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.

Claims

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.sub.3O.sub.4.

16. The theranostic method of claim 15, wherein: the nano-particle formulation of Fe.sub.3O.sub.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.sub.3O.sub.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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] These and other features of the invention will be understood from the drawings and the description herein, taken together with the above-cited international Application WO 2014/031727 published 27 Feb. 2014 which is hereby incorporated herein in its entirety by reference. The drawings, description, cited peers and claims, infra, describe methods and materials of the invention and intended variations and extensions thereof, together with certain representative and proof-of-principle measurements and experiments, wherein

[0019] FIG. 1 is graph of temperature increases observed with several heat substrate agents using low power microwave stimulation;

[0020] FIG. 2 is a chart showing effective temperature and heating profiles with several iron-based formulations, CsCl concentrations and polymer in vitro; and

[0021] FIGS. 3A, 3B and 3C illustrate CT imaging characteristics of a cesium chloride heat substrate revealing its dual utility for microwave beating and x-ray imaging.

DETAILED DESCRIPTION

[0022] The invention may be viewed as an advance in image-guided thermal ablation (IGTA), a conventional treatment which uses needle-like applicators to deliver energy into tumors and cause instantaneous cell death. Aspects of the invention also promise improved ablation or heating characteristics for treating tumors or isolated metastatic tissue portions that have been targeted with imageable theranostic preparations, such as image enhancement preparations containing mAB-targeted ferritin nanoparticles as described in the aforementioned International Application WO 2014/031727 and technical papers referenced therein. Some embodiments involve heat-mediated release of a treatment agent. A central discovery behind the improved tissue ablation procedures and materials described herein is the realization that iron-loaded imaging agents and theranostic preparations such as the aforesaid ferritin or iron oxide preparations arc efficient absorbers of microwave radiation, and may be employed for, or further enhanced for carrying out, processes of microwave hyperthermal ablation, localized fixation and drug delivery, and also enhanced imaging of treatment processes.

[0023] FIG. 1 illustrates microwave heating and heat transfer characteristics of several iron-based formulations, as well as the non-iron material cesium chloride which is identified herein as an effective and useful microwave-absorbing heat substrate, and polymer formulations.

Microwave heating was carried out using a 15 watt 0.915 gigaherz microwave source directed at a vial of each preparation, and the resulting temperature rise was plotted over the course of approximately six minutes. Increasing concentrations of cesium chloride in water resulted in increased heating; similar microwave heating characteristics are expected for cesium iodide.

[0024] FIG. 2 is a Table summarizing the effective heating and endpoints achieved with various concentrations of the indicated materials in small sample vials located in a beaker of soft agar. The beaker provides a consistent external temperature surround so as to closely model expected heat transfer and temperature increase profiles that would be expected in the body under the applied levels of microwave heating. The microwave energy was 15 W for all but the first sample, for which various power levels were applied to assess heating of a plain water control, and for all samples was a 915 MHz microwave signal, which was applied with a coaxial dipole antenna of construction similar to that used for clinical therapy, e.g., a needle-like microwave applicator. Ferritin, the iron oxide formulation Ferumoxytol and polymer each displayed useful microwave heating characteristics, and cesium chloride solutions achieved higher temperature increases, while cesium chloride in polymer resulted in such a fast temperature rise that it needed to be shut off before an explosion could occur. These tests established that the iron-based agents, in addition to the polymer, possessed suitable microwave absorption characteristics, so that the imaging agents could also be used for microwave hyperthermal ablation of the imaged tissue. The tests also established that addition of cesium chloride in suitable concentrations would enhance the ablation efficacy.

[0025] It was further determined that CsCl in relevant concentrations is itself readily imaged in CT devices. Small vials of distilled water and of various concentrations of CsCl were placed in a jig as shown in FIG. 3A and imaged with a GE Optima 580 W CT scanner, using a brain CT protocol: 120 kV, 50 mA, 0.8 second rotation, 0.562 pitch and 16x.625 detector configuration. The radiation output (CTDIvol) was 12.08 mGy, Dose Length Product was 193.88 mGy-cm. The images were evaluated to determine the radiodensity in Hounsfield units. FIGS. 3B and 3C display the radiographic images and the radiodensities, establishing that a range of salt concentrations are suitable for x-ray imaging. Thus cesium chloride (as well as cesium iodide) can be both an effective microwave heat substrate as well as an x-ray CT contrast agent.

[0026] Thus for the methods claimed herein, the cesium salt may be imaged by CT, and heated by microwave energy, and the iron-based heat substrate materials may be imaged by MRI or other means, and heated by applying electromagnetic or microwave energy. These properties advantageously are applied herein to provide enhanced imaging and treatment protocols.

[0027] FIGS. 3A-3C thus illustrate effective CT imaging of various concentrations of CsCl solution, demonstrating suitability of this material for the heat substrate compositions and image-guided thermal ablation methods described herein.

