Radiolabeled liposomes for treating leptomeningeal metastases and methods of use - Patents.com

Abstract

Radiolabeled liposomes can be used to treat cancer. These local therapies can be used to treat cancer, including but not limited to leptomeningeal metastasis. In one embodiment, radiolabeled liposomes containing (186Re) Ovis Bemeda can be administered to a patient through an Ommaya reservoir. The therapy can further include imaging the radiolabeled liposome in conjunction with or following administration. TIFF2025508997000015.tif84128

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 302,953, filed January 25, 2022; U.S. Provisional Application No. 63 / 333,050, filed April 20, 2022; and U.S. Provisional Application No. 63 / 343,034, filed May 17, 2022, all of which are incorporated by reference herein. [Background technology]

[0002] 2. Background of the Invention Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. The standard treatment for GBM over the past decade has been surgery followed by chemoradiotherapy with temozolomide, a regimen in which radiation contributes significantly to survival. External beam radiotherapy (EBRT) remains a central component of the management of primary brain tumors, but the therapy is limited by the tolerance of surrounding normal brain tissue. As most recurrences occur within 2 centimeters of the resection margin, there remains an urgent need to develop local therapies such as brachytherapy.

[0003] Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis, is typically, though not commonly, a fatal complication of many advanced cancers where cancer cells metastasize. Although any solid tumor has the potential for LM, most commonly LM originates from four common primary cancers: breast, lung, melanoma, and gastrointestinal cancer, which metastasize to the central nervous system (CNS) and are found in either the leptomeninges (the membrane surrounding the brain and spinal cord) or the cerebrospinal fluid (CSF) (which circulates nutrients and chemicals to the brain and spinal cord). LM often goes undiagnosed due to a lack of symptoms and causes neurological complications such as difficulty thinking, double vision, and headaches. LM is diagnosed in approximately 5% of patients with metastatic cancer. LM occurs in 5-8% of patients with solid tumors. There is no good treatment in the accepted standard of care, and patients often must choose between toxic treatments or a very short life expectancy.

[0004] While most solid tumors are known to cause LM, the most common solid tumors that cause LM are breast cancer, lung cancer, melanoma, gastrointestinal tumors, and primary central nervous system tumors. Other categories of LM include hematological malignancies (leukemia and lymphoma) and primary CNS tumors (medulloblastoma, among others). Standard treatment includes radiation therapy (RT) to the affected area followed by chemotherapy delivered to the cerebrospinal fluid (CSF) or systemic treatment of the underlying malignancy. Most intrathecal and systemic chemotherapy have difficult side effects. Median survival depends on the source of the primary tumor and is usually 2-4 months. If untreated, survival is usually around 6-8 weeks. Neurological symptoms are usually fixed and rarely improve with treatment. Novel treatment approaches that can prolong survival and maintain quality of life by delaying further neurological deterioration are desperately needed for LM patients. Treatment of LM with external beam radiation must pass through the surrounding normal tissue before reaching the tumor, thus damaging the surrounding normal tissue. In this relatively radioresistant tumor, the risk of significant side effects from whole-neuraxis radiation therapy generally outweighs the benefits. Localized radiation therapy alleviates neurological symptoms but has no significant effect on survival. Other radiotherapy drugs typically cannot reach and destroy tumors through systemic administration due to the blood-brain barrier.

[0005] Thalamic tumors constitute approximately 5% of brain tumors. Thalamic tumors are difficult to surgically remove due to their location. Selected examples of thalamic tumors are gliomas, such as astrocytomas and glioblastomas.

[0006] Brain stem tumors are difficult to surgically remove due to their location and can affect basic functions such as breathing and heart rate. Selected examples of brain stem tumors are diffuse intrinsic brain stem gliomas (DIPGs) and focal brain stem gliomas.

[0007] There remains a need to develop local therapies for a full range of cancers, including 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, thalamic tumors, brain stem tumors, glioma, glioblastoma, medulloblastoma, ependymoma, diffuse intrinsic pontine glioma, leptomeningeal metastases, and pediatric high-grade glioma. Summary of the Invention

[0008] Provided herein, in one aspect, is a method of treating a disease or disorder in a subject in need thereof, comprising: Liposomes and a compound of formula I: or a pharma- ceutically acceptable salt thereof. wherein M is 99m Tc, 186 Re, 188 Re, or any combination thereof; X is NR 1 and; R 1 is CH2CH2NEt2 or CH2CH2CH2CH3; and R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2) or CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3), This is the method.

[0009] In some embodiments, R 1 is CH2CH2NEt2, 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.

[0010] In some embodiments, the compound is incorporated into or attached to a liposome.

[0011] In some embodiments, the liposome further comprises a drug incorporated within the liposome.

[0012] In some embodiments, the drug is a compound that contains 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.

[0013] In some embodiments, the liposome comprises a lipid, hi some embodiments, the liposome comprises a phospholipid.

[0014] In some embodiments, the liposomes comprise cholesterol or a cholesterol analog, hi some embodiments, the liposomes comprise distearoylphosphatidylcholine.

[0015] In some embodiments, radiolabeled liposomes contain from about 0.01 mCi to about 400 mCi of compound per 50 mg of lipid used to prepare the liposomes.

[0016] In some embodiments, the liposome further comprises a chemotherapeutic agent, an antibiotic agent, or a therapeutic molecule, where the chemotherapeutic agent, an antibiotic agent, or a therapeutic molecule is incorporated into or attached to the liposome.

[0017] 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 pediatric high-grade glioma. 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.

[0018] In some embodiments, the subject has not previously received treatment including bevacizumab.

[0019] In some embodiments, the radiolabeled liposomes are administered via injection of an infusion solution containing the radiolabeled liposomes.

[0020] In some embodiments, the radiolabeled liposomes are administered via convection-enhanced delivery. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via one or more catheters. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via one catheter. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via two catheters. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via three catheters. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via four catheters. In some embodiments, the convection-enhanced delivery comprises

[0021] In some embodiments, the infusion solution is about 1 μL -1 ~about 50μL -1 In some embodiments, the infusion is administered at a maximum flow rate of about 5 μL / min. -1 ~About 20μL -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. -1In 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 is administered at a maximum flow rate of 100 mg / kg.

[0022] 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.

[0023] In some embodiments, the volume of the infusion liquid is about 0.1 mL to about 25 mL. In some embodiments, the volume of the infusion liquid is about 0.5 mL to about 10 mL. In some embodiments, the volume of the infusion liquid is about 1 mL to about 5 mL. In some embodiments, the volume of the infusion liquid is about 2 mL to about 15 mL. In some embodiments, the volume of the infusion liquid is about 5 mL to about 10 mL. In some embodiments, the volume of the infusion liquid is about 10 mL to about 15 mL. In some embodiments, the volume of the infusion liquid is about 15 mL to about 20 mL. In some embodiments, the volume of the infusion liquid is about 0.66 mL. In some embodiments, the volume of the infusion liquid is about 1 mL. In some embodiments, the volume of the infusion liquid is about 1.32 mL. In some embodiments, the volume of the infusion liquid is about 2 mL. In some embodiments, the volume of the infusion liquid is about 2.64 mL. In some embodiments, the volume of the infusion liquid is about 3 mL. In some embodiments, the volume of the infusion liquid is about 4 mL. In some embodiments, the volume of the infusion liquid is about 5 mL. In some embodiments, the volume of the infusion fluid is about 5.28 mL. In some embodiments, the volume of the infusion fluid is about 6 mL. In some embodiments, the volume of the infusion fluid is about 7 mL. In some embodiments, the volume of the infusion fluid is about 8 mL. In some embodiments, the volume of the infusion fluid is about 8.8 mL. In some embodiments, the volume of the infusion fluid is about 9 mL. In some embodiments, the volume of the infusion fluid is about 10 mL. In some embodiments, the volume of the infusion fluid is about 11 mL. In some embodiments, the volume of the infusion fluid is about 12 mL. In some embodiments, the volume of the infusion fluid is about 12.3 mL. In some embodiments, the volume of the infusion fluid is about 13 mL. In some embodiments, the volume of the infusion fluid is about 14 mL. In some embodiments, the volume of the infusion fluid is about 15 mL. In some embodiments, the volume of the infusion fluid is about 16 mL. In some embodiments, the volume of the infusion fluid is about 16.35 mL. In some embodiments, the volume of the infusion fluid is about 17 mL. In some embodiments, the volume of the infusion fluid 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, the volume of the infusion is delivered to a single hemisphere of the brain (e.g., containing a glioblastoma).In some embodiments, the volume of infusate is delivered to both hemispheres of the brain (eg, containing the glioblastoma).

[0024] In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 0.1 mCi mL -1 ~about 50mCi 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 ~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 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 ~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 ~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 ~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 ~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 -1In 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 -1 In 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 mCi mL -1 In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 10 mCi mL -1 It is.

[0025] In some embodiments, the method further comprises imaging the radiolabeled liposome in conjunction with administration.In some embodiments, the method further comprises imaging the radiolabeled liposome subsequent to administration.

[0026] INCORPORATION BY REFERENCE 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]

[0027] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the nature and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [Figure 1] 1 shows the absorbed dose of 186Re nanoliposomes relative to tumor volume in patients previously treated with bevacizumab and in bevacizumab naive patients. [Diagram 2] The tumor volume of each patient treated with 186Re nanoliposomes is shown. [Diagram 3] The ratio of treatment volume to infusion volume versus infusion volume after treatment with 186Re nanoliposomes is shown. [Figure 4] 1 shows the difference in survival time after treatment with 186Re nanoliposomes between patients previously treated with bevacizumab and bevacizumab naive patients. [Diagram 5] The mean absorbed doses to the brain, whole body, and tumor volume for different dose levels of 186Re nanoliposomes are shown. [Figure 6] 1 shows baseline magnetic resonance images (MRI) and single photon emission computed tomography (SPECT) images after treatment with 186Re nanoliposomes. [Figure 7] Magnetic resonance imaging (MRI) and perfusion scan images are shown at baseline and 56 days after treatment with 186Re nanoliposomes. [Figure 8] 3D images are shown demonstrating the extent of radiation delivered (measured in absorbed dose) over an 8-day period following treatment with 186Re nanoliposomes. [Figure 9]1 shows a chart demonstrating overall survival of subjects with various mean absorbed doses and TuV / TrV percentages. [Figure 10] Images are shown including baseline MRI and SPECT images at the end of infusion, 24 hours post-infusion, 120 hours post-infusion, and 192 hours post-infusion. [Figure 11] Images are shown including baseline MRI and SPECT images after 20% infusion, at the end of infusion, 24 hours post-infusion, 120 hours post-infusion, and 192 hours post-infusion. [Figure 12] Kaplan-Meier curves are shown comparing overall survival for patients receiving >100 Gy compared with patients receiving <100 Gy. [Figure 13] A baseline MRI and multiple SPECT images taken at various time points are shown. [Figure 14A] Shown is the 3D dose distribution of 186Re nanoliposome (e.g., 186RNL) brachytherapy. [Figure 14B] Dose-volume histograms with percent coverage on the Y-axis and absorbed dose (in Gy) on the X-axis are shown for multiple patients. [Figure 14C] As a comparison, the isodose distribution of stereotactic body radiation therapy (SBRT) doses is shown. [Figure 15] 1 shows baseline magnetic resonance images (MRI) and single photon emission computed tomography (SPECT) images after treatment with 186Re nanoliposomes. [Figure 16] MRI scans of tumor responses observed through day 362 are shown. [Figure 17] 1 illustrates the process of convection-enhanced delivery for treating GBM. [Figure 18] Efficacy and survival data for ReSPECT-GBM are presented. [Figure 19] 186 Shown are the results of SPECT CT, planar imaging, and CSF liquid biopsy of a patient after RNL treatment. [Figure 20]20A and 20B show the production process of rhenium-188 nanoliposomes and rhenium-188 nanoliposome biodegradable alginate microspheres. [Figure 21] 1 illustrates an approach for non-surgical locoregional treatment options for solid organ tumors. [Figure 22] A plot of radiodensity and a table of density versus injection volume are shown. [Diagram 23] 1 shows a table of patient vs. injection volume. [Figure 24] RNL Kaplan-Meier plots comparing overall survival for patients receiving >100 Gy compared with patients receiving <100 Gy for up to 40 months are shown. [Diagram 25] RNL Kaplan-Meier plot comparing overall survival of GBM patients receiving >100 Gy compared to patients receiving <100 Gy for up to 42 months. [Figure 26] Mortality plots by dose and tumor coverage are shown. [Figure 27] Shown is a radiotherapy formulation of rhenium (186Re) ovisbemeda and rhenium-188 nanoliposome biodegradable alginate microspheres. [Figure 28] 1 shows plots of tumor retention based on percent of injected activity versus time for 186Re-nanoliposomal, 186Re-BMEDA, and 186Re-perrenate (CED intratumoral administration in head and neck SCC xenografts in nude rats). [Figure 29] 1 shows plots of tumor response based on tumor volume versus time for 186Re-nanoliposomal, 186Re-BMEDA, 186Re-perrenate, and nanoliposome control (intratumoral administration of CED in head and neck SCC xenografts in nude rats). [Diagram 30] Survival percentage (overall survival) versus months by percent of tumor volume treated is shown. [Diagram 31] The survival rate (overall survival rate) versus months is shown by mean tumor absorbed dose. [Diagram 32] Showing leptomeningeal administration and rapid diffusion of rhenium (186Re) Ovis Bemeda targeted to the CSF. [Diagram 33] Provides an update on the ReSPECT-LM clinical trial. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Detailed Description of the Invention definition Unless otherwise defined, 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.

[0029] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0030] 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, alpha emission, beta emission, gamma emission, X-ray emission, conversion electron emission, or Auger electron emission. The 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 the 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 herein by reference in its entirety.

[0031] As used herein, "radiolabeled liposome" refers to a liposome that contains a radiolabeled compound provided herein that is incorporated into or attached to the liposome. The term "liposome" refers to any vesicle that contains a bilayer membrane. "Liposome" includes unilamellar and multilamellar liposomes.

[0032] As used herein, the term "incorporated" refers to embedding in the liposomal bilayer a compound of formula I. Because the liposomal bilayer is lipophilic, highly lipophilic compounds can be trapped within the liposomal bilayer.

[0033] "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition other than the active ingredient that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives known in the art, such as those described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0034] As used herein, "treatment" or "treating" refers to an approach to obtain 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: reduction in symptoms caused by disease, increase in the quality of life of the person suffering from the disease, reduction in the dosage of other medicines required for the treatment of the disease, delay in the progression of the disease, and / or prolongation of the life of an individual.

[0035] As used herein, an "effective dosage" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to produce beneficial or desired results. In the case of prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, reducing the severity, or delaying the onset of disease, including the biochemical, histological, and / or behavioral symptoms of disease, complications of disease, and intermediate pathological phenotypes expressed during the development of disease. In the case of therapeutic use, beneficial or desired results include clinical results such as reducing one or more symptoms caused by disease, increasing the quality of life of the person suffering from the disease, reducing the dose of other medicines required to treat the disease, enhancing the effect of another medicine through targeting, etc., delaying the progression of disease, and / or extending survival time. In the case of cancer or tumor, an effective amount of a drug may have the effect of reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing to some extent and preferably stopping) the invasion of cancer cells into peripheral organs; inhibiting (i.e., slowing to some extent and preferably stopping) tumor metastasis; inhibiting to some extent tumor growth; and / or alleviating to some extent one or more symptoms associated with the disorder. An effective dosage may be administered in one or more administrations. For purposes of the present invention, an effective dosage of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve prophylactic or therapeutic treatment, either directly or indirectly. As will be understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective dosage" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if a desired result can be or is achieved in conjunction with one or more other agents.

[0036] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that supports the administration of an active agent to and absorption by a subject and can be included in the composition of the present invention without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solution, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (e.g. Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethycellulose, polyvinylpyrrolidine, and colors. Such preparations can be sterilized and, if desired, mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0037] The term "preparation" is intended to include the formulation of active compound with an encapsulating material as a carrier to provide a capsule in which active component is surrounded by a carrier, with or without other carriers, and thus the active component is associated with the carrier.Also includes cachets and lozenges.Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.The term is intended to include radiolabels.

[0038] As used herein, the term "administer" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, convective (e.g., via convection-enhanced delivery), or subcutaneous administration to a subject, or implantation of a sustained release device, such as a mini-osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery modes include, but are not limited to, the use of liposomal compositions, intravenous infusion, transdermal patches, and the like.

[0039] As used herein, the term "delivered" and variations thereof (e.g., "deliver") are used interchangeably with the term "administered" and variations thereof (e.g., "administer").

