Sonosensitization

Abstract

An improved method for MRI-guided sonosensitized focused ultrasound treatment of malignant tissue is disclosed herein.

What is claimed is: 
     
         1 . A method for selectively inducing a directly cytotoxic effect within malignant tissue in a subject, the method comprising:
 a) providing an effective amount of 5-aminolevulinic acid, or a pharmaceutically acceptable salt or ester thereof, to the malignant tissue; and   b) exposing the tissue to ultrasound energy (“sonicating”) using a focused ultrasound device, at a frequency of about 0.1 MHz to about 3 MHz, at an intensity at the ultrasound beam focus of about 3 W/cm 2  to about 100 W/cm 2 .   
     
     
         2 . A method for selectively inducing apoptosis within malignant tissue in a subject, the method comprising:
 a) providing an effective amount of 5-aminolevulinic acid, or a pharmaceutically acceptable salt or ester thereof, to the malignant tissue; and   b) exposing the tissue to ultrasound energy (“sonicating”) using a focused ultrasound device, at a frequency of about 0.1 MHz to about 3 MHz, at an intensity at the ultrasound beam focus of about 3 W/cm 2  to about 100 W/cm 2 .   
     
     
         3 . The method of  claim 1  or  2 , wherein the 5-aminolevulinic acid comprises gamma-irradiated 5-aminolevulinic acid. 
     
     
         4 . The method of any one of  claims 1  to  3 , wherein the malignant tissue is exposed to ultrasound for a duration of about 1 min to about 6 hours. 
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the malignant tissue is exposed to ultrasound for a duration of about 1 min to about 180 min. 
     
     
         6 . The method of any one of  claims 1  to  5 , wherein the intensity is from about 5 W/cm 2  to about 80 W/cm 2 . 
     
     
         7 . The method of any one of  claims 1  to  6 , wherein the intensity is from about 5 W/cm 2  to about 60 W/cm 2 . 
     
     
         8 . The method of any one of  claims 1  to  7 , wherein the energy applied at the focus is between 10 J and 2000 J. 
     
     
         9 . The method of any one of  claims 1  to  8 , wherein the energy applied at the focus is between 10 J and 2000 J. 
     
     
         10 . The method of any one of  claims 1  to  9 , wherein there is an incubation period between providing 5-aminolevulinic acid and soniciating the malignant tissue. 
     
     
         11 . The method of  claim 10 , wherein the incubation period is from about 1 hour to about 72 hours. 
     
     
         12 . The method of  claim 10  or  11 , wherein the incubation period is about 3 hours. 
     
     
         13 . The method of any one of  claims 1  to  12 , wherein the malignant tissue comprises tumor tissue. 
     
     
         14 . The method of  claim 13 , wherein the tumor tissue comprises glioblastoma multiforme, optical pathway glioma, diffuse intrinsic pontine glioma, astrocytoma, ependymoma, medulloblasoma, oligodendroglioma, hemangioblastoma, rhabdoid tumor, brain metastases from another cancer (selected from breast adenocarcinoma, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma, metastatic malignant melanoma, and prostate carcinoma), meningioma, primary pituitary gland malignancy, malignant nerve sheath tumor, neurofibroma, cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphomas associated with human T-cell lymphotropic virus (HTLV), adult T-cell leukemia/lymphoma (ATLL), acute lymphocytic leukemia, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, multiple myeloma, neuroblastoma, retinoblastoma, Wilms' Tumor, bone tumors, soft-tissue sarcomas, infiltrating or metastatic squamous cell carcinoma, salivary gland tumors, nasopharyngeal carcinomas, oral, laryngeal, esophageal tumors, urethral cancer, ureteral cancer, renal cell cancer, bladder carcinoma, bladder carcinoma in situ, metastatic carcinoma of the prostate, bladder, renal, uterine, ovarian, testicular, cancers, uterine, cervical, and uterine carcinoma, rectal or colon cancer, lung cancer, mesothelioma, small cell lung carcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma, breast cancer, gastric cancer, esophageal cancer, and colon carcinoma, cholangiocarcinoma, hepatic carcinoma, pancreatic adenocarcinoma, melanoma, infiltrating basal cell carcinomas, other skin cancers, liver cancer or thyroid cancer. 
     
