosurg. 2005 November; 103(5):923-9, which is incorporated herein by reference in its entirety, and U.S. Patent Application Publication No. US2007 / 0088295 A1, which is incorporated herein by reference in its entirety, and U.S. Patent Application Publication No. US2006 / 0135945 A1, which is incorporated herein by reference in its entirety.

[0189] In one embodiment, the stepped design cannula is compatible with chronic administration. In other embodiments, the stepped design cannula is compatible with acute administration. In other embodiments, the stepped design cannula is compatible with a combination of chronic administration with periods of acute administration interspersed with higher infusion rates or with higher levels of therapeutic agents.

[0190] Alternative catheters

[0191] CED may be performed using a neurosurgical device including a CED-compatible catheter, such as the catheter disclosed in WO 2013 / 127884, which is incorporated herein by reference in its entirety.

[0192] Neurosurgical device can comprise guide device and conduit.Guide device can comprise elongated tube, and this tube has head at its proximal end.In use, elongated tube can be inserted into the brain towards target brain region through the hole formed in skull.Head can be used to firmly attach guide device to skull.This insertion can be carried out using the technology based on stereotactic instrument (stereoguide) or surgical robot.Internal passage is provided by the head of tube and drilling.Then, conduit can pass through this passage downward, and enter the brain near selected target.

[0193] The present disclosure provides a delivery kit or device comprising a pump capable of effecting delivery of radiolabeled nanoliposomes (e.g., 186 The kit or device further comprises a pharmaceutical composition comprising a radiolabeled nanoliposome, other therapeutic agent, or a combination thereof, such as any of those disclosed herein. The kit or device further comprises a CED-compatible cannula or catheter. The cannula or catheter may be compatible with chronic or acute administration.

[0194] radiation

[0195] In some embodiments, provided herein are pharmaceutical compositions for delivering radiation. In some embodiments, the pharmaceutical composition comprises liposomes. In some embodiments, the liposomes comprise nanoliposomes. In some embodiments, the pharmaceutical composition comprises an isotope of rhenium. In some embodiments, the isotope of rhenium comprises 186-rhenium ( 186 In some embodiments, the pharmaceutical composition comprises liposomes (e.g., nanoliposomes) and isotope rhenium (e.g., 186 Re). In some embodiments, the pharmaceutical composition comprises a compound of Formula I and liposomes. In some embodiments, the pharmaceutical composition comprises 186 Re nanoliposomes, which include isotopes of rhenium (e.g. 186 Re) and nanoliposomes.

[0196] In some embodiments, the pharmaceutical composition delivers radiation. In some embodiments, the pharmaceutical composition delivers beta rays. In some embodiments, the pharmaceutical composition delivers gamma rays. In some embodiments, the pharmaceutical composition delivers one type of radiation. The pharmaceutical composition delivers two types of radiation (e.g., beta rays and gamma rays). In some embodiments, provided herein is a pharmaceutical composition (e.g., comprising liposomes (e.g., nanoliposomes) and isotopes (e.g., 186) rhenium) for delivering radiation (e.g., two types of radiation) (e.g., beta rays and / or gamma rays).

[0197] In some embodiments, the pharmaceutical composition is administered to a subject. In some embodiments, the subject is a patient in need of treatment. In some embodiments, the patient in need of treatment comprises cancer.

[0198] Radiation, particularly beta-rays, may be useful for the treatment of patients including cancer. Gamma-rays may be used for visualization purposes. In some embodiments, visualization includes imaging. Pharmaceutical compositions that deliver both gamma-rays and beta-rays may be useful for delivering therapy (e.g., radiation for treating cancer) and allowing visualization of the delivered therapy. For example, gamma-rays may have sufficient energy for use during treatment delivery (e.g., during 186 Re nanoliposomes during administration) and for biodistribution assessment. Imaging using gamma rays can be beneficial for modifying one or more delivery parameters in order to dose a subject.

[0199] By delivering both beta-rays and gamma rays, one or more delivery parameters of therapy can be adjusted to allow therapy to be modified. In some embodiments, the pharmaceutical composition is delivered and visualized (e.g., imaging). In some embodiments, the pharmaceutical composition is delivered and visualized simultaneously. In some embodiments, the pharmaceutical composition is delivered and subsequently visualized. In some embodiments, the pharmaceutical composition is delivered (e.g., by CED), visualized (e.g., simultaneously), and one or more delivery parameters are modified. In some embodiments, the modification of one or more delivery parameters occurs during the delivery (e.g., convection) of the pharmaceutical composition. In some embodiments, the modification of one or more delivery parameters occurs after the delivery of the pharmaceutical composition.

[0200] In some embodiments, the modification of the therapy (e.g., one or more delivery parameters) is responsive to the delivery and visualization (e.g., imaging) of the pharmaceutical composition. In some embodiments, one or more delivery parameters include an infusion rate, a volumetric amount, one or more concentrations, one or more administration locations, a number of catheters, and / or a device for delivering the pharmaceutical composition. Any of the volume, radiation dose, or dose of the pharmaceutical composition disclosed herein may be sufficient to deliver beta-rays and gamma-rays.

[0201] In some embodiments, the delivery of a pharmaceutical composition (e.g., a drug that delivers beta-rays and gamma-rays) 186 Re nanoliposomes) allow monitoring of treatment to ensure successful delivery of the drug composition to the target (e.g., a tumor).

[0202] Imaging

[0203] Gamma rays can be useful for visualization (e.g., viewing) purposes. In some embodiments, visualization includes imaging. For example, the pharmaceutical composition can deliver a sufficient dose of beta rays to allow treatment of cancer, and a sufficient dose of gamma rays to allow imaging (e.g., in vivo imaging). In some embodiments, visualization includes imaging. In some embodiments, the composition further includes a tracer. In some embodiments, the pharmaceutical composition does not include a tracer. In some cases, gamma rays are sufficient for visualization without the use of a tracer.

[0204] In some embodiments, imaging comprises single photon emission computed tomography-computed tomography (SPECT-CT). In some embodiments, imaging comprises single photon emission computed tomography (SPECT). In some embodiments, imaging comprises computed tomography (CT). In some embodiments, imaging comprises magnetic resonance imaging (MRI). In some embodiments, imaging may include alternative forms of imaging, such as radiography (e.g., X-ray), X-ray fluoroscopy, nuclear medicine, positron emission tomography (PET) (e.g., single photon emission computed tomography), computed tomography (CT), intraoperative imaging, and mammography, or a combination thereof. In some embodiments, imaging comprises planar imaging. In some embodiments, imaging comprises a combination of any imaging techniques disclosed herein (e.g., SPECT and MRI). In some embodiments, imaging comprises static images. In some embodiments, imaging comprises dynamic images.

[0205] Treatment

[0206] In some embodiments, provided herein are methods of using the radiolabeled liposomes disclosed herein, which can be incorporated into any pharmaceutical composition disclosed herein.

[0207] In one aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a radiolabeled liposome comprising a liposome (e.g., a nanoliposome) and a compound of Formula I:

[0208]

[0209] or a pharmaceutically acceptable salt thereof, wherein:

[0210] M is 99m Tc, 186 Re, 188 Re or a combination thereof;

[0211] X is NR 1 ;

[0212] R1 is CH2CH2NEt2 or CH2CH2CH2CH3; and

[0213] R 2 It is CH2CH2N(CH2CH2SH)(CH2CH2NEt2) or CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3).

[0214] In some embodiments, R 1 is CH2CH2NEt2. In some embodiments, R 1 is CH2CH2CH2CH3. In some embodiments, R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2). In some embodiments, R 2 is CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3). In some embodiments, R 1 is CH2CH2NEt2 and R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2). In some embodiments, R 1 is CH2CH2CH2CH3 and R 2 It is CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3).

[0215] In some embodiments, M is 99m In some embodiments, M is 186 Re. In some embodiments, M is 188 In some embodiments, when M is 186 When the liposomes include nanoliposomes, the radiolabeled liposomes are referred to as 186 Re nanoliposomes.

[0216] In some embodiments, the compound is incorporated into or attached to the liposome.

[0217] In some embodiments, the liposome further comprises a drug incorporated into the liposome.

[0218] In some embodiments, the drug is a compound comprising at least one thiol group. In some embodiments, the drug reacts with the compound. In some embodiments, the drug comprises glutathione, cysteine, N-acetylcysteine, 2-mercaptosuccinic acid, 2,3-dimercaptosuccinic acid, captopril, or a combination thereof. In some embodiments, the drug comprises glutathione. In some embodiments, the drug comprises cysteine. In some embodiments, the drug comprises N-acetylcysteine. In some embodiments, the drug comprises 2-mercaptosuccinic acid. In some embodiments, the drug comprises 2,3-dimercaptosuccinic acid. In some embodiments, the drug comprises captopril. In some embodiments, the drug comprises a combination.

[0219] In some embodiments, the liposomes comprise lipids. In some embodiments, the liposomes comprise phospholipids.

[0220] In some embodiments, the liposomes include cholesterol or a cholesterol analog. In some embodiments, the liposomes include cholesterol. In some embodiments, the liposomes include a cholesterol analog. In some embodiments, the liposomes include distearoylphosphatidylcholine.

[0221] In some embodiments, the radiolabeled liposomes (e.g., nanoliposomes) include about 0.01mCi to about 400mCi of the compound / 50mg of lipids for preparing the liposomes. In some embodiments, the radiolabeled liposomes include about 1mCi to about 200mCi of the compound / 50mg of lipids for preparing the liposomes. In some embodiments, the radiolabeled liposomes include about 10mCi to about 100mCi of the compound / 50mg of lipids for preparing the liposomes. In some embodiments, the radiolabeled liposomes include about 25mCi to about 50mCi of the compound / 50mg of lipids for preparing the liposomes. In some embodiments, the radiolabeled liposomes include about 1.5mCi of the compound / 50mg of lipids for preparing the liposomes. In some embodiments, the radiolabeled liposomes include about 2.5mCi of the compound / 50mg of lipids for preparing the liposomes.

[0222] In some embodiments, the liposome (e.g., nanoliposome) further comprises a chemotherapeutic agent, an antibiotic agent, or a therapeutic molecule, wherein the chemotherapeutic agent, the antibiotic agent, or the therapeutic molecule is incorporated into or attached to the liposome. In some embodiments, the liposome further comprises a chemotherapeutic agent. In some embodiments, the liposome further comprises an antibiotic agent. In some embodiments, the liposome further comprises a therapeutic molecule.