[0040] "Co-administered" means that the compound described herein is administered at the same time, immediately before, or immediately after the administration of one or more additional therapies, such as anti-cancer drugs as described herein.The compounds described herein can be administered to a patient alone or can be co-administered.Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound or agent).Thus, the preparation can also be combined with other active substances (e.g., anti-cancer drugs) if desired.

[0041] Co-administration includes administering an 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). Also contemplated herein are embodiments in which co-administration includes administering an 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 administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Co-administration can be achieved by co-formulation, i.e., by preparing a single pharmaceutical composition that includes both active agents. In other embodiments, the active agents can be formulated separately. In some embodiments, the active agents and / or adjuncts are linked or conjugated to each other. In some embodiments, the compounds described herein are combined with cancer treatments, such as chemotherapy or radiation therapy.

[0042] "Patient", "subject", "patient in need thereof" and "subject in need thereof" are used interchangeably herein and refer to an organism suffering from or susceptible to a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, bovine animals, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient is a human. A "cancer patient" is a patient suffering from or susceptible to developing cancer.

[0043] Unless expressly indicated otherwise, the term "individual" as used herein refers to a mammal, including but not limited to a bovine, horse, cat, rabbit, dog, rodent, or primate (e.g., human). In some embodiments, the individual is a human. In some embodiments, the individual is a non-human primate, such as chimpanzees and other apes and monkey species. In some embodiments, the individual is a farm animal, such as cows, horses, sheep, goats, and pigs; pets, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; and the like. In some embodiments, the present invention finds use in both human and veterinary medical contexts.

[0044] "Disease" or "condition" refers to an existing or health state of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, disease as used herein refers to cancer.

[0045] "Chemotherapeutic agent" or "chemotherapeutic agent" is used according to its plain and ordinary meaning to refer to a chemical composition or compound having anti-tumor properties or the ability to inhibit cell growth or proliferation.

[0046] "Cancer model organism" as used herein is an organism that exhibits a phenotype indicative of cancer or exhibits the activity of a factor that causes cancer in the organism. The term cancer is defined above. A wide variety of organisms can serve as cancer model organisms, including, for example, cancer cells and mammalian organisms such as rodents (e.g., mice or rats) and primates (e.g., humans). Cancer cell lines are widely understood by those skilled in the art as cells that exhibit a phenotype or genotype similar to in vivo cancer. Cancer cell lines as used herein include cell lines derived from animals (e.g., mice) and humans.

[0047] Radiolabeled nanoliposomes Brachytherapy may be useful for treating cancers 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, thalamic tumor, brain stem tumor, leptomeningeal metastasis, and pediatric high-grade glioma. 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.

[0048] Liposomes containing phospholipids and / or sphingolipids can be used to deliver hydrophilic (water-soluble) therapeutic compounds or precipitated therapeutic compounds encapsulated in the internal liposome volume, and / or to deliver hydrophobic therapeutic agents dispersed in the hydrophobic bilayer membrane.In certain aspects, liposomes contain lipids selected from sphingolipids, ether lipids, sterols, phospholipids, phosphoglycerides, and glycolipids.In certain aspects, lipids include, for example, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine).

[0049] Liposomes are of interest to be considered because of their value as diagnostic agents, especially as carriers for radiopharmaceutical products for tracer and imaging studies. There are many advantages to using liposomes as carriers for therapeutic radionuclides. Some advantages include: (1) the biocompatibility of liposomes; (2) by using extrusion techniques, liposome particles of various sizes can be easily achieved with a uniform size range of population; (3) the surface of liposomes can be modified with different kinds of functional groups; (4) the distribution of liposomes can be functional and microtargeted; and (5) the mechanism of diffusion of radioisotopes from liposomes can be monitored, which is useful for delivering a uniform dose distribution in tumor tissue.

[0050] Radionuclides have been widely used as a non-invasive method to study drug distribution in vivo. However, attempts to label liposomes with radionuclides as imaging agents have produced variable results. Many radionuclides bind weakly to liposomes, which leads to leaching of the radionuclides from the liposomes and inaccurate biodistribution data. In addition, entrapment of water-soluble radionuclides within liposomes during preparation is relatively inefficient.

[0051] In one embodiment, occult tumor cells are responsible for tumor recurrence. In one embodiment, targeted killing of both the tumor and specific penumbra of abnormal tissue is achieved while sparing normal neural tissue and cells.

[0052] An embodiment of the present disclosure is a method for delivering a large increment of a composition in a patient who has received a maximum dose of previous radiation therapy for the treatment of the patient's primary disease, secondary disease, or both. An embodiment of the present disclosure is a method for delivering a large increment of a composition in a patient who has received a maximum dose of previous radiation therapy for the treatment of the patient's primary disease, secondary disease, or both. In one embodiment, the radiation is selected from beta radiation or alpha particle therapy, including isotopes Ac225, Pb212, or Cu67. In one embodiment, the radiolabeled liposomal formulation delivers a sufficient amount of radiation and residence time to eradicate cancer cells in the cerebrospinal fluid, leptomeningeal lining, or both, but does not damage the surrounding brain or other systemic organs and tissues. In one embodiment, the composition includes a step of simultaneously delivering and visualizing the radiotherapeutic drug delivery to ensure successful delivery or to modify the administration of key delivery parameters. In some embodiments, the subject receiving the radiation increment has previously received a maximum dose of radiation. In some embodiments, the subjects receiving the radiation increments have previously received a maximum dose of radiation for the treatment of their primary and / or secondary disease. In some embodiments, the subjects have previously received a maximum dose of radiation for the treatment of cancer (e.g., glioblastoma). In some cases, the maximum dose of radiation includes a maximum tolerated dose (e.g., the upper limit of tolerated radiation that a subject can receive without risk of significant side effects).

[0053] In one embodiment, radiolabeled nanoliposome (RNL) can be used to treat cancer. In one embodiment, RNL can be used to treat cancer via brachytherapy. In one embodiment, RNL can be used to treat glioblastoma, leptomeningeal metastasis, thalamic tumor, and brainstem tumor.

[0054] In some embodiments, provided herein is a method of delivering and visualizing (e.g., imaging) radiotherapy delivery. In some embodiments, the radiotherapy comprises a pharmaceutical composition disclosed herein. In some embodiments, provided herein is a method of delivering and visualizing (e.g., imaging) pharmaceutical composition (e.g., radiolabeled liposome (e.g., 186Re nanoliposome)) delivery. In some embodiments, the method includes ensuring delivery to a target. In some embodiments, the target is a 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., making changes to) one or more delivery parameters during delivery. In some embodiments, a radiotherapy (e.g., pharmaceutical composition) is delivered. In some embodiments, the method includes modifying one or more delivery parameters during delivery and ensuring delivery of the pharmaceutical composition to a target during delivery.

[0055] In some embodiments, the visualizing (e.g., imaging) step comprises any of the imaging methods disclosed herein (e.g., SPECT, SPECT-CT, MRI, etc.). In some embodiments, the visualizing step (e.g., delivery of a radiotherapeutic agent (radiolabeled liposome (e.g., mRe)) comprises imaging the whole body. In some embodiments, the visualizing step comprises imaging a region (e.g., a local region) of the body (e.g., the head). In some embodiments, the visualizing step comprises imaging a target (e.g., a tumor). In some embodiments, the visualizing step comprises imaging a primary tumor. In some embodiments, the visualizing step comprises imaging a secondary tumor. In some embodiments, the visualizing step comprises imaging a primary tumor and a secondary tumor. In some embodiments, the visualizing step comprises imaging the tumor as well as the area surrounding the tumor (e.g., the area where the tumor is located and / or the area within 6 inches of the tumor). In some embodiments, the visualizing step comprises imaging one or more organs (e.g., including and / or within the region of the tumor). In some embodiments, the visualizing step comprises imaging the primary tumor or the diseased region. In some embodiments, a surrogate marker is measured in conjunction with visualization of the diseased region.

[0056] Rhenium-186 isotope Dual energy emitters: Beta (cytotoxicity) and Gamma (imaging) -Short average path length (1.8mm): High accuracy ·Low dose rate: safer for normal tissue High radiation density: Overwhelms innate DNA repair mechanisms

[0057] Rhenium-188 Dual energy emitters: Beta (cytotoxicity) and Gamma (imaging) Short path length average (3.1mm): gives higher accuracy ·Low dose rate: safer for normal tissue High radiation density: Overwhelms innate DNA repair mechanisms Generated by a generator for quick use

[0058] The therapeutic agent may be a chemotherapeutic agent or a radiotherapeutic agent. In certain aspects, the chemotherapeutic agent is a taxane, an epothilone, or a vinca alkaloid. In certain aspects, the radiotherapeutic agent is 131 I, 90 Y, 99 mTc, 177 Lu, 186 Re, 188 Re, 125 I, 123 In other aspects, the radiotherapeutic agent is 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-9 In some embodiments, the metal may be one or more of: 9m, 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.

[0059] In one embodiment, 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 or diagnostic agent is selected from the group consisting of 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-104, tungsten-106, tungsten-108, tungsten-109, tungsten-110, tungsten-111, tungsten-112, tungsten-113, tungsten-114, tungsten-115, tungsten-116, tungsten-117, tungsten-118, tungsten-119 ... In some embodiments, the iodine-123 element may be one or more of uranium-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.

[0060] Notable substances that can be encapsulated include radiotherapeutic agents (e.g., rhenium-188), radiolabels (e.g., technetium-99m), chemotherapy agents (doxorubicin), magnetic particles (e.g., 10 μm iron nanoparticles), and radiopaque substances (e.g., iodine contrast agents). In certain aspects, rhenium-188 liposomes can be used to treat liver tumors, specifically hepatocellular carcinoma (HCC). In more particular aspects, HCC treatment can be by radioembolization, where the microspheres block the blood supply from the arteries to the tumor, while rhenium-188 also delivers high doses of radiation that primarily target cancer cells.

[0061] In one 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, 226Ra, 221Fr, 222Ra, 223Ra, 224Ra, 225Ra, 226Ra, 227Ra, 228Ra, 229Ra, 230Ra, 231Ra, 232Ra, 233Ra, 234Ra, 235Ra, 236Ra, 237Ra, 238Ra, 239Ra, 240Ra, 241Ra, 242Ra, 243Ra, 244Ra, 245Ra, 246Ra, 247Ra, 248Ra, 249Ra, 250Ra, 251Ra, 252Ra, 253Ra, 254Ra, 255Ra, 256Ra, 257Ra, 258Ra, 259Ra, 260Ra, 261Ra, 262Ra, 263Ra, 264Ra, 265Ra, 266Ra, 267Ra, 268Ra, 269Ra, 270Ra, 271Ra, 272Ra, 273Ra, 274Ra, 275Ra, 276Ra, 277Ra, 278Ra, 279Ra, 25Ac, 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.

[0062] In certain aspects, the radiotherapeutic agent is a beta emitter ( 131 I, 90 Y, 177 Lu, 186 Re, 188 Re, any one of which may be specifically excluded) or gamma emitters ( 125 I, 123 I, 99m Tc), or any combination thereof. In certain aspects, the radiotherapeutic agent is 188Re. Furthermore, the term "radiotherapeutic agent" may be more broadly interpreted to include any moiety that is radioactively labeled, and may include any liposome associated with or containing a radionuclide. Nuclear reactors are the source of many radioisotopes, some from cyclotrons. Generally, nuclear fission [reactors] produces neutron-rich isotopes, whereas neutron-depleted isotopes, e.g., PET radionuclides, are produced by cyclotrons [cyclotron energies for typical PET positron isotopes are about 10-20 MeV, whereas single photon products usually require higher cyclotron energies [about 30 MeV]. In certain embodiments, the radiotherapeutic agent may be a reactor radioisotope or a cyclotron radioisotope. Nuclear radioisotopes may include (1) therapeutic [Rx], which are both beta and alpha radiation and low energy x-rays [for brachytherapy], and / or (2) diagnostic [Dx], which are both positrons and single photons. The Rx or Dx listed here are exemplary embodiments of how the radioisotopes may be used. The scope of the invention includes the use of the radioisotopes listed here in other Rx or Dx. Reactor radioisotopes include Bismuth-213 (Alpha), Cesium-131 ​​(X-ray brachytherapy Rx), Chromium-51 (Dx), Cobalt-60 (Universally used for EBRT in the past, sterilization today; HSACo-60 in the past 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 uses), Iodine-131 (Beta Rx [fission product]; higher energy but has gamma for imaging), Iridium-192 (Beta Rx; often in wire form for brachytherapy of the prostate etc), Iron-59 (Dx in the past for iron metabolism studies), lead-212 (alpha Rx), lutetium-177 (Rx beta; has gamma emission for imaging), molybdenum-99 (Dx - parent [fission product] of Tc99m), palladium-103 (Rx low energy x-rays; example of permanent implant brachytherapy), phosphorus-32 (beta Rx;Previous Rx for polycythemia vera), potassium-42 (Dx Previous measurement of exchangeable K+ in coronary blood flow), radium-223 (Rx alpha; Previous Rx brachy with low energy x-rays), rhenium-186 (beta Rx with photons for imaging; Previous Rx bone pain), rhenium-188 (beta Rx; Previous coronary artery via stent), samarium-153 (beta Rx; Previous product for bone pain / metastasis [Quadramet]), scandium-47 (beta Rx with imaging capabilities; similar to Lu-177; produced by irradiating Ca-46 to produce Ca-47 which decays to Sc-47), selenium-75 (Dx; Previous seleno-methionine for GI studies), sodium-24 (Dx Previous electrolyte studies), strontium-89 (Rx These include, but are not limited to, technetium-99m (Dx; the workhorse Dx isotope in nuclear medicine; produced in a generator from Mo-99), thorium-227 (Rx alpha; decays to another alpha Rx, Ra-223), xenon-133 (Dx [gaseous fission product]), ytterbium-169 (Dx; used before In-111 for CSF flow studies), ytterbium-177 (Rx Yb-176; precursor to Lu-177 via neutron irradiation), and yttrium-90 (Rx pure beta emitter [fission product]). Cyclotron radioisotopes include actinium-225 (Rx alpha), astatine-211 (Rx alpha), bismuth-212 (Rx alpha), 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;These include, but are not limited to, copper-67 (Rx beta), gallium-67 (Dx single photon), gallium-68 (Dx positron), germanium-68 (Dx - parent for Ga-68 generator), indium-111 (Dx), iodine-123 (Dx, no beta emission), iodine-124 (Dx positron), krypton-81m (Dx [generated by gas generator from Rb-81 at bedside T1 / 2=13 seconds]), rubidium-82 (Dx positron potassium analog for perfusion imaging; generated by generator at patient's location T1 / 2=75 seconds), strontium-82 (Dx --- parent for Rb-82 generator), and thallium-201 (Dx). The liposomes may be associated with the radionuclide through some other means such as a chelator, direct chemical conjugation, or a linker protein;

[0063] In one aspect, the chelating agent is capable of forming a chelate complex with a radiolabeling agent, such as a transition metal or a radionuclide.

[0064] In one embodiment, the chelator is selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and derivatives thereof; 1,4,8,11-tetraazacyclotetradecane (cyclam) and derivatives thereof; 1,4,7,10-tetraazacyclododecane (cyclen) and derivatives thereof; 1,4-ethano-1,4,8,11-tetraazacyclotetradecane (et-cyclam) and derivatives thereof; 1,4,7,11-tetraazacyclotetradecane (isocyclam) and derivatives thereof; 1,4,7,10-tetraazacyclotridecane (

[13] aneN4) and derivatives thereof; 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A) and derivatives thereof; 1,4,7,10-tetraazacyclododecane The 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 adamantanes and their derivatives.

[0065] In one embodiment, the chelator is selected from the group consisting of macrocycles including adamanzan; 1,4,7,10-tetraazacyclododecane (

[12] aneN4) or a derivative thereof; 1,4,7,10-tetraazacyclotridecane (

[13] aneN4) or a derivative thereof; 1,4,8,11-tetraazacyclotetradecane (

[14] aneN4) or a derivative thereof; 1,4,8,12-tetraazacyclopentadecane (

[15] aneN4) or a derivative thereof; 1,5,9,13-tetraazacyclohexadecane (

[16] aneN4) or a derivative thereof; and other chelators capable of binding metal ions, such as ethylene-diamine-tetraacetic acid (EDTA) or a derivative thereof, diethylene-triamine-penta-acetic acid (DTPA) or a derivative thereof.

