MIXTURE OF LAFESIH MAGNETIC NANOPARTICLES WITH DIFFERENT CURIE TEMPERATURES TO IMPROVE INDUCTIVE HEATING EFFICIENCY FOR HYPERTHERMIA THERAPY

Description

Field of the invention

[0001] The present invention concerns an injectable formulation for treatment of selected cells by alternating magnetic field induced hyperthermia, said injectable formulation comprising a liquid carrier and two or more populations of heat-generating nanoparticles. Said injectable formulation may be introduced into the vascular circulation, may be introduced directly into tissue to be heated, or may be contained within a microcatheter for insertion in proximity with tissue to be heated.

Background of the invention

[0002] Proliferative diseases, such as for example, cancer, represent a tremendous burden to the health-care system. Cancer, which is typically characterized by the uncontrolled division of a population of cells frequently results in the formation of a solid or semi-solid tumor, as well as subsequent metastases to one or more sites. In addition to surgery, conventional methods of cancer treatment include radiotherapy, which operates to effectuate physical damage to malignant cells so as to render them incapable of cell division, and/or chemotherapy, which generally involves systemically administering cytotoxic chemotherapeutic drugs that alter the normal structure, function or replication of DNA.

[0003] However, a problem with these approaches is that radiation in the case of radiotherapy, and chemotherapeutic drugs in the case of chemotherapy, are also toxic to normal tissues, and often create life-threatening side effects.

[0004] A very promising therapeutic approach which may be applied either alone or in combination with radiotherapy and/or chemotherapy in the treatment of cancer is hyperthermia, as indicated by recent clinical trials (M. H. FaIk, R.D. Issel, "Hyperthermia in oncology", Int. J. Hyperthermia 17 : 1-18 (2001); P. Wust, B. Hildebrandt, G. Sreenivasa, B. Rau, J. Gellermann, H. Riess, R. Felix.

[0005] P. Schlag, "Hyperthermia in combined treatment of cancer", The Lancet Oncology, 3 : 487-497 (2002); A. Jordan, T. Rheinlander, et al. "Increase of the specific absorption rate (SAR) by magnetic fractionation of magnetic fluids", Journal of Nanoparticle Research 5 (5-6) : 597-600 (2003); A. Jordan, W. Schmidt et al., "A new model of thermal inactivation and its application to clonogenic survival data for human colonic adenocarcinoma cells", Radiation Research 154(5) : 600-607 (2000); A. Jordan, R Schlolz, et al., "Presentation of a new magnetic field therapy system for the treatment of human solid tumors with magnetic fluid hyperthermia", Journal of Magnetism and Magnetic Materials 225(1-2) : 118-126 (2001).

[0006] Hyperthermia may be defined as a therapeutic procedure used to increase temperature of organs or tissues affected by cancer between 41 to 46 °C in order to induce apoptosis of cancer cells.

[0007] Hyperthermia, when used in combination with radiotherapy, is known to enhance radiation injury of tumor cells, and when used in combination with chemotherapy, is known to enhance chemotherapeutic efficacy.

[0008] Further, even mildly elevated temperatures are known to significantly potentiate the effects of radiotherapy and chemotherapy.

[0009] Such combinations of treatment modalities could result in lower doses of chemotherapeutic agents or radioactivity necessary to achieve a given effect, thus resulting in less toxicity.

[0010] Therefore, using hyperthermia should be considered as an advantageous treatment modality allowing to reduce life-threatening side effects caused by radiotherapy and chemotherapy.

[0011] Amongst the various techniques proposed for achieving the required temperature increase, it may be cited for example those reported in details by P. Wust, B. Hildebrandt, G. Sreenivasa, B. Rau, J. Gellermann, H. Riess, R. Felix, P. Schlag, "Hyperthermia in combined treatment of cancer" in The Lancet Oncology, 3 : 487-497 (2002) and by P. Moroz, S. K. Jones and Bruce N. Gray, "Status of Hyperthermia in the Treatment of Advanced Liver Cancer", in J. Surg. Oncol. 77 : 259-269 (2001).

[0012] However, these various techniques used so far to induce hyperthermia still suffer from significant limitations, the most important of which being a poor control of the heat delivered to the tumor, a poor control of the intratumoral space filling, and a poor control of the precise localization of the hyperthermic effect.

[0013] Therefore, providing a hyperthermia technique to reach a controlled temperature at moderate temperatures in a defined tumor target site is a technical challenge still under development.

[0014] Some methods for inducing a localized and targeted hyperthermia by using heat-generating nanoparticles have been proposed.