[0223] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is selected from lung cancer, breast cancer, colorectal cancer, prostate cancer, skin cancer, gastric cancer, bladder cancer, liver cancer, leukemia, lymphoma, ovarian cancer, pancreatic cancer, hepatocellular carcinoma, melanoma, sarcoma, head and neck cancer, glioma, glioblastoma, medulloblastoma, ependymoma, diffuse intrinsic pontine glioma, leptomeningeal metastasis and high-grade glioma in children. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is glioma. In some embodiments, the cancer is glioblastoma. In some embodiments, the glioblastoma is recurrent glioblastoma. In some embodiments, the cancer is leptomeningeal metastasis. In some embodiments, the cancer is medulloblastoma. In some embodiments, the cancer is ependymoma. In some embodiments, the cancer is diffuse intrinsic pontine glioma. In some embodiments, the cancer is childhood high grade glioma.

[0224] In some embodiments, the subject has previously received a therapy comprising bevacizumab. In some embodiments, the subject has not previously received a therapy comprising bevacizumab.

[0225] In some embodiments, the pharmaceutical composition (e.g., comprising radiolabeled nanoliposomes) is an infusion. In some embodiments, the radiolabeled nanoliposomes are administered by infusion as an infusion comprising radiolabeled liposomes. In some embodiments, the infusion comprises infusion through a ventricular reservoir.

[0226] In some embodiments, the radiolabeled liposomes (e.g., in a pharmaceutical composition) are administered by convection-enhanced delivery. In some embodiments, the convection-enhanced delivery comprises administering the radiolabeled liposomes through one or more catheters. In some embodiments, the convection-enhanced delivery comprises administering the radiolabeled liposomes through one catheter. In some embodiments, the convection-enhanced delivery comprises administering the radiolabeled liposomes through two catheters. In some embodiments, the convection-enhanced delivery comprises administering the radiolabeled liposomes through three catheters. In some embodiments, the convection-enhanced delivery comprises administering the radiolabeled liposomes through four catheters. In some embodiments, the convection-enhanced delivery comprises administering the radiolabeled liposomes through more than four catheters.

[0227] In some embodiments, the concentration of the mixture is about 1 μL min -1 About 50 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 5 μL min -1 About 20 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 1 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 2 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 5 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 10 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 15 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 20 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 25 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of greater than about 25 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 30 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 35 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 40 μL min -1 In some embodiments, the infusion is administered at a maximum flow rate of about 45 μL min -1In some embodiments, the maximum flow rate is the maximum flow rate of each catheter.

[0228] In some embodiments, the infusion is administered at an outlet velocity of about 0.001 mm / min to about 1.0 mm / min. In some embodiments, the infusion is administered at an outlet velocity of about 0.001 mm / min to about 0.1 mm / min. In some embodiments, the infusion is administered at an outlet velocity of about 0.001 mm / min to about 0.5 mm / min. In some embodiments, the infusion is administered at an outlet velocity of about 0.1 mm / min to about 1.0 mm / min. In some embodiments, the infusion is administered at an outlet velocity of about 0.5 mm / min to about 1.0 mm / min. In some embodiments, the infusion is administered at an outlet velocity of about 0.009, 0.022, 0.045, 0.067, or 0.090 mm / min. In some embodiments, the infusion is administered at an outlet velocity of about 0.081, 0.201, 0.403, 0.604, or 0.806 mm / min. In some embodiments, the infusate is administered at an exit velocity of about 0.020, 0.050, 0.101, 0.151, or 0.201 mm / min.

[0229] In some embodiments, administration of the pharmaceutical composition comprises one catheter, two catheters, three catheters, or four catheters.

[0230] In some embodiments, the infusate delivery rate per catheter is 1 ul / min, 2 ul / min, 3 ul / min, 4 ul / min, 5 ul / min, 6 ul / min, 7 ul / min, 8 ul / min, 9 ul / min, 10 ul / min, 11 ul / min, 12 ul / min, 13 ul / min, 14 ul / min, 15 ul / min, 16 ul / min, 17 ul / min, 18 ul / min, 19 ul / min, 20 ul / min, 30 ul / min, 35 ul / min, or about 40 ul / min.

[0231] In some embodiments, the minimum dosing interval is about 5 min, about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, about 40 min, about 50 min, about 60 min, about 90 min, about 120 min, or about 150 min.

[0232] In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes (e.g., radiolabeled nanoliposomes in a pharmaceutical composition) is about 0.1 mCi to about 50 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 1 mCi to about 40 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 1 mCi to about 30 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 1 mCi to about 20 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 10 mCi to about 30 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 20 mCi to about 30 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 1 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 2mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 3mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 4mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 5mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 6mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 7mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 8mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 9mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 10mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 11 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 12 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 13 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 13.4 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 14 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 15 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 16 mCi.In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 17mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 18mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 19mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 20mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 21mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 22mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 22.3mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is greater than about 22.3mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 23mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 24mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 25mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 26mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 27mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 28mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 29mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 30mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 31mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 31.2mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is greater than about 31.2 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 35 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 40 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 41.5 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is greater than about 41.5 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 45 mCi.In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is greater than about 45 mCi.

[0233] In some embodiments, the volume of the infusion is about 0.1 mL to about 25 mL. In some embodiments, the volume of the infusion is about 0.5 mL to about 10 mL. In some embodiments, the volume of the infusion is about 0.66 mL. In some embodiments, the volume of the infusion is about 1 mL. In some embodiments, the volume of the infusion is about 1.32 mL. In some embodiments, the volume of the infusion is about 2 mL. In some embodiments, the volume of the infusion is about 2.64 mL. In some embodiments, the volume of the infusion is about 3 mL. In some embodiments, the volume of the infusion is about 4 mL. In some embodiments, the volume of the infusion is about 5 mL. In some embodiments, the volume of the infusion is about 5.28 mL. In some embodiments, the volume of the infusion is about 6 mL. In some embodiments, the volume of the infusion is about 7 mL. In some embodiments, the volume of the infusion is about 8 mL. In some embodiments, the volume of the infusion is about 8.8 mL. In some embodiments, the volume of the infusion is greater than about 8.8 mL. In some embodiments, the volume of the infusion is about 9 mL. In some embodiments, the volume of the infusion is about 10 mL. In some embodiments, the volume of the infusion is about 11 mL. In some embodiments, the volume of the infusion is about 12 mL. In some embodiments, the volume of the infusion is about 12.3 mL. In some embodiments, the volume of the infusion is about 13 mL. In some embodiments, the volume of the infusion is about 13.2 mL. In some embodiments, the volume of the infusion is about 14 mL. In some embodiments, the volume of the infusion is about 15 mL. In some embodiments, the volume of the infusion is about 16 mL. In some embodiments, the volume of the infusion is about 16.35 mL. In some embodiments, the volume of the infusion is about 17 mL. In some embodiments, the volume of the infusion is about 18 mL. In some embodiments, the volume of the infusion is about 18.5 mL. In some embodiments, the volume of the infusion is greater than about 18.5 mL. In some embodiments, a volume of the infusion is delivered to a single hemisphere of the brain (e.g., comprising a glioblastoma). In some embodiments, a volume of the infusion is delivered to both hemispheres of the brain (e.g., comprising a glioblastoma).

[0234] In some embodiments, the volume of distribution is about 2 mL, about 2.64 mL, about 5 mL, about 5.28 mL, about 10 mL, about 10.5 mL, about 13 mL, about 13.2 mL, about 19 mL, about 19.4 mL, about 26 mL, about 26.4 mL, about 33 mL, about 33.3 mL, or about 35 mL.

[0235] In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 0.1 mCi mL -1 to about 50 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 0.5 mCi mL -1 to about 10mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 1 mCimL -1 to about 5mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 1 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 1.5 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 2 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 2.24 mCimL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 2.36 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 2.5 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 2.53 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 2.54 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is greater than about 2.54 mCi mL -1 .

[0236] In some embodiments, the amount of absorbed dose (e.g., absorbed radiation dose) is about 10 Gy, about 20 Gy, about 30 Gy, about 40 Gy, about 50 Gy, about 80 Gy, about 100 Gy, about 120 Gy, about 150 Gy, about 200 Gy, about 225 Gy, about 250 Gy, about 300 Gy, about 350 Gy, about 400 Gy, about 425 Gy, about 450 Gy, about 500 Gy, about 550 Gy, about 575 Gy, about 600 Gy, about 625 Gy, about 650 Gy, about 675 Gy, about 700 Gy, about 740 Gy, about 750 Gy, or about 800 Gy. In some embodiments, the amount of absorbed dose is less than 100 Gy. In some embodiments, the amount of absorbed dose is greater than 100 Gy.

[0237] In some embodiments, the method further comprises imaging the radiolabeled liposomes while administering. In some embodiments, the method further comprises imaging the radiolabeled liposomes after administration. In some embodiments, the method results in sustained intratumoral accumulation.

[0238] Delivering new radial increments

[0239] In some embodiments, provided herein are methods of delivering a radiation increment to a subject. In some embodiments, the method comprises delivering a radiation increment to a subject who has previously received a dose of radiation therapy. In some embodiments, the previously received radiation therapy dose is a maximum dose of radiation therapy. In some embodiments, the radiation increment comprises beta-rays. In some embodiments, the subject comprises a patient comprising cancer. In some embodiments, the increment comprises an additional portion of radiation.

[0240] In some embodiments, the methods provided herein include delivering an additional portion of radiation (e.g., beta-rays) to a subject in need thereof (e.g., a patient including cancer) by delivering any pharmaceutical composition provided herein. In some embodiments, the increment includes an amount of radiation greater than the amount of radiation received in the treatment just before. In some embodiments, the increment includes the same amount of radiation received in a previous treatment (e.g., a treatment received prior to the current treatment). In some embodiments, delivering a radiation increment includes delivering a different amount of radiation by modifying one or more delivery parameters (e.g., volume, dose, infusion rate, infusion time, etc.) of a pharmaceutical composition provided herein. In some embodiments, delivering a modified amount of radiation includes changing the volume of the infusate and / or the dose of the radiation.

[0241] In some embodiments, delivering an increment of radiation comprises delivering a larger dose of radiation than previously received (e.g., previously received from a pharmaceutical composition disclosed herein). In some embodiments, the increment comprises any dose or volume provided herein. In some embodiments, the increment comprises a portion of a dose. In some embodiments, delivering an increment of radiation comprises delivering an amount of radiation greater than previously received (e.g., with reference to a current round of treatment or with reference to receiving radiation from a pharmaceutical composition disclosed herein). The increment can be any dose disclosed throughout the application, including but not limited to those disclosed in the Examples (e.g., Example 4).

[0242] In some embodiments, delivering the radiation increment comprises delivering beta rays. In some embodiments, delivering the radiation increment comprises delivering gamma rays. In some embodiments, delivering the radiation increment comprises delivering beta rays and gamma rays.

