Nanoparticle loaded stem cells and their use in MRI guided hyperthermia

a stem cell and nanoparticle technology, applied in the field of nanoparticle-loaded stem cells and their use in mri guided hyperthermia, can solve the problems that hyperthermia has not yet been established in the clinic, and achieve the effects of enhancing mr properties, and sufficient time for nlsc to localiz

Inactive Publication Date: 2012-11-08
OSTROVSKA LYUBOV PHD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0008]In accordance with an embodiment, the present invention provides the use of NP that become heated in AMF for magnetic resonance imaging (MRI). Use of bi-functional nanoparticles allows tracking the tissue distribution of infused NP and nanoparticle loaded stem cells (NLSC). The magnetic NP with enhanced MR properties, and which become heated in AMF enables therapeutic applications of NLSC of the present invention.
[0009]In accordance with an embodiment, the present invention provides a method for treatment of cancer in a subject comprising: a) obtaining NLSC comprising a bi-functional nanoparticle; b) administering to the subject, an effective amount of the NLSC; c) allowing sufficient time for the NLSC to localize to the tumor; d) detecting the NLSC in the tumor by imaging the tumor through MRI; and / or e) applying a sufficient amount of an AMF to the subject such that the NP within the NLSC will heat the tumor in the subject when exposed to an AMF and sensitize the tumor to further treatment; and f) administering an effective amount of a pharmaceutical composition comprising one or more chemotherapeutic agents.
[0010]In accordance with another embodiment, the present invention provides a method for treatment of cancer in a subject comprising: a) obtaining NLSC comprising a bi-functional nanoparticle; b) administering to the subject, an effective amount of the NLSC; c) allowing sufficient time for the NLSC to localize to the tumor; d) detecting the NLSC in the tumor by imaging tumor through MRI; and / or e) applying a sufficient amount of an AMF to the subject such that the NLSC will heat the tumor in the subject when exposed to an AMF and sensitize the tumor to further treatment; and f) administering an effective amount of radiotherapy to the tumor.
[0011]In accordance with a further embodiment, the present invention provides a method for treatment of cancer in a subject comprising: a) obtaining NLSC comprising a bi-functional nanoparticle; b) administering to the subject, an effective amount of the NLSC; c) allowing sufficient time for the NLSC to localize to the tumor; d) detecting the NLSC in the tumor by imaging the tumor through MRI; and / or e) applying a sufficient amount of an AMF to the subject such that the NLSC will heat the tumor in the subject when exposed to an AMF and sensitize the tumor to further treatment; f) administering an effective amount of a pharmaceutical composition comprising one or more chemotherapeutic agents; and g) administering an effective amount of radiotherapy to the tumor.
[0012]In accordance with a yet another embodiment, the present invention provides the use of NLSC for treatment of a tumor in a subject comprising: a) obtaining NLSC comprising a bi-functional nanoparticle; b) administering to the subject, an effective amount of the NLSC; c) allowing sufficient time for the NLSC to localize to the tumor; d) detecting NLSC in the tumor by imaging tumor through MRI; and / or e) applying a sufficient amount of an AMF to the subject such that the NLSC will heat the tumor in the subject when exposed to an alternating magnetic field and sensitize the tumor to further treatment.

Problems solved by technology

Despite promising results, hyperthermia has not yet been established in the clinic because technological limitations preclude selective deposition of heat to the tumor, especially to treatment resistant hypoxic areas.
One of the many challenges in biomedicine is to deliver treatment at the right place, at the right dose, and at the right time.

Method used

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  • Nanoparticle loaded stem cells and their use in MRI guided hyperthermia
  • Nanoparticle loaded stem cells and their use in MRI guided hyperthermia
  • Nanoparticle loaded stem cells and their use in MRI guided hyperthermia

Examples

Experimental program
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example 1

[0077]Particle heating and loading characteristics. BNF particles have unique characteristics including that they heat in an AMF. FIG. 1 demonstrates the heating rates of the BNF particles as a function of AMF amplitude. The magnetic field amplitude (peak-to-peak) in Oersteds is a measure of power of the magnetic field. Higher power (higher field amplitude and more intense magnetic flux density) extracts more heat from the particles.