[0015] WO 01-58458 proposes a method for inducing a localized and targeted hyperthermia in a cell or tissue by delivering nanoparticles of the nanoshell type having a discrete dielectric or semiconducting core section of silica doped with rare earth emitter, or gold sulfide, surrounded by a metal conducting shell layer of gold, to said cell or tissue and exposing said nanoparticles to electromagnetic radiation under conditions wherein said nanoparticles emit heat upon exposure to said electromagnetic radiation. The core and the shell constituting the nanoparticle may be linked by using biodegradable materials such as a polyhydroxy acid polymer which degrades hydrolytically in the body, in order to facilitate the removal of the particles after a period of time.

[0016] WO 03-055469 discloses a method for inducing a localized and targeted hyperthermia by incorporating into tumor cells, through ionic targeting, nanoparticles of the shell type, having a superparamagnetic core containing iron oxide and at least two shells surrounding said core, more particularly a cationic inner shell and an anionic outer shell, and exposing said nanoparticles to electromagnetic radiation under conditions wherein said nanoparticles emit heat upon exposure to said electromagnetic radiation.

[0017] U.S. Patent No. 6,514,481 proposes the so-called "nanoclinics" that consist in iron oxide nanoparticles in a silica shell and surrounded by a targeting agent, and optionally containing a tracking dye. Application of a constant magnetic field is thought to destroy targeted cells through a magnetically induced lysis - in contrast to the heat generation obtained under an alternative magnetic field.

[0018] U.S. Patent No. 6,541,039 by A. Jordan and coworkers also proposes iron oxide particles, embedded in at least two shells. The outer shell having neutral and/or anionic groups allows an appropriate distribution into the tumoral tissue. The inner shell displays cationic groups to promote adsorption/absorption by the cells. The nanoparticles are injected as a suspension ("magnetic fluid") and subsequently exposed to an alternative magnetic field for hyperthermic treatment.

[0019] However, these methods do not allow the tissue to reach a controlled temperature at moderate temperatures in a defined target volume and to repeat the heating procedure in the defined target volume without repeated administration of the formulation containing nanoparticles.

[0020] JP 10-328314 discloses a shaped material implant which is invasively implanted in a bone for hyperthermia treatment, said shaped material implant comprising an alumina powder, magnetite powder having a diameter over 50 nm which is capable of generating heat in an alternating magnetic field, and a polymerized methacrylate monomer.

[0021] U.S. Patent No. 7,918,883 discloses a magnetically heated article which employs an externally applied high frequency magnetic field in conjunction with two grades of magnetically susceptible nanomaterials having different Curie temperatures (Tci, T_C2) to limit the upper temperatures to which the article will be heated upon application of an alternating magnetic field. The Curie temperature (Tc), or Curie point, is the temperature at which a ferromagnetic or a ferrimagnetic material becomes paramagnetic on heating; the effect is reversible. Upon subjecting the nanoparticles to an alternating magnetic field, self-limiting induction heating occurs as a result of magnetic hysteresis losses which ceases when the temperature of the nanoparticles reach their respective Curie temperatures.

[0022] In a disclosed application, a self-expanding Nitinol stent is heated to effect either one-way or two-way shape memory changes in the stent configuration. In an alternate application, heating to the first Curie temperature is employed to effect a one-way shape memory expansion and when the stent has deployed, further heating to the second Curie temperature is used to deliver a therapeutic agent through thermal release from a carrier. In a further alternate application, a material having an appropriate Curie temperature may be used to achieve local temperatures sufficient to inhibit restenosis by heating the cells proximate the stent to induce cell apoptosis; however the stent does not continue to heat beyond the Curie temperature which might otherwise damage the wall of vessel. In this application, the stent may be periodically reheated in situ to inhibit recurring restenosis without invasive treatment.

[0023] Barati et al. ("Extraordinary induction heating effect near the first order Curie transition", Appl. Physics Letters 105,162412 (2014)) discloses a material having the composition LaFe_11.57Si_1.43H_1.75 and a Tc of 319 K (45.85 °C), which is in the range (315 to 319 K) appropriate for hyperthermia treatment of cancerous cells. Barati further discloses that the Curie temperature may be tuned between 204 K and 350 K by altering the degree of hydrogen incorporation. In addition, Barati discloses that the family of compositions undergoes a dramatic increase in hysteresis loss near Tc which has been attributed to phase coexistence in which the ferromagnetic phase is induced by a magnetic field in a matrix of the paramagnetic phase resulting in an enhanced loss power from 10 ± 0.6 kJm^-3 at 315 K to 80 ± 5.7 kJm^-3 at 317.7 K. Their analysis showed that the energy loss of the LaFe_11.57Si_1.43H_1.75 compound is highly dependent on the temperature and the expected power loss is maximized just below Tc followed by immediate attenuation of the heating effect at Tc. A similar increase in the induction heating effect immediately below Tc is expected for rotational relaxation processes in magnetic fluids. Similarly, WO 2015/089579 A1 discloses La(Fe,Si)₁₃H_y, wherein y is between 1.7 to 1.8.