[0066] In one embodiment, the chelator is 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)acetic acid (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 a derivative thereof; 1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphonic acid) (DO2P) or a derivative thereof; 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P) or a derivative thereof; 1,4,8,11-15 tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) or a derivative thereof; 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A) or a derivative thereof; 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A) or a derivative thereof; and other adamantanes or derivatives thereof.

[0067] Rhenium-186( 186 Re) is a beta-emitting therapeutic radionuclide with a half-life of approximately 90 hours, a radiation path range of 1.8 mm, and a high beta / gamma energy ratio suitable for cancer brachytherapy. 186Re has sufficient gamma energy to allow imaging of in vivo drug behavior using standard SPECT / CT. Therapeutic radionuclides require carriers to ensure that they are sequestered within the tumor and slowly redistributed. Liposomal nanoparticles (nanoliposoms) provide a means to encapsulate radionuclides and support sustained intratumoral accumulation. The inventors have 186 We have successfully developed a method for loading Re into nanoliposomes with high efficiency and specific activity. The process offers significantly higher levels of specific activity than previously described and has the potential to provide significantly higher delivered therapeutic radiation doses with reduced toxicity.

[0068] In certain aspects, contrast 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 from groups 3 to 12 of 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), and 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 including positron emission tomography (PET), single photon emission computed 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). The imaging agent includes, but is not limited to, a radiolabel, a fluorophore, a fluorescent dye, an optical reporter, a magnetic reporter, an X-ray reporter, an ultrasound imaging reporter, or a nanoparticle reporter. In another aspect of the invention, the imaging agent is a radiolabel selected from the group including a radioisotope 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 radiolabel is 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( 201 Tl), carbon-11, nitrogen-13 ( 13 N), oxygen-15( 15 O), Fluorine-18( 18 F), and rubidium-82 ( 82 Ru).

[0069] Provided herein, in one aspect, is a method for preparing a liposome comprising administering to a subject a composition comprising: or a pharma- ceutically acceptable salt thereof, wherein: M is 99m Tc, 186 Re, 188 Re, or any combination thereof; X is NR 1 and; R 1 is CH2CH2NEt2 or CH2CH2CH2CH3; and R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2) or CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3), The radiolabeled liposome.

[0070] In some embodiments, R 1is 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, R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2). In some embodiments, R 1 is CH2CH2CH2CH3, and R 2 is CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3).

[0071] In some embodiments, M is 99m In some embodiments, M is 186 In some embodiments, M is Re. 188 In some embodiments, M is 186 When Re and the liposome comprises a nanoliposome, the radiolabeled liposome is 186 These are called Re nanoliposomes.

[0072] In some embodiments, the compound is incorporated into or attached to a liposome (eg, a nanoliposome).

[0073] In some embodiments, the liposome further comprises a drug incorporated within the liposome.

[0074] In some embodiments, the drug is a compound that contains at least one thiol group. In some embodiments, the drug reacts with the compound. In some embodiments, the drug includes glutathione, cysteine, N-acetylcysteine, 2-mercaptosuccinic acid, 2,3-dimercaptosuccinic acid, captopril, or a combination thereof. In some embodiments, the drug includes glutathione. In some embodiments, the drug includes cysteine. In some embodiments, the drug includes N-acetylcysteine. In some embodiments, the drug includes 2-mercaptosuccinic acid. In some embodiments, the drug includes 2,3-dimercaptosuccinic acid. In some embodiments, the drug includes captopril. In some embodiments, the drug includes a combination.

[0075] In some embodiments, the liposome comprises a lipid. In one embodiment, the liposome is a nanoliposome. In some embodiments, the liposome comprises a phospholipid.

[0076] In some embodiments, the liposomes comprise cholesterol or a cholesterol analog. In some embodiments, the liposomes comprise cholesterol. In some embodiments, the liposomes comprise a cholesterol analog. In some embodiments, the liposomes comprise distearoylphosphatidylcholine.

[0077] In some embodiments, the liposome comprises cholesterol or a cholesterol analog. In some embodiments, the liposome comprises cholesterol. In one embodiment, the liposome comprises cholesterol. In one embodiment, the liposome comprises distearoylphosphatidylcholine. In one embodiment, the composition delivers gamma and beta radiation. In one embodiment, the drug emits beta radiation, gamma radiation, or a combination thereof.

[0078] Pharmaceutical Compositions The pharmaceutical composition of the present disclosure can be formulated into any suitable pharmaceutical preparation.The pharmaceutical composition of the present disclosure typically contains active ingredient and one or more pharma- ceutically acceptable excipients or carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.The composition of the present disclosure can be formulated into any suitable pharmaceutical preparation. 186 A pharmaceutical composition comprising Re nanoliposomes is 186 Rhenium-lipid nanoparticles ( 186 In some embodiments, the pharmaceutical composition comprises: 186 In some embodiments, the pharmaceutical composition comprises a Re nanoliposome. 186 Re nanoliposome, 188 Re nanoliposome, 99m Tc nanoliposome, or any combination thereof. In some embodiments, the pharmaceutical composition provides sustained intratumoral accumulation.

[0079] The pharmaceutical composition may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein may be formulated in a dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, intraventricular, intraleptomeningeal (e.g., for treating leptomeningeal metastasis), and / or intraperitoneal administration. In some embodiments, the pharmaceutical composition is formulated for administration via convection-enhanced delivery (CED). In some embodiments, the pharmaceutical composition is suitable for infusion via a ventricular reservoir.

[0080] The administered radiolabeled nanoliposomes (e.g. 186 The amount of Re nanoliposome) will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician.

[0081] In some embodiments, the radiolabeled nanoliposomes may 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) either simultaneously or sequentially with the radiolabeled nanoliposomes. When administered sequentially, the radiolabeled nanoliposomes may be administered before or after the one or more second agents. When administered simultaneously, the radiolabeled nanoliposomes and the one or more second agents may be administered by the same route (e.g., convection-enhanced delivery to the same location), by different routes (e.g., a tablet taken orally while undergoing convection-enhanced delivery), or as part of the same combination (e.g., a solution comprising the radiolabeled nanoliposomes and one or more second agents). In some embodiments, the radiolabeled nanoliposomes (e.g., 186 Re nanoliposomes) are delivered within a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 186 Re nanoliposomes.

[0082] The combination treatments according to the invention may be effective over a wide dosage range, the exact dosage depending on the agent selected, the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician.

[0083] In some embodiments, pharmaceutical composition comprises one or more surfactants.Surfactants that can be used to form pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and their mixtures.That is, a mixture of hydrophilic surfactants can be adopted, a mixture of lipophilic surfactants can be adopted, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be adopted.

[0084] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, whereas suitable lipophilic surfactants may generally have an HLB value of about 10 or less. 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, whereas surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with HLB values ​​above about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values ​​of about 10 or less. However, the HLB value of a surfactant is only a rough guideline that is generally used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0085] Hydrophilic surfactant can be either ionic or nonionic.Suitable ionic surfactant includes but is not limited to alkyl ammonium salt; fusidate salt; fatty acid derivatives of amino acid, oligopeptide and polypeptide; glyceride derivatives of amino acid, oligopeptide and polypeptide; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salt; salts of alkyl sulfate; fatty acid salts; sodium docusate; acylactylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citrate esters of mono- and diglycerides; and mixtures thereof.

[0086] Within the aforementioned group, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl acrylates; mono- and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citrate esters of mono- and diglycerides; and mixtures thereof.

[0087] Ionic surfactants are the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactyl esters of fatty acids (lactylic esters), stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0088] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol 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 at least one member of the group of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols with polyols; polyoxyethylene sterols, 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 at least one member of the group of triglycerides, vegetable oils, and hydrogenated vegetable oils with polyols. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0089] 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 Glyceryl Trioleate, 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-4 0 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 Caprate / Caprylate Glycerides, PEG-8 Caprate / Caprylate Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols, Examples of suitable polyglyceryl-10 oleate include PEG-20 trioleate, PEG-40 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, tocopheryl 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.

[0090] 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, mono- and diglyceride lactic acid derivatives, the hydrophobic transesterification product of at least one member of the group of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols with polyols, 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 the surfactant is the hydrophobic transesterification product of at least one member of the group of vegetable oils, hydrogenated vegetable oils, and triglycerides with polyols.

[0091] In one embodiment, the composition may contain 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. Solubilizing agents may also be added to increase the solubility of other components, such as hydrophilic drugs and / or surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0092] Examples of suitable solubilizing agents include, but are not limited to, alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transacetol, dimethylisosorbide, 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 (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2 -piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, 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 solubilizing agents known in the art, such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0093] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transquitol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0094] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited by the biotolerance, which can be easily determined by one of ordinary skill in the art. In some circumstances, for example to maximize the concentration of the drug, it may be advantageous to include an amount of solubilizer that far exceeds the biotolerance, and then remove the excess solubilizer using conventional techniques such as distillation or evaporation before providing the composition to the patient. If present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, can also be used. Typically, the solubilizer can be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0095] The composition may further comprise one or more pharma- ceutically acceptable additives and excipients, including, but not limited to, detackifiers, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavors, colors, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0096] In addition, acids or bases can be incorporated into the composition to facilitate processing, to 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 hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. Also suitable are bases that are salts of pharma- ceutically acceptable acids, such as 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, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, may also be used. When the base is a salt, the cation may be any convenient and pharma-ceutically acceptable cation, such as, for example, ammonium, an alkali metal, an alkaline earth metal, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0097] Suitable acids are pharma- ceutically acceptable organic or inorganic acids. 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 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, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0098] Pharmaceutical Compositions for Injection In some aspects, the present disclosure provides radiolabeled nanoliposomes (e.g., 186 The present invention provides a pharmaceutical composition for injection, such as convection-enhanced delivery, comprising a medicament for the treatment of pulmonary artery disease (PDA) and a pharmaceutical excipient suitable for injection. The components and amounts of the agent in the composition are as described herein. In some embodiments, the pharmaceutical composition is suitable for injection via a ventricular reservoir.

[0099] Forms into which the radiolabeled nanoliposomes of the present disclosure may be incorporated for administration by injection include aqueous or oily suspensions or emulsions, including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0100] Aqueous solutions in physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. Proper fluidity can be maintained, for example, by using a coating such as lecithin to maintain the required particle size in the case of dispersions, and by using surfactants. Prevention of microbial activity can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0101] Sterile injectable solutions are prepared by incorporating the radiolabeled nanoliposomes of the present disclosure in the required amount with various other ingredients listed above, as necessary, in a suitable solvent, followed by filtration sterilization.Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other ingredients required from the ingredients listed above.In the case of sterile powders for preparing sterile injectable solutions, a particular desired preparation method is vacuum drying and freeze-drying techniques, which obtain a powder of active ingredients and any desired additional ingredients from the solution that has been previously sterile filtered.

[0102] 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.

[0103] Convection Enhanced Delivery Convection-enhanced delivery (CED) involves stereotactic placement of one or more catheters directly into brain tissue through a cranial burr hole. Therapeutic agents can be continuously administered through the catheters by a microinjection delivery system to create a positive pressure gradient at the catheter tip. When pressure is maintained, the pressure creates fluid convection or flow to supplement diffusion throughout the extracellular space and enhance distribution of the therapeutic agent to the target area. The goals of CED can be to provide uniform distribution of therapeutic agents to a larger volume of brain tissue, to provide higher drug concentrations directly to the tissue, and to utilize therapeutic agents that cannot cross the blood-brain barrier (BBB) ​​for treatment.

[0104] Convection-enhanced delivery can be long-term delivery, acute delivery, or a combination thereof. For example, the treatment method can include long-term delivery of radiolabeled nanoliposomes to brain regions, where the radiolabeled nanoliposomes are delivered at a continuous infusion rate over a period of days, weeks, months, or years. The treatment method can include acute delivery of radiolabeled nanoliposomes, where the radiolabeled nanoliposomes are delivered in separate boluses over the course of minutes or hours. The treatment method can include a combination of long-term and acute delivery, where the radiolabeled nanoliposomes are delivered at a continuous first infusion rate over a period of days, weeks, months, or years, interspersed with infusions of limited duration at a second, faster rate at regular or irregular intervals. Infusion rate and infusion time can be important factors in achieving adequate delivery. Moreover, infusion rate and infusion time can be a proxy for infusion pressure. Methods for assessing sufficiency of delivery include, but are not limited to, dosimetry, imaging, brain biopsy, treatment response assessment map (TRAM), and cerebral blood volume (CBV).

[0105] CED of a pharmaceutical composition or formulation containing a radiolabeled nanoliposome, another therapeutic agent, or a combination thereof may involve an infusion rate of about 0.1 μL / min to about 20 μL / min.

[0106] The CED of a pharmaceutical composition or formulation comprising a radiolabeled nanoliposome, another therapeutic agent, or a combination thereof is greater than about 0.1 μL / min, greater than about 0.5 μL / min, greater than about 0.7 μL / min, greater than about 1 μL / min, greater than about 1.2 μL / min, greater than about 1.5 μL / min, greater than about 1.7 μL / min, greater than about 2 μL / min, greater than about 2.2 μL / min, greater than about 2.5 μL / min, greater than about 2.7 μL / min, greater than about 3 μL / min, greater than about 4 μL / min, greater than about 5 μL / min, greater than about 6 μL / min, greater than about 7 μL / min, greater than about 8 μL / min, greater than about 9 μL / min, greater than about 10 μL / min, greater than about 11 μL / min, greater than about 12 μL / min, greater than about 13 μL / min, greater than about 14 μL / min, greater than about 15 μL / min, greater than about 16 μL / min, greater than about 17 μL / min, greater than about 18 μL / min, greater than about 19 μL / min, greater than about 20 μL / min, greater than about 21 μL / min, greater than about 22 μL / min, greater than about 25 μL / min, greater than about 26 μL / min, greater than about 27 μL / min, greater than about 28 μL / min, greater than about 29 μL / min, greater than about 30 μL / min, greater than about 31 μL / min, greater than about 32 μL / min, greater than about 33 μL / min, greater than about 34 μL / min, greater than about 35 μL / min, greater than about 36 μL / min, greater than about 37 μL / min, In some embodiments, the infusion rate may include infusion rates of greater than about 3.5 μL / min, greater than about 4 μL / min, greater than about 5 μL / min, greater than about 6 μL / min, greater than about 7 μL / min, greater than about 7.5 μL / min, greater than about 10 μL / min, greater than about 15 μL / min, greater than about 20 μL / min, greater than about 25 μL / min, greater than about 30 μL / min, greater than about 35 μL / min, greater than about 40 μL / min, greater than about 45 μL / min, greater than about 50 μL / min, or greater than 50 μL / min.

[0107] The CED of a pharmaceutical composition or formulation comprising a radiolabeled nanoliposome, another therapeutic agent, or a combination thereof may comprise, or may further comprise, an infusion rate of less than about 50 μL / min, less than about 45 μL / min, less than about 40 μL / min, less than about 35 μL / min, less than about 30 μL / min, less than about 25 μL / min, less than about 20 μL / min, less than about 15 μL / min, less than about 12 μL / min, less than about 10 μL / min, less than about 7.5 μL / min, or less than about 5 μL / min.

[0108] CED of a pharmaceutical composition or formulation containing a radiolabeled nanoliposome, another therapeutic agent, or a combination thereof may include or further include a stepwise increase in flow rate during delivery, referred to as "stepping." Stepping may include an infusion rate of about 0.1 μL / min to about 20 μL / min. Stepping CED may include one or more increases in infusion rate at periodic intervals of about 0.1 μL / min, about 0.2 μL / min, about 0.3 μL / min, about 0.4 μL / min, about 0.5 μL / min, about 0.6 μL / min, about 0.7 μL / min, about 0.8 μL / min, about 0.9 μL / min, about 1 μL / min, about 1.25 μL / min, about 1.5 μL / min, about 2 μL / min, about 2.5 μL / min, about 3 μL / min, or more.

[0109] The effective amount of radioactivity delivered by radiolabeled liposomes in a pharmaceutical composition or formulation administered by CED can be between 1 mCi and 1000 mCi. For example, the effective amount can be between 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, i, 5~75mCi, 5~50mCi, 5~25mCi, 5~10mCi, 10~1000mCi, 10~500mCi, 10~250mCi, 10~1 50mCi, 10~100mCi, 10~75mCi, 10~50mCi, 10~25mCi, 25~1000mCi, 25~500mCi, 25~25 0mCi, 25~150mCi, 25~100mCi, 25~75mCi, 25~50mCi, 50~1000mCi, 50~500mCi, 50~25 0mCi, 50~150mCi, 50~100mCi, 50~75mCi, 75~1000mCi, 75~500mCi, 75~250mCi, 75~1 It can be 50mCi, 75-100mCi, 100-1000mCi, 100-500mCi, 100-250mCi, 100-150mCi, 150-1000mCi, 150-500mCi, 150-250mCi, 250-1000mCi, 250-500mCi, or 500-1000mCi. In some embodiments, the effective amount is 10mCi-250mCi. In some embodiments, the effective amount of radioactivity delivered by the radiolabeled liposome is 50mCi-150mCi. In some embodiments, the effective amount of radioactivity delivered by the radiolabeled liposome is 10mCi-500mCi.

