Voltage-Activated Therapeutic, Diagnostic, And/Or Theranostic Constructs

Abstract

The present invention provides constructs that can be used for delivering therapeutic and/or diagnostic agents to a subject's tissue or organ. In certain embodiments, the invention provides a doubly ultrasound-voltage-activated imaging agent. In other embodiments, the invention provides methods of selectively imaging a portion of a subject's body.

What is claimed is: 
     
         1 . A construct comprising a liposome comprising a nesting shell, wherein the nesting shell encloses an inner compartment comprising an inner core liquid and at least one liquid droplet, wherein the at least one liquid droplet is insoluble in the inner core liquid. 
     
     
         2 . The construct of  claim 1 , which is more acoustically active in the presence of an electric field than in the absence of an electric field. 
     
     
         3 . The construct of  claim 2 , wherein the at least one liquid droplet comprises an echogenic agent, which (a) is devoid of acoustic activity when the construct is subjected to ultrasound in the absence of an electric field, and which has acoustic activity when the construct is subjected to ultrasound in the presence of an electric field, or (b) has higher acoustic activity when the construct is subjected to ultrasound in the presence of an electric field as compared to in the absence of an electric field. 
     
     
         4 . The construct of  claim 1 , wherein the inner compartment further comprises a therapeutic, diagnostic, or theranostic agent, which crosses the nesting shell at a higher rate in the presence of an electric field than in the absence of an electric field. 
     
     
         5 . The construct of  claim 1 , wherein the at least one liquid droplet comprises a perfluorocarbon. 
     
     
         6 . The construct of  claim 5 , wherein the at least one liquid droplet is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, and any mixtures thereof 
     
     
         7 . The construct of  claim 1 , wherein the at least one liquid droplet is coated with a coating that prevents contact of the inner core liquid with the at least one liquid droplet. 
     
     
         8 . The construct of  claim 7 , wherein in the absence of an electric field the coating prevents or minimizes at least one selected from the group consisting of aggregation, fusion, and coalescence of liquid droplets. 
     
     
         9 . The construct of  claim 7 , wherein the coating comprises at least one selected from the group consisting of polysorbate  20 , albumin, galactose, and polyethylene glycol. 
     
     
         10 . The construct of  claim 1 , wherein the nesting shell comprises at least one selected from the group consisting of a phospholipid and a polymer. 
     
     
         11 . The construct of  claim 10 , wherein the at least one phospholipid comprises at least one phospholipid selected from the group consisting of saturated phospholipid, unsaturated phospholipid, phospholipid charged, and uncharged or zwitterion phospholipid. 
     
     
         12 . The construct of  claim 10 , wherein the nesting shell comprises only uncharged or zwitterion phospholipids or polymers. 
     
     
         13 . The construct of  claim 10 , wherein the nesting shell comprises at least two lipids, wherein one of the at least two lipids is saturated and the other lipid is unsaturated, and wherein one of the at least two lipids is charged and the other lipid is uncharged or zwitterion. 
     
     
         14 . The construct of  claim 13 , wherein the two or more lipids are selected from the group consisting of stearoyl, oleoylphosphatidylglycerol (SOPG); di stearoylphosphatidylcholine (DSPC); stearoyl, oleoylphosphatidylcholine (SOPC); distearoylphosphatidylglycerol (DSPG); cholesterol; and triolein. 
     
     
         15 . The construct of  claim 14 , wherein the nesting shell comprises at least one lipid pair selected from the group consisting of (a)SOPG and SOPC; (b) SOPG and DSPG; (c) DSPC and SOPC; and (d) DSPC and DSPG. 
     
     
         16 . The construct of  claim 14 , wherein the at least one saturated lipid and at least one unsaturated lipid are selected from the group consisting of (a) SOPG and DSPC; and (b) SOPC and DSPG. 
     
     
         17 . The construct of  claim 1 , wherein the nesting shell further comprises at least one selected from the group consisting of poly(vinyl alcohol) and at least one pegylated lipid. 
     
     
         18 . The construct of  claim 1 , wherein the nesting shell comprises at least one selected from the group consisting of (a) DSPC, SOPG, cholesterol and triolein, and (b) DSPG, SOPC, cholesterol and triolein. 
     