[0024] The Specific Absorption Rate (SAR) is a useful comparative measure of the rate at which power is absorbed per mass in these processes and usually has units of watts per kilogram (W/kg) when applied to absorption of a radio frequency (RF) electromagnetic field by the human body. SAR varies as a function of frequency (kHz) and the magnetic field intensity (H). The SAR for LaFe_11.57Si_1.43H_1.75 has been reported as 522 W/g at 279 kHz and 8.8 kA/m, while more conventional materials such FeO have been reported to exhibit a SAR of 15 (ferromagnetic) to 89 (superparamagnetic) W/g under those conditions. Similarly high SAR values are expected for LaFe_11.57Si_1.43H_x over the range 0 < x ≤ 2.27.

[0025] While the high SAR and appropriate Tc of the LaFe_11.57Si_1.43H_x materials make them attractive as agents for magnetic field induced hyperthermia treatment of selected cells, the narrow temperature range (~ 3 °C) associated with the observed SAR enhancement and the need to raise core tissue temperatures by about 4 to 8 °C requires a combination of longer exposure times, higher fields, and/or higher frequencies than would otherwise be desirable.

Summary

[0026] In some aspects, the invention relates to an injectable formulation for alternating magnetic field induced hyperthermia treatment of selected cells comprising a liquid carrier and two or more populations of nanoparticles, wherein each population of nanoparticles has a mean Curie temperature in the range 37 to 47 °C and wherein the mean Curie temperature of each population of the two or more populations of nanoparticles differs from the mean Curie temperature of each of the remaining populations of nanoparticles by at least 2 °C.

[0027] In addition or alternatively, the invention relates to an injectable formulation wherein the two or more populations of nanoparticles have compositions corresponding to LaFe_11.57Si_1.43H_x where 0 < x ≤ 2.27.

[0028] The injectable formulations include a first population of nanoparticles which has a mean Curie temperature in the range 37 to 40 °C and a second population of nanoparticles has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the first population of nanoparticles and 3 °C greater than mean Curie temperature of the first population of nanoparticles.

[0029] In some aspects, the injectable formulation may further comprise a third population of nanoparticles which has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the second population of nanoparticles and 3 °C greater than mean Curie temperature of the second population of nanoparticles.

[0030] In addition, the injectable formulation may further comprising a fourth population of nanoparticles which has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the third population of nanoparticles and 3 °C greater than mean Curie temperature of the third population of nanoparticles; a fifth population of nanoparticles which has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the fourth population of nanoparticles and 3 °C greater than mean Curie temperature of the fourth population of nanoparticles; and in some aspects may further comprise a sixth population of nanoparticles which has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the fifth population of nanoparticles and 3 °C greater than mean Curie temperature of the fifth population of nanoparticles.

[0031] In addition, the liquid carrier of injectable formulation may be selected from the group consisting of water, saline, dimethyl sulfoxide, ethanol, aqueous solutions of acetic acid, pyrrolidones, glycerol, and propylene glycol.

[0032] In another aspect, the liquid carrier of the injectable formulation may further comprises an in situ polymerizing component. In addition or alternatively, the liquid carrier of the injectable formulation may further comprise an in situ cross-linking component and/or a precipitating polymer component.

[0033] In some aspects, at least one of the two or more populations of nanoparticles may include an attached therapeutic agent which may include an anti-tumor agent.

[0034] In some aspects, an injectable formulation for magnetic field induced hyperthermia treatment of selected cells may comprise a liquid carrier and two or more populations of nanoparticles, wherein each population of nanoparticles has a mean Curie temperature in the range 37 to 47 °C and wherein the mean Curie temperature of each population of the two or more populations of nanoparticles differs from the mean Curie temperature of each of the remaining populations of nanoparticles by at least 2 °C such that each of the populations of nanoparticles exhibits a region of enhanced specific absorption rate within 3 °C of the respective mean Curie temperatures of the population of nanoparticles.

[0035] In such aspects, the regions of enhanced specific absorption rate of each population of nanoparticles may overlap at least one region of enhanced specific absorption rate of another population of nanoparticles and the aggregate regions of enhanced specific absorption rate may continuously span a temperature range of 5 to 10 °C.

[0036] In addition or in the alternative, the aggregate regions of enhanced specific absorption rate may continuously span a temperature range of 37 to 47 °C. In the alternative, the aggregate regions of enhanced specific absorption rate may continuously span a temperature range of 37 to 41 °C.