[0110] The effective amount of radioactivity delivered by radiolabeled liposomes administered by CED is 1-2000μL, 1-1500μL, 1-1000μL, 1-750μL, 1-500μL, 1-250μL, 1-100μL, 1-50μL, 1-10μL, 10-2000μL, 10-1500μL, 10-1000μL, 10-750μL, 10-500μL, 10-250μL, 10-100μL, 10-50μL, 50-2000μL, 50-1500μL, 50-1000μL, 50-750μL, 50-500μL, 50-250μL, 50-1 The volume can be 00μL, 100-2000μL, 100-1500μL, 100-1000μL, 100-750μL, 100-500μL, 100-250μL, 250-2000μL, 250-1500μL, 250-1000μL, 250-750μL, 250-500μL, 500-2000μL, 500-1500μL, 500-1000μL, 500-750μL, 750-2000μL, 750-1500μL, 750-1000μL, 1000-2000μL, 1000-1500μL, or 1500-2000μL.

[0111] An effective amount of radioactivity delivered by a radiolabeled liposome (e.g., in a pharmaceutical composition) administered by CED can be at a concentration of 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.

[0112] For further teachings regarding methods of CED, 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 by reference herein 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 by reference in its entirety.

[0113] Convection-enhanced delivery and imaging The advantage of convection-enhanced delivery may be the ability to use imaging technology to view drug distribution during injection.Gadolinium and iodine-based imaging compounds may be used as tracers to safely and accurately track the distribution of active ingredients in real time, for example, using magnetic resonance imaging or computed tomography imaging.These tracers may show the distribution of both low and high molecular weight compounds with similar convection properties during injection.In addition, radiolabeled nanoliposomes may be imageable without the use of tracers (e.g., by gamma-ray emission of radiolabeled nanoliposomes).In some embodiments, the methods and compositions provided herein do not include tracing agents.

[0114] In the method comprising the step of delivering a pharmaceutical composition comprising a radiolabeled nanoliposome, another therapeutic agent, or a combination thereof by CED, the pharmaceutical composition may comprise a tracing agent. The tracing agent may allow for monitoring the distribution of the tracing agent as it travels through the CNS, and for halting delivery of the pharmaceutical composition when the radiolabeled nanoliposome, another therapeutic agent, or a combination thereof is distributed in a predetermined volume within the CNS. The movement of the tracing agent through solid tissue may 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 tracing agent may have substantially similar mobility in CNS tissue as the therapeutic agent (e.g., radiolabeled nanoliposome), and delivery may be halted when the tracing agent is observed to reach a desired region or achieve a desired volume of distribution, or to reach, nearly reach, or exceed the edge of the target tissue. In some embodiments, the radiolabeled nanoparticles of the present disclosure may provide the same functionality (e.g., monitoring distribution) as compositions comprising a tracer.

[0115] The desired volume may correspond to a particular region of the brain targeted by the therapy. The desired volume of distribution may be "substantially similar" to the volume of distribution observed for the tracing agent monitored to follow the infusion. "Substantially similar" refers to a volume difference of less than 20%. More preferably, the volume difference is less than 15%, more preferably less than 10%, more preferably less than 5%. By monitoring the distribution of the tracing agent, the infusion may be stopped when a predetermined volume of distribution is reached.

[0116] The desired volume of distribution can be determined, for example, by using imaging software that is standard in the art, such as iFLOW™.See, 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.

[0117] The tracers may include paramagnetic ions for use with MRI. Suitable metal ions include those having atomic numbers between 22 and 29 (inclusive), 42, 44, and 58 and 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).

[0118] In embodiments in which X-ray imaging (e.g., CT) is used to monitor CED, the tracer may comprise 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 agents include barium, diatrizoic acid, ethiodized oil, gallium citrate, iocarmic acid, iosetamic acid, iodamide, iodipamide, iodoxamic acid, ioglamide, iohexol, iopamidol, iopanoic acid, ioprocemic acid, iosephamic acid, ioceric acid, iosuramide meglumine, iosmethic acid, iotasul, iotetric acid, iothalamic acid, iotroxic acid, ioxaglic acid, ioxotriroic acid, ipodate, meglumine, metrizamide, metrizoic acid, propriodone, and thallous chloride.

[0119] Devices for convection-enhanced delivery (CED) It is contemplated that any suitable device may be used in the methods disclosed herein in which a pharmaceutical composition or formulation comprising a radiolabeled nanoliposome, another therapeutic agent, or a combination thereof is administered to a brain region by CED.

[0120] The delivery device may include a pump capable of delivering a pharmaceutical composition or formulation including radiolabeled nanoliposomes, another therapeutic agent, or a combination thereof by CED. The pump may be an osmotic pump or an infusion pump. These pumps may include a backpressure sensor used to force a shutdown if the backpressure rises above a threshold, so that these pumps may be useful in preventing undesirable problems associated with pump failure, such as problems associated with backpressure and / or blockage. The device may include or be used with a catheter or cannula that facilitates localized delivery to the brain region of interest. The catheter or cannula may include multiple outlet ports. The catheter or cannula may include an outer tube to provide structural rigidity to the catheter or cannula. The catheter or cannula may be a reflux-free step-design cannula.

[0121] One or more catheters or cannuli can be inserted into or near one or more brain regions of the subject. Stereotactic map and positioning devices are available, for example, from ASI Instruments, Warren, Mich. 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.

[0122] Step design cannula with no reflux CED may be performed using a reflux-free step design cannula compatible with CED, such as those disclosed in Krauze et al., J Neurosurg. 2005 November; 103(5):923-9, which is incorporated by reference herein in its entirety, as well as U.S. Patent Application Publication No. US 2007 / 0088295 A1, which is incorporated by reference herein in its entirety, and U.S. Patent Application Publication No. US 2006 / 0135945 A1, which is incorporated by reference herein in its entirety.

[0123] In one embodiment, the step design cannula is compatible with chronic administration. In another embodiment, the step design cannula is compatible with acute administration. In another embodiment, the step design cannula is compatible with a combination of chronic administration interspersed with periods of acute administration at higher infusion rates or higher therapeutic agent levels.

[0124] Alternative Catheters CED may be performed using neurosurgical equipment, including a catheter compatible with CED, such as that disclosed in WO 2013 / 127884, the entirety of which is incorporated herein by reference.

[0125] The neurosurgical equipment may include a guide device and a catheter. The guide device may include an elongated tube having a head at its proximal end. In use, the elongated tube may be inserted into the brain through a hole formed in the skull toward the target brain region. The head may be used to securely attach the guide device to the skull. The insertion may be performed using a stereo guide or a surgical robot-based technique. An internal channel is provided through the head and lumen of the tube. The catheter may then be passed down through this channel into the brain near the selected target.

[0126] The present disclosure relates to radiolabeled nanoliposomes (e.g., 186The present invention provides a delivery kit or device that includes a pump capable of effecting the delivery of a pharmaceutical composition or formulation comprising a radiolabeled nanoliposome (e.g., when the pharmaceutical composition comprises a radiolabeled nanoliposome), another therapeutic agent, or a combination thereof, by CED. The kit or device further includes a pharmaceutical composition comprising a radiolabeled nanoliposome, another therapeutic agent, or a combination thereof, such as any of those disclosed herein. The kit or device further includes a cannula or catheter that is compatible with CED. The cannula or catheter can be compatible with chronic or acute administration.

[0127] radiation In some embodiments, provided herein are pharmaceutical compositions for delivering radiation. In some embodiments, the pharmaceutical composition comprises a liposome. In some embodiments, the liposome comprises a nanoliposome. In some embodiments, the pharmaceutical composition comprises a rhenium isotope. In some embodiments, the rhenium isotope is 186-rhenium ( 186 In some embodiments, the pharmaceutical composition comprises a liposome (e.g., a nanoliposome) and an isotope of rhenium (e.g., 186 In some embodiments, the pharmaceutical composition comprises a compound of formula I and a liposome. In some embodiments, the pharmaceutical composition comprises an isotope of rhenium (e.g., 186 Re) and nanoliposomes 186 Re nanoliposomes.

[0128] In some embodiments, the pharmaceutical composition delivers radiation. In some embodiments, the pharmaceutical composition delivers beta radiation. In some embodiments, the pharmaceutical composition delivers gamma radiation. In some embodiments, the pharmaceutical composition delivers one type of radiation. The pharmaceutical composition delivers two types of radiation (e.g., beta radiation and gamma radiation). In some embodiments, provided herein are pharmaceutical compositions (e.g., comprising liposomes (e.g., nanoliposomes) and an isotope (e.g., 186) rhenium) for delivering radiation (e.g., two types of radiation) (e.g., beta radiation and / or gamma radiation).

[0129] 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 has cancer.

[0130] Radiation, particularly beta radiation, can be useful in treating patients with cancer. Gamma radiation can be useful for visualization purposes. In some embodiments, the visualization step includes imaging. Pharmaceutical compositions that deliver both gamma and beta radiation can be beneficial for delivering therapy (e.g., radiation for the treatment of cancer) and for allowing visualization of the delivered therapy. For example, gamma radiation can be useful for imaging during the delivery of therapy (e.g., radiation for the treatment of cancer). 186 The gamma ray may have an appropriate energy for visualization (e.g., imaging) of the Re nanoliposomes during administration and for assessing biodistribution. Imaging using gamma rays may be useful for modifying one or more delivery parameters for dosing a subject.

[0131] By delivering both beta and gamma radiation, one or more delivery parameters of the therapy can be adjusted to allow for modifications to the therapy. In some embodiments, the pharmaceutical composition is delivered and visualized (e.g., imaged). In some embodiments, the pharmaceutical composition is delivered and visualized simultaneously. In some embodiments, the pharmaceutical composition is delivered and visualized later. In some embodiments, the pharmaceutical composition is delivered (e.g., by CED) and visualized (e.g., simultaneously) and modifications are made to one or more delivery parameters. In some embodiments, modifications to one or more delivery parameters are made during delivery (e.g., convection) of the pharmaceutical composition. In some embodiments, modifications to one or more delivery parameters are made after delivery of the pharmaceutical composition.

[0132] In some embodiments, modifications to the therapy (e.g., one or more delivery parameters) are made depending on the delivery and visualization (e.g., imaging) of the pharmaceutical composition. In some embodiments, the one or more delivery parameters include the injection rate, volume amount, concentration, location of administration, number of catheters, and / or device used to deliver the pharmaceutical composition. Any volume, radiation amount, or dose of the pharmaceutical composition disclosed herein may be sufficient to deliver beta and gamma radiation.

[0133] In some embodiments, pharmaceutical compositions (e.g., those that deliver beta and gamma radiation) are 186 Delivery of the pharmaceutical composition via the endothelial cell membrane (e.g., nanoliposome) makes it possible to monitor therapy to ensure successful delivery of the pharmaceutical composition to the target (e.g., tumor).

[0134] Imaging Gamma radiation can be useful for visualization (e.g., viewing) purposes. In some embodiments, the visualizing step includes imaging. For example, the pharmaceutical composition may deliver a sufficient dose of beta radiation to allow treatment of cancer, and a sufficient dose of gamma radiation to allow imaging (e.g., in vivo imaging). In some embodiments, the visualizing step 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, the gamma radiation is sufficient to visualize without the use of a tracer.

[0135] In some embodiments, the imaging includes single photon emission computed tomography-computed tomography (SPECT-CT). In some embodiments, the imaging includes single photon emission computed tomography (SPECT). In some embodiments, the imaging includes computed tomography (CT). In some embodiments, the imaging includes magnetic resonance imaging (MRI). In some embodiments, the imaging may include alternative forms of imaging, such as radiography (e.g., X-ray), fluoroscopy, nuclear medicine, positron emission tomography (PET) (e.g., single photon emission computed tomography), computed tomography (CT), intraoperative imaging, and mammography, or combinations thereof. In some embodiments, the imaging includes planar imaging. In some embodiments, the imaging includes any combination of imaging techniques disclosed herein (e.g., SPECT and MRI). In some embodiments, the imaging includes still images. In some embodiments, the imaging includes dynamic images.

[0136] Treatment Provided herein are methods of using the radiolabeled liposomes disclosed herein, which in some aspects may be incorporated into any of the pharmaceutical compositions disclosed herein.

[0137] Provided herein, in one aspect, is a method of treating a disease or disorder in a subject in need thereof, comprising: A liposome (e.g., a nanoliposome) and a liposome having Formula I: or a pharma- ceutically acceptable salt thereof, wherein: M is 99m Tc, 186 Re, 188 Re, or any combination thereof; X is NR 1 and; R 1 is CH2CH2NEt2 or CH2CH2CH2CH3; and R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2) or CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3), This is the method.

[0138] 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, R 2 is CH2CH2N(CH2CH2SH)(CH2CH2NEt2). In some embodiments, R 1 is CH2CH2CH2CH3, and R 2 is CH2CH2N(CH2CH2SH)(CH2CH2CH2CH3).

[0139] In some embodiments, M is 99m In some embodiments, M is 186In some embodiments, M is Re. 188 In some embodiments, M is 186 When Re and the liposome comprises a nanoliposome, the radiolabeled liposome is 186 These are called Re nanoliposomes.

[0140] In some embodiments, the compound is incorporated into or attached to a liposome.

[0141] In some embodiments, the liposome further comprises a drug incorporated within the liposome.

[0142] In some embodiments, the drug is a compound that contains at least one thiol group. In some embodiments, the drug reacts with the compound. In some embodiments, the drug includes glutathione, cysteine, N-acetylcysteine, 2-mercaptosuccinic acid, 2,3-dimercaptosuccinic acid, captopril, or a combination thereof. In some embodiments, the drug includes glutathione. In some embodiments, the drug includes cysteine. In some embodiments, the drug includes N-acetylcysteine. In some embodiments, the drug includes 2-mercaptosuccinic acid. In some embodiments, the drug includes 2,3-dimercaptosuccinic acid. In some embodiments, the drug includes captopril. In some embodiments, the drug includes a combination.

[0143] In some embodiments, the liposome comprises a lipid, hi some embodiments, the liposome comprises a phospholipid.

[0144] In some embodiments, the liposomes comprise cholesterol or a cholesterol analog. In some embodiments, the liposomes comprise cholesterol. In some embodiments, the liposomes comprise a cholesterol analog. In some embodiments, the liposomes comprise distearoylphosphatidylcholine.

[0145] In some embodiments, the radiolabeled liposomes (e.g., nanoliposomes) contain about 0.01 mCi to about 400 mCi of the compound per 50 mg of lipid used to prepare the liposomes. In some embodiments, the radiolabeled liposomes contain about 1 mCi to about 200 mCi of the compound per 50 mg of lipid used to prepare the liposomes. In some embodiments, the radiolabeled liposomes contain about 10 mCi to about 100 mCi of the compound per 50 mg of lipid used to prepare the liposomes. In some embodiments, the radiolabeled liposomes contain about 25 mCi to about 50 mCi of the compound per 50 mg of lipid used to prepare the liposomes. In some embodiments, the radiolabeled liposomes contain about 1.5 mCi of the compound per 50 mg of lipid used to prepare the liposomes. In some embodiments, the radiolabeled liposomes contain about 2.5 mCi of the compound per 50 mg of lipid used to prepare the liposomes.

[0146] In some embodiments, the liposome (e.g., nanoliposome) further comprises a chemotherapeutic agent, an antibiotic agent, or a therapeutic molecule, where the chemotherapeutic agent, antibiotic agent, or 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.

[0147] 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 pediatric high-grade glioma. 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 aspects, the cancer is hepatocellular carcinoma. In some aspects, the cancer is melanoma. In some aspects, the cancer is sarcoma. In some aspects, the cancer is head and neck cancer. In some aspects, the cancer is glioma. In some aspects, the cancer is glioblastoma. In some aspects, the glioblastoma is recurrent glioblastoma. In some aspects, the cancer is a leptomeningeal metastasis. In some aspects, the cancer is a medulloblastoma. In some aspects, the cancer is an ependymoma. In some aspects, the cancer is diffuse intrinsic pontine glioma. In some aspects, the cancer is a pediatric high-grade glioma.