[0028] Image guided thermal ablation (IGTA) is a safe, low-cost, minimally invasive method that can treat numerous tumor types, and is often an alternative to surgical resection. However, while IGTA is effective for local treatment and palliation of symptoms, high treatment variability may be expected when targeting heterogeneous tissue and tumor types, and raises concerns. The present invention instead uses a drug-device combination to improve local control such as localization and effectiveness of heating and, in some embodiments, more effective or precise delivery to a tumor site, so as to improve patient outcomes and broaden the utility of such directed thermal therapy. Specifically, rather than the conventional use of ultrasound to position a microwave ablation antenna, the heat substrates and imaging agents described herein further enable CT imaging of percutaneous microwave ablation procedures and enhanced hyperthermic response of the identified tissue sites.

[0029] One further aspect of the invention may utilize the local tissue heating effects of electromagnetic or microwave treatments by reducing blood flow, by means of arterial blockade in the treated or thermally-communicating/proximate tissue. Blockade may be effectively achieved in a thermal ablation methodology that employs a polymer and a heat substrate. The term heat substrate herein refers to a material that may be heated in situ by an applied field, such as an alternating magnet field of suitable strength and frequency, or such as a microwave field (which may be applied with a conventional microwave ablation setup or hand piece—e.g, a needle-like antenna).

[0030] As described above, these heat substrates may include iron oxide-nanoparticle material (Fe.sub.3O.sub.4-Np, e.g., ferumoxytol or an engineered ferritin.) which in certain embodiments may be presented in an imaging enhancement agent and/or a treatment agent. Heat substrates may alternatively include other materials that have high efficiency for absorbing the applied energy, e.g., microwave or electromagnetic radiofrequency field, and generating heat. As described above, cesium chloride has been found to substantially accelerate heating under low (15 W) applied microwave power, and also to provide CT contrast, and is thus another suitable heat substrate that provides imageability as well as improved heating during microwave ablation.

[0031] In addition to augmentation by blockade, local tissue heating effects may in some embodiments also be achieved by placing polymer/ferumoxytol or engineered ferritin nanoparticles into tumors percutaneously, intraductally, or intravenously with specific antibody-targeted delivery. Further enhancements are achieved by combining these heat substrate components with a biodegradable reverse-phase transition polymer, to operate as an embolization medium or a local fixation/delivery mechanism. Once injected, the solution becomes gel-like and heats via a non-invasive, extracorporeal, or interstitial applied energy field. The methodology targets an exact ablation volume and provides a controllable, uniform ablation temperature. Unlike chemotherapy, which can diffuse from the injection site, the heat substrate/polymer localizes to the site. The iron oxide/gel combination, or CsCl/gel also acts as an imaging or contrast agent, allowing for image-guided delivery and verification of the volume occupied by the gel, and these are expected to be highly cost effective and safer than prior treatment protocols not involving blockade because components are metabolized within weeks.

[0032] Several points of innovation merit specific mention. First, the combination of heat substrate and polymer creates a suspension where the applied external electromagnetic field or percutaneous microwave field heats the material uniformly. Second, the biphasic polymer becomes gelatinous at body temperature and localizes at the injection point. Third, the polymer may be one that solidifies and expels liquid at temperatures consistent with ablation procedures. Fourth, the polymer/heat substrate combination is viewable under magnetic resonance imaging or CT imaging so localization can be verified prior to electromagnetic or microwave excitation. Finally, the polymer with appropriate characteristics may be one such as a block-co-polymer consisting of polyethylene glycol, which is covalently esterified by an FDA-approved poly lactic-co-glycolic acid on both ends. For ferumoxytol as the iron-based heat substrate, a standard dose is two intravenous administrations of 510 mg (Fe content) over eight days. For this application, ferumoxytol (5-10 mg, Fe content), currently used to treat iron deficiency anemia in adult patients with chronic kidney disease, may be dissolved in the polymer solution (<100 μL) per tumor volume (<1 cm.sup.3), which is 50 to 100 times less than a clinical dose. The heat substrate being trapped in a gel that slowly releases the iron oxide, mitigates or effectively reduces the risk of arty significant toxicity, thus providing low-dose but highly effective treatment.

[0033] The improved tissue imaging and localized tissue heating of the invention should provide better treatment for hepatocellular and other carcinomas. Hepatocellular carcinoma is the fifth most common malignancy worldwide. In addition, the liver is the most common metastatic site of colorectal cancer: the second most common cause of cancer-related deaths in the United States. Current liver-directed therapies have been largely applied as palliative measures—some at high cost—with high recurrence rates. If hepatic disease burden were to be lessened by this less toxic and more cost-effective means, patient costs should be reduced substantially. Thus, Fe.sub.3O.sub.4-Np block co-polymer, or CsCl reverse phase change polymer blockade by image-guided delivery, both have great treatment potential in this large group of patients.

[0034] Methods of the invention employ an electromagnetic (EM) field or microwave source as the energy source and a combination of ferumoxytol (Fe.sub.3O.sub.4-Np) or CsCl, and a biodegradable reverse-phase transition polymer solution as a heat substrate for blockade. The polymer solution is a liquid at ambient temperature, but a gel at typical body temperature (35 to 37 degrees Celsius). Upon a further increase in temperature, the polymer precipitates by expelling water molecules from the polymeric lattice structure while nanoparticles are still trapped.