[0037] In some aspects, the injectable formulation may comprise two or more populations of nanoparticles have compositions corresponding to LaFe_11.57Si_1.43H_x where 0 < x ≤ 2.27.

[0038] In certain aspects, the liquid carrier of the injectable formulation may selected from the group consisting of water, saline, dimethyl sulfoxide, ethanol, aqueous solutions of acetic acid, pyrrolidones, glycerol, and propylene glycol. In addition or alternatively, the liquid carrier may further comprise an in situ polymerizing component, an in situ cross-linking component, and/or a precipitating polymer component.

[0039] In certain aspects, the at least one of the two or more populations of nanoparticles may include an attached therapeutic agent which may be an anti-tumor agent.

[0040] In another aspect, the invention relates to a method of heating selected cells to magnetically induce hyperthermia comprising positioning two or more populations of nanoparticles in proximity to the selected cells to be heated, wherein each population of nanoparticles has a mean Curie temperature in the range 37 to 47 °C and wherein the mean Curie temperature of each population of the two or more populations of nanoparticles differs from the mean Curie temperature of each of the remaining populations of nanoparticles by at least 2 °C and subjecting the two or more populations of nanoparticles to an alternating magnetic field, thereby causing the two or more populations of nanoparticles to generate heat locally whereupon the selected cells experience hyperthermia. In some aspects, the alternating magnetic field results in a specific absorption rate within the selected cells of no more than 2 W/kg.

[0041] In certain additional aspects local heating of at least one of the two or more populations of nanoparticles releases a therapeutic agent which may be an anti-tumor agent.

[0042] In some aspects, the positioning step is accomplished by direct injection of the at least two populations of nanoparticles into the vicinity of the selected cells to be heated while in the alternative or in addition, the positioning step is accomplished by containing the at least two populations of nanoparticles within a microcatheter and positioning the contained at least two populations of nanoparticles in the vicinity of the selected cells to be heated, and/or the positioning step may be accomplished by injecting the at least two populations of nanoparticles within a body to be heated and subsequently concentrating the at least two populations of nanoparticles in the vicinity of the selected cells to be heated by application of a magnetic field.

Brief Description of Drawings

[0043] 

Figure 1 illustrates the narrow range of temperatures for which an enhanced induction heating effect has been reported by Baratti et al. for LaFe11.57Si1.43H1.75 ("Extraordinary induction heating effect near the first order Curie Transition", Applied Physics Letters 105 162412 (2014); 279 kHz and 8.8 kA/m.)

Figure 2 somewhat schematically illustrates one aspect of the invention.

Figure 3 somewhat schematically illustrates an alternate aspect of the invention.

Figure 4 somewhat schematically illustrates another aspect of the invention.

Figure 5 illustrates simulated heating profiles for nanoparticle populations.

Figure 6 illustrates an injectable dispersion of nanoparticles.

Figure 7 illustrates schematically a nanoparticle of the invention which includes an attached therapeutic agent.

Detailed Description

[0044] The following description should be read with reference to the drawings wherein like reference numerals indicate like elements throughout the several views. The drawings, which are not necessarily to scale, are not intended to limit the scope of the claimed invention. The detailed description and drawings illustrate example embodiments of the claimed invention.

[0045] Although some suitable dimensions, ranges and/or values pertaining to various components, features and/or specifications are disclosed, one of skill in the art, incited by the present disclosure, would understand desired dimensions, ranges and/or values may deviate from those expressly disclosed unless the context clearly indicates an intended limitation.

[0046] All numbers are herein assumed to be modified by the term "about." The recitation of numerical ranges by endpoints includes all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

[0047] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include the plural referents unless the content clearly dictates otherwise. As used in this specification and the appended claims, the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.

[0048] It is noted that references in the specification to "an aspect", "some aspects", "other aspects", etc., indicate that the aspect described may include a particular feature, structure, or characteristic, but every aspect may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same aspect. Further, when a particular feature, structure, or characteristic is described in connection with an aspect, it would be within the knowledge of one skilled in the art to effect such feature, structure, or characteristic in connection with other aspects, whether or not explicitly described, unless clearly stated to the contrary.

[0049] Within this specification and the appended claims, it will be understood that a reference to a Curie temperature of a population is understood to encompass variation within a population of nanoparticles such that the intent is to refer to the mean Curie temperature of the population if that qualifier is omitted.