[0148] In some embodiments, the subject has previously received a treatment that includes bevacizumab. In some embodiments, the subject has not previously received a treatment that includes bevacizumab.

[0149] In some embodiments, the pharmaceutical composition (e.g., comprising radiolabeled nanoliposomes) is an infusion. In some embodiments, the radiolabeled nanoliposomes are administered via infusion as an infusion comprising the radiolabeled liposomes. In some embodiments, the infusion comprises infusion via a ventricular reservoir.

[0150] In some embodiments, the radiolabeled liposomes (e.g., in a pharmaceutical composition) are administered via convection-enhanced delivery. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via one or more catheters. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via one catheter. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via two catheters. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via three catheters. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via four catheters. In some embodiments, the convection-enhanced delivery comprises administration of the radiolabeled liposomes via more than four catheters.

[0151] In some embodiments, the infusion solution is about 1 μL -1 ~about 50μL -1 In some embodiments, the infusion is administered at a maximum flow rate of about 5 μL / min. -1 ~About 20μL -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 about 25 μL / min. -1 In some embodiments, the infusion is administered at a maximum flow rate of about 30 μL per minute. -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 -1In some embodiments, the infusion is administered at a maximum flow rate of about 45 μL min -1 In some embodiments, the maximum flow rate is the maximum flow rate per catheter.

[0152] In some embodiments, the infusion fluid is administered at an exit velocity of about 0.001 mm / min to about 1.0 mm / min. In some embodiments, the infusion fluid is administered at an exit velocity of about 0.001 mm / min to about 0.1 mm / min. In some embodiments, the infusion fluid is administered at an exit velocity of about 0.001 mm / min to about 0.5 mm / min. In some embodiments, the infusion fluid is administered at an exit velocity of about 0.1 mm / min to about 1.0 mm / min. In some embodiments, the infusion fluid is administered at an exit velocity of about 0.5 mm / min to about 1.0 mm / min. In some embodiments, the infusion fluid is administered at an exit velocity of about 0.009, 0.022, 0.045, 0.067, or 0.090 mm / min. In some embodiments, the infusate is administered at an exit 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.

[0153] In some embodiments, administration of the pharmaceutical composition comprises one catheter, two catheters, three catheters, or four catheters.

[0154] 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.

[0155] In some embodiments, the minimum interval between administrations is about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 90 minutes, about 120 minutes, or about 150 minutes.

[0156] In some embodiments, the amount of radioactivity delivered by the radiolabeled liposome (e.g., radiolabeled nanoliposome in a pharmaceutical composition) is about 0.1 mCi to about 50 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposome is about 1 mCi to about 40 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposome is about 1 mCi to about 30 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposome is about 1 mCi to about 20 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposome is about 10 mCi to about 30 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposome is about 20 mCi to about 30 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposome is about 1 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposome is about 2 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 3 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 5 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 6 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 7 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 9 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes is about 10 mCi. 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 liposome is about 13.4 mCi.In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 14 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 15 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 16 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 17 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 18 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 19 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 20 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 21 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 22 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 22.3 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is greater than about 22.3 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 23 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 24 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 25 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 26 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 27 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 28 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 29 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 30 mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 31 mCi. In some embodiments, the amount of radioactivity delivered by the radiolabeled liposome is about 31.2 mCi.In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is greater than about 31.2mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 35mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 40mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 41.5mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is greater than about 41.5mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is about 45mCi. In some embodiments, the amount of radioactivity delivered by radiolabeled liposomes is greater than about 45mCi.

[0157] In some embodiments, the volume of the infusion fluid is about 0.1 mL to about 25 mL. In some embodiments, the volume of the infusion fluid is about 0.5 mL to about 10 mL. In some embodiments, the volume of the infusion fluid is about 0.66 mL. In some embodiments, the volume of the infusion fluid is about 1 mL. In some embodiments, the volume of the infusion fluid is about 1.32 mL. In some embodiments, the volume of the infusion fluid is about 2 mL. In some embodiments, the volume of the infusion fluid is about 2.64 mL. In some embodiments, the volume of the infusion fluid is about 3 mL. In some embodiments, the volume of the infusion fluid is about 4 mL. In some embodiments, the volume of the infusion fluid is about 5 mL. In some embodiments, the volume of the infusion fluid is about 5.28 mL. In some embodiments, the volume of the infusion fluid is about 6 mL. In some embodiments, the volume of the infusion fluid is about 7 mL. In some embodiments, the volume of the infusion fluid is about 8 mL. In some embodiments, the volume of the infusion fluid is about 8.8 mL. In some embodiments, the volume of the infusion fluid is more than about 8.8 mL. In some embodiments, the volume of the infusion fluid is about 9 mL. In some embodiments, the volume of the infusion fluid is about 10 mL. In some embodiments, the volume of the infusion fluid is about 11 mL. In some embodiments, the volume of the infusion fluid is about 12 mL. In some embodiments, the volume of the infusion fluid is about 12.3 mL. In some embodiments, the volume of the infusion fluid is about 13 mL. In some embodiments, the volume of the infusion fluid is about 13.2 mL. In some embodiments, the volume of the infusion fluid is about 14 mL. In some embodiments, the volume of the infusion fluid is about 15 mL. In some embodiments, the volume of the infusion fluid is about 16 mL. In some embodiments, the volume of the infusion fluid is about 16.35 mL. In some embodiments, the volume of the infusion fluid is about 17 mL. In some embodiments, the volume of the infusion fluid is about 18 mL. In some embodiments, the volume of the infusion fluid is about 18.5 mL. In some embodiments, the volume of the infusion fluid is greater than about 18.5 mL. In some embodiments, the infusate volume is delivered to a single hemisphere of the brain (e.g., containing the glioblastoma). In some embodiments, the infusate volume is delivered to both hemispheres of the brain (e.g., containing the glioblastoma).

[0158] 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.

[0159] In some embodiments, the amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 0.1 mCi mL -1 ~about 50mCi 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 ~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 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 mCi mL -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 -1In 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 about 2.54 mCi mL -1 More than.

[0160] In some embodiments, the amount of absorbed dose (e.g., absorbed radiation dose) is about 10Gy, about 20Gy, about 30Gy, about 40Gy, about 50Gy, about 80Gy, about 100Gy, about 120Gy, about 150Gy, about 200Gy, about 225Gy, about 250Gy, about 300Gy, about 350Gy, about 400Gy, about 425Gy, about 450Gy, about 500Gy, about 550Gy, about 575Gy, about 600Gy, about 625Gy, about 650Gy, about 675Gy, about 700Gy, about 740Gy, about 750Gy, or about 800Gy. In some embodiments, the amount of absorbed dose is less than 100Gy. In some embodiments, the amount of absorbed dose is more than 100Gy.

[0161] In some embodiments, the method further comprises imaging the radiolabeled liposome in conjunction with administration. In some embodiments, the method further comprises imaging the radiolabeled liposome subsequent to administration. In some embodiments, the method results in sustained intratumoral accumulation.

[0162] Deliver a new increment of radiation In some aspects, provided herein are methods of delivering an increment of radiation to a subject. In some aspects, the method includes delivering the increment of radiation to a subject who has previously received a dose of radiation therapy. In some aspects, the previously received dose of radiation therapy was a maximum dose of radiation therapy. In some aspects, the increment of radiation includes beta radiation. In some aspects, the subject includes a patient with cancer. In some aspects, the increment includes an additional portion of radiation.

[0163] In some embodiments, the methods provided herein include delivering an additional portion of radiation (e.g., beta radiation) to a subject in need thereof (e.g., a patient with cancer) by delivering any of the pharmaceutical compositions provided herein. In some embodiments, the increment includes an amount of radiation that exceeds the amount of radiation received in the immediately preceding treatment. In some embodiments, the increment includes the same amount of radiation received in the previous treatment (e.g., the treatment received before the current treatment). In some embodiments, delivering the increment of radiation includes delivering a varying amount of radiation by modifying one or more delivery parameters (e.g., volume, dose, injection rate, injection time, etc.) of the pharmaceutical compositions provided herein. In some embodiments, delivering the modified amount of radiation includes changing the volume of infusate and / or the dose of radiation.

[0164] In some embodiments, delivering an increment of radiation includes delivering a dose of radiation greater than previously received (e.g., previously received from a pharmaceutical composition disclosed herein). In some embodiments, the increment includes any of the doses or volumes provided herein. In some embodiments, the increment includes a portion of a dose. In some embodiments, delivering an increment of radiation includes delivering an amount of radiation greater than previously received (e.g., with reference to a current treatment round or with reference to receiving radiation from a pharmaceutical composition disclosed herein). The increment can be any of the doses disclosed throughout this application, including but not limited to the doses disclosed in the Examples (e.g., Example 4).

[0165] In some aspects, the step of delivering the increments of radiation comprises delivering beta rays. In some aspects, the step of delivering the increments of radiation comprises delivering gamma rays. In some aspects, the step of delivering the increments of radiation comprises delivering beta rays and gamma rays.

[0166] In some embodiments, the radiation includes new radiation. In some embodiments, the new radiation includes radiation (e.g., beta radiation) and / or pharmaceutical compositions that have not been received by the subject prior to receiving any of the pharmaceutical compositions disclosed herein.

[0167] In some embodiments, the methods include delivering increments of radiation to a subject (e.g., a patient with cancer) that has previously received radiation, hi some embodiments, delivering the increments includes delivering increasingly larger doses of radiation.

[0168] 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 the treatment of their primary and / or secondary disease. In some embodiments, the subject has previously received a maximum dose of radiation for the treatment of cancer (e.g., glioblastoma). In some cases, the maximum dose of radiation includes a maximum tolerated dose (e.g., the upper limit of tolerated radiation that a subject can receive without risk of significant side effects).

[0169] In some embodiments, the subject has not previously undergone treatment for the treatment of the disease (e.g., cancer) or condition. In some embodiments, the subject has not previously undergone radiation treatment for the treatment of the disease (e.g., cancer) or condition. In some embodiments, the subject has previously undergone non-radiotherapy (e.g., bevacizumab) for the treatment of the disease (e.g., cancer) or condition. In some embodiments, the subject has not previously undergone non-radiotherapy for the treatment of the disease. In some embodiments, the subject has previously undergone radiation therapy, including beta-rays from a pharmaceutical composition other than those disclosed herein for the treatment of the disease. In some embodiments, the subject has previously undergone radiation therapy, including beta-rays from a pharmaceutical composition disclosed herein for the treatment of the disease. In some embodiments, the step of delivering the radiation increment comprises delivering the radiation increment to a subject who has previously undergone a maximum dose of a previous therapy (e.g., radiation therapy) for the treatment (e.g., the treatment of the subject's primary and / or secondary disease).

[0170] Administration and visualization In some aspects, provided herein are methods of delivering and visualizing (e.g., imaging) radiotherapeutic agent delivery. In some aspects, the radiotherapeutic agent comprises a pharmaceutical composition disclosed herein. ... (e.g., a radiolabeled liposome (e.g., 186A method of delivering and visualizing (e.g., imaging) Re nanoliposomes))) delivery. In some embodiments, the method includes ensuring delivery to the target. In some embodiments, the target is a 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., making changes to) one or more delivery parameters during delivery. In some embodiments, a radiotherapeutic agent (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 delivery of the pharmaceutical composition to the target during delivery.

[0171] In some embodiments, the visualizing (e.g., imaging) step is performed prior to administering the pharmaceutical composition (e.g., by CED). In some embodiments, the method includes administering the pharmaceutical composition (e.g., radiation therapy (e.g., pharmaceutical composition) (e.g., radiolabeled liposomes (e.g., 186 Re))) delivery. Parallel (e.g., simultaneous or real-time) administration (e.g., by CED) and visualization can allow real-time modifications to be made to one or more delivery parameters. Additionally, parallel administration and visualization can help ensure delivery of the pharmaceutical composition to the target (e.g., tumor). Parallel (e.g., simultaneous) visualization (e.g., imaging) and adjustment of one or more delivery parameters can be useful to ensure safety and / or efficacy. In some embodiments, the visualization is performed after administration (e.g., by CED) of the pharmaceutical composition.

[0172] Gamma radiation may allow for monitoring the distribution of the pharmaceutical composition as it travels through the CNS and for delivery of the pharmaceutical composition to cease when the radiolabeled nanoliposome, another therapeutic agent, or a combination thereof, is distributed in a predetermined volume within the CNS. Visualization of the gamma radiation may help ensure that delivery of the pharmaceutical composition is ceased when the gamma radiation reaches a desired area or achieves a desired volume of distribution, or is observed to reach, nearly reach, or pass the edge of the target tissue.

[0173] In some embodiments, the method comprising administering (e.g., by CED) and (e.g., simultaneously) visualizing a pharmaceutical composition (e.g., including a radiotherapeutic agent) further comprises evaluating one or more delivery parameters. In response to visualizing the pharmaceutical composition, evaluation of one or more delivery parameters can be performed. Evaluation can be performed before, during, or after administering and / or visualizing the pharmaceutical composition.

[0174] In some embodiments, the method comprising administering (e.g., by CED) a pharmaceutical composition (including, e.g., a radiotherapeutic agent), visualizing (e.g., simultaneously), and evaluating 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 existing delivery parameters (e.g., maintaining an injection rate, concentration, dose, 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, ceasing a delivery parameter, or initiating a delivery parameter. In case embodiments, the one or more delivery parameters include any one or more of the following: a dose of pharmaceutical composition, a dose of radiation, a volume of infusate, an infusion rate, a site of administration, an administration interval, a number of catheters, a rate of infusate per catheter, an interval of injection (e.g., administration), a device for delivering the pharmaceutical composition, a number of catheters (e.g., changing to one, two, three, or four catheters), a rate per catheter, or any combination thereof. In some embodiments, the one or more delivery parameters include one delivery parameter. In some embodiments, the one or more delivery parameters include two, three, four, or five delivery parameters. The one or more delivery parameters can be any delivery parameter disclosed herein.

[0175] In some embodiments, administering (e.g., by CED) and visualizing (e.g., simultaneously) the pharmaceutical composition further comprises ensuring delivery of the pharmaceutical composition to a target (e.g., a tumor). In some cases, ensuring delivery of the pharmaceutical composition to a target comprises delivering a minimum effective dose of the pharmaceutical composition to the target. In some cases, ensuring delivery of the pharmaceutical composition to a target comprises delivering at least a portion (e.g., at least 10%, at least 20%, at least 30%, or at least 40%) of the pharmaceutical composition. In some cases, ensuring delivery comprises 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%, about at least about 98%, or at least about 99% of the pharmaceutical composition.

[0176] In some embodiments, the visualizing (e.g., imaging) step is performed after administration of the pharmaceutical composition (e.g., by CED). Visualization after administration can be useful for modifying one or more delivery parameters for subsequent administration of the pharmaceutical composition. In some embodiments, the visualizing step is performed 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 of the pharmaceutical composition. In some embodiments, the visualizing step is performed after administration of the pharmaceutical composition (e.g., radiolabeled liposomes (e.g., 186Re) before administration. In some embodiments, the visualizing step is performed 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 administration of the pharmaceutical composition. In some embodiments, the visualizing step is performed after the start of administration of the pharmaceutical composition. In some embodiments, the visualizing step is performed while administering the pharmaceutical composition.

[0177] In some embodiments, the visualizing (eg, imaging) step comprises any of the imaging methods disclosed herein (eg, SPECT, SPECT-CT, MRI, etc.).

[0178] In some embodiments, (e.g., radiotherapeutic agents (radiolabeled liposomes (e.g., 186 The step of visualizing the delivery of Re)) comprises imaging the whole body. In some embodiments, the step of visualizing comprises imaging a region (e.g., a local region) of the body (e.g., the head). In some embodiments, the step of visualizing comprises imaging a target (e.g., a tumor). In some embodiments, the step of visualizing comprises imaging a primary tumor. In some embodiments, the step of visualizing comprises imaging a secondary tumor. In some embodiments, the step of visualizing comprises imaging a primary tumor and a secondary tumor. In some embodiments, the step of visualizing comprises imaging the tumor as well as the area surrounding the tumor (e.g., the area where the tumor is located and / or within 6 inches of the tumor). In some embodiments, the step of visualizing comprises imaging one or more organs (e.g., including the tumor and / or in the area of ​​the tumor). In some embodiments, the step of visualizing comprises imaging the primary tumor.