     
         15 . The method of any one of  claims 1  to  14 , wherein the tumor tissue comprises glioblastoma. 
     
     
         16 . The method of any one of  claims 1  to  15 , wherein the malignant tissue is sonicated at a plurality of individual points. 
     
     
         17 . The method of any one of  claims 1  to  16 , further comprising locating the malignant tissue by magnetic resonance imaging prior to sonicating. 
     
     
         18 . The method of any one of  claims 1  to  17 , wherein the tissue sonicated comprises malignant tissue and non-malignant tissue. 
     
     
         19 . The method of any one of  claims 1  to  18 , wherein the tissue sonicated comprises malignant tissue and a margin around the malignant tissue. 
     
     
         20 . The method of  claim 19 , wherein the outer edge of the margin is 0.2 cm to 5 cm from the malignant tissue. 
     
     
         21 . The method of  claim 19  or  20 , wherein the outer edge of the margin is 1 cm to 3 cm from the malignant tissue. 
     
     
         22 . The method of any one of  claims 1  to  18 , wherein the tissue sonicated comprises a margin around a resection location after resection of malignant tissue. 
     
     
         23 . The method of  claim 22 , wherein the outer edge of the margin is 0.2 cm to 5 cm from the malignant tissue resection site. 
     
     
         24 . The method of any one of  claims 1  to  18 , wherein the tissue sonicated comprises a complete anatomic region of the brain. 
     
     
         25 . The method of  claim 30 , wherein the complete anatomic region of the brain is a temporal lobe, a parietal lobe, a frontal lobe, an occipital lobe, the thalamus, the pituitary gland, the pons, the corpus callosum, the basal ganglia, the brainstem, a hemisphere, the supratentorial region, or the infratentorial region. 
     
     
         26 . The method of  claim 30 , wherein the complete anatomic region of the brain is the brain FLAIR region. 
     
     
         27 . The method of any one of  claims 1  to  26 , wherein less than about 25% of non-malignant tissue in the ultrasound beam focus is damaged. 
     
     
         28 . The method of any one of  claims 1  to  27 , wherein less than about 10% of the non-malignant tissue in the ultrasound beam focus is damaged. 
     
     
         29 . The method of any one of  claims 1  to  28 , wherein less than about 5% of the non-malignant tissue in the ultrasound beam focus is damaged. 
     
     
         30 . The method of any one of  claims 1  to  29 , wherein the temperature of the malignant tissue is raised by sonication no more than about 10° C. 
     
     
         31 . The method of any one of  claims 1  to  30 , wherein the temperature of the malignant tissue is raised by sonication no more than about 5° C. 
     
     
         32 . The method of any one of  claims 1  to  30 , wherein the temperature of the malignant tissue is raised by sonication no more than about 2° C. 
     
     
         33 . The method of any one of  claims 1  to  32 , wherein the 5-aminolevulinic acid is provided to the malignant tissue by oral administration of an oral formulation, or intravenous administration of an i.v. formulation, to the subject. 
     
     
         34 . The method of any one of  claims 1  to  33 , wherein the 5-aminolevulinic acid is provided by intravenous administration. 
     
     
         35 . The method of any one of  claims 1  to  34 , wherein the subject is human. 
     
     
         36 . The method of any one of  claims 1  to  35 , further comprising providing an effective amount of a 5-ALA potentiating agent to the malignant tissue. 
     
     
         37 . The method of  claim 36 , wherein the potentiating agent is selected from the group consisting of doxycycline, methotrexate, minocycline, and Vitamin D 3  or a derivative thereof. 
     
     
         38 . The method of any one of  claims 1  to  37 , further comprising providing an effective amount of microbubbles to the malignant tissue. 
     
     
         39 . The method of  claim 38 , wherein the microbubbles are enhanced contrast ultrasound microbubbles. 
     
     
         40 . The method of  claim 38  or  39 , wherein the microbubbles comprise sulfur hexafluoride or a perfluorocarbon. 
     
