Ultrasound mediated delivery of drugs

Abstract

Disclosed is an ultrasound (US) mediated delivery of therapeutic agents, such as the delivery of a drug, gene, nanoparticle or radioisotope, using a bi-phasic microparticle system including gas microbubbles, emulsion microdroplets and clusters thereof. Also, disclosed are a cluster composition and a pharmaceutical composition, and their use for delivery of therapeutic agents and as a contrast agent for ultrasound imaging. Moreover, disclosed are a method for delivering such therapeutic agents and the use of said compositions.

1 . A cluster composition which comprises a suspension of clusters in an aqueous biocompatible medium, wherein said clusters have a diameter in the range of 1 to 10 μm, and a circularity of <0.9 and comprises:
 (i) a first component which comprises a gas microbubble and a first stabilizer to stabilize said gas microbubble; and 
 (ii) a second component which comprises a microdroplet comprising an oil phase and a second stabilizer to stabilize said microdroplet, wherein the oil phase comprises a diffusible component capable of diffusing into said gas microbubble so as to at least transiently increase the size thereof, wherein said second component optionally further comprises a first therapeutic agent; 
 wherein the microbubble and the microdroplet of said first and second components have opposite surface charges and form said clusters via attractive electrostatic interactions. 
 
     
     
         2 . The cluster composition of  claim 1 , wherein a gas of the gas microbubble of the first component comprises sulphur hexafluoride, a C 3-6  perfluorocarbon, nitrogen, air or mixtures thereof. 
     
     
         3 . The cluster composition of  claim 1 , wherein the first stabilizer and the second stabilizer each have a net electrostatic charge that is opposite to that of the other. 
     
     
         4 . The cluster composition of  claim 3 , wherein the first stabilizer and the second stabilizer each independently comprises a phospholipid, a protein, a polymer, a polyethyleneglycol, a fatty acid, a positively charged surfactant, a negatively charged surfactant or a mixture thereof. 
     
     
         5 . The cluster composition of  claim 1 , wherein the oil phase of the microdroplet of the second component comprises a partly halogenated hydrocarbon, a fully halogenated hydrocarbon or a mixture thereof. 
     
     
         6 . (canceled) 
     
     
         7 . A pharmaceutical composition comprising:
 (i) the cluster composition of  claim 1 ;   (ii) an optional second therapeutic agent, provided either in mixture with (i), or as a separate composition to (i);   wherein said pharmaceutical composition comprises at least one therapeutic agent.   
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the first therapeutic agent of the cluster composition (i) is absent, and the second therapeutic agent is present and is provided as a separate composition to (i). 
     
     
         9 . The pharmaceutical composition of  claim 7 , wherein the first therapeutic agent of the cluster composition (i) is present, and the second therapeutic agent is present and is provided as a separate composition to (i). 
     
     
         10 . The pharmaceutical composition of  claim 7 , wherein the first and second therapeutic agents are independently selected from the group of: consisting of a drug molecule, a nanoparticle and a nanoparticle delivery system, a gene, and a radioisotope. 
     
     
         11 . An ultrasound contrast agent comprising the cluster composition of  claim 1 . 
     
     
         12 . A method of delivering at least one therapeutic agent to a mammalian subject, comprising:
 (i) administering the pharmaceutical composition of  claim 7  to the mammalian subject;   (ii) optionally imaging the microbubbles of said pharmaceutical composition by using ultrasound imaging to identify a region of interest for a treatment within said mammalian subject;   (iii) activating a phase shift of the diffusible component of the second component of the cluster composition from the step (i) by ultrasound irradiation of a region of interest within said mammalian subject, such that:
 (a) the microbubbles of said clusters are enlarged by said diffusible component of the step (iii) to give enlarged bubbles which are localised at said region of interest due to temporary blocking of a microcirculation at said region of interest by said enlarged bubbles; and 
 (b) said activating step (iii) facilitates extravasation of the therapeutic agent(s) administered in the step (i). 
   (iv) optionally, facilitating further extravasation of the therapeutic agent(s) administered in the step (i) by further ultrasound irradiation.   
     
     
         13 . The method of  claim 12 , wherein the ultrasound irradiation applied in the step (iv) has a frequency in the range of 0.05 to 2 MHz. 
     
     
         14 . The method of  claim 12 , wherein the ultrasound irradiation applied in the step (iii) has a mechanical index below 0.7. 
     
     
         15 . The method of  claim 12 , which further comprises a quantification of an amount of the therapeutic agent(s) released by an analysis of an acoustic signature produced by the enlarged bubbles of the step (iii)(a). 
     
     
         16 . A method of treatment of the mammalian subject comprising the method of  claim 12 . 
     
     
         17 . A method of treatment of a mammalian subject comprising:
 administering the cluster composition of  claim 1 , and   applying a High Intensity Focused Ultrasound (HIFU) to a region of interest in the mammalian subject.   
     
     
         18 . (canceled) 
     
     
         19 . A method of an ultrasound imaging, comprising:
 imaging a mammalian subject previously administered with the ultrasound contrast agent of  claim 11 .