Patent Application: US-95176810-A

Abstract:
a method of treating a condition associate with accumulation of an agent in cells in a patient includes exposing the cells to ultrasound , to selectively kill or induce apoptosis in the cells . the cells include the accumulated agent .

Description:
the present invention makes use of the discovery that the differential resonant frequency of a cell caused by the accumulation of at least one agent that causes , or is associated with , a pathological or undesired condition , such as proteins , lipids , bacteria , viruses , parasites or particles , may be used to distinguish and eliminate cells in which the accumulated agent leads to a difference in the resonant frequency of the cell , by applying ultrasound treatment . the cells associated with the accumulated agent have a resonant frequency which is distinct from cells of the same type . by selecting the frequency of the ultrasound applied to the tissue to feed energy into the resonant frequency , the cells with the accumulated agent will be destroyed or induced to undergo apoptosis . in an aspect of the invention , the cells are not age - modified cells . in another aspect of the invention , the cells are not tumor cells . in yet another aspect of the invention , the cells are not cancerous . the ultrasound technique for removing cell - associated accumulation from a patient is selected for its ability to selectively kill or induce apoptosis in cells having accumulation of the agent associated with the pathological condition , while avoiding removal or destruction of cells that do not present the accumulation . for example , cells expressing high levels of nucleolin on the plasma membrane of the cell may be selected due changes in the stiffness and deformability of the cell . as used herein , “ selectively kill or induce apoptosis ” means that more of the cells which are the target of the killing or inducing apoptosis are so affected , as compared to other cell subject to the same exposure . ultrasound devices can be used according to practices well known to those skilled in the art to destroy cells by vibrational techniques , for example u . s . pat . no . 5 , 601 , 526 ( 1997 ) and international publication no . wo2009 / 143411 ( 2009 ). ultrasound parameters , such as frequency , power and pulsation , can be screened for effectiveness in selectively destroying the targeted cells . differential destruction or inducement of apoptosis may be by selection of the stiffer cells , or by selection of the cells by their resonant frequencies . ultrasound as described above can be applied to a subject with monitoring to determine that inflammatory responses such as fever or swelling do not exceed limits well known to be safe . this process can be repeated at intervals to maintain a level of therapeutic benefit . evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of ultrasound according to the present invention . the application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms , such as removal of cells and cellular debris by scavenging cells . a variety of techniques are available to determine whether ultrasound may be used to selectively remove or kill the cells having the accumulated agent , that leads to , or is associated with , a pathological or undesired condition . the stiffness of individual cells may be determined , by techniques such as those described in u . s . pat . no . 6 , 067 , 859 ( 2000 ). elastic properties of tissue may be measured , by techniques such as those described in u . s . pat . no . 7 , 751 , 057 ( 2010 ). furthermore , application of a variety of ultrasound parameters to cells or a tissue sample , followed by examination of the cells or the tissue sample for destruction or subsequent apoptosis , may also be used to determine whether ultrasound may selectively remove or kill the cells . blood of a patient containing leukemia cells expressing nucleolin on the cell surface is treated with ultrasound . after first diagnosing the patient , a blood sample is taken for further analysis . leukemia cells are isolated from the blood sample , and examined using an optical stretcher ( u . s . pat . no . 6 , 067 , 859 ), to determine the relative stiffness of the cells and / or the resonant vibrational frequencies of the cell . this information is then used to select driving frequencies , intensity and length of time of treatment of the ultrasound , to selectively destroy or induce apoptosis , in the leukemia cells in vivo or ex vivo . colon tissue from a patient containing colon cancer cells that present a multidrug resistance ( mdr ) phenotype are examined and determined to be overexpressing p - glycoprotein on the cell surface . the cells are then examined using an optical stretcher ( u . s . pat . no . 6 , 067 , 859 ), to determine the relative stiffness of the cells and / or the resonant vibrational frequencies of the cell . this information is then used to select driving frequencies , intensity and length of time of treatment of the ultrasound . for example , an ultrasound generating probe may be included at the tip of a colonoscopy device . the ultrasound generating probe could generate pulses of ultrasound at the appropriate frequency , to selectively destroy colon cancer cells that present a multidrug resistance ( mdr ) phenotype , after the probe has been placed proximate to the tumor . the success of the treatment is monitored by subsequent colonoscopy . blood of a patient , containing erythrocytes infected with plasmodium , is treated with ultrasound . after first diagnosing the patient , a blood sample is taken for further analysis . erythrocytes infected with plasmodium are isolated from the blood sample , and examined using an optical stretcher ( u . s . pat . no . 6 , 067 , 859 ), to determine the relative stiffness of the erythrocytes and / or the resonant vibrational frequencies of the erythrocytes . in addition , the plasmodium parasite could also be examined using the optical stretcher , to determine ultrasound parameters capable of direct destruction of the parasite . this information is then used to select driving frequencies , intensity and length of time of treatment of the ultrasound , to selectively destroy infected erythrocytes and / or the plasmodium parasites , in the patient &# 39 ; s blood either in vivo or ex vivo . a biopsy of an area in the lung of a patient containing tubercles and macrophages infected with m . tubercolosis is taken . the biopsy is treated with ultrasound applied at a range of frequencies and intensities , to determine conditions necessary to selectively destroy or induce apoptosis in the infected marcophages , the tubercles and / or the m . tubercolosis bacterial cells . the lungs of the patient are then treated with ultrasound . time of exposure may range from three to sixty minutes daily for up to 20 days . at the end of the treatment , the patients are tested to determine the reduction in the size and / or number of tubercles present in the lungs of the patient . removal of alginates caused by pseudomonas aeruginosa infection in the lungs of patients with cystic fibrosis an alginate sample from the lungs of the patient is treated with ultrasound applied at a range of frequencies and intensities , to determine conditions necessary to selectively destroy or break down the alginate . the lungs of the patient are then treated with ultrasound . time of exposure may range from three to sixty minutes daily for up to 20 days . at the end of the treatment , the patient is tested to determine the reduction of alginates in the lungs . 1 . mi y , et al . apoptosis in leukemia cells is accompanied by alterations in the levels and localization of nucleolin . j biol chem 278 : 8572 - 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