[0243] In some embodiments, the radiation comprises new radiation. In some embodiments, the new radiation comprises radiation (eg, beta-rays) and / or a pharmaceutical composition that the subject has not received prior to receiving any pharmaceutical composition disclosed herein.

[0244] In some embodiments, the method comprises delivering radiation increments to a subject previously irradiated (eg, a patient comprising cancer). In some embodiments, delivering the increments comprises delivering increasingly larger doses of radiation.

[0245] In some embodiments, the subject receiving the radiation increment has previously received a maximum dose of radiation. In some embodiments, the subject receiving the radiation increment has previously received a maximum dose of radiation for treating one or more of its primary and / or secondary diseases. In some embodiments, the subject has previously received a maximum dose of radiation to treat cancer (e.g., glioblastoma). In some cases, the maximum radiation dose comprises a maximum allowable dose (e.g., an upper limit of allowable radiation that a subject can receive without significant risk of side effects).

[0246] In some embodiments, the subject has not previously received treatment for the treatment of a disease (e.g., cancer) or condition. In some embodiments, the subject has not previously received radiation therapy for the treatment of a disease (e.g., cancer) or condition. In some embodiments, the subject has previously received non-radiation therapy (e.g., bevacizumab) for the treatment of a disease (e.g., cancer) or condition. In some embodiments, the subject has not previously received non-radiation therapy for the treatment of a disease. In some embodiments, the subject has previously received radiation therapy including beta-rays from a pharmaceutical composition different from the pharmaceutical composition disclosed herein for the treatment of a disease. In some embodiments, the subject has received radiation therapy including beta-rays from a pharmaceutical composition disclosed herein for the treatment of a disease. In some embodiments, delivering radiation increments includes delivering radiation increments to a subject who has previously received a maximum dose of therapy (e.g., radiation therapy) for a previous treatment (e.g., treatment of their primary and / or secondary diseases).

[0247] Drug administration and visualization

[0248] In some embodiments, provided herein are methods of delivering and visualizing (e.g., imaging) the delivery of a radioactive therapeutic substance. In some embodiments, the radioactive therapeutic substance comprises a pharmaceutical composition disclosed herein. In some embodiments, provided herein are methods of delivering and visualizing (e.g., imaging) a pharmaceutical composition (e.g., a radiolabeled liposome (e.g., 186 Re nanoliposomes)) delivery method. In some embodiments, the method includes ensuring delivery to a target. In some embodiments, the target is cancer. In some embodiments, the target is a tumor. In some embodiments, the tumor is a primary tumor. In some embodiments, the tumor is a secondary tumor. In some embodiments, the method includes modifying (e.g., changing) one or more delivery parameters during delivery. In some embodiments, a radioactive therapeutic substance (e.g., a pharmaceutical composition) is delivered (e.g., by CED). In some embodiments, the method includes modifying one or more delivery parameters during delivery and ensuring that the pharmaceutical composition is delivered to the target during delivery.

[0249] In some embodiments, visualization (e.g., imaging) is performed prior to administration (e.g., by CED) of the pharmaceutical composition. In some embodiments, the method includes visualizing the pharmaceutical composition (e.g., radiotherapy (e.g., pharmaceutical composition) (e.g., radiolabeled liposomes (e.g., 186Concurrent (e.g., simultaneous or real-time) administration (e.g., by CED) and visualization can allow for real-time modification of one or more delivery parameters. In addition, concurrent administration and visualization can help ensure that the pharmaceutical composition is delivered to the target (e.g., tumor). Concurrent (e.g., simultaneous) visualization (e.g., imaging) and adjustment of one or more delivery parameters can be useful for ensuring safety and / or efficacy. In some embodiments, visualization is performed after administration (e.g., by CED) of the pharmaceutical composition.

[0250] Gamma rays can be used to monitor the distribution of the pharmaceutical composition as it moves through the CNS, and to stop the delivery of the pharmaceutical composition when the radiolabeled nanoliposomes, other therapeutic agents, or a combination thereof are distributed in the CNS in a predetermined volume. Visualizing the gamma rays can help ensure that the delivery of the pharmaceutical composition is stopped when the gamma rays are observed to reach the desired area or reach the desired distribution volume, or reach or nearly reach or exceed the boundaries of the target tissue.

[0251] In some embodiments, the method comprising administering (e.g., by CED) and visualizing (e.g., simultaneously) a pharmaceutical composition (e.g., comprising a radioactive therapeutic substance) further comprises evaluating one or more delivery parameters. The evaluation of one or more delivery parameters can be responsive to the visualization of the pharmaceutical composition. The evaluation can be performed before, during, or after administration and / or visualization of the pharmaceutical composition.

[0252] In some embodiments, the method comprising administration (e.g., by CED), visualization (e.g., simultaneously) of a pharmaceutical composition (e.g., including a radioactive therapeutic substance) and evaluation of one or more delivery parameters further comprises modifying one or more delivery parameters. In some embodiments, evaluating one or more delivery parameters comprises maintaining (e.g., not changing) one or more previously existing delivery parameters (e.g., maintaining infusion rate, concentration, dosage, and / or volume). In some embodiments, modifying one or more delivery parameters comprises modifying one or more delivery parameters. In some embodiments, modifying one or more delivery parameters comprises lowering a delivery parameter, raising a delivery parameter, stopping a delivery parameter, or starting a delivery parameter. In the case of an embodiment, one or more delivery parameters comprise any one or more of the following: the dose of the pharmaceutical composition, the radiation dose, the volume of the infusion, the infusion rate, one or more administration sites, the dosing interval, the number of catheters, the infusion rate of each catheter, the infusion (e.g., dosing) interval, the device for delivering the pharmaceutical composition, the number of catheters (e.g., changed to one, two, three, or four catheters), the rate of each catheter, or any combination thereof. In some embodiments, one or more delivery parameters comprise one delivery parameter. In some embodiments, one or more delivery parameters comprise two, three, four, or five delivery parameters. The one or more delivery parameters can be any delivery parameter disclosed herein.

[0253] In some embodiments, administration (e.g., by CED) and visualization (e.g., simultaneously) of a pharmaceutical composition further includes ensuring that the pharmaceutical composition is delivered to a target (e.g., a tumor). In some cases, ensuring that the pharmaceutical composition is delivered to a target includes delivering a minimum effective dose of the pharmaceutical composition to the target. In some cases, ensuring that the pharmaceutical composition is delivered to a target includes delivering at least a portion of the pharmaceutical composition (e.g., at least 10%, at least 20%, at least 30%, or at least 40%). In some cases, ensuring that delivery includes delivering at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the pharmaceutical composition.

[0254] In some embodiments, visualization (e.g., imaging) is performed after administration (e.g., by CED) of a pharmaceutical composition. Post-administration visualization can be useful for modifying one or more delivery parameters for one or more subsequent administrations of a pharmaceutical composition. In some embodiments, visualization occurs at 0 minutes, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, 1 hour, 1.25 hours, 1.5 hours, 2 hours, 4 hours, 5 hours, 10 hours, 24 hours, 48 ​​hours, 72 hours, 4 days, 5 days, 1 week, 8 days, 2 weeks, or 4 weeks after administration ... (e.g., comprising radiolabeled liposomes (e.g., 186 In some embodiments, the visualization occurs 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, 1 hour, 1.25 hours, 1.5 hours, 2 hours, 4 hours, 5 hours, 10 hours, 24 hours, 48 ​​hours, 72 hours, 4 days, 5 days, 6 days, 8 days, 1 week, 2 weeks or 4 weeks before the administration of the pharmaceutical composition. In some embodiments, the visualization is performed after the pharmaceutical composition begins to be administered. In some embodiments, the visualization is performed while administering the pharmaceutical composition.

[0255] In some embodiments, visualization (eg, imaging) comprises any imaging method disclosed herein (eg, SPECT, SPECT-CT, MRI, etc.).

[0256] In some embodiments, visualization (e.g., radioactive therapeutic material (radiolabeled liposomes (e.g., 186 Re)) delivery) comprises imaging the whole body. In some embodiments, visualization comprises imaging an area (e.g., a local area) of the body (e.g., the head). In some embodiments, visualization comprises imaging a target (e.g., a tumor). In some embodiments, visualization comprises imaging a primary tumor. In some embodiments, visualization comprises imaging a secondary tumor. In some embodiments, visualization comprises imaging a primary tumor and a secondary tumor. In some embodiments, visualization comprises imaging a tumor and an area surrounding the tumor (e.g., an area where the tumor is located and / or within 6 inches of the tumor). In some embodiments, visualization comprises imaging one or more organs (e.g., including a tumor and / or within a region of a tumor). In some embodiments, visualization comprises imaging a primary tumor.

[0257] In some embodiments, provided herein are methods of improving the survival of a subject with cancer, comprising delivering greater than 100 Gy of radiation to the subject. In some embodiments, delivering greater than 100 Gy of radiation to the subject comprises delivering a pharmaceutical composition (e.g., 186 Re nanoliposomes). In some embodiments, provided herein is a method of improving the survival of a group of subjects having cancer, comprising delivering greater than 100 Gy of radiation to one or more subjects in the group of subjects. In some embodiments, the method comprises delivering greater than 100 Gy to each of one or more subjects in the group of subjects. In some embodiments, the survival comprises overall survival. In some embodiments, the absorbed dose of radiation comprises an absorbed dose of beta-rays. In some embodiments, it is a method of improving overall survival in a group of patients including glioblastoma (e.g., recurrent glioblastoma), comprising delivering greater than 100 Gy of radiation (e.g., beta-rays) to the patient. In some embodiments, delivering greater than 100 Gy of radiation to one or more subjects in the group comprises delivering a pharmaceutical composition (e.g. 186 Re nanoliposomes).

[0258] In some embodiments, a group of subjects with cancer (e.g., glioblastoma) that received greater than 100 Gy (e.g., absorbed dose) of radiation (e.g., beta-rays) includes an improved survival (e.g., overall survival) compared to a second group of subjects that includes one or more subjects with cancer (e.g., glioblastoma) that received less than 100 Gy of radiation (e.g., beta-rays). In some embodiments, the method includes delivering less than 100 Gy of radiation to each of one or more subjects in the second group of subjects. In some embodiments, the absorbed dose includes administering a pharmaceutical composition disclosed herein (radiolabeled liposomes (e.g., 186 Re)). In some embodiments, administration of the pharmaceutical composition to one or more subjects in the subject group results in an absorbed radiation dose of greater than 100 Gy.