[0050] Fig. 1 illustrates the change in static hysteresis loss as a function of temperature for a population of LaFe_11.57Si_1.43H_x nanoparticles reported by Barati et al. ("Extraordinary induction heating effect near the first order Curie transition", Appl. Physics Letters 105,162412 (2014)) at 279 kHz and 8.8 kA/m which illustrates both the narrow temperature range over which the enhanced induction heating effect has been observed and the abrupt cessation of hysteresis loss heating at the Tc of the sample tested.

[0051] While the high SAR and appropriate Tc of the LaFe_11.57Si_1.43H_x materials make them attractive as agents for magnetic field induced hyperthermia treatment of selected cells, the narrow temperature range (~ 3 °C) associated with the observed SAR enhancement as well as the need to raise tissue temperatures to about 4 to 8 °C above adjacent, often core, body temperature, the requires a combination of longer exposure times, higher fields, and/or higher frequencies than would otherwise be desirable in treating a subject; however this difficulty may be overcome by employing two or more populations of injectable nanoparticles, which populations differ with regard to their Tcs such that the narrow temperature ranges associated with the observed SAR enhancements below those Tcs overlap and at least collectively span the temperature range between a core body temperature, nominally 37 °C, and the desired hyperthermia temperature, typically either 41 to 45 °C or 41 to 47 °C.

[0052] In contrast to more conventional hyperthermic treatment techniques using invasive probes that may result in local overheating inducing thermoablation and subsequent tissue necrosis, the hyperthermic implantable formulations developed by the present inventors are expected to deliver a rapid and self-limiting local heating with typical temperature increases in the range of 5 °C to 10 °C. In some aspects, the available range of temperature increases may be even greater.

[0053] The use of a plurality of nanoparticle populations each having a different mean Curie point temperature and an enhanced SAR in the thermal region immediately below the mean Curie point temperature of the population is expected to result in rapid heating at relatively low magnetic field intensities such that the enhanced SAR exhibited by a first population of nanoparticles having a mean Curie temperature slightly above the ambient temperature of the selected cells to be heated will, upon excitation by an alternating magnetic field, heat the selected cells and the remaining populations of nanoparticles to the Curie temperature of the first population of nanoparticle, whereupon the induced heating of that first population of nanoparticles will cease as they reach their Curie temperature.

[0054] By selecting the mean Curie temperature of a second population of nanoparticles such that the enhanced SAR region immediately below the mean Curie temperature of the second population overlaps the mean Curie temperature of the first population of nanoparticles, it is possible to begin to excite the enhanced SAR region of the second population as the first population of nanoparticles becomes insensitive to further excitation by virtue of having reached its Curie temperature. The selection process may be extended to the inclusion of a third, fourth, fifth, sixth or more populations of nanoparticles as necessary to reach the desired treatment temperature. By employing a succession of populations of nanoparticles, each of which is within its enhanced SAR region as the temperature of the tissue to be heated is increased, it is expected that the overall time to reach an effective hyperthermia temperature may be decreased because heat generation will be enhanced at all temperatures up to the desired treatment temperature and yet the heating process will be self-limiting by the Curie temperature of the final population of nanoparticles to be activated as the temperature thus effectively preventing over heating.

[0055] For example, if the region of enhanced SAR for a first population of nanoparticles has a temperature range of ~ 3 °C, such as that of the LaFe_11.57Si_1.43H_x materials described herein, and the selected cells to be heated have an initial temperature of 37 °C, a first population of nanoparticles having a Curie temperature of 40 °C is expected to be efficiently heated by an appropriate alternating magnetic field to a temperature of 40 °C thereby raising the temperature of the selected cells and any remaining populations of nanoparticles to that temperature. When a second population of nanoparticles having a Curie temperature of 43 °C is also present with the selected cells at 40 °C, the second population of nanoparticles is expected to be efficiently heated by an appropriate alternating magnetic field to a temperature of 43 °C thereby raising the temperature of the selected cells and any remaining populations of nanoparticles to that temperature. When a third population of nanoparticles having a Curie temperature of 45 °C is also present with the selected cells at 43 °C, the third population of nanoparticles is expected to be efficiently heated by an appropriate alternating magnetic field to a temperature of 45 °C thereby raising the temperature of the selected cells and any remaining populations of nanoparticles to that temperature, thereby inducing apoptosis within the selected cells to be heated. This successive overlap of three populations of nanoparticles, each exhibiting the enhanced SAR effect immediately below the Tc of the respective population, is illustrated somewhat schematically in Fig. 2 in which three populations of nanoparticles may be used to increase the temperature of a tissue environment from an initial temperature T_i to a final temperature T_f as the successive populations are heated by an applied alternating magnetic field having an appropriate frequency and magnetic field strength.