[0035] This expulsion effect is advantageously utilized in an embodiment of the invention as a mechanism for delivering a therapy agent from the fixed polymer/heat substrate body. The Fe.sub.3O.sub.4-nanoparticles (Nps) are coated with a poly-carbohydrate molecule (a cross-linked dextran with non-reducing end, decomposition temperature less than 240 degrees Celsius) so as to be hydrophilic and, thus, miscible with the aqueous polymer solution. The homogeneous distribution of Fe.sub.3O.sub.4-Np in the polymer solution permits uniform heating within the target ablation volume. With image-guidance like CT or MRI, the desired solution volume with a known Fe.sub.3O.sub.4-Np (or CsCl) concentration is deposited in and around the tumor or other tissue target. Subsequently, the injected polymer containing Fe.sub.3O.sub.4-Np or CsCl turns into a gel of predetermined ablation shape and volume. Fe.sub.3O.sub.4-Np in the gel may then be heated by a non-invasive EM field produced by an inductive EM generator, or interstitial microwave energy may be applied to heat the CsCl substrate. The temperature is controlled and ablation optimized by varying several parameters: duration (minutes), electric current (A), power (kW), and frequency (kHz), the iron and cesium concentration (mM), and ablation volume (cm.sup.3). The exact iron and cesium concentration of the intra-arterial and directly injected compound, along with the EM field and MW parameters to optimize the efficacy of tumor heating, may be determined by routine experimental assay, calibration and adjustment before application to patients in vivo.

[0036] Historically, transcatheter arterial chemoembolization (TACE) and thermal ablation procedures have been most widely applied to hepatocellular carcinoma patients who are not eligible for surgery. Initial implementation and evaluation of the methodology described herein may be carried out and efficacy confirmed with TACE, microwave ablation (MWA), and direct intra-tumoral injection using an animal model, such as rabbit VX2 liver tumor model. A dose escalation study can identify the optimal iron concentration in the Fe.sub.3O.sub.4/polymer solution for intrarterial and direct injection and the optimal power and time settings of electromagnetic activation (EMA). After iron concentration and EMA parameter optimization, live animal studies may be undertaken along the route to evaluate and qualify the method for clinical use. For animal studies, a 3T MRI imaging unit can be used to monitor the distribution of the Fe.sub.3O.sub.4-Np/polymer solution as well as treatment effects within the liver and liver tumors. Histopathologic analyses including viability staining would preferably also performed to assess vascular thrombosis, necrosis, and tumor viability.

[0037] As described herein the thermal substrate properties of engineered ferritin and other iron-based nanoparticle agents, and the demonstrated characteristics of ordinary CsCl as a thermal substrate together with its imageabiliy by several common healthcare imaging systems, amply support the efficacy of the improved, low-cost and safe treatment methods and image-based diagnostic methods, as well as new useful compositions for carrying out the methods described herein. In addition, simple screening methods may quickly identify additional inorganic salts or small molecules with suitable properties to form heat substrate materials with enhanced safety and heating characteristics. Reference is made to the U.S. provisional patent application of which priority is claimed and the appendices thereto, as well as the above mentioned international patent application WO 2014/031727, as well as to various technical papers useful for understanding or preparation of photothermal and reverse phase gel or polymer preparations, including the following papers: Ninh, C., Cramer, M., Bettinger C J., (2014). Photoresponsive hydrogel networks using melanin nanoparticle photothermal sensitizers. Biomater. Sci., 2, 766-774; Brown D B, Geschwind J F, Soulen M C, Millward S F, Sacks D (2006). “Society of Interventional Radiology position statement on chemoembolization of hepatic malignancies”. J Vasc Interv Radiol 17(2): 217-23; M. Ginsburg, T. Doshi, A. Miller, T. Robbins, R. Kunnavakkam, L. H. Kang, T. VanHa. (2013). Comparison between transarterial chemoembolization in combination with radiofrequency ablation versus microwave ablation in the management of hepatocellular carcinoma. J Vasc Interv Radiol, 24(4) S43-44; Qian T, Chen M, Gao F, Meng F, Gao X, Yin H. (2014). Diffusion-weighted magnetic resonance imaging to evaluate microvascular density after transarterial embolization ablation in a rabbit VX2 liver tumor model. Magn Reson Imaging. 32(8);1052-7; Duan X, Zhou G, Zheng C, Liang H, Liang B, Song S, Peng G. (2014). Heat shock protein 70 expression and effect of combined transcatheter arterial embolization and radiofrequency ablation in the rabbit VX2 liver tumour model. Clin Radiol. 69(2):186-93; and Mostafa E M, Ganguli S, Faintuch S, Mertyna P, Goldberg S N. (2008). Optimal strategies for combining transcatheter arterial chemoembolization and radiofrequency ablation in rabbit VX2 hepatic tumors. J Vasc Interv Radiol. 19(12):1740-8. The foregoing documents and papers are all hereby incorporated herein by reference.

[0038] The invention being thus described, variations, and modifications thereof will occur to those of ordinary skill in the art, and all such variations and modifications are considered to be within the scope of the invention and the claims appended hereto.