[0259] In some embodiments, the methods provided herein improve overall survival. In some embodiments, overall survival comprises administering a pharmaceutical composition (e.g., comprising a radiolabeled liposome (e.g., 186Re nanoliposomes)) after the subject survives. In some embodiments, the total survival of subjects receiving more than 100Gy includes about 100 days, about 150 days, about 200 days, about 250 days, about 300 days, about 350 days or about 400 days. In some embodiments, the total survival of subjects receiving an amount insufficient to result in a pharmaceutical composition greater than 100Gy (e.g., reaching a dose less than 100Gy) includes about 50 days, about 100 days, about 125 days or about 150 days. In some embodiments, the total survival of subjects receiving more than 100Gy is about 20 days, about 30 days, about 45 days, about 60 days, about 70 days, about 80 days, about 90 days, about 100 days, about 110 days, about 120 days or about 130 days more than the total survival of the second group of subjects receiving less than 100Gy.

[0260] Alternative Implementation

[0261] In some embodiments, provided herein are radioactive therapeutic substances for delivering beta-rays and gamma-rays (e.g., 186 Re nanoliposomes). In some embodiments, the radioactive therapeutic substance is incorporated into the pharmaceutical composition.

[0262] Also provided herein are pharmaceutical compositions (e.g. 186 Re nanoliposomes) comprising a method of emitting a liposome sufficient to emit beta rays for treating cancer (e.g., glioblastoma) and gamma rays for visualizing a pharmaceutical composition (e.g., 186 Re nanoliposomes) is administered (e.g., by CED) to a pharmaceutical composition (e.g., 186 In some embodiments, the method further comprises ensuring that the pharmaceutical composition is delivered to a target (e.g., a tumor). In some embodiments, the method further comprises modifying one or more delivery parameters. In some embodiments, modifying one or more delivery parameters while administering the pharmaceutical composition. In some embodiments, modifying one or more delivery parameters after administering the pharmaceutical composition.

[0263] Also provided herein are methods of delivering beta-ray enhancement to a subject (e.g., a patient), comprising administering a pharmaceutical composition (e.g., 186 In some embodiments, the subject received a previous dose of treatment. In some embodiments, the subject received a maximum dose of treatment. In some embodiments, the previous dose of treatment was radiation therapy. In some embodiments, the subject received a previous dose of treatment for the primary disease. In some embodiments, the subject received a previous dose of treatment for the secondary disease.

[0264] Also provided herein is a method of improving the overall survival of a group of subjects (e.g., patients) suffering from cancer (e.g., glioblastoma), comprising delivering radiation (e.g., β-rays) greater than 100 Gy. In some embodiments, the subject group receiving radiation (e.g., β-rays) greater than 100 Gy leads to a higher overall survival compared to the subject group receiving less than 100 Gy radiation (e.g., β-rays).

[0265] Further provided herein are methods of delivering a high (e.g., greater than 100 Gy) absorbed radiation dose comprising delivering a pharmaceutical composition (e.g., 186 Re nanoliposomes). In some embodiments, the method of delivering a high (e.g., greater than 100 Gy) absorbed radiation dose comprises changing the number of catheters, the flow rate (e.g., the flow rate of the infusate), and the volume of the infusate. In some embodiments, the method of delivering a high (e.g., greater than 100 Gy) absorbed radiation dose comprises changing the number of catheters. In some embodiments, the method of delivering a high (e.g., greater than 100 Gy) absorbed radiation dose comprises changing the flow rate. In some embodiments, the method of delivering a high (e.g., greater than 100 Gy) absorbed radiation dose comprises changing the volume of the infusate.

[0266] In an embodiment, up to 13.2 cc of radiation is delivered via the supratentorial region to a single brain hemisphere containing an existing tumor in the same hemisphere.

[0267] Fig.15 Baseline magnetic resonance images (MRI) and single photon emission computed tomography (SPECT) images after treatment with 186Re nanoliposomes are shown. MRI scans showed an initial increase in size, which peaked at day 118, with some associated edema, pseudoprogression. They also showed tumor shrinkage at least until day 362. The subject was still alive 160 weeks after a single treatment.

[0268] Fig.16 MRI scans of tumor responses observed through day 362 are shown.

[0269] Fig.17 A process for convection-enhanced delivery for treating GBM is shown.

[0270] Fig.18 Efficacy and survival data for ReSPECT-GBM are shown.

[0271] Fig.19 Shown are SPECT CT, planar imaging, and CSF liquid biopsy results for patients after 186RNL treatment.

[0272] FIG. 20A shows a method of producing Re-186 nanoliposomes, and FIG. 20B shows a method of producing Re-188 nanoliposome biodegradable alginate microspheres.

[0273] Fig.21 Methods for non-surgical locoregional treatment options for solid organ tumors are shown. In embodiments, a single intra-arterial injection of 188RNL-BAM, wherein the biodegradable microspheres block blood flow to the targeted solid organ tumor and simultaneously deliver radiation for the therapeutic payload. Compared to the 2 currently available radioembolization therapies, 188RNL-BAM may offer the following potential advantages:

[0274] Biodegradable microspheres

[0275] Higher quality imaging

[0276] Predictive testing of final clinical outcomes

[0277] Shorter generation time

[0278] Improved patient access

[0279] Higher margins

[0280] Better translation into other indications

[0281] Liver cancer is the 6th most common and 3rd most deadly cancer. The treatments disclosed herein pursue new and relevant routes of administration and delivery and mechanisms of action. These treatments offer the opportunity to extend the lives of liver cancer patients through safer, more targeted, and convenient treatment methods.

[0282] about Fig. 22 and 23 , these graphs indicate how much irradiated volume is produced by the infusion volume and the correlation with absorbed dose. In an embodiment, an infusion volume of XX mL and YY mCi of radiation produce an irradiated volume of AA (with an average absorbed dose of <1 / 4, <1 / 2, <1 / 8, or <1 / 1 of the tumor).

[0283] Fig.24 RNL Kaplan-Meier plots are shown comparing overall survival of patients receiving greater than 100 Gy to those receiving less than 100 Gy up to 40 months. The figure compares patients who received therapeutic radiation (e.g., greater than 100 Gy) (red) to non-therapeutic radiation (e.g., less than 100 Gy) (blue). The group of patients who received greater than 100 Gy had greater overall survival than the group of patients who received less than 100 Gy. Fig.25RNL Kaplan-Meier plots are shown comparing overall survival for patients who received greater than 100 Gy to those who received less than 100 Gy for 42 months.

[0284] Fig.26 A plot of mortality with dose and tumor coverage is shown. The circle size is proportional to the overall survival time. The alive are colored green and the dead are colored red. It appears that the survival time increases with both the absorbed dose and the TuV / Trv percentage.

[0285] Fig. 27 Radiotherapeutic formulations of rhenium (186Re)obisbemeda and rhenium-188 nanoliposomal biodegradable alginate microspheres are shown.

[0286] Fig.28 Shown are graphs of tumor retention based on percent injected activity versus time (intratumoral administration of CED in head / neck SCC xenografts in nude rats).

[0287] Fig.29 Shown are graphs of tumor response based on tumor volume versus time (intratumoral administration of CED in head / neck SCC xenografts in nude rats).

[0288] Fig.30 Shown are the percentage of tumor volume treated, with the proportion alive versus months. OS = overall survival.

[0289] Fig.31 The mean absorbed dose to the tumor is shown, with the proportion alive versus the number of months.

[0290] Fig.32 Pial administration and rapid diffusion of rhenium (186Re)obisbemeda targeting CSF are shown.

[0291] Fig.33 Shows the latest information about the ReSPECT-LM clinical trial.

[0292] Exit speed

[0293] The exit velocity is based on the volume of fluid discharged in a set time and the size of the opening through which the volume is discharged. Exit velocity (combines the flow rate and the catheter tip inner diameter (ID)). Exit velocity = volume flow / area (v = Q / A). The smaller the opening or resistance of the outlet, the higher the exit velocity. The exit velocity affects the distribution of the fluid being discharged. It would be expected that the fluid with a higher exit velocity would be more distributed.

[0294] Table 1.

[0295]

[0296] Examples:

[0297] Q=20ul / min=0.02ml / min=0.02mm 3 / min

[0298] A =πr 2 =3.14*0.267mm*0.267mm(Smart Flow)

[0299] A = 0.223 mm 2

[0300] v=0.02mm 3 / min / 0.223mm 2 =.090mm / min

[0301] Example

[0302] Example 1: Phase 1 clinical trial

[0303] A single-center, consecutive-cohort, open-label, volume- and dose-escalation phase 1 clinical trial was conducted to evaluate the efficacy of convection-enhanced delivery of sirolimus in patients with recurrent or progressive malignant glioma following standard surgical, radiotherapy, and / or chemotherapy. 186 Safety, tolerability, and distribution of Re nanoliposomes. The study used a modified Fibonacci dose escalation and a standard 3+3 design.

[0304] Brainlab iPlan Flow software was used to plan the placement of the SmartFlow catheter within the tumor volume while avoiding white matter tracts and cerebrospinal fluid spaces such as fissures, sulci, cisterns, ventricles, and resection cavities. Frameless image-guided catheter placement was achieved with the Brainlab Varioguide stereotactic system. 186 Re nanoliposomes were administered by convection-enhanced delivery using 1 to 3 catheters with a maximum flow rate of up to 0.90 mL / hour per catheter (15 μL / min per catheter).

[0305] Dynamic planar imaging was performed continuously for 1 minute during the infusion period. 186Single photon emission computed tomography (SPECT) / computed tomography (CT) imaging and serial whole-body planar imaging scans were performed immediately after Re nanoliposome infusion and on days 1, 3, 5, and 8 after infusion to assess the radiation absorbed dose to the tumor and other organs during treatment. Activity counts were also performed on serial blood samples and serial 24-hour urine collections. Dosimetry was performed using region of interest data and OLINDA dose calculation software.

[0306] Fifteen patients were treated, fourteen of whom had recurrent glioblastoma and 47% had failed treatment with bevacizumab. The infusion dose was gradually increased from 1.0 mCi to 13.4 mCi using 1 to 3 convection-enhanced delivery catheters, and the volume of the infusate was increased from 0.66 mL to 5.28 mL. The therapy was well tolerated and no dose-limiting toxicity was observed, although the absorbed dose in previously treated patients was significantly higher than that in external beam radiation therapy (EBRT). The study design and overall survival of each patient are summarized in Table 2 below.

[0307] Table 2: Phase 1 clinical trial design

[0308]

[0309] The median survival duration of patients who failed bevacizumab (n=7) was 4.8 months. The median survival duration of patients who had not used bevacizumab (n=8) was 10.9 months, with 4 patients still alive at the end of the study.

[0310] exist Figure 1 The differences in tumor volume between patients previously treated with bevacizumab and those who had not received bevacizumab were summarized in 186 Absorbed dose of Re nanoliposomes. Figure 2 The tumor volume for each patient is summarized in Figure 3 The ratio of the volume of treatment to the volume of the infusate is summarized in . Figure 4 The differences in survival between patients previously treated with bevacizumab and those who had not received bevacizumab were summarized in .