[0056] One of ordinary skill in the art would appreciate that the foregoing description is representative and not intended to be limiting. For example, it would be understood that the first population of nanoparticles may have a Curie temperature of 39.5 °C; a second population of nanoparticles may have a Curie temperature of 42 °C; a third population of nanoparticles may have a Curie temperature of 44.5 °C; and a fourth population of nanoparticles may have a Curie temperature of 47 °C if desired. Other combinations of populations of nanoparticles may be selected to span a desired temperature increase if the temperature range of the region of enhanced SAR is other than 3 °C. In general, it is believed desirable to employ a minimal number of nanoparticle populations to span a given desired temperature increase in order to minimize the total mass of nanoparticles necessary to achieve the desired final temperature.

[0057] If, for example, the initial temperature of tissue to be heated by this method, is different from 37 °C or a higher final temperature is desirable, a larger number of nanoparticle populations may be employed, such that a temperature increase of 12 °C is desirable, the result may be accomplished by employing six populations of nanoparticles, each of which is responsible for increasing the temperature of the tissue by approximately 2 °C. This successive overlap of six populations of nanoparticles, each exhibiting the enhanced SAR effect immediately below the Tc of the respective population, is illustrated somewhat schematically in Fig. 3 in which six populations of nanoparticles (100A to 100F) may be used to increase the temperature of a tissue environment from an initial temperature T_i to a final temperature T_f as the successive populations are heated by an applied alternating magnetic field having an appropriate frequency and magnetic field strength.

[0058] In addition to, or instead of, varying the number of populations employed, as in the examples given above, it is believed that different heating profiles may usefully be achieved by varying the ratios of the masses of the populations of nanoparticles. As an example, an initial temperature increase is accomplished by two smaller populations, 200A and 200B to attain a temperature above the initial or core tissue temperature, but below the temperature expected to result in significant apoptosis, followed by a larger population 200C which is expected to raise the tissue temperature more rapidly to a final temperature which will produce the desired apoptosis as illustrated somewhat schematically in Fig. 4. It will be appreciated that other combinations of unequal particle populations may be employed to achieve different heating profiles.

[0059] In some aspects, similar effects may be achieved by employing non-uniform spacing of the Tcs of the populations of nanoparticles such that the number of nanoparticles which are subject to excitation with an enhanced SAR varies with temperature.

[0060] Figure 5, illustrates comparisons of numerical simulations of expected temperature increases in which a single superparamagnetic nanoparticle population (1) is heated; in which enhanced SAR nanoparticle population heating has been modeled (2) using published data; in which the SAR of a population of LaFe_11.57Si_1.43H_x nanoparticles having a 46 °C Curie temperature has been modeled (3); and in which the SAR of three combined populations of LaFe_11.57Si_1.43H_x nanoparticles having Tcs of 40, 43, and 46 °C have been modeled (4).

[0061] Positioning of the nanoparticle populations described may be accomplished by methods known in the art, for example, the nanoparticles 20 may be dispersed in a liquid carrier 10, as shown in Fig. 6 for delivery by direct injection, by injection of targetable particles into the general circulation, or by introduction within a microcatheter positioned adjacent to the tissue to be heated. In some aspects, the carrier 10 may be selected to precipitate, gel, polymerize, and/or be cross-linked once injected into the tissue.

[0062] In some aspects, at least a portion of the particles 20A may include an attached therapeutic agent 25, as illustrated in Figure 7, which in some aspects may be an anti-tumor agent. In such aspects, the carrier 10 may include compounds which enhance the activity of the anti-tumor agent.

[0063] Although the illustrative examples described above relate to LaFe_11.57Si_1.43H_x nanoparticles useful for heating tissue, populations of other nanoparticles having an enhanced SAR region and/or other materials to be heated also are contemplated.

Claims

1. An injectable formulation for magnetic field induced hyperthermia treatment of selected cells comprising:

a liquid carrier; and

two or more populations of nanoparticles,

wherein each population of nanoparticles has a mean Curie temperature in the range 37 to 47 °C and

wherein the mean Curie temperature of each population of the two or more populations of nanoparticles differs from the mean Curie temperature of each of the remaining populations of nanoparticles by at least 2 °C.

2. The injectable formulation of claim 1, wherein the two or more populations of nanoparticles have compositions corresponding to LaFe_11.57Si_1.43H_x.

3. The injectable formulation of claim 2, wherein 0 < x ≤ 2.27.

4. The injectable formulation of any of claims 1 to 3, wherein a first population of nanoparticles has a mean Curie temperature in the range 37 to 40 °C.

5. The injectable formulation of claim 4, wherein a second population of nanoparticles has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the first population of nanoparticles and 3 °C greater than mean Curie temperature of the first population of nanoparticles.