[0179] In some embodiments, provided herein are methods of increasing survival time of a subject having 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 administering a pharmaceutical composition (e.g., 186 Re nanoliposomes). In some embodiments, provided herein is a method of increasing survival time of a group of subjects having cancer, comprising delivering greater than 100 Gy of radiation to one or more subjects in the group. In some embodiments, the method comprises delivering greater than 100 Gy to each of one or more subjects in the group. In some embodiments, the survival time comprises overall survival time. In some embodiments, the absorbed dose of radiation comprises an absorbed dose of beta radiation. In some embodiments, a method of increasing overall survival time of a group of patients comprising glioblastoma (e.g., recurrent glioblastoma), comprising delivering greater than 100 Gy of radiation (e.g., beta radiation) to the patients. In some embodiments, delivering greater than 100 Gy of radiation to one or more subjects in the group comprises administering a pharmaceutical composition (e.g., 186 Re nanoliposome).

[0180] In some embodiments, a group of subjects having cancer (e.g., glioblastoma) receiving more than 100 Gy (e.g., absorbed dose) of radiation (e.g., beta radiation) comprises an increase in survival (e.g., overall survival) compared to a second group of subjects including one or more subjects having cancer (e.g., glioblastoma) receiving less than 100 Gy of radiation (e.g., beta radiation). In some embodiments, the method comprises delivering less than 100 Gy of radiation to each of one or more subjects in the second group of subjects. In some embodiments, the absorbing dose ... a pharmaceutical composition disclosed herein (e.g., radiolabeled liposomes (e.g., 186 In some embodiments, administering the pharmaceutical composition to one or more subjects in the group of subjects results in an absorbed radiation dose of greater than 100 Gy.

[0181] In some embodiments, the methods provided herein increase overall survival. In some embodiments, overall survival is increased by administering a pharmaceutical composition (e.g., a radiolabeled liposome (e.g., 186 The overall survival time of the subject after administration of the pharmaceutical composition (including Re nanoliposomes) is 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 overall survival time of the subject receiving more than 100 Gy is about 50 days, about 100 days, about 125 days, or about 150 days. In some embodiments, the overall survival time of the subject receiving the pharmaceutical composition in an amount insufficient to provide more than 100 Gy (e.g., to achieve a dose of less than 100 Gy) 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 longer than the overall survival time of the second group of subjects receiving less than 100 Gy.

[0182] Alternative Aspects Provided herein, in some embodiments, are radiotherapeutic agents for the delivery of beta and gamma rays (e.g., 186 Re nanoliposomes). In some embodiments, a radiotherapeutic agent is incorporated into the pharmaceutical composition.

[0183] Also provided herein is a method for the treatment of cancer (e.g., glioblastoma) in an amount sufficient to emit beta radiation and in a pharmaceutical composition (e.g., 186 and administering the pharmaceutical composition (e.g., 186 Re nanoliposomes) (e.g., by CED) and visualizing (e.g., imaging) delivery of the pharmaceutical composition. 186Re nanoliposomes). In some embodiments, the method further comprises ensuring delivery of the pharmaceutical composition to a target (e.g., a tumor). In some embodiments, the method further comprises modifying one or more delivery parameters. In some embodiments, the modifying one or more delivery parameters is performed while administering the pharmaceutical composition. In some embodiments, the modifying one or more delivery parameters is performed after administering the pharmaceutical composition.

[0184] Also provided herein are pharmaceutical compositions (e.g., 186 In some embodiments, the subject has received a previous dose of therapy. In some embodiments, the subject has received a maximum dose of therapy. In some embodiments, the previous dose of therapy is radiation therapy. In some embodiments, the subject has received a previous dose of therapy for the treatment of a primary disease. In some embodiments, the subject has received a previous dose of therapy for the treatment of a secondary disease.

[0185] Also provided herein is a method for increasing the overall survival of a group of subjects (e.g., patients) with cancer (e.g., glioblastoma), comprising delivering more than 100 Gy of radiation (e.g., β-radiation).In some embodiments, the group of subjects receiving more than 100 Gy of radiation (e.g., β-radiation) has a longer overall survival than the group of subjects receiving less than 100 Gy of radiation (e.g., β-radiation).

[0186] Further provided herein are pharmaceutical compositions (e.g., 186In some embodiments, the method of delivering a high (e.g., greater than 100 Gy) absorbed radiation dose comprises varying the number of catheters, the flow rate (e.g., of infusate), and the volume of infusate. In some embodiments, the method of delivering a high (e.g., greater than 100 Gy) absorbed radiation dose comprises varying the number of catheters. In some embodiments, the method of delivering a high (e.g., greater than 100 Gy) absorbed radiation dose comprises varying the flow rate. In some embodiments, the method of delivering a high (e.g., greater than 100 Gy) absorbed radiation dose comprises varying the volume of infusate.

[0187] In one embodiment, up to 13.2 cc of radiation is delivered via the supratentorial region to a single hemisphere of the brain containing an actual tumor within the same hemisphere.

[0188] Figure 15 shows baseline magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) images after treatment with 186Re nanoliposomes. MRI scans showed an initial increase in size, accompanied by some edema, pseudoprogression, peaking at day 118. They also showed tumor shrinkage by at least day 362. The subject was still alive at 160 weeks after a single treatment.

[0189] FIG. 16 shows MRI scans of tumor responses observed through day 362.

[0190] FIG. 17 illustrates the process of convection-enhanced delivery to treat GBM.

[0191] FIG. 18 shows efficacy and survival data for ReSPECT-GBM.

[0192] FIG. 19 shows the results of SPECT CT, planar imaging, and CSF liquid biopsy of a patient after 186RNL treatment.

[0193] FIG. 20A shows the process for producing rhenium-186 nanoliposomes, and FIG. 20B shows the process for producing rhenium-188 nanoliposome biodegradable alginate microspheres.

[0194] Figure 21 shows an approach for a non-surgical locoregional treatment option for solid organ tumors. In one embodiment, a single intra-arterial injection of 188RNL-BAM in which biodegradable microspheres block blood flow to the targeted solid organ tumor and simultaneously deliver a therapeutic payload of radiation. Potential advantages 188RNL-BAM may confer the following compared to the two currently available radioembolization therapies: Biodegradable microspheres Better quality imaging Workup to predict final clinical outcome -Shorter generation time Improved patient access Higher margins Good conversion to other indications Liver cancer is the sixth most common and the third most lethal cancer.The treatment disclosed herein pursues new and reasonable administration route, and delivery and mechanism of action.The treatment provides the opportunity to prolong the life of patients with liver cancer through safer, more targeted and convenient treatment approach.

[0195] With reference to Figures 22 and 23, the figures show how much radiation volume is produced by the injected volume and the correlation to absorbed dose. In one embodiment, an injected volume of XX mL and YY mCi of radiation produces a volume of radiation AA that is either (<1 / 4, <1 / 2, <1 / 8, or <1 / 1 of the average absorbed dose to the tumor.

[0196] FIG. 24 shows an RNL Kaplan-Meier plot comparing overall survival of patients receiving >100 Gy compared to patients receiving <100 Gy over a period of up to 40 months. The plot compares patients receiving therapeutic radiation (e.g., >100 Gy) (red) to patients receiving non-therapeutic radiation (e.g., <100 Gy) (blue). The patient group receiving >100 Gy had a longer overall survival compared to the patient group receiving <100 Gy. FIG. 25 shows an RNL Kaplan-Meier plot comparing overall survival of patients receiving >100 Gy compared to patients receiving <100 Gy over a period of 42 months.

[0197] Figure 26 shows a plot of mortality by dose and tumor coverage. Bubble size is proportional to overall survival time. Survival is colored green and death is colored red. Survival time appears to increase with both absorbed dose and TuV / Trv percent.

[0198] FIG. 27 shows a radiotherapy formulation of rhenium (186Re) Ovis Bemeda and rhenium-188 nanoliposome biodegradable alginate microspheres.

[0199] FIG. 28 shows a plot of tumor retention based on percent of injected activity versus time (CED intratumoral administration in head and neck SCC xenografts in nude rats).

[0200] FIG. 29 shows a plot of tumor response based on tumor volume versus time (intratumoral administration of CED in head and neck SCC xenografts in nude rats).

[0201] Figure 30 shows the percent of tumor volume treated versus survival percentage in months. OS = overall survival.

[0202] FIG. 31 shows the mean absorbed dose to the tumor as survival fraction versus months.

[0203] FIG. 32 shows leptomeningeal administration and rapid diffusion of rhenium (186Re) ovis bemeda targeted to the CSF.

[0204] FIG. 33 shows an update on the ReSPECT-LM clinical trial.

[0205] exit speed Exit velocity is based on the volume of fluid that is ejected in a set time and the size of the opening through which that volume is ejected. Exit velocity (coupled with flow rate and catheter tip inner diameter (ID)). Exit velocity = volumetric flow rate / area (v=Q / A). The smaller the opening or the less resistance to the exit, the higher the exit velocity. Exit velocity affects the distribution of the ejected fluid. The higher the exit velocity, the greater the expected distribution of the fluid.

[0206] (Table 1) TIFF2025508997000005.tif48150

[0207] example: Q = 20ul / min = 0.02ml / min = 0.02mm 3 / min A=πr 2 =3.14*0.267mm*0.267mm(Smart Flow) A=0.223mm 2 v=0.02mm 3 / min / 0.223mm 2 = .090mm / min EXAMPLES

[0208] Example 1: Phase 1 Clinical Trial Administered via convection-enhanced delivery to patients with recurrent or progressive malignant gliomas following standard surgical, radiation, and / or chemotherapy treatment 186 We conducted a single-center, sequential-cohort, open-label, volume- and dose-escalation phase 1 clinical trial of the safety, tolerability, and distribution of Re nanoliposomes. The study utilized modified Fibonacci dose-escalation and a standard 3+3 design.

[0209] Brainlab iPlan Flow software was used to plan SmartFlow catheter placement 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 via convection-enhanced delivery utilizing one to three catheters at a maximum flow rate of 0.90 mL per hour per catheter (15 μL per min per catheter).

[0210] Continuous 1-minute dynamic planar imaging was performed during the injection period. To assess the radiation absorbed dose to the tumor and other organs during the treatment, 186 Single photon emission computed tomography (SPECT) / computed tomography (CT) imaging and serial whole-body planar imaging scans were performed immediately after injection of Re nanoliposomes, and 1, 3, 5, and 8 days later. Serial blood samples and serial 24-hour urine collections were also counted for activity. Dosimetry was performed using region of interest data and OLINDA dose calculation software.

[0211] Fifteen patients were treated, 14 of whom had recurrent glioblastoma and 47% had failed treatment with bevacizumab. Using one to three convection-enhanced delivery catheters, the infusion dose was gradually increased from 1.0 mCi to 13.4 mCi and the infusion volume was increased from 0.66 mL to 5.28 mL. The therapy was well tolerated and no dose-limiting toxicities were observed, despite the absorbed dose being significantly higher than with external beam radiotherapy (EBRT) in previously treated patients. The study design and overall survival of each patient are summarized in Table 2 below.

[0212] Table 2: Phase 1 clinical trial design TIFF2025508997000006.tif69159

[0213] Median survival in patients who failed bevacizumab treatment (n=7) was 4.8 months. Median survival in bevacizumab-naive patients (n=8) was 10.9 months, with 4 patients still alive at the end of the study.

[0214] Percentage of tumor volume in bevacizumab-previously treated and bevacizumab-naive patients 186 The absorbed dose of Re nanoliposomes is summarized in Figure 1. The tumor volume for each patient is summarized in Figure 2. The ratio of treatment volume to infusate volume versus infusate volume is summarized in Figure 3. The difference in survival between patients previously treated with bevacizumab and bevacizumab naive patients is summarized in Figure 4.

[0215] At various dose levels 186 The mean absorbed doses of Re nanoliposomes to the brain, whole body, and tumor volume are summarized in Figure 5. The median absorbed dose to the tumor volume across all patients (n = 15) was 143 Gy (range 9-593 Gy). In patients who failed bevacizumab (n = 7), the median absorbed dose was 38 Gy (range 9-593 Gy), whereas in bevacizumab-naive patients (n = 8), the median absorbed dose was 367 Gy (range 56-517 Gy). The maximum absorbed dose to the tumor volume was 593 Gy. The mean retention of the administered dose at 24 hours was 64% (CI 50-78). The whole body absorbed dose was 0.70 Gy or less. The mean absorbed dose to organs was 0.70 Gy or less. The ratio of the mean tumor volume absorbed dose to the mean whole body absorbed dose in the last two cohorts was ≥ 3,000.

[0216] The most common adverse events were fatigue (40%), diarrhea (27%), gait abnormality (27%), headache (27%), hemiparesis (27%), dizziness (20%), scalp discomfort (20%), seizures (20%), and cerebral edema (20%). 186The incidence of serious adverse events did not appear to increase with increasing dose of Re nanoliposomes. Four serious adverse events were reported, including seizures in three patients and cerebral edema in one patient. However, of these serious adverse events, 186 None were deemed to be causally related to Re nanoliposome treatment. Most adverse events, with the exception of scalp discomfort, were deemed related to surgery. 186 Re was not considered to be causally related to nanoliposome treatment.

[0217] Example 2: Case Study 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 a combination of radiation and temozolomide followed by three cycles of maintenance temozolomide. A follow-up MRI was consistent with recurrent disease. The patient underwent another right frontal craniotomy 9 months after the initial presentation of recurrent glioblastoma and entered a phase 0 study of sacituzumab, receiving the first dose of cycle 1 of sacituzumab (C1D1) 1 month later. Disease progression was again noted 16 months after the initial presentation. Within 4 weeks, 186 The patient was treated with Re nanoliposomes (13.4 mCi, 5.28 mL, 3 catheters).

[0218] 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 tumor coverage was 87%. The absorbed dose delivered to the tumor was 336 Gy, and the absorbed dose delivered to the volume of distribution (Vd) was 245 Gy. At 24 hours, the anterior portion of the tumor (indicated by the yellow arrow in Figure 6) was outside the volume of distribution (indicated by the gold line in Figure 6). By day 5 after treatment, the entire tumor was within the volume of distribution (indicated by the light purple line in Figure 6).

[0219] Baseline and 186Magnetic resonance imaging (MRI) and perfusion scan images at day 56 after treatment with Re nanoliposomes are shown in Figure 7. MRI at day 56 showed a partial response with no evidence of edema. Perfusion scan showed a significant reduction in the previously enhancing tumor area.

[0220] As demonstrated by the above examples, 186 Re nanoliposomes can deliver up to 20 times the absorbed dose of radiation administered by external beam radiotherapy without significant toxicity. Through convection-enhanced delivery at doses up to 13.4 mCi in 5.28 mL of injectate. 186 Intratumoral administration of Re nanoliposomes was safe and well tolerated. Prior administration of bevacizumab 186 Re appears to have a negative effect on the convection of nanoliposomes.

[0221] While 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 by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents are covered thereby.

[0222] Example 3: Image-guided rhenium-186 nanoliposomes in the treatment of recurrent glioblastoma (Glionella gracilis) 186 RNL) Brachytherapy: Technique, Image Analysis, Dosimetry, and Monitoring 186 Rhenium-lipid nanoparticles ( 186 Includes RNLs 186 Re nanoliposomes) have been introduced for intensive brachytherapy of cancer via image-guided injection into the tumor interstitial space; first for the treatment of recurrent glioblastoma (GBM) in the brain. 186Re) is a radionuclide (half-life: 89.24 hours) that emits therapeutic beta radiation particles (path range: 1.8 mm). One in ten emissions is accompanied by a 137 KeV gamma ray, allowing imaging of in vivo drug distribution, retention, and calculation of radiation absorbed dose distribution and therapy evaluation. Herein, we report our Phase I clinical trial study, focusing on the techniques used, image analysis, radiation dosimetry, and therapy monitoring.

[0223] External beam radiotherapy (EBRT) remains a central component of the management of gliomas, but the therapy is limited by the tolerance of surrounding normal brain tissue. 186 RNL) (e.g. 186 We hypothesized that focused brachytherapy with Re nanoliposomes could enable selective delivery of high specific activity beta-emitting radiation with excellent retention in tumors, and emitted gamma radiation would allow real-time image-guided delivery and monitoring. Herein, we report the techniques used, imaging of nanoliposome distribution and retention, image analysis, radiation dosimetry, and therapy monitoring.

[0224] Administered by convection-enhanced delivery (CED) through the Brainlab flexible subacute catheter to treat recurrent glioblastoma 186 A Phase 1 clinical trial of RNL was performed. BrainLab iPlan Flow Software and the Varioguide system were used for procedure planning and catheter placement. 186 RNL (e.g. 186 Tumor and whole-body retention and distribution of Re nanoliposomes were obtained by planar and SPECT / CT imaging midway through the infusion up to 8 days after radiation source administration. Locoregional and whole-body drug retention was analyzed from whole-body planar images. SPECT / CT and follow-up MRI images were co-registered to planning MRI images for 3D drug distribution and therapy evaluation. Radiation absorbed doses to regional volumes and whole-body organs were calculated.