[0311] exist Figure 5 The results for each dose level are summarized in 186Re nanoliposomes, mean absorbed doses to brain, whole body, and tumor volume. The median absorbed dose to the tumor volume for all patients (n=15) was 143Gy (range 9-593Gy). The median absorbed dose for patients who failed bevacizumab (n=7) was 38Gy (range 9-593Gy), while the median absorbed dose for patients who had not used bevacizumab (n=8) was 367Gy (range 56-517Gy). The maximum absorbed dose to the tumor volume was 593Gy. The average retention of the administered dose at 24 hours was 64% (Cl 50-78). The whole body absorbed dose was less than or equal to 0.70Gy. The mean absorbed dose to the organ was less than or equal to 0.70Gy. In the last two cohorts, the ratio of the mean tumor volume absorbed dose to the mean whole body absorbed dose was greater than or equal to 3,000.

[0312] The most common adverse events were fatigue (40%), diarrhea (27%), gait disturbance (27%), headache (27%), hemiparesis (27%), dizziness (20%), scalp discomfort (20%), seizures (20%), and cerebral edema (20%). Neither the incidence nor the severity of adverse events appeared to increase with the treatment period. 186 Four serious adverse events were reported: convulsions in three patients and cerebral edema in one patient. However, none of these serious adverse events was considered to be related to 186 Re nanoliposome treatment was causally related. Most adverse events were considered to be related to 186 Re nanoliposome treatment was not causally associated, with the exception of scalp discomfort, which was considered to be related to the surgical procedure.

[0313] Example 2: Case Study

[0314] The patient was a 51-year-old Caucasian female who presented with neurological symptoms and possible seizures. Magnetic resonance imaging (MRI) of the brain showed a right frontal mass. Craniotomy revealed a grade 2 diffuse astrocytoma, IDH wild-type, MGMT unmethylated (cIMPACT-NOW grade IV). She was treated with combined radiation and temozolomide, followed by three cycles of temozolomide maintenance. Follow-up MRI was consistent with recurrent disease. The patient entered the Phase 0 trial of Sacituzumab via a repeat right frontal craniotomy 9 months after the initial presentation of recurrent glioblastoma and received the first dose of Sacituzimab in cycle 1 (C1D1) one month later. Disease progression was again noted 16 months after the initial presentation. Less than 4 weeks later, the patient received 186 Treatment with Re nanoliposomes (13.4 mCi, 5.28 mL, 3 catheters).

[0315] MRI and SPECT images at baseline, 24 hours and 120 hours after treatment are shown in Figure 6 The tumor volume was 18.8 mL and the tumor coverage was 87%. The absorbed dose delivered to the tumor was 336 Gy and the absorbed dose delivered to the distribution volume (Vd) was 245 Gy. At 24 hours, the anterior part of the tumor ( Figure 6 outside the distribution volume (indicated by yellow arrows in Figure 6 By day 5 after treatment, the entire tumor was within the distribution volume ( Figure 6 shown with light purple line in the figure).

[0316] Figure 7 The baseline and the 186 Magnetic resonance images (MRI) and perfusion scan images 56 days after Re nanoliposome treatment. MRI on day 56 showed a partial response with no signs of edema. Perfusion scan showed a significant reduction in previously enhanced tumor areas.

[0317] As demonstrated by the above examples, 186 Re nanoliposomes can deliver up to twenty times the absorbed radiation dose administered by external beam radiotherapy without significant toxicity. Convection-enhanced delivery was performed at doses up to 13.4 mCi in 5.28 mL infusion. 186 Intratumoral administration of Re nanoliposomes was safe and well tolerated. Prior administration of bevacizumab appeared to be 186 Re nanoliposomes have a negative impact on the convection.

[0318] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Without departing from the present invention, many changes, modifications and substitutions will now occur to those skilled in the art. It should be understood that various alternatives to the embodiments of the present invention described herein may be adopted in practicing the present invention. The following claims are intended to define the scope of the present invention, and methods and structures within the scope of these claims and their equivalents are thus covered.

[0319] Example 3: Image-guided Re-186 Nanoliposomes in the Treatment of Recurrent Glioblastoma 186 RNL) Brachytherapy: Techniques, Image Analysis, Dosimetry, and Monitoring

[0320] 186 Rhenium-lipid nanoparticles (including 186 RNL 186Re nanoliposomes) have been introduced into focused brachytherapy for cancer by image-guided infusion into the tumor interstitial space; first, for the treatment of recurrent glioblastoma (GBM) of the brain. 186 Re) is a radionuclide (half-life: 89.24 hours) that emits therapeutic beta-radiation particles (path range: 1.8 mm). One out of every 10 emissions is associated with 137 KeV gamma rays, allowing imaging of in vivo drug distribution, retention, and for radiation absorption dose distribution calculation and treatment assessment. In this article, we report our Phase I clinical trial study, which focused on the techniques used, image analysis, radiation dosimetry, and treatment monitoring.

[0321] Although external beam radiation therapy (EBRT) remains a mainstay of glioma treatment, it is limited by the tolerance of surrounding normal brain tissue. We hypothesized that rhenium-186 nanoliposomes ( 186 RNL) (e.g. 186 Re nanoliposomes) focused brachytherapy may allow selective delivery of high specific activity beta emitting radiation with good retention in tumors, and the emitted gamma rays will allow real-time image-guided delivery and monitoring. Herein, we report on the techniques used, imaging of nanoliposome distribution and retention, image analysis, radiation dosimetry, and treatment monitoring.

[0322] A Phase 1 clinical trial was conducted to administer the drug via convection-enhanced delivery (CED) via the Brainlab Flexible Subacute Catheter 186 RNL for the treatment of recurrent glioblastoma. BrainLab iPlan Flow software and Varioguide system were used for treatment planning and catheter placement. Planar and SPECT / CT imaging was obtained from mid-infusion to 8 days after radiation source administration. 186 RNL (e.g. 186 Retention and distribution of Re nanoliposomes within tumors and throughout the body. Analysis of local regional and systemic drug retention from whole body planar images. Co-registration of SPECT / CT and follow-up MRI images with planning MRI images for 3D drug distribution and treatment assessment. Calculation of radiation absorbed dose to local volumes and whole body organs.

[0323] Using MIM MRT quantitative SPECT image reconstruction and 3D dose calculation, we calculated 186 The 3D radiation absorbed dose distribution during 8 days of RNL treatment was evaluated with tumor treatment response.

[0324] like Fig.13 As shown, CED delivered to patients with recurrent glioblastoma 186 RNL (e.g., 186Re nanoliposomes) can lead to predictable distribution and stable retention of nanoparticle radiation sources in target tissues, providing continuous, localized radiation therapy to tumors for days. Fig.13 Shows 186 Distribution and retention of RNL radionuclide over 8 days after infusion. 186 The RNL radiation source had sustained retention and stable local regional distribution at the treated tumor in the brain, providing a continuous radiotherapy effect for more than 8 days. The subject from which these images were obtained included a tumor volume of 6.5 mL and tumor coverage was greater than 90%. The absorbed dose delivered to the tumor was 419 Gy.

[0325] The use of up to four catheters effectively improves locoregional drug distribution and tumor volume coverage as well as infusion speed, improving patient convenience. The mean locoregional retention of brain volume at the end of infusion was 85.9% ± 17.1% ID (n = 18), and 46.6% ± 16.7% ID (n = 17) on day 8 after infusion. After dose escalation, the mean radiation absorbed dose of the tumor volume in the last two cohorts was 354.7 ± 144.0 Gy, the mean radiation absorbed dose of the whole brain was 1.32 ± 1.06 Gy, and the mean radiation absorbed dose of the whole body was 0.16 ± 0.04 Gy (n = 6).

[0326] Fig.14A Shows 186 RNL (e.g., 186 Re nanoliposomes) for brachytherapy, and Fig. 14B Shows 186 RNL (e.g., 186 Dose volume histogram of brachytherapy with Re nanoliposomes. As shown, over 8 days, the maximum dose in the treatment volume was >500Gy, the average dose to the GTV was 323Gy, and the minimum dose to the GTV was 55.6Gy. An important feature of the treatment technique can be the highly focused treatment of the volume with the radiation source delivery. The 3D dose distribution has shown a very steep dose gradient; the 5Gy isodose line has been shown (white arrow). For comparison, Fig. 14C Iso-dose distribution in tumor and surrounding normal tissues for SBRT case is illustrated. In SBRT case, a prescribed dose of 30-Gy was delivered to the radiotherapy planning target volume (PTV). The white line shows the 5-Gy isodose line.

[0327] Treatment with focused brachytherapy allows high radiation doses to be delivered for tumor eradication with low toxicity to uninvolved tissue. With this treatment technique, the radiation absorbed dose within the treatment volume is several hundred Gy or more, while the radiation absorbed dose outside the radiation source distribution volume falls rapidly to minimal levels; for reference see Fig.14AThe white arrow in the figure shows the 5-Gy isodose line.

[0328] Based on the results of this study, 186 RNL (e.g., 186 Re nanoliposome) brachytherapy can deliver high radiation absorbed doses to tumors with minimal brain and whole body radiation exposure. Therapy with this technology can also deliver continuous radiation from high to low radiation dose rates to the target for more than 8 days, which can be beneficial in the radiobiology of tumor control.

[0329] The results of this study showed that, compared with sealed source brachytherapy, 186 RNL (e.g., 186 Re nanoliposome) brachytherapy can be advantageous in terms of minimal invasiveness, planning and delivery convenience, and this therapy is bioabsorbable. In addition, image monitoring capabilities can provide a predictive tool for evaluating therapy delivery and therapeutic effectiveness, and the development of 3D dose distribution calculations can provide a convenient mechanism for dose and therapy effect assessment and for applying additional therapies to better control tumors.

[0330] Example 4: Rhenium-186 Nanoliposomes ( 186 Safety and feasibility of RNL in recurrent glioma

[0331] EBRT, a mainstay of primary brain tumor therapy, is limited by the tolerance of surrounding normal brain tissue. 186 RNL) allows the delivery of high specific activity of β-emitting radiation with good retention in tumors.