     
         41 . The method of any one of  claims 1  to  40 , wherein the 5-aminolevulinic acid is provided in a container, the container further comprising a machine-readable identifier, wherein the machine-readable identifier identifies the source of the 5-aminolevulinic acid, the amount of 5-aminolevulinic acid, the subject to which the 5-aminolevulinic acid is to be administered, the focused ultrasound treatment parameters prescribed for the subject, an identification code or serial number, or a combination thereof. 
     
     
         42 . The method of  claim 41 , wherein the focused ultrasound treatment parameters comprise the ultrasound frequency, power, energy, duration, or a combination thereof. 
     
     
         43 . The method of  claim 41  or  42 , wherein the focused ultrasound device comprises a scanning element capable of scanning the machine-readable identifier, wherein the treatment parameters of the focused ultrasound device are set in response to the machine-readable identifier. 
     
     
         44 . The method of any one of  claims 41  to  43 , wherein the focused ultrasound device is locked in the absence of a machine-readable identifier. 
     
     
         45 . The method of any one of  claims 1  to  44 , wherein the effective amount of 5-ALA is between about 1 mg/kg body weight and 1000 mg/kg body weight. 
     
     
         46 . The method of any one of  claims 1  to  45 , wherein the effective amount of 5-ALA is between about 10 mg/kg body weight and 750 mg/kg body weight. 
     
     
         47 . The method of any one of  claims 1  to  46 , wherein the effective amount of 5-ALA is between about 20 mg/kg body weight and 500 mg/kg body weight. 
     
     
         48 . The method of any one of  claims 1  to  47 , wherein steps a) through b) are repeated at a treatment interval of about 1 day to about 60 days. 
     
     
         49 . The method of any one of  claims 1  to  48 , wherein the ultrasound exposure duration comprises at least one rest period. 
     
     
         50 . The method of any one of  claims 1  to  49 , wherein the ultrasound exposure duration comprises rest periods of about 10 seconds to about 120 seconds, separated by sonication periods of about 10 seconds to about 180 seconds. 
     
     
         51 . The method of  claim 50 , wherein the sonication periods are about 60 to about 90 seconds, and the rest periods are about 45 to about 75 seconds. 
     
     
         52 . A dosage form for use with a FUS device in the treatment of a subject in need of treatment, the dosage form comprising:
 a) a container, comprising an effective amount of 5-aminolevulinic acid sufficient to treat the subject; and   b) a machine-readable identifier readable by the FUS device, wherein the machine-readable identifier identifies the source of the 5-aminolevulinic acid, the amount of 5-aminolevulinic acid, the subject for which the 5-aminolevulinic acid has been prescribed, the FUS treatment parameters prescribed for the subject, an identification code or serial number, or a combination thereof.   
     
     
         53 . The dosage form of  claim 52 , wherein the machine-readable identifier is encrypted, and comprises information for automatically programming the FUS. 
     
     
         54 . A system for treating malignant tissue in a subject, the system comprising:
 a) an effective amount of 5-aminolevulinic acid; and   b) a focused ultrasound (FUS) device.   
     
     
         55 . The system of  claim 54 , further comprising:
 c) an effective amount of a potentiating agent and/or an effective amount of microbubbles.   
     
     
         56 . The system of  claim 54  or  55 , further comprising a container sufficient to contain the effective amount of 5-aminolevulinic acid, an effective amount of a potentiating agent, and/or an effective amount of microbubbles; wherein the container comprises a machine-readable identifier readable by the FUS device, wherein the machine-readable identifier identifies the source of the 5-aminolevulinic acid, the amount of 5-aminolevulinic acid, the subject for which the 5-aminolevulinic acid has been prescribed, the FUS treatment parameters prescribed for the subject, an identification code or serial number, or a combination thereof. 
     
     
         57 . The system of  claim 56 , wherein the machine-readable identifier is encrypted, and comprises information for automatically programming the FUS device. 
     
     
         58 . The system of any one of  claims 54  to  57 , wherein the FUS device is locked in the absence of the machine-readable identifier. 
     
     
         59 . The system of any one of  claims 54  to  58 , wherein the FUS device is a magnetic resonance-guided FUS device (MRgFUS).