[0225] Using MIM MRT quantitative SPECT image reconstruction and 3D dose calculation, 186 The 3D radiation absorbed dose distribution of RNL therapy was calculated and evaluated using tumor therapy response.

[0226] As shown in Figure 13, delivered by CED to a patient with recurrent glioblastoma 186 RNL (e.g. 186 The Re nanoliposomes provide predictable distribution and stable retention of nanoparticle radioactive sources in target tissues, providing sustained localized radiation treatment to tumors for several days. 186 The distribution and retention of RNL radioactive sources is shown. 186 The RNL radiation source had sustained retention and stable locoregional distribution in the treated tumors within the brain, providing continuous radiotherapy effects over 8 days. The subject from which these images were obtained contained a tumor volume of 6.5 mL, with tumor coverage of >90%. The absorbed dose delivered to the tumor was 419 Gy.

[0227] The use of up to four catheters effectively enhances locoregional drug distribution and tumor volume coverage, while the infusion rate improves patient convenience. Mean locoregional retention in brain volume at the end of infusion was 85.9% ± 17.1% ID (n = 18) and 46.6% ± 16.7% ID (n = 17) 8 days after infusion. After dose escalation, the mean radiation absorbed dose in the two most recent cohorts was 354.7 ± 144.0 Gy to tumor volume, 1.32 ± 1.06 Gy to whole brain, and 0.16 ± 0.04 Gy to whole body (n = 6).

[0228] FIG. 14A is a 186 RNL (e.g. 186 Figure 14B shows the distribution of brachytherapy with Re nanoliposomes. 186 RNL (e.g. 18614C shows the dose-volume histogram of Re nanoliposome brachytherapy. As shown, 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 over 8 days. The important feature of the treatment technique may be the highly focused treatment to the volume by the radiation source delivery. The 3D dose distribution shows a very steep dose gradient; the 5Gy isodose line is shown (white arrow). For comparison, FIG. 14C illustrates the isodose distribution of the SBRT case in the tumor and surrounding normal tissue. In the SBRT case, a prescribed dose of 30Gy was delivered to the radiation therapy planning target volume (PTV). The white line shows the 5Gy isodose line.

[0229] Intensive brachytherapy treatment allows high radiation dose treatment for tumor eradication with low toxicity to unaffected tissue. The treatment technique results in radiation absorbed doses of hundreds of Gy or more in the treatment volume, while the radiation absorbed dose beyond the distribution volume of the radiation source drops rapidly to a minimal level; for reference, see the white arrow indicating the 5Gy isodose line in Figure 14A.

[0230] Based on the results of this study, 186 RNL (e.g. 186 Re nanoliposome) brachytherapy can provide high absorbed radiation doses to tumors with minimal radiation exposure to the brain and whole body. Therapy with this technique can also provide sustained radiation to the target from high to low dose rates over a period of 8 days, which may be beneficial in radiation biology for tumor control.

[0231] The results of this study compared with sealed source brachytherapy: 186 RNL (e.g. 186We demonstrate that Re nanoliposome (RE) brachytherapy can be advantageous in terms of minimal invasiveness, planning, and convenience of delivery, and that this therapy is bioabsorbable. Furthermore, image monitoring capabilities can provide a predictive tool for evaluating therapy delivery and treatment efficacy, and the development of 3D dose distribution calculations can provide a convenient mechanism for the evaluation of dose and therapy efficacy, as well as for the application of additional therapy for better tumor control.

[0232] Example 4: Renium-186 Nanoliposomes in Recurrent Glioma ( 186 Safety and feasibility of RNL EBRT, a central component of the management of primary brain tumors, is limited by the tolerance of surrounding normal brain tissue. 186 RNLs allow the delivery of high specific activity beta-emitting radiation with excellent retention within the tumor.

[0233] In recurrent gliomas using a standard 3+3 design 186 The RNL Phase 1 dose escalation study 186 The purpose was to determine the maximum tolerated dose of RNL. 186 RNLs were administered by convection-enhanced delivery (CED). Injections were followed under whole-body planar imaging and SPECT / CT. Immediately after administration, and 186Repeat SPECT / CT imaging was performed on days 1, 3, 5, and 8 after injection of the RNLs to obtain dosimetry and distribution. Subjects were followed until disease progression by RANO criteria. Eighteen subjects were treated across six cohorts, each consisting of three subjects. Table 3 shows information related to dosing for each cohort, such as the amount of radioactivity delivered, injectate volume, and injectate concentration. The mean tumor volume was 9.4 mL (range 1.1–23.4). Injection doses ranged from 1.0 mCi to 22.3 mCi, and injectate volumes ranged from 0.66 mL to 8.80 mL. One to four CED catheters were used for delivery. The maximum catheter flow rate was 15 μl / min. The mean absorbed dose was 239 Gy (CI 141-337; range 9-593) to the tumor volume, 0.72 Gy (CI 0.34-1.09; range 0.005-2.73) to normal brain, and 0.07 Gy (CI 0.04-0.10; range 0.001-0.23) to the whole body. The mean absorbed dose to the tumor volume when the percentage of tumor volume in the treatment volume was 75% or more (n=10) was 392 Gy (CI 306-478; range 143-593). Surgery-related scalp discomfort and tenderness occurred in three subjects. The therapy was well tolerated, no dose-limiting toxicities were observed, and no treatment-related serious adverse events occurred, despite a significantly higher absorbed dose than typically delivered by EBRT in previously treated patients. Responses supporting clinical activity were observed.

[0234] Administered by CED to patients with recurrent glioma 186 RNL resulted in a higher absorbed dose of radiation to the tumor without significant toxicity compared with EBRT. 186 RNL may be useful in the treatment of recurrent gliomas. Specifically, a dose of 22.3 mCi in 8.8 mL of injectate may be useful in the treatment of recurrent gliomas.

[0235] (Table 3) Dose characteristics TIFF2025508997000007.tif57156

[0236] Example 5: Overall Survival of Rhenium-186 Nanoliposomes in Recurrent Glioblastoma (GBM) Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. The standard of care for GBM over the past decade has been surgery followed by chemoradiotherapy with temozolomide, with radiation contributing significantly to survival in this regimen. As most recurrences occur within 2 centimeters of the resection margin, locoregional therapies that bypass the blood-brain barrier are attractive potential alternatives. External beam radiotherapy (EBRT) is a central component of primary brain tumor management but may be limited by the tolerance of surrounding normal brain and skeletal tissue. Rhenium-186 ( 186 Re) is an intense electron source with short path length, low dose rate, and high radiation density. 186 Re can be a beta-emitting therapeutic radionuclide with a half-life of 90 hours, a radiation path range of 1.8 mm, and a high beta / gamma energy ratio suitable for cancer brachytherapy. 186 Re may have sufficient gamma ray energy to allow imaging of in vivo radiopharmaceutical product distribution using standard SPECT / CT.

[0237] Rhenium-186 nanoliposomes may allow for the delivery of high specific activity beta radiation with excellent retention in tumors. Therapeutic radionuclides may require carriers to ensure that they are sequestered within tumors and slowly redistributed. Liposomal nanoparticles (nanoliposoms) may provide a means to encapsulate radionuclides and support sustained intratumoral accumulation while also convecting within tumors. The inventors have 186 We have successfully developed a method to load Re into nanoliposomes with high efficiency and high specific activity. This process can provide significantly higher levels of specific activity than previously described and may have the potential to provide significantly higher delivered therapeutic radiation doses with reduced toxicity. Preclinically, liposomal encapsulation delivered via convection-enhanced delivery (CED) has been shown to be effective in treating pulmonary tuberculosis. 186 RNL (e.g. 186Re nanoliposomes) can achieve very high doses of targeted radiation and a wide therapeutic index. 186 RNL (e.g. 186 We report the results of the first-in-human Phase 1 study (ReSPECT) of Re nanoliposomes.

[0238] This study evaluated the efficacy and safety of RNL given by convection-enhanced delivery (CED) in patients with recurrent or progressive malignant gliomas following standard surgery, radiation, and / or chemotherapy treatment (e.g., 186 This is a multicenter, sequential cohort, open-label, volume- and dose-escalation phase 1 clinical trial of the safety, tolerability, and distribution of 100 mg of 100 mg of Re nanoliposomes. The study will use modified Fibonacci dose escalation and a standard 3+3 design.

[0239] Brainlab iPlan Flow software was used to plan SmartFlow catheter placement within the tumor volume while avoiding white matter tracts as well as CSF cavities (fissures, sulci, cisterns, ventricles, and resection cavities). Frameless image-guided catheter placement was achieved using the Brainlab Varioguide Stereotactic system. A single dose of RNL is delivered by CED utilizing 1-4 catheters at a maximum flow rate of up to 20 μL / min / catheter.

[0240] During the infusion period, continuous 1-minute dynamic planar imaging was performed. To assess the radiation absorbed dose to the tumor and other organs during treatment, RNL (e.g., 186 SPECT / CT imaging and serial whole-body planar imaging scans were performed immediately after injection of 1000 μg / kg of Re nanoliposomes, and at 1, 3, 5, and 8 days later. Serial blood samples and serial 24-hour urine collections were also counted for activity. Dosimetry was performed using region of interest data and OLINDA dose calculation software. The dose escalation scheme for each cohort is shown in Table 4.

[0241] Table 4. Dose escalation scheme for each cohort TIFF2025508997000008.tif85156*Cohort 6* utilized the same volume and dose as Cohort 6, but increased the maximum flow rate to 20 microliters / minute.

[0242] Between 2015 and 2021, 22 patients across seven dosing cohorts were treated. Fourteen patients were male and eight were female. Mean tumor size was 8.3 mL (range 0.9-22.8 mL). Mean number of previous treatments (Tx) was 1.7 (range 1-3 Tx). Five patients had previously received bevacizumab. Pathological grade was grade IV glioma in 20 patients and grade III in 2 patients. IDH mutation status was wild type in 18 patients and mutated in 2 patients (2 patients did not have status), and MGMT status was methylated in 4 patients and unmethylated in 12 patients (6 patients did not have status).

[0243] 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 administration rates ranged from 5–20 μl / min, with one to four catheters per patient. The mean absorbed radiation dose to the tumor was 273 Gy (8.9–740 Gy), with negligible exposure outside the brain. The tumor in treatment volume (TuV), i.e., TuV / TrV percent, was 70.9% (19.8%–100%) and correlated with the mean absorbed radiation dose to the tumor. In five patients who had previously received bevucizamab therapy, the mean absorbed dose to TuV was 149.2 Gy, with a TuV / TrV percent of 47.9%. However, in 17 patients who had not previously received bevacizamab, the mean absorbed dose to TuV patients was 302 Gy and the TuV / TrV percentage was 77.7%. Based on poor convection in these convection inputs, further enrollment of bevacizamab patients was stopped.

[0244] FIG. 8 shows a 3D view of the extent of radiation delivered (measured in absorbed dose). 186 RNL (e.g. 186 The images were taken 8 days after treatment with Re nanoliposomes.

[0245] Figure 9 shows charts demonstrating overall survival in terms of mean absorbed dose and TuV / TrV percent. The analysis was based on a proportional hazards model of overall survival in days in terms of mean absorbed dose, TuV / Trv percent, and interaction terms, and suggests that survival time increases with both absorbed dose and TuV / Trv percent (p=0.065) based on a sample size of N=22.

[0246] 186 RNL (e.g. 186 In 22 subjects with recurrent glioblastoma (GBM) receiving a single dose of 100 mg / kg of 1000 mg of 1000 mg of Re nanoliposomes, 186 RNL may be safe and well tolerated. Specifically, there were no adverse events (AEs) with fatal outcomes or discontinuations due to AEs. The majority of reported AEs were mild or moderate in intensity (grade 1 or 2) and not serious. The most common AEs were fatigue (50.0%), muscle weakness and headache (33.3% each), and gait disturbance (27.8%). Most AEs were not considered related to surgery, except for one case of scalp discomfort and one case of cerebral edema. 186 Grade 3 AEs were considered unrelated to RNL. Grade 3 AEs were leukocytosis, hyperglycemia, muscle weakness, seizures, cerebral edema, avascular necrosis of the shoulder (worsening), vasogenic cerebral edema, and pneumonia; all of these events were 186 With the exception of one subject with cerebral edema, which was deemed possibly related to RNL by the principal investigator, 186 It was deemed unrelated to RNL.

[0247] Serious adverse events were reported in two subjects in Cohort 2 (seizures and vasogenic cerebral edema), one subject each in Cohort 4 and Cohort 5 (both seizures), and two subjects in Cohort 6 (pneumonia, avascular necrosis of the shoulder (worsening), and cerebral edema). All of these events were 186 With the exception of cerebral edema in one subject, which was deemed potentially related to RNL and / or oral corticosteroid tapering by the investigator, 186 RNL (e.g. 186 Re nanoliposomes) and none of them were considered to be related to the study and led to the discontinuation of the study.

[0248] There were no meaningful differences or patterns in the incidence of relevant TEAEs reported across individual treatment groups (cohorts). Neither the incidence nor severity of AEs was significant. 186 RNL (e.g. 186 Re nanoliposomes) did not appear to increase with increasing dose.

[0249] FIG. 10 shows images including baseline MRI and SPECT images after 20% infusion, at the end of infusion, 24 hours post-infusion, 120 hours post-infusion, and 192 hours post-infusion.

[0250] FIG. 11 shows 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.

[0251] FIG. 12 shows Kaplan-Meier curves comparing patients receiving therapeutic radiation (e.g., >100 Gy) with patients receiving non-therapeutic radiation (e.g., <100 Gy). The curves show a statistically significant difference between the groups (p=.0002). As demonstrated, the patient group receiving >100 Gy had a longer overall survival compared to the patient group receiving <100 Gy. A statistically significant overall survival benefit was observed in patients who achieved absorbed radiation dose adequacy (>100 Gy) compared to those who did not. Moreover, absorbed radiation dose adequacy (>100 Gy) could be achieved in 80% of patients treated in cohorts 5-7.

[0252] Based on the research results, 186 Intratumoral convection-enhanced delivery of RNLs can precisely deliver up to 20 times the absorbed dose of radiation that can be administered by EBRT. 186 A single administration of RNLs may be safe with no dose-limiting toxicities observed, and SPECT / CT can accurately and reliably visualize the location of RNLs and residual radioactivity levels as they disintegrate. Finally, this study demonstrated that increasing drug volumes and radiation doses given in later dosing cohorts correlated with improved overall survival.

[0253] Example 6: Efficacy of Rhenium-186 Nanoliposomes Delivered by Convection-Enhanced Delivery for Recurrent, Refractory, or Progressive Ependymoma and High-Grade Gliomas (HGG) and Newly Diagnosed Diffuse Intrinsic Pontine Gliomas (DIPG) 186 Research on RNL Ependymomas, HGGs, and DIPGs are often difficult to treat, are often aggressive, and have poor prognoses. Radiation therapy remains the mainstay of management, but is limited by the tolerance of the surrounding brain tissue. 186 RNL) (e.g. 186 Re nanoliposomes) allow for the selective delivery of high specific activity beta-emitting radiation with excellent retention within the tumor.

[0254] Conduct a two-part Phase 1 dose-finding study with subsequent expansion cohorts to explore efficacy in pediatric patients based on Phase 1 data in adults. Part 1 will enroll up to 18 subjects and will be administered by convection-enhanced delivery (CED). 186 RNL (e.g. 186The maximum feasible dose of 100 mg / kg of 1000 mg of 1000 mg of Re nanoliposomes was determined. Tumors are limited to 4 cm in diameter and 34 mL in volume. The dose-limiting toxicity period (DLT) is 28 days after injection. Part 2 will include 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 with newly diagnosed DIPG. 186 RNL (e.g. 186 The primary endpoint is overall response rate (ORR) according to the Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria. Secondary endpoints are progression-free survival at 24 months (PFS-24) and overall survival at 24 months (OS-24) in cohort A, and PFS-12 and OS-12 in cohorts B and C.

[0255] In a phase 1 trial (NCT01906385) of adults with recurrent glioblastoma, the mean dose to tumors at ≥75% coverage (n=10) was 392 Gy (CI 306–478). The therapy was well tolerated, with no dose-limiting toxicities and no serious adverse events (n=18).

[0256] Administered by CED 186 RNL (e.g. 186 Delivery of Re nanoliposomes is well tolerated at significantly higher doses of radiation therapy than with standard modalities in adults with recurrent HGG. Further studies will be performed in adult and pediatric subjects. Administered by CED. 186 RNLs can be useful in treating HGG (eg, recurrent HGG).

