Heat Substrate and/or Image Enhancement Compositions and Enhanced Tissue Ablation Methods

Abstract

Ferritin or iron-based image enhancement agents identify target tissue for treatment or ablation and are heated by microwave absorption. Microwave heat substrates enhance microwave hyperthermal ablation treatment, and may be percutaneously delivered and imaged by x-ray CT during placement of the microwave treatment antenna, allowing more precise positioning and more complete ablation of a tumor site. One method of treating a target tissue uses image-guided delivery of a heat substrate with a reverse-phase change polymer, and may apply energy to fix a mass of the material in the tissue. The fixed polymer may increase hyperthermia, form a thermal boundary, or blockade a vessel or passage so as to reduce or prevent undesired conductive cooling by contiguous tissue, or may deliver a localized treatment drug at the site, upon heating or as it degrades over time.

1 . A localized therapy drug delivery method comprising:
 administering to a patient a combination therapy formulation, the combination therapy formulation comprising:
 a therapy drug; 
 a heat substrate agent; and 
 a polymer, the combination therapy formulation formulated for direct delivery to a target tissue at a target site; and 
   fixing the heat substrate agent by hardening the polymer at the target site, wherein:
 hardening the polymer at the target site comprises heating the heat substrate agent with an external energy source to increase the temperature of the combination therapy formulation substantially uniformly beyond a given temperature; and 
 hardening the polymer expels the therapy drug agent at the target site to deliver the therapy drug over an extended time. 
   
     
     
         2 . The method of  claim 1 , wherein heating the heat substrate agent with an external energy source comprises:
 applying microwave energy via a percutaneous microwave ablation probe positioned in the vicinity of the target tissue; or   applying electromagnetic energy via applying a magnetic field at the target site.   
     
     
         3 . The method of  claim 1 , wherein the heat substrate agent is a material imageable by x-ray CT. 
     
     
         4 . The method of  claim 1 , wherein the polymer comprises a reverse phase change polymer. 
     
     
         5 . The method of  claim 1 , wherein:
 the heat substrate agent enhances microwave energy or electromagnetic energy absorption, such that applying microwave energy or electromagnetic energy to a region of the target tissue elevates the temperature of the heat substrate agent and thermally ablates the target tissue;   the heat substrate agent exponentially increases microwave of electromagnetic heating so as to effectively ablate the target tissue; or   the heat substrate agent is delivered into or surrounding the target site to elevate temperature forming a thermal boundary thereby enhancing treatment of the target tissue.   
     
     
         6 . The method of  claim 5 , wherein the heat substrate agent combined with the reverse change polymer fixes the therapy drug to the target tissue so as to deliver the therapy drug over time as the heat substrate agent is degraded in position. 
     
     
         7 . The method of  claim 1 , wherein the heat substrate agent comprises at least one of: engineered ferritin; ferumoxitol; CsCl; or CsI. 
     
     
         8 . The method of  claim 1 , wherein the therapy drug comprises a chemotherapeutic, or a monoclonal antibody. 
     
     
         9 . The method of  claim 1 , wherein:
 the combination therapy formulation is a first combination therapy formulation; and   further comprising:   following fixing the heat substrate agent, administering to the patient a second combination therapy formulation, the second combination therapy formulation comprising:
 a second therapy drug; 
 a second heat substrate agent; and 
 a second polymer, the second combination therapy formulation formulated for direct delivery to the target tissue at the target site; and 
   fixing the second heat substrate agent by hardening the second polymer at the target site, wherein:
 hardening the second polymer at the target site comprises heating the second heat substrate agent with an external energy source to increase the temperature of the second combination therapy formulation substantially uniformly beyond a given temperature; and 
 hardening the second polymer expels the second therapy drug agent at the target site to deliver the second therapy drug over an extended time. 
   
     
     
         10 . A tissue-targeting theranostic method, comprising:
 administering to a patient a heat substrate disposed in a polymer carrier configured for direct delivery to a target tissue at a target site; and   applying electromagnetic energy or microwave energy to increase the temperature of the heat substrate to enhance hyperthermal ablation of the target tissue.   
     
     
         11 . The theranostic method of  claim 10 , wherein:
 the polymer is a first polymer;   the electromagnetic energy or microwave energy is a first electromagnetic energy or a first microwave energy; and   further comprising:
 administering to the patient a second polymer comprising a treatment agent configured for direct delivery to the target tissue at the target site; and 
 applying a second electromagnetic energy or a second microwave energy to increase the temperature of the second polymer to release the treatment agent. 
   