6. The injectable formulation of claim 5, further comprising a third population of nanoparticles which has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the second population of nanoparticles and 3 °C greater than mean Curie temperature of the second population of nanoparticles.

7. The injectable formulation of claim 6, further comprising a fourth population of nanoparticles which has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the third population of nanoparticles and 3 °C greater than mean Curie temperature of the third population of nanoparticles.

8. The injectable formulation of claim 7, further comprising a fifth population of nanoparticles which has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the fourth population of nanoparticles and 3 °C greater than mean Curie temperature of the fourth population of nanoparticles.

9. The injectable formulation of claim 8, further comprising a sixth population of nanoparticles which has a mean Curie temperature between a temperature 2 °C greater than mean Curie temperature of the fifth population of nanoparticles and 3 °C greater than mean Curie temperature of the fifth population of nanoparticles.

10. The injectable formulation of claim 1, wherein the liquid carrier is selected from the group consisting of water, saline, dimethyl sulfoxide, ethanol, aqueous solutions of acetic acid, pyrrolidones, glycerol, and propylene glycol.

11. The injectable formulation of claim 10, wherein the liquid carrier further comprises an in situ polymerizing component.

12. The injectable formulation of claim 10, wherein the liquid carrier further comprises an in situ cross-linking component.

13. The injectable formulation of claim 10, wherein the liquid carrier further comprises a precipitating polymer component.

14. The injectable formulation of claim 1, wherein at least one of the two or more populations of nanoparticles include an attached therapeutic agent.

15. The injectable formulation of claim 14, wherein the therapeutic agent is an anti-tumor agent.

Ansprüche

1. Injizierbare Formulierung zur magnetfeldinduzierten Hyperthermiebehandlung ausgewählter Zellen, die aufweist:

einen flüssigen Träger; und

zwei oder mehr Populationen von Nanopartikeln,

wobei jede Population von Nanopartikeln eine mittlere Curie-Temperatur im Bereich von 37 bis 47°C aufweist, und

wobei sich die mittlere Curie-Temperatur jeder Population der zwei oder mehreren Populationen von Nanopartikeln von der mittleren Curie-Temperatur jeder der restlichen Populationen von Nanopartikeln um mindestens 2°C unterscheidet.

2. Injizierbare Formulierung nach Anspruch 1, wobei die zwei oder mehreren Populationen von Nanopartikeln Zusammensetzungen aufweisen, die LaFe_11,57Si_1,43H_x entsprechen.

3. Injizierbare Formulierung nach Anspruch 2, wobei 0 < x ≤ 2,27.

4. Injizierbare Formulierung nach einem der Ansprüche 1 bis 3, wobei eine erste Population von Nanopartikeln eine mittlere Curie-Temperatur im Bereich von 37 bis 40°C aufweist.

5. Injizierbare Formulierung nach Anspruch 4, wobei eine zweite Population von Nanopartikeln eine mittlere Curie-Temperatur zwischen einer Temperatur, die 2°C höher als die mittlere Curie-Temperatur der ersten Population von Nanopartikeln ist, und eine Temperatur, die 3°C höher als die mittlere Curie-Temperatur der ersten Population von Nanopartikeln ist, aufweist.

6. Injizierbare Formulierung nach Anspruch 5, die ferner eine dritte Population von Nanopartikeln aufweist, die eine mittlere Curie-Temperatur zwischen einer Temperatur, die 2°C höher als die mittlere Curie-Temperatur der zweiten Population von Nanopartikeln ist, und eine Temperatur, die 3°C höher als die mittlere Curie-Temperatur der zweiten Population von Nanopartikeln ist, aufweist.

7. Injizierbare Formulierung nach Anspruch 6, die ferner eine vierte Population von Nanopartikeln aufweist, die eine mittlere Curie-Temperatur zwischen einer Temperatur, die 2°C höher als die mittlere Curie-Temperatur der dritten Population von Nanopartikeln ist, und eine Temperatur, die 3°C höher als die mittlere Curie-Temperatur der dritten Population von Nanopartikeln ist, aufweist.

8. Injizierbare Formulierung nach Anspruch 7, die ferner eine fünfte Population von Nanopartikeln aufweist, die eine mittlere Curie-Temperatur zwischen einer Temperatur, die 2°C höher als die mittlere Curie-Temperatur der vierten Population von Nanopartikeln ist, und eine Temperatur, die 3°C höher als die mittlere Curie-Temperatur der vierten Population von Nanopartikeln ist, aufweist.