[0332] 186 A phase 1 dose-escalation study of RNL in recurrent gliomas was conducted using a standard 3+3 design to determine 186 The maximum tolerated dose of RNL. 186 RNL was administered by convection-enhanced delivery (CED). Whole-body planar imaging and SPECT / CT were performed after infusion. 186Repeated SPECT / CT imaging was performed on days 1, 3, 5, and 8 after RNL infusion to obtain dose determination and distribution. Subjects were followed up according to RANO criteria until disease progression. Eighteen subjects were treated in 6 cohorts, each consisting of 3 subjects. Table 3 shows information related to dosing for each cohort, such as the amount of radioactivity delivered, the volume of the infusate, and the concentration of the infusate. The average tumor volume was 9.4 mL (range 1.1–23.4). The dose range of the infusion was 1.0 mCi to 22.3 mCi, and the volume range of the infusate was 0.66 mL to 8.80 mL. 1-4 CED catheters were used for delivery. The maximum flow rate of the catheter was 15 μl / min. The mean absorbed dose to the tumor volume was 239 Gy (CI 141–337; range 9–593), the mean absorbed dose to the normal brain was 0.72 Gy (CI 0.34–1.09; range 0.005–2.73), and the mean absorbed dose to the whole body was 0.07 Gy (CI 0.04–0.10; range 0.001–0.23). When the percentage of tumor volume in the treatment volume was 75% or greater (n=10), the mean absorbed dose to the tumor volume was 392 Gy (CI 306–478; range 143–593). Three subjects experienced scalp discomfort and tenderness related to the surgery. The treatment was well tolerated, no dose-limiting toxicities were observed, and no serious adverse events related to treatment occurred, despite the fact that previously treated patients generally delivered significantly higher absorbed doses with EBRT. Responses supporting clinical activity were observed.

[0333] Compared with EBRT, CED in patients with recurrent glioma 186 RNL resulted in higher radiation absorbed doses to the tumor without significant toxicity. 186 RNL may be useful for the treatment of recurrent gliomas. In particular, a dose of 22.3 mCi in an 8.8 mL infusion may be used to treat recurrent gliomas.

[0334] Table 3. Dosage characteristics.

[0335] queue Activity (mCi) Infusion volume (mL) Concentration (mCi / mL) Average absorbed dose (Gy) 1 1.0 0.66 1.5 198 2 2.0 1.32 1.5 122 3 4.0 2.64 1.5 234 4 8.0 5.28 1.5 171 5 13.4 5.28 2.5 423 6 22.3 8.80 2.5 287

[0336] Example 5: Overall survival of rhenium-186 nanoliposomes in recurrent glioblastoma (GBM)

[0337] Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor in adults. For the past decade, the standard treatment for GBM has been surgery followed by chemoradiation with temozolomide, with radiation therapy being the major factor in survival in this regimen. As most recurrences occur within two centimeters of the resection margin, locoregional therapies that circumvent the blood-brain barrier are attractive potential alternatives. External-beam radiation therapy (EBRT) is a mainstay of primary brain tumor treatment but can be limited by tolerance to radiation from surrounding normal brain and bone tissue. 186 Re) is an efficient electron source with short path length, low dose rate and high radiation density. In particular, 186 Re can be a β-emitting therapeutic radionuclide with a half-life of 90 hours, a 1.8-mm radiation path range, and a high β / γ-energy ratio suitable for cancer brachytherapy. 186 Re may have gamma ray energy sufficient to allow imaging of the radiopharmaceutical distribution in vivo using standard SPECT / CT.

[0338] Re-186 nanoliposomes may allow for the delivery of high specific activity beta radiation with good retention in tumors. Therapeutic radionuclides may require carriers to ensure they are sequestered within the tumor and slowly redistributed. Liposomal nanoparticles (nanoliposomes) may provide a means of encapsulating radionuclides and aiding in sustained intratumoral accumulation while also convecting within the tumor. We have successfully developed a method to deliver 186 A method for loading Re into nanoliposomes with high efficiency and specific activity. This method can produce significantly higher levels of specific activity than previously described and has the potential to provide significantly higher delivered therapeutic radiation doses with reduced toxicity. Preclinically, liposome-encapsulated Re delivered by convection enhanced delivery (CED) 186 RNL (e.g., 186 Re nanoliposomes) can achieve very high doses of targeted radiation and a wide therapeutic index. We report 186 RNL (e.g. 186 Results of a first-in-human phase 1 trial (ReSPECT) of Re nanoliposomes in recurrent glioma.

[0339] The study was a multicenter, consecutive cohort, open-label, volume and dose-escalation Phase 1 clinical trial: RNL (e.g., 100 mg / kg / day) given by convection-enhanced delivery (CED) was administered to patients with recurrent or progressive malignant glioma after standard surgical, radiotherapy and / or chemotherapy treatment. 186 The study used a modified Fibonacci dose escalation and a standard 3+3 design.

[0340] Brainlab iPlan Flow software was used to plan the placement of the SmartFlow catheter within the tumor volume while avoiding white matter tracts and CSF spaces (fissures, sulci, cisterns, ventricles, and resection cavities). Frameless image-guided catheter placement was achieved with the Brainlab Varioguide stereotactic system. Single RNL administration was delivered via CED using 1-4 catheters at a maximum flow rate of up to 20 μL / min / catheter.

[0341] Dynamic planar imaging was performed continuously for 1 minute during the infusion period. 186 Immediately after Re nanoliposome infusion and on the 1st, 3, 5 and 8th day after infusion, SPECT / CT imaging and continuous whole body planar imaging scans were performed to assess the radiation absorbed dose of tumors and other organs during treatment. Continuous blood samples and continuous 24-hour urine collection were also counted for activity. Dosimetry was performed using region of interest data and OLINDA dose calculation software. The dose escalation scheme for each queue is shown in Table 4.

[0342] Table 4: Dose escalation schedule for each cohort.

[0343]

[0344] * Cohort 6 * The same volumes and doses as cohort 6 were used, but the maximum flow rate was increased to 20 μl / min.

[0345] Twenty-two patients were treated across seven dosing cohorts from 2015 to 2021. Fourteen were male and eight were female. The mean tumor size was 8.3 mL (range 0.9-22.8 mL). The mean number of prior therapies (Txs) was 1.7 (range 1-3Txs). Five patients had previously received bevacizumab. Pathological grade was grade IV glioma in 20 patients and grade III glioma in 2 patients. IDH mutation status was wild type in 18 patients, and mutated in 2 patients (no status in 2 patients), and MGMT status was methylated in 4 patients, and unmethylated in 12 patients (no status in 6 patients).

[0346] Twenty-two patients across seven dosing cohorts received a range of 1.0-31.2 mCi in volumes of 0.6-12.3 mL. Maximum CED dosing rates ranged from 5-20 μl / min, and 1-4 catheters were used per patient. The mean absorbed radiation dose to the tumor was 273 Gy (8.9-740 Gy), with negligible extracerebral exposure. The percentage of tumor in the treatment volume (TrV) (TuV) or TuV / TrV was 70.9% (19.8%-100%) and correlated with the mean absorbed radiation dose to the tumor. In the five patients who had previously received bevacizumab, the mean absorbed dose to TuV was 149.2 Gy, and the TuV / TrV percentage was 47.9%. However, in the 17 patients who had not previously received bevacizumab, the mean absorbed dose to TuV patients was 302 Gy, and the TuV / TrV percentage was 77.7%. Based on the poor convection of these convection inputs, further recruitment of patients on bevacizumab was stopped.

[0347] Figure 8 A 3D view of the extent of the delivered radiation (measured in absorbed dose) is shown. This image was taken with 186 RNL (e.g. 186 Re nanoliposomes) taken 8 days after treatment.

[0348] Fig. 9 A graph showing overall survival in terms of mean absorbed dose and TuV / TrV percentage is shown. The analysis was based on a proportional hazards model for overall survival (in days) in terms of mean absorbed dose, TuV / Trv percentage and interaction term, indicating that survival time increased with both absorbed dose and TuV / Trv percentage (p=0.065), based on a sample size of N=22.

[0349] After receiving a single dose 186 RNL (e.g. 186 Re nanoliposomes) in 22 subjects with recurrent glioblastoma (GBM). 186 RNL was safe and well tolerated. In particular, there were no adverse events (AEs) with mortality as a result or discontinuations due to AEs. Most AEs reported were mild or moderate in intensity (grade 1 or 2) and not serious. The most frequent adverse events (AEs) were: fatigue (50.0%), muscle weakness and headache (33.3% each), and gait disturbance (27.8%). Most AEs were considered to be related to 186 RNL was causally unrelated, except for one case of scalp discomfort, which was considered to be related to the surgery, and one case of cerebral edema. Grade 3 AEs were leukocytosis, hyperglycemia, myasthenia, convulsion, cerebral edema, avascular necrosis of the shoulder (worsening), vasogenic cerebral edema, and pneumonia; all of these events were considered by the principal investigator to be related to the procedure.186 RNL was not associated, except for cerebral edema in one subject, which was considered a possible 186 RNL related.

[0350] Serious adverse events were reported in two subjects in Cohort 2 (convulsion and vasogenic cerebral edema), one subject each in Cohorts 4 and 5 (both convulsions), and two subjects in Cohort 6 (pneumonitis, avascular necrosis of the shoulder (exacerbation), and cerebral edema). All of these events were considered by the investigators to be 186 RNL (e.g. 186 Re nanoliposomes) except for one subject with cerebral edema, which was considered a possible 186 Reductions in RNL and / or oral corticosteroids were associated and did not lead to study discontinuation.

[0351] There were no major differences or patterns in the incidence of relevant TEAEs reported across treatment groups (cohorts). Neither the incidence nor the severity of AEs appeared to increase with treatment. 186 RNL (e.g. 186 Re nanoliposomes) increased with the increase of dose.

[0352] Fig.10 Images including baseline MRI, and SPECT images after 20% infusion, at the end of infusion, 24 hours after infusion, 120 hours after infusion, and 192 hours after infusion are shown.

[0353] Fig.11 Images including baseline MRI, and SPECT images at the end of infusion, 24 hours post-infusion, 120 hours post-infusion, and 192 hours post-infusion are shown.

[0354] Fig.12 Kaplan-Meier curves are shown, comparing patients receiving therapeutic radiation (e.g., greater than 100Gy) with non-therapeutic radiation (e.g., less than 100Gy). The curve shows a statistically significant difference between the groups (p=.0002). As shown, the group of patients receiving greater than 100Gy had a greater overall survival than the group of patients receiving less than 100Gy. Statistically significant overall survival benefits were observed in patients who reached a sufficient absorbed radiation dose (>100Gy) compared to patients who did not reach a sufficient absorbed radiation dose. In addition, a sufficient absorbed radiation dose (>100Gy) can be reached in 80% of the patients treated in the 5-7 cohort.