     
         19 . The construct of  claim 18 , wherein the nesting shell comprises at least one selected from the group consisting of (a) about 10-32.5 wt % DSPC, about 10-32.5 wt % SOPG, about 15-50 wt % cholesterol, and about 10-40 wt % triolein, and (b) about 10-32.5 wt % DSPG, about 10-32.5 wt % SOPC, about 15-50 wt % cholesterol, and about 10-40 wt % triolein. 
     
     
         20 . A method of selectively delivering a therapeutic, imaging or theranostic agent to a portion of a subject's body, the method comprising:
 administering to the subject the construct of  claim 1 , wherein the inner compartment comprises a therapeutic, imaging or theranostic agent, and
 if the portion of the subject's body produces a sufficient voltage gradient to render the nesting shell more permeable to the inner core liquid than in the absence of the voltage gradient, no further voltage gradient is applied to the portion of the subject's body; or 
 if the portion of the subject's body does not produce a sufficient voltage gradient to render the nesting shell permeable to the inner core liquid, further voltage gradient is applied to the portion of the subject's body so as to render the nesting shell permeable to the inner core liquid. 
   
     
     
         21 . A method of selectively imaging the portion of the subject's body, the method comprising:
 administering to the subject the construct of  claim 1 , wherein the at least one liquid droplet comprises an echogenic agent, which (a) is devoid of acoustic activity when the construct is subjected to ultrasound in the absence of an electric field and has acoustic activity when the construct is subjected to ultrasound in the presence of an electric field, or (b) has higher acoustic activity when the construct is subjected to ultrasound in the presence of an electric field as compared to in the absence of an electric field; and   applying ultrasound radiation to the portion of the subject's body, wherein:
 if the portion of the subject's body produces a sufficient voltage gradient to render the construct more acoustically active, no further voltage gradient is applied to the portion of the subject's body; or 
 if the portion of the subject's body does not produce a sufficient voltage gradient to render the construct more acoustically active than in the absence of the voltage gradient, further voltage gradient is applied to the portion of the subject's body so as to render the construct more acoustically active. 
   
     
     
         22 . The method of  claim 21 , wherein the at least one liquid droplet comprises a perfluorocarbon. 
     
     
         23 . The method of  claim 20 , wherein the portion of the subject's body is selected from the group consisting of heart, lung, liver, gallbladder, spleen, pancreas, kidneys, bladder, uterus, ovaries, eye, thyroid, parathyroid, scrotum, testicles, and abdominal cavity. 
     
     
         24 . The method of  claim 21 , wherein the portion of the subject's body is selected from the group consisting of heart, lung, liver, gallbladder, spleen, pancreas, kidneys, bladder, uterus, ovaries, eye, thyroid, parathyroid, scrotum, testicles, and abdominal cavity. 
     
     
         25 . The method of  claim 21 , wherein the portion of the subject's body is the heart or a section thereof. 
     
     
         26 . The method of  claim 20 , wherein the nesting shell comprises at least one lipid pair selected from the group consisting of: SOPG and SOPC; SOPG and DSPG; DSPC and SOPC; and DSPC and DSPG. 
     
     
         27 . The method of  claim 20 , wherein the nesting shell comprises at least one selected from the group consisting of (a) DSPC, SOPG, cholesterol and triolein, and (b) DSPG, SOPC, cholesterol and triolein. 
     
     
         28 . The method of  claim 20 , wherein the nesting shell comprises at least one selected from the group consisting of (a) about 10-32.5 wt % DSPC, about 10-32.5 wt % SOPG, about 15-50 wt % cholesterol, and about 10-40 wt % triolein, and (b) about 10-32.5 wt % DSPG, about 10-32.5 wt % SOPC, about 15-50 wt % cholesterol, and about 10-40 wt % triolein. 
     
     
         29 . The method of  claim 21 , wherein the nesting shell comprises at least one selected from the group consisting of (a) DSPC, SOPG, cholesterol and triolein, and (b) DSPG, SOPC, cholesterol and triolein. 
     
     
         30 . The method of  claim 21 , wherein the nesting shell comprises at least one selected from the group consisting of (a) about 10-32.5 wt % DSPC, about 10-32.5 wt % SOPG, about 15-50 wt % cholesterol, and about 10-40 wt % triolein, and (b) about 10-32.5 wt % DSPG, about 10-32.5 wt % SOPC, about 15-50 wt % cholesterol, and about 10-40 wt % triolein.