[0257] Example 7: Intraventricular Rhenium-186 Nanoliposomes for Leptomeningeal Metastases 186 Maximum Tolerable Dose, Safety, and Efficacy of RNL Leptomeningeal metastasis (LM) is a rare but typically fatal complication of advanced cancer that affects the fluid-covered structures of the central nervous system and is diagnosed in approximately 5% of patients with metastatic cancer. As survival is measured in weeks to months, novel approaches that can improve both the quality and quantity of life are needed. 186 RNLs allow for the direct, selective delivery of high specific activity beta-emitting radiation to the tumor. In a phase 1 study (NCT01906385) in adults with recurrent glioblastoma, the mean absorbed dose to the tumor at ≥75% coverage (n=10) was 392 Gy (CI 306–478). The therapy was well tolerated with one potentially treatment-related serious adverse event, cerebral edema, which resolved after steroid treatment.

[0258] This is a two-part Phase 1 dose-finding study followed by an expansion cohort to explore efficacy. In Part 1, the drug will be administered intracerebroventricularly via the Ommaya reservoir. 186 Up to 21 subjects will be enrolled to characterize the safety and tolerability of a single dose of RNL and to identify the maximum tolerated dose (MTD) / maximum feasible dose (MFD) for future studies. The dose-limiting toxicity period is 28 days after infusion. Part 2 will enroll up to 21 subjects in two different cohorts: 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. 186 RNL will be evaluated independently. The primary endpoint is 186 The objective of this study is to estimate the antitumor activity of RNL. 186 The objectives of this study were to characterize the pharmacokinetic and dosimetry profile of a single dose of RNL, to determine the overall response rate (ORR) based on CSF and radiological findings, and to describe survival distributions.

[0259] Example 8: Intraventricular Rhenium-186 Nanoliposomes for Leptomeningeal Metastases ( 186 Preclinical safety and activity of RNL LM is a clinical complication that can occur when cancer cells invade the leptomeninges and cerebrospinal fluid of patients with malignant tumors. Once diagnosed, there are limited treatment options and poor survival. 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 RNLs may be useful in treating LM.

[0260] By intracerebroventricular (IT) injection 186 To establish the maximum tolerated dose (MTD) of RNL, eight cohorts of Wistar rats (n=3 each) were treated with 0 (control), 0.480, 0.800, 1.000, 1.150, and 1.340 mCi doses. 186 Increasing activity of RNLs was injected IT. Toxicity was assessed by observing daily food and water intake, daily body weight, and neurological deficits. To assess efficacy, C6-Luc glioma cells were injected IT and animals were treated with 0.69 mCi of glioma cells 15 days after inoculation. 186 The mice were treated with RNL. The absorbed dose was assessed by gamma camera imaging at 0, 24, and 48 hours after treatment. Tumor growth was assessed by luciferase bioluminescence.

[0261] In rats, after administration of an absorbed dose of up to 1.34 mCi up to 1075 Gy for 3 months, 186 No evidence of adverse effects related to RNL was observed; therefore, the MTD exceeded the doses evaluated in this study. A significant difference in survival between the control and treatment groups (n=8 each) was observed at 2 weeks post-treatment, with 50% survival in the control group and 100% survival in the treatment group (p=0.0087). The only significant histological finding among treated rats was leptomeningeal thickening overlying the median eminence, suggesting mild reactive meningeal hypertrophy. This evidence supports the conclusion that in a rat model of LM, 186 This data demonstrates that intraventricular delivery of RNLs can be well tolerated and can improve animal survival at two weeks.186 We demonstrate that RNLs may be useful in treating LM.

[0262] Example 9: 186 Maximum Tolerable Dose of RNL Nanoliposome BMEDA-chelation- 186 rhenium( 186 RNLs allow the delivery of high specific activity beta-emitting radiation with excellent retention within the tumor. 186 In recurrent gliomas using a standard 3+3 design to determine the maximum tolerated dose of RNL 186 A Phase 1 dose escalation study of RNL has been initiated. 186 RNLs will be administered by convection using a BrainLab Flexible Catheter with placement guided using the iPlan Flow and Varioguide systems. Injections will be tracked under whole body planar imaging and SPECT / CT. 186 Repeat SPECT / CT imaging will be performed immediately after RNL injection and on days 1, 3, 5, and 8 after injection to obtain dosimetry and distribution.

[0263] Thirteen patients were treated, 12 with recurrent glioblastoma, and 54% had failed treatment with bevacizumab. The infusion dose was gradually increased from 1.0 mCi to 13.4 mCi and the infusion volume from 1.0 mL to 5.28 mL using one or two CED catheters. 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, and there were no treatment-related adverse effects, despite a significantly higher absorbed dose than EBRT in previously treated patients. The plan is to increase the dose to 22.3 mCi and the infusion volume to 8.8 mL. Based on the results of this study, intratumoral 186 RNL can deliver up to 20 times the absorbed dose of radiation administered by EBRT without significant toxicity.

[0264] Example 10: Via an intraventricular catheter for the treatment of leptomeningeal metastases (LM) 186 An open-label phase I clinical study administering a single dose of RNL It will be administered through an intraventricular catheter (Ommaya reservoir) in participants with leptomeningeal metastases (LM) 186 RNL (Radionuclide Clinical Research Drug) (e.g., in a pharmaceutical composition 186 This is a Phase I clinical study evaluating a single dose of Re nanoliposomes. The clinical study treatment is a dose of 5cc per participant. 186 It consists of a single administration of RNL. The clinical study includes the evaluation of three separate dose levels. Three to six participants may be treated at each dose. The maximum number of participants enrolled in the study is 18. The clinical study treatment will be administered on an outpatient basis by a clinical research physician following the CSF flow study. Participants will be followed for up to 12 months following administration of the clinical study drug.

[0265] The study includes dose escalation for cohorts 1 to 3. Each participant 186 Participants will receive a single 5 cc dose of RNL. At each dose level, a minimum of 3 and a maximum of 6 participants will be enrolled. If no dose-limiting toxicity is observed in the first 3 participants, then the next higher dose level cohort will be opened for enrollment. The dose escalation scheme will follow modified Fibonacci dose escalation as shown: Cohort 1 (6.6 mCi), Cohort 2 (13.2 mCi), Cohort 3 (26.4 mCi).

[0266] Outcome measures include primary and secondary outcome measures. Primary outcome measures include a.) incidence and severity of adverse events (AEs) and serious adverse events (SAEs) over a 12-month time frame (safety will be assessed by incidence of AEs and SAEs graded according to CTCAE version 5.0), and b.) incidence of dose-limiting toxicities (DLTs) over a 12-month time frame (maximum tolerated dose (MTD) will be assessed by testing escalating doses for cohorts 1-3 with 3-6 participants per cohort). The MTD reflects the highest dose of drug that did not cause dose-limiting toxicities (DLTs) in >33% of participants.

[0267] Secondary outcome measures include: a.) determination of overall response rate (ORR) over a 12-month time frame (determine overall response rate (ORR) defined as the proportion of all evaluable participants who achieved a response as best overall response at the time of progression); b.) determination of duration of response (DoR) over a 12-month time frame (determine duration of response (DoR) defined as the time from first response to LM progression); c.) determination of progression-free survival (PFS) (determine progression-free survival (PFS) defined as the time from first treatment to the date of LM progression or date of death from any cause); and d.) determination of overall survival (OS) (determine overall survival (OS) defined as the time from first treatment to the date of death).

[0268] Participant eligibility criteria included inclusion and exclusion criteria. Inclusion criteria included: being at least 18 years old at screening; being able to understand the purpose and risks of the study and having signed a written informed consent document approved by the institution-specific IRB; and having proven and documented LM: any primary type that meets the requirements of the study according to the EANO-ESMO Clinical Practice Guidelines. Subjects had Type 1 and 2 (except 2D) LM; Karnofsky performance status 60-100; a.) acceptable liver function: bilirubin ≤ 1.5x upper limit of normal, b.) acceptable renal function with AST (SGOT) and ALT (SGPT) ≤ 5.0x upper limit of normal, and c.) serum creatinine ≤ 2x upper limit of normal; acceptable hematological status (without hematological support): a.) ANC ≥ 1000 cells μL, b.) platelet count ≥ 75,000 / μL, c.) hemoglobin ≥ 9.0 g / dL; all women of childbearing potential had to have a negative serum pregnancy test at screening; male and female subjects had to agree to use effective contraception with their partners (e.g., sterilization, or the use of spermicidal gel or IUD in combination with barrier contraception, either condoms or diaphragms), from study entry through 6 months after the final dose.

[0269] Exclusion criteria included the following: subjects had not recovered from an AE (except for alopecia, anemia, and lymphopenia) due to antineoplastic agents, investigational drugs, or other medications administered prior to the study to a National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v5.0 Grade ≤ 1); obstructive or symptomatic communicating hydrocephalus; contraindications to ventriculo-peritoneal or ventriculo-atrial shunts without a ventricular valve or Ommaya reservoir placement; women of childbearing potential who are pregnant, breastfeeding, or who may be pregnant without a negative serum pregnancy test; serious intercurrent illness, e.g., progressive systemic (extramingletal) disease, clinically significant cardiac 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, seizure disorder with any attacks occurring within 14 days prior to consent, or encephalopathy; active severe non-hematologic organ toxicity, e.g., renal, cardiac, hepatic, pulmonary, or gastrointestinal systemic toxicity grade 3 or greater; significant coagulation abnormality, e.g., inherited bleeding diathesis or acquired coagulation disorder with an unacceptable risk of bleeding; 186 craniospinal irradiation (for intraparenchymal or dural metastases) or intrathecal cytotoxic anticancer therapy <3 weeks prior to the first dose of RNL; 186 Myelopathy after spinal irradiation more than 3 weeks before the first dose of RNL; systemic chemotherapy agents with CNS penetration (e.g., temozolomide, carmustine, lomustine, capecitabine, carboplatin, vinorelbine, bevacizumab, irinotecan, or topotecan), unless they have developed or have had progressive or persistent leptomeningeal metastases while taking these agents; investigational drugs ( 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 RNL; 186nitrosoureas or mitomycin C within 42 days prior to the first dose of RNL, or metronomic / delayed low-dose chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days; and impaired CSF flow study performed on days -4 to -2 based on study imaging and determined by the investigator.

[0270] Example 11: Treatment of leptomeningeal metastases To determine 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.The primary objectives are to characterize the safety and tolerability of a single dose of 186RNL via the intraventricular route, as well as to identify the maximum tolerated dose (MTD) and / or maximum feasible dose (MFD) and to develop a collaborative study for CSF biomarker analysis. Secondary objectives are to characterize the pharmacokinetic and dosimetry profile of a single dose of 186RNL when administered intracerebroventricularly via the Ommaya reservoir, to develop a multiple dosing strategy of 186RNL for subsequent clinical trials, to determine the overall response rate (ORR), defined as the proportion of all evaluable participants who achieved a response as best overall response at the time of progression, to determine the duration or response (DoR), defined as the time from first response to LM progression, to determine progression-free survival (PFS), defined as the time from first treatment to the date of LM progression or date of death from any cause, and to determine overall survival (OS), defined as the time from first treatment to date of death. Primary endpoints are to determine the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well as the incidence of dose-limiting toxicities (DLTs).

[0271] Example 12: 186RNL in leptomeningeal carcinoma Leptomeningeal cancer, also known as carcinomatosis, is a cancer that begins in one part of the body and spreads to the leptomeningeal lining of the brain and spinal cord that surrounds the cerebrospinal fluid (CSF) cavity. Administering 100 nm nanoliposomes, which circulate freely throughout the CSF, migrate to the meningeal surface where the LMC is located, have a prolonged half-life of weeks versus hours for unencapsulated drug, and are safe and effective in preclinical models.

[0272] Example 13. Dose Escalation Scheme for Leptomeningeal Metastases The injection dose will be gradually increased from 6.6 mCi to 82.5 mCi with an injection volume of 5 mL. The study design is summarized in Table 5 below.

[0273] Table 5. Dose Escalation Scheme TIFF2025508997000009.tif84156*Theoretical maximum absorbed dose is the radiation absorbed dose in the absence of clearance from the CSF volume (100% sustained retention in the CSF volume) after RNL injection.

[0274] Example 13: Additional Patient Data for Treating GBM Twenty-three patients were treated, of which 30.4% had failed bevacizumab. The infusion dose was gradually increased from 1.0 mCi to 31.2 mCi, and the infusion volume 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 current as of the date of table creation.

[0275] Table 6: Phase 1 clinical trial design TIFF2025508997000010.tif155156

[0276] Median survival in patients who failed bevacizumab treatment (n=7) was 145 days. Median survival in bevacizumab-naive patients (n=16) was 350.5 days, with 3 patients still alive at the end of the study.

[0277] Example 16: ReSPECT-LM Clinical Update A multicenter Phase 1 study is being conducted with the primary objective of determining the maximum tolerated / maximum feasible dose, safety, and efficacy of single-dose rhenium (186Re) ovis bemeda administered via intraventricular for leptomeningeal metastases (LM). Secondary objectives are to determine the pharmokinetic and dosimetric profile of a single dose of 186RNL when administered intraventricularly via the Ommaya reservoir, to develop a multiple dosing strategy of 186RNL for subsequent clinical trials, and to determine the overall response rate (ORR), duration of response (DoR), progression-free survival, and overall survival (OS). 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). Figure 32 shows leptomeningeal administration and rapid spread of rhenium (186Re) ovis bemeda targeted to the CSF. Figure 33 shows an update on the ReSPECT-LM clinical trial.

[0278] Example 17: Animal studies with RNL and immunotherapeutic agents Animal studies are performed in which RNLs and one or more immunotherapy treatments are administered. Immunotherapy treatments that can be administered with RNLs include, but are not limited to, monoclonal antibodies and immune checkpoint inhibitors, PARP inhibitors, non-specific 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 RNLs or administered before or after RNLs. Immunotherapy treatments that can be administered with RNLs also include, but are not limited to, the drugs listed in Table 7. Various doses and treatment schedules are tested. Immunotherapy treatments are delivered systemically or into cerebrospinal fluid (CSF).

[0279] Table 7: Immunotherapeutic drugs TIFF2025508997000011.tif176132TIFF2025508997000012.tif233132TIFF2025508997000013.tif198132

[0280] 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. It is thus to be understood that numerous modifications can be made to the illustrative embodiments and that other arrangements can be devised without departing from the spirit and scope of the technology as defined by the appended claims.

Claims

1. 1. A method of treating leptomeningeal metastases in a subject in need thereof, comprising: Liposomes and a compound of formula I: or a pharma- cerebroventricularly administering a therapeutically effective amount of a radiolabeled liposome comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof. wherein M is 99m Tc, 186 Re, 188 Re, or a combination thereof; X is NR 1 and R 1 is CH 2 CH 2 NEt 2 and R 2 is CH 2 CH 2 N(CH 2 CH 2 SH)(CH 2 CH 2 NEt 2 ), The method.

2. M, 186 2. The method of claim 1, wherein Re is

3. The method of claim 1 , wherein the compound is incorporated into or attached to the liposome.

4. The method of claim 1 , wherein the liposome comprises a phospholipid and cholesterol or a cholesterol analog.

5. The method of claim 4, wherein the liposome comprises distearoylphosphatidylcholine.

6. 2. The method of 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. 10. The method of claim 1, wherein the leptomeningeal metastasis originated from lung cancer, breast cancer, or melanoma.

8. 10. The method of claim 1, wherein the radiolabeled liposome is administered as an infusion comprising the radiolabeled liposome.

9. 10. The method of claim 8, wherein the radiolabeled liposomes are administered as an infusion via an Ommaya reservoir.

10. The injection solution is about 1 μL -1 ~Approx. 50μL -1 The method of claim 8, wherein the therapeutic agent is administered at a maximum flow rate of 0.1 mg / kg.

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

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

13. 13. The method of claim 12, wherein the volume of the infusion solution is about 5.0 mL.

14. The amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 0.1 mCi mL -1 ~about 50mCi mL -1 9. The method of claim 8, wherein

15. The amount of radioactivity delivered by the radiolabeled liposomes per volume of infusion is about 1.32 mCi mL -1 ~Approx. 5.28mCi mL -1 15. The method of claim 14, wherein

16. 10. The method of claim 8, wherein the infusion fluid is administered at an exit velocity of about 0.001 mm / min to about 1.0 mm / min.

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

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

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

20. The method of claim 1, further comprising imaging the radiolabeled liposome in conjunction with or following administration.

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