[0355] Based on the research results, intratumoral convection-enhanced delivery 186 RNL to the brain can precisely deliver up to twenty times the absorbed radiation dose that can be delivered via EBRT. 186RNL can be safe, no dose-limiting toxicity was observed, and SPECT / CT can precisely and reliably visualize the location of RNL and the level of residual radioactivity as it decays. Finally, this study showed that increasing the volume of drug and radiation dose administered was associated with improved overall survival in the later-dose cohort.

[0356] Example 6: Re-186 Nanoliposomes Delivered by Convection Enhanced Delivery ( 186 RNL) for recurrent, refractory, or progressive ependymoma and high-grade glioma (HGG) and newly diagnosed diffuse intrinsic pontine glioma (DIPG)

[0357] Ependymomas, HGG, and DIPG are often difficult to treat, often aggressive, and often have a poor prognosis. While radiation therapy remains the mainstay of treatment, it is limited by the tolerance of surrounding brain tissue. 186 RNL) (e.g. 186 Re nanoliposomes) allow for the selective delivery of high specific activity of β-emitting radiation with good retention in tumors.

[0358] A two-part Phase 1 dose-finding study will be conducted, followed by an expansion cohort based on data from the adult Phase 1 trial to explore efficacy in pediatric patients. Part 1 will enroll up to 18 subjects to determine the efficacy of the drug, which is administered via convection-enhanced delivery (CED). 186 RNL (e.g. 186 Re nanoliposomes). Tumor diameter will be limited to 4 cm and volume to 34 mL. Dose-limiting toxicity (DLT) is 28 days after infusion. Part 2 will be evaluated independently in 3 different cohorts 186 RNL (e.g. 186 Re nanoliposomes): A: up to 12 subjects diagnosed with recurrent, refractory or progressive ependymoma; B: up to 12 subjects diagnosed with recurrent, refractory or progressive HGG; C: up to 15 subjects newly diagnosed with DIPG. The primary endpoint is the overall response rate (ORR) of the Radiographic Assessment of Pediatric Neuro-Oncology (RAPNO) criteria. Secondary endpoints are 24-month progression-free survival (PFS-24) and 24-month overall survival (OS-24) in cohort A, and PFS-12 and OS-12 in cohorts B and C.

[0359] In a phase 1 trial (NCT01906385) in adults with recurrent glioblastoma, the mean dose to the tumor was 392 Gy (CI 306–478) when coverage was 75% or greater (n = 10). Treatment was well tolerated, with no dose-limiting toxicities observed, and no serious adverse events observed (n = 18).

[0360] Drug administration via CED 186 RNL (e.g. 186 Delivery of Re nanoliposomes was well tolerated in adults with recurrent HGG, with significantly higher doses of radiation therapy compared with standard physical therapy. Further studies will be conducted in adult and pediatric subjects. 186 RNL can be used to treat HGG (eg, recurrent HGG).

[0361] Example 7: Intraventricular Re-186 Nanoliposomes ( 186 The maximum tolerated dose, safety and efficacy of RNL for leptomeningeal metastases

[0362] Leptomeningeal metastases (LM) are a rare but typically fatal complication of advanced cancer affecting the fluid-lined structures of the central nervous system and are diagnosed in approximately 5% of patients. With survival measured in weeks to months, new approaches are needed that can improve both the quality and quantity of life. 186 RNL) allows selective delivery of high-specific-activity beta-emitting radiation directly to the tumor. In a phase 1 trial (NCT01906385) in adults with recurrent glioblastoma, the mean absorbed dose to the tumor was 392 Gy (CI 306–478) when coverage was 75% or greater (n=10). Treatment was well tolerated, with the one serious adverse event that was possibly related to treatment, cerebral edema, resolving after steroid treatment.

[0363] This is a two-part Phase 1 dose-finding study, followed by an expansion cohort to explore efficacy. Part 1 will enroll up to 21 subjects to characterize the efficacy of a single dose of Ommaya administered intracerebroventricularly via the Ommaya reservoir. 186 The safety and tolerability of RNL will be evaluated in 2 separate cohorts and the maximum tolerated dose (MTD) / maximum feasible dose (MFD) will be determined for future studies. The dose-limiting toxicity period is 28 days after infusion. 186 RNL: Cohort A: up to 20 subjects diagnosed with LM from primary breast cancer; Cohort B: up to 20 subjects diagnosed with LM from primary non-small cell lung cancer. The primary endpoint is to evaluate 186The antitumor activity of RNL as a single agent was evaluated by a secondary endpoint to characterize the 186 The pharmacokinetic and dosimetric profiles of RNL were determined, the overall response rate (ORR) was determined based on CSF and radiographic findings, and the survival distribution was described.

[0364] Example 8: Intraventricular Re-186 Nanoliposomes ( 186 Preclinical safety and activity of RNL for leptomeningeal metastases

[0365] LM is a clinical complication that can occur when cancer cells invade the leptomeninges and cerebrospinal fluid of patients with malignant tumors. Once diagnosed, limited treatment options exist and survival is short. 186 RNL) is a liposome-encapsulated beta emitter with a short path length of 1.8 mm, allowing high specific activity brachytherapy with limited exposure to surrounding tissue. 186 RNL may be useful in the treatment of LM.

[0366] To establish via intraventricular (IT) injection 186 Eight cohorts of Wistar rats (n=3 per cohort) were injected IT at the maximum tolerated dose (MTD) of RNL. 186 RNL activity increased at doses of 0 (control), 0.480, 0.800, 1.000, 1.150, and 1.340 mCi. Toxicity was assessed by daily food and water intake, daily body weight, and observation of neurological deficits. To evaluate efficacy, C6-Luc glioma cells were injected IT 15 days after inoculation with 0.69 mCi of 186 Animals were treated with RNL. Absorbed dose was assessed by gamma camera imaging at 0 h, 24 h, and 48 h after treatment. Tumor growth was assessed by luciferase bioluminescence.

[0367] No adverse reactions were observed in rats after administration of up to 1.34 mCi and up to 1075 Gy absorbed doses within 3 months. 186 There was no evidence of RNL-related side effects. Therefore, the MTD exceeded the dose evaluated in this study. At 2 weeks after treatment, a significant difference in survival between the control and treatment groups (n=8 each) was observed, with a survival rate of 50% in the control group and 100% in the treatment group (p=0.0087). The only significant histological finding in the treated rats was thickening of the pia mater covering the median eminence, indicating mild reactive meningeal hypertrophy. This evidence suggests that in the rat model of LM, 186 Intraventricular delivery of RNL was well tolerated and improved animal survival at 2 weeks. 186 RNL may be useful in the treatment of LM.

[0368] Embodiment 9: 186 Maximum tolerated dose of RNL

[0369] Nanoliposomal BMEDA-chelated- 186 rhenium( 186 RNL) allows the delivery of high specific activity of β-emitting radiation with good retention in tumors. Using a standard 3+3 design, 186 RNL conducted a phase 1 dose-escalation study in recurrent gliomas to determine the efficacy of stereotactic biopsy after 186 The maximum tolerated dose of RNL. 186 RNL was administered with a BrainLab flexible catheter via convection, guided by the iPlan Flow and Varioguide systems. Whole-body planar imaging and SPECT / CT were performed after infusion. 186 Repeat SPECT / CT imaging was performed immediately after RNL infusion and on days 1, 3, 5, and 8 to obtain dosimetry and distribution.

[0370] Thirteen patients were treated, 12 for recurrent glioblastoma, and 54% had failed bevacizumab. The infusion dose was escalated from 1.0 mCi to 13.4 mCi using 1 to 2 CED catheters, and the volume of the infusate was increased from 1.0 mL to 5.28 mL. The mean absorbed dose to the volume of distribution was 175 Gy (CI 97–254). The maximum absorbed dose to the tumor volume was 593 Gy. The mean retention of the administered dose at 24 hours was 61.4% (CI 45.4–77.5). The therapy was well tolerated, and no dose-limiting toxicities were observed as well as no treatment-related adverse events, although the absorbed dose was significantly higher than EBRT in previously treated patients. It is planned to increase the dose to 22.3 mCi and increase the infusate volume to 8.8 mL. Based on the results of this study, intratumoral 186 RNL can deliver up to twenty times the absorbed radiation dose administered via EBRT without significant toxicity.

[0371] Example 10: Administration of a single dose via an intraventricular catheter 186 An open-label phase I clinical study of RNL for the treatment of leptomeningeal metastases (LM).

[0372] This phase I study evaluated a single dose of 100 mg / dL given via an intraventricular catheter (Ommaya reservoir) in participants with leptomeningeal metastases (LM). 186 RNL (Radionuclide Clinical Research Drug) (e.g. 186 Re nanoliposomes). Clinical study treatment consisted of a single 5cc dose of each participant. 186RNL. The clinical study will include an evaluation of three separate dose levels. Three to six participants can be treated at each dose. The maximum number of participants to be recruited in this study is 18. Clinical study treatment will be administered by the clinical study physician on an outpatient basis after a CSF flow study. Participants will be followed up for up to 12 months after administration of the clinical study drug.

[0373] The study will include dose escalation in cohorts 1-3. Each participant will receive 186 A single dose of 5cc of RNL. At each dose level, a minimum of three to a maximum of six participants will be enrolled. If no dose-limiting toxicity is observed in the initial three participants, the next higher dose level cohort will be open for enrollment. The dose escalation schedule will follow a modified Fibonacci dose escalation schedule as shown: Cohort 1 (6.6mCi), Cohort 2 (13.2mCi), Cohort 3 (26.4mCi).

[0374] Outcome measures will include primary and secondary outcome measures. Primary outcome measures will include: a.) the incidence and severity of adverse events (AEs) and serious adverse events (SAEs) over a 12-month time frame (safety will be assessed by the incidence of AEs and SAEs graded according to CTCAE version 5.0), and b.) the incidence of dose-limiting toxicities (DLTs) over a 12-month time frame (the maximum tolerated dose (MTD) will be assessed by testing escalating doses in cohorts 1 to 3, with 3 to 6 participants in each cohort. The MTD reflects the highest dose of the drug that does not cause dose-limiting toxicity (DLT) in >33% of participants).

[0375] Secondary outcome measures will include: a.) determining the overall response rate (ORR) within a 12-month time frame (the ORR, defined as the proportion of all evaluable participants achieving a response that is a best overall response at the time of progression, will be determined); b.) determining the duration of response (DoR) within a 12-month time frame (the DoR, defined as the time from first response to LM progression, will be determined); c.) determining progression-free survival (PFS) (the PFS, defined as the time from first treatment to date of LM progression or death from any cause, will be determined); and d.) determining overall survival (OS) (the OS, defined as the time from first treatment to date of death, will be determined).