9. Injizierbare Formulierung nach Anspruch 8, die ferner eine sechste Population von Nanopartikeln aufweist, die eine mittlere Curie-Temperatur zwischen einer Temperatur, die 2°C höher als die mittlere Curie-Temperatur der fünften Population von Nanopartikeln ist, und eine Temperatur, die 3°C höher als die mittlere Curie-Temperatur der fünften Population von Nanopartikeln ist, aufweist.

10. Injizierbare Formulierung nach Anspruch 1, wobei der flüssige Träger aus der Gruppe ausgewählt ist, die aus Wasser, Kochsalzlösung, Dimethylsulfoxid, Ethanol, wässrigen Lösungen von Essigsäure, Pyrrolidonen, Glyzerin und Propylenglykol besteht.

11. Injizierbare Formulierung nach Anspruch 10, wobei der flüssige Träger ferner eine in situ polymerisierende Komponente aufweist.

12. Injizierbare Formulierung nach Anspruch 10, wobei der flüssige Träger ferner eine in situ vernetzende Komponente aufweist.

13. Injizierbare Formulierung nach Anspruch 10, wobei der flüssige Träger ferner eine Fällungspolymerkomponente aufweist.

14. Injizierbare Formulierung nach Anspruch 1, wobei mindestens eine der zwei oder mehreren Populationen von Nanopartikeln ein angebrachtes Therapeutikum enthält.

15. Injizierbare Formulierung nach Anspruch 14, wobei das Therapeutikum ein Antitumormittel ist.

Revendications

1. Formulation injectable pour traitement d'hyperthermie induite par champ magnétique de cellules sélectionnées comprenant :

un support liquide ; et

deux populations de nanoparticules ou plus,

où chaque population de nanoparticules présente une température de Curie moyenne dans l'intervalle de 37 à 47°C et

où la température de Curie moyenne de chaque population des deux populations de nanoparticules ou plus est différente de la température de Curie moyenne de chacune des populations de nanoparticules restantes d'au moins 2°C.

2. Formulation injectable selon la revendication 1, où les deux populations de nanoparticules ou plus présentent des compositions correspondant à LaFe_11,57Si_1,43H_x.

3. Formulation injectable selon la revendication 2, où 0 < x ≤ 2,27.

4. Formulation injectable selon l'une quelconque des revendications 1 à 3, où une première population de nanoparticules présente une température de Curie moyenne dans l'intervalle de 37 à 40°C.

5. Formulation injectable selon la revendication 4, où une seconde population de nanoparticules présente une température de Curie moyenne d'une température de 2°C supérieure à la température de Curie moyenne de la première population de nanoparticules à 3°C supérieure à la température de Curie moyenne de la première population de nanoparticules.

6. Formulation injectable selon la revendication 5, comprenant de plus une troisième population de nanoparticules qui présente une température de Curie moyenne d'une température de 2°C supérieure à une température de Curie moyenne de la seconde population de nanoparticules à 3°C supérieure à la température de Curie moyenne de la seconde population de nanoparticules.

7. Formulation injectable selon la revendication 6, comprenant de plus une quatrième population de nanoparticules qui présente une température de Curie moyenne d'une température de 2°C supérieure à la température de Curie moyenne de la troisième population de nanoparticules à 3°C supérieure à la température de Curie moyenne de la troisième population de nanoparticules.

8. Formulation injectable selon la revendication 7, comprenant de plus une cinquième population de nanoparticules qui présente une température de Curie moyenne d'une température de 2°C supérieure à la température de Curie moyenne de la quatrième population de nanoparticules à 3°C supérieure à la température de Curie moyenne de la quatrième population de nanoparticules.

9. Formulation injectable selon la revendication 8, comprenant de plus une sixième population de nanoparticules qui présente une température de Curie moyenne d'une température de 2°C supérieure à la température de Curie moyenne de la cinquième population de nanoparticules à 3°C supérieure à la température de Curie moyenne de la cinquième population de nanoparticules.

10. Formulation injectable selon la revendication 1, où le support liquide est choisi dans le groupe consistant en eau, solution saline, diméthylsulfoxyde, éthanol, solutions aqueuses d'acide acétique, pyrrolidones, glycérol, et propylène glycol.

11. Formulation injectable selon la revendication 10, où le support liquide comprend de plus un constituant polymérisant in situ.

12. Formulation injectable selon la revendication 10, où le support liquide comprend de plus un constituant de réticulation in situ.

13. Formulation injectable selon la revendication 10, où le support liquide comprend de plus un constituant polymère de précipitation.

14. Formulation injectable selon la revendication 1, où au moins une des deux populations de nanoparticules ou plus inclut un agent thérapeutique attaché.

15. Formulation injectable selon la revendication 14, où l'agent thérapeutique est un agent anti-tumoral.

Drawing