     
     
         12 . The theranostic method of  claim 11 , wherein the polymer comprises a reverse phase polymer. 
     
     
         13 . The theranostic method of  claim 11 , wherein the treatment agent comprises an iron oxide-nanoparticle material. 
     
     
         14 . The theranostic method of  claim 13 , wherein the iron oxide-nanoparticle material comprises ferumoxytol or an engineered ferritin. 
     
     
         15 . The theranostic method of  claim 13 , wherein the iron oxide-nanoparticle material comprises a nano-particle formulation of Fe 3 O 4 . 
     
     
         16 . The theranostic method of  claim 15 , wherein:
 the nano-particle formulation of Fe 3 O 4  is coated with a poly-carbohydrate molecule; and   the poly-carbohydrate molecule is a cross-linked dextran with a non-reducing end.   
     
     
         17 . The theranostic method of  claim 15 , wherein the nano-particle formulation of Fe 3 O 4  coated with the poly-carbohydrate molecule has a decomposition temperature lower than 240 degrees Celsius. 
     
     
         18 . A localized therapy drug delivery method, comprising:
 administering a nanoparticle formulation, the nanoparticle formulation comprising a surface functionalized for tumor- or tissue-specific targeting of a target tissue; and   applying an electromagnetic energy or a microwave energy to increase the temperature of the surface functionalized nanoparticle formulation by hyperthermal ablation of the target tissue.   
     
     
         19 . The drug delivery method of  claim 18 , wherein the nanoparticle formulation comprises ferumoxytol, an engineered ferritin, or an iron-based nanoparticle formulation that allows MRI imaging to confirm existence of the target tissue and presence of an agent at a target site. 
     
     
         20 . The drug delivery method of  claim 18 , further comprising:
 applying a microwave heat substrate to enhance the hyperthermal ablation of the target tissue.   
     
     
         21 . The drug delivery method of  claim 18 , further comprising:
 contacting the target tissue by image guided catheter delivery of a flowable or a conformable heat substrate composition including a reverse-phase change polymer that thickens or solidifies at body temperature to thereby fix a mass of the flowable or the conformable heat substrate composition at the target site.   
     
     
         22 . The drug delivery method of  claim 21 , further comprising:
 applying electromagnetic energy or microwave energy to heat the mass and thereby more effectively achieve hyperthermal ablation of the contacted target tissue and/or deliver a drug from the mass to the target tissue.   
     
     
         23 . The drug delivery method of  claim 22 , wherein the drug comprises at least one of: a chemotherapeutic treatment; a monoclonal antibody (mAB); a ferritin; or a ferumoxytol. 
     
     
         24 . A therapy formulation comprising:
 a heat substrate agent configured to be hardened at and fixed to an in-vivo target site when subjected to externally applied heat to increase the temperature of the heat substrate agent; and   a polymer configured to contain a therapy drug agent, the polymer configured to expel the therapy drug agent at the target site after its temperature increases to deliver the therapy drug over an extended time,   the heat substrate agent and polymer forming a combination therapy formulation formulated for direct delivery to target tissue at the target site;   the combination therapy formulation being formulated so that a simultaneous increase in the temperature of the therapy drug, heat substrate agent and polymer is substantially uniformly beyond a given temperature.   
     
     
         25 . The therapy formulation of  claim 24 , wherein the combination therapy formulation comprises the therapy drug agent. 
     
     
         26 . The therapy formulation of  claim 24 , wherein the heat substrate agent is a material imageable by x-ray CT. 
     
     
         27 . The therapy formulation of  claim 24 , wherein the polymer comprises a reverse phase change polymer. 
     
     
         28 . The therapy formulation of  claim 24 , wherein the externally applied heat is applied by a microwave energy source or an electromagnetic energy source. 
     
     
         29 . The therapy formulation of  claim 28 , wherein the heat substrate agent enhances the temperature increase of the therapy drug, heat substrate agent and polymer upon application of the externally applied heat by the microwave energy source or electromagnetic energy source. 
     
     
         30 . The therapy formulation of  claim 24 , wherein the polymer is a hydrogel. 
     
     
         31 . The therapy formulation of  claim 24 , wherein the heat substrate agent is a thermal accelerant. 
     
     
         32 . The therapy formulation of  claim 24 , wherein the heat substrate agent comprises at least one of: engineered ferritin; ferumoxitol; CsCl; or CsI.