[0376] Participant eligibility criteria included both inclusion and exclusion criteria. Inclusion criteria included the following: age at least 18 years at screening; able to understand the purpose and risks of the study and signed a written informed consent document approved by the specific site IRB; subjects had demonstrated and documented LM that met the study requirements: any major type of EANO-ESMO Clinical Practice Guideline Type 1 and 2 (except 2D) LM; Karnofsky performance status of 60 to 100; a.) acceptable liver function: bilirubin ≤ 1.5 times the upper limit of normal, b.) AST (SGOT) and ALT (SGPT) ≤ 5.0 times the upper limit of normal, and c.) acceptable renal function with serum creatinine ≤ 2 times the upper limit of normal; acceptable hematologic status (no hematologic support (hematologic support)): a.) ANC ≥ 1000 cells μL, b.) platelet count ≥ 75,000 / μL, c.) hemoglobin ≥ 9.0 g / dL; All women of childbearing potential must have a negative serum pregnancy test at screening; Male and female subjects must agree to use effective contraception with their partners from study entry until 6 months after the last dose (e.g., surgical sterilization or barrier contraception using condoms or vaginal diaphragms combined with spermicidal gel or IUD).

[0377] Exclusion criteria included the following: Subjects who had not recovered to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) due to AEs (except alopecia, anemia, and lymphopenia) caused by antineoplastic agents, study drugs, or other drugs administered prior to the study. v5.0 grade ≤1); obstructive or symptomatic communicating hydrocephalus; ventriculoperitoneal or ventriculoatrial shunts without contraindications to programmable valve or Ommaya reservoir placement; females of childbearing potential who are pregnant, breastfeeding, or who may become pregnant, without a negative serum pregnancy test; serious concurrent illness, such as progressive systemic (extra-leptomeningeal) disease, clinically significant arrhythmias, uncontrolled systemic infection, symptomatic congestive heart failure or unstable angina within 3 months prior to study drug, myocardial infarction, stroke, transient ischemic attack (within 6 months), any seizure with convulsive disorder or encephalopathy occurring within 14 days prior to consent; active severe non-hematologic organ toxicity, such as renal, cardiac, hepatic, pulmonary, or gastrointestinal system toxicity grade 3 or higher; significant coagulopathy, such as inherited bleeding diathesis or acquired coagulopathy with unacceptable bleeding risk; 186 Craniospinal irradiation (for intraparenchymal or dural metastases) or intrathecal cytotoxic anticancer therapy less than 3 weeks before RNL; 186Myelopathy following spinal cord irradiation greater than 3 weeks prior to RNL; CNS-penetrating systemic chemotherapeutic agents (such as temozolomide, carmustine, lomustine, capecitabine, carboplatin, vinorelbine, bevacizumab, irinotecan, or topotecan), unless they developed or had progressive or persistent leptomeningeal metastases while taking these agents; 186 Systemic therapy (including investigational agents and small molecule kinase inhibitors) within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug ( 186 RNL), nitrosourea or mitomycin C within 42 days, or metronomic / long-term low-dose chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days; and impaired CSF flow studies performed between days 4 and 2 based on study imaging and as determined by the investigator.

[0378] Example 11: Treatment of Leptomeningeal Metastases

[0379] The maximum tolerated dose / maximum feasible dose, safety and efficacy of a single dose of rhenium-186 nanoliposomes (186RNL) administered via the intraventricular route for leptomeningeal metastases will be determined. The primary objective is to characterize the safety and tolerability of a single dose of 186RNL via the intraventricular route and to determine the maximum tolerated dose (MTD) and / or maximum feasible dose (MFD), and to develop collaboration for CSF biomarker analysis. The secondary objectives are to characterize the pharmacokinetic and dosimetric spectrum of a single dose of 186RNL when administered intraventricularly via the Ommaya reservoir; to develop a multiple-dose dosing strategy for 186RNL for subsequent clinical trials; to determine the overall response rate (ORR), which is defined as the proportion of all evaluable patients who achieve a response that is the best overall response at the time of progression; to determine the duration of response (DoR), which is defined as the time from the first response to LM progression; to determine progression-free survival (PFS), which is defined as the time from the first treatment to the date of LM progression or death from any cause; and to determine overall survival (OS), which is defined as the time from the first treatment to the date of death. The primary endpoints were to determine the incidence and severity of adverse events (AEs) and serious adverse events (SAEs) and the incidence of dose-limiting toxicities (DLTs).

[0380] Example 12: 186RNL in Leptomeningeal Carcinoma

[0381] Leptomeningeal cancer, also known as carcinomatosis, is a cancer that begins in one part of the body and spreads to the pia mater lining of the brain and spinal cord surrounding the cerebrospinal fluid (CSF) space. 100nm nanoliposomes will be administered. The nanoliposomes circulate freely throughout the CSF, migrate to the surface of the meninges where LMCs are located, have an extended half-life - weeks compared to hours for unencapsulated drugs, and are safe and effective in preclinical models.

[0382] Example 13. Dose escalation regimen for leptomeningeal metastases.

[0383] The infusion dose will be gradually increased from 6.6 mCi to 82.5 mCi, and the volume of the infusate will be 5 mL. Table 5 below summarizes the study design.

[0384] Table 5: Dose escalation schedule

[0385]

[0386] *Theoretical maximum absorbed dose is the radiation absorbed dose under conditions of no CSF ​​volume clearance (100% continuous retention of CSF volume) after RNL infusion.

[0387] Example 13: Additional Patient Data for Treatment of GBM

[0388] Twenty-three patients were treated with bevacizumab, of whom 30.4% failed treatment. The infusion dose was gradually increased from 1.0 mCi to 31.2 mCi, and the volume of the infusion was increased from 0.66 mL to 12.3 mL. The study design and overall survival of each patient are summarized in Table 6 below. Overall survival is as of the date the table was generated.

[0389] Table 6: Phase 1 clinical trial design

[0390]

[0391] The median survival duration of patients who failed bevacizumab (n=7) was 145 days. The median survival duration of patients who had not used bevacizumab (n=16) was 350.5 days, with 3 patients still alive at the end of the study.

[0392] Example 16: Latest clinical information of ReSPECT-LM

[0393] A multicenter Phase 1 study is ongoing with the primary objective of determining the maximum tolerated dose / maximum feasible dose, safety, and efficacy of a single dose of rhenium (186Re)obisbemeda administered intraventricularly for leptomeningeal metastases (LM). Secondary objectives are to determine the pharmacokinetic and dosimetric profile of a single dose of 186RNL when administered intraventricularly via the Ommaya reservoir, to develop a multiple-dose dosing strategy for 186RNL for subsequent clinical trials, and to determine the overall response rate (ORR), duration of response (DoR), progression-free survival, and overall survival (OS). The primary endpoints are the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well as the incidence of dose-limiting toxicities (DLTs). Fig.32Pial administration and rapid diffusion of rhenium (186Re)obisbemeda targeting CSF are shown. Fig.33 Shows the latest information about the ReSPECT-LM clinical trial.

[0394] Example 17: Animal Studies Using RNL and Immunotherapy Drugs

[0395] Animal studies will be conducted with administration of RNL and one or more immunotherapy treatments. Immunotherapy treatments that can be administered with RNL include, but are not limited to, monoclonal antibodies and immune checkpoint inhibitors, PARP inhibitors, nonspecific immunotherapy, oncolytic virus therapy, T cell therapy, and cancer vaccines. T cell therapy includes, but is not limited to, CAR T-cell therapy and tumor infiltrating lymphocytes. Immunotherapy treatments can be co-administered with RNL, or administered before or after RNL. Immunotherapy treatments that can be administered with RNL also include, but are not limited to, the drugs listed in Table 7. Various doses and treatment regimens will be tested. Immunotherapy treatments will be delivered systemically or into the cerebrospinal fluid (CSF).

[0396] Table 7. Immunotherapy drugs

[0397]

[0398]

[0399]

[0400] Although the technology herein has been described with reference to embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the technology. Therefore, it should be understood that various modifications may be made to the exemplary embodiments and other arrangements may be designed without departing from the spirit and scope of the technology as defined by the appended claims.

Claims

1. A method of treating leptomeningeal metastases in a subject in need thereof, comprising intraventricularly administering a therapeutically effective amount of radiolabeled liposomes, the radiolabeled liposomes comprising liposomes and a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: M is 99m Tc, 186 Re, 188 Re or a combination thereof; X is NR 1 ; R 1 is CH2CH2NEt2; and R 2 It is CH2CH2N(CH2CH2SH)(CH2CH2NEt2).

2. The method according to claim 1, wherein: M is 186 Re.

3. The method according to claim 1, wherein: The compound is incorporated into or attached to the liposomes.

4. The method according to claim 1, wherein: The liposomes include phospholipids and cholesterol or a cholesterol analog.

5. The method according to claim 4, wherein: The liposomes include distearoylphosphatidylcholine.

6. The method according to claim 1, wherein: The liposome further comprises a chemotherapeutic agent, an antibiotic agent, or a therapeutic molecule, wherein the chemotherapeutic agent, the antibiotic agent, or the therapeutic molecule is incorporated into or attached to the liposome.

7. The method according to claim 1, wherein: The leptomeningeal metastases are derived from lung cancer, breast cancer or melanoma.

8. The method according to claim 1, wherein: The radiolabeled liposomes are administered as an infusion comprising the radiolabeled liposomes.

9. The method according to claim 8, wherein: The radiolabeled liposomes were administered as an infusion via an Ommaya reservoir.

10. The method according to claim 8, wherein: At about 1 μL min -1 About 50 μL min -1 The infusate is administered at a maximum flow rate of .

11. The method according to claim 8, wherein: The amount of radioactivity delivered by the infusion is from about 0.1 mCi to about 50 mCi.

12. The method according to claim 8, wherein: The volume of the infusion is from about 0.1 mL to about 25 mL.

13. The method according to claim 12, wherein: The volume of the infusion was approximately 5.0 mL.

14. The method according to claim 8, wherein: The amount of radioactivity delivered by the radiolabeled liposomes per volume of the infusion was approximately 0.1 mCi mL -1 to about 50 mCi mL -1 .

15. The method according to claim 14, wherein: The amount of radioactivity delivered by the radiolabeled liposomes per volume of the infusion was approximately 1.32 mCi mL -1 to about 5.28 mCi mL -1 .

16. The method according to claim 8, wherein: The infusate is administered at an exit velocity of about 0.001 mm / min to about 1.0 mm / min.

17. The method of claim 8, further comprising an absorbed dose of about 5 Gy to about 100 Gy.

18. The method of claim 8, further comprising an absorbed dose of about 100 Gy to about 800 Gy.

19. The method of claim 8, further comprising an absorbed dose of about 50 Gy to about 200 Gy.

20. The method according to claim 1, wherein: The method further comprises imaging the radiolabeled liposomes simultaneously with or after administration.

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