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

Abstract

The disclosure pertains to mixtures of LaFeSiH magnetic nanoparticles having different Curie temperatures useful for improved inductive hyperthermia efficiency, injectable formulations containing the nanoparticles, and methods of raising the temperature of selected cells using the nanoparticles.

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 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.

3. The injectable formulation of claim 2, wherein the regions of enhanced specific absorption rate of each population of nanoparticles overlaps at least one region of enhanced specific absorption rate of another population of nanoparticles.

4. The injectable formulation of claim 2, wherein the aggregate regions of enhanced specific absorption rate continuously span a temperature range of 5 to 10 C.

5. The injectable formulation of claim 4, wherein the aggregate regions of enhanced specific absorption rate continuously span a temperature range of 37 to 47 C.

6. The injectable formulation of claim 4, wherein the aggregate regions of enhanced specific absorption rate continuously span a temperature range of 37 to 41 C.

7. The injectable formulation of claim 1, wherein the two or more populations of nanoparticles have compositions corresponding to LaFe.sub.11.57Si.sub.1.43H.sub.x.

8. The injectable formulation of claim 7, wherein 0<x2.27.

9. 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.

10. The injectable formulation of claim 9, wherein the liquid carrier further comprises an in situ polymerizing component.

11. The injectable formulation of claim 9, wherein the liquid carrier further comprises an in situ cross-linking component.

12. The injectable formulation of claim 9, wherein the liquid carrier further comprises a precipitating polymer component.

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

14. The injectable formulation of claim 13, wherein the therapeutic agent is an anti-tumor agent.

15. A method of heating selected cells by magnetically induced 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.

16. The method of claim 15, wherein the alternating magnetic field results in a specific absorption rate within the selected cells of no more than 2 W/kg.

17. The method of claim 15, wherein at least one of the two or more populations of nanoparticles releases a therapeutic agent.

18. The method of claim 15, wherein 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.

19. The method of claim 15, wherein 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.

20. A method of heating selected cells by magnetically induced hyperthermia comprising: positioning two or more small 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 raise the temperature of the selected cells to a target hyperthermia temperature.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0044] FIG. 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.)

[0045] FIG. 2 somewhat schematically illustrates one aspect of the invention.

[0046] FIG. 3 somewhat schematically illustrates an alternate aspect of the invention.

[0047] FIG. 4 somewhat schematically illustrates another aspect of the invention.

[0048] FIG. 5 illustrates simulated heating profiles for nanoparticle populations.

[0049] FIG. 6 illustrates an injectable dispersion of nanoparticles.

[0050] FIG. 7 illustrates schematically a nanoparticle of the invention which includes an attached therapeutic agent.

DETAILED DESCRIPTION

[0051] 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.

[0052] 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.

[0053] 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).

[0054] 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.

[0055] 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.

[0056] 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.

[0057] FIG. 1 illustrates the change in static hysteresis loss as a function of temperature for a population of LaFe11.57Si1.43Hx 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.

[0058] While the high SAR and appropriate TC of the LaFe11.57Si1.43Hx 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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 LaFe11.57Si1.43Hx 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 Ti to a final temperature Tf as the successive populations are heated by an applied alternating magnetic field having an appropriate frequency and magnetic field strength.

[0063] 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.

[0064] 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 Ti to a final temperature Tf as the successive populations are heated by an applied alternating magnetic field having an appropriate frequency and magnetic field strength.

[0065] 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.

[0066] 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.

[0067] FIG. 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 LaFe11.57Si1.43Hx nanoparticles having a 46 C. Curie temperature has been modeled (3); and in which the SAR of three combined populations of LaFe11.57Si1.43Hx nanoparticles having TCs of 40, 43, and 46 C. have been modeled (4).

[0068] 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.

[0069] In some aspects, at least a portion of the particles 20A may include an attached therapeutic agent 25, as illustrated in FIG. 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.

[0070] Although the illustrative examples described above relate to LaFe11.57Si1.43Hx nanoparticles useful for heating tissue, populations of other nanoparticles having an enhanced SAR region and/or other materials to be heated also are contemplated.

[0071] Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the scope and principles of this invention, and it should be understood that this invention is not to be unduly limited to the illustrative embodiments set forth hereinabove. All publications and patents are herein incorporated by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.