[0078]To test the hypothesis that stem cells can be efficiently loaded with bi-functional BNF particles for imaging and hyperthermia, we examined loading characteristics and optimized loading conditions for mouse mesenchymal stem cells with BNF-particles (FIG. 2). According to ICP-mass spectrometry results (FIG. 2B), iron cell load varied from 0.6 to 1.6 pg / cell after overnight cells loading with BNF particles (2.5 μl / ml concentration in growth media). Loading of MSC with Feridex resulted in iron concentrations of 1-5 pg iron per cell. Iron content per c...

example 2

[0079]Cell survival, proliferation, differentiation. The effect of loading with the BNF particles on NLSC survival and growth was examined by using the Trypan Blue exclusion method which demonstrates cell viability. Viable cells were calculated after overnight cell loading with the BNF particles. Cells were re-suspended in the complete growth medium and plated in 24-well plates (in triplicates) for cells proliferation assay. Count of viable cells after 24, 48, 72, and 96 hours demonstrated that mouse mesenchymal stem cells can be efficiently loaded with iron-oxide BNF-particles without disturbing their viability and proliferation potential (FIG. 3A).

[0080]Standard differentiation assay also demonstrated that BNF-loaded cells can differentiate into adipocytes and osteocytes as unloaded control cells, so their differentiation potential also was not altered by BNF-labeling (data not shown). That suggests that BNF-loaded NLSC are capable to differentiate accordingly to microenvironment ...

example 3

[0081]Effect of AMF. To examine sensitivity of BNF-loaded NLSC to AMF, cells suspensions were exposed to 600, 800, and 1100 Gauss AMF for 20 minutes. In these experiments temperature (measured in a separate tube with the same loaded cells concentration) raised maximum to 44.3° C. (at 1100 G). BNF-loaded cells were sensitive to AMF in a dose-dependent manner. The fraction of surviving cells after exposure to AMF was extremely low in comparison to control unloaded cells: 9% after 600 G exposure, 5% after 800 G, and 0.4% after 1100 G AMF (FIG. 4A). Average count of unloaded cells exposed to AMF at the same conditions was 3.9×105 / well.

[0082]Two weeks after 800 G AMF exposure, surviving BNF-loaded NLSC formed colonies (data not shown), while control cells (unloaded or BNF-loaded unexposed to AMF) were confluent by day 4 and detached from the surface after one week. NLSC colony forming ability was significantly reduced if cells exposed to AMF were subsequently exposed to gamma-irradiation...

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Abstract

The present invention provides stem cells loaded with bi-functional magnetic nanoparticles (nanoparticle-loaded stem cells (NLSC)) that both: a) heat in an alternating magnetic field (AMF); and b) provide MRI contrast enhancement for MR-guided hyperthermia. The nanoparticles in the NLSC are non-toxic, and do not alter stem cell proliferation and differentiation, the nanoparticles do however, become heated in an alternating magnetic field, enabling therapeutic applications for cancer treatment. NLSC can deliver hyperthermia to hypoxic areas in tumors for sensitization of those areas to subsequent treatment, thus delivering therapy to the most treatment-resistant tumor regions. The heating of diseased tissue either results in direct cell killing or makes the tumor more susceptible to radio- and/or chemotherapy. The NLSC of the present invention can be used for MR image-guided hyperthermia in oncology, in stem cell research for cell tracking and heating, and for elimination of mis-injected stem cells.

Description

REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application No. 61 / 480,468, filed on Apr. 29, 2011, which is hereby incorporated by reference for all purposes as if fully set forth herein.STATEMENT OF GOVERNMENTAL INTEREST[0002]This invention was made with U.S. government support under NIEHS grant no. P30 ES00319. The U.S. government has certain rights in the inventionBACKGROUND OF THE INVENTION[0003]Magnetic Iron oxide nanoparticles (MION) are increasingly used for clinical applications, such as magnetic resonance imaging (MRI), drug delivery, and hyperthermia. Injection of magnetic fluids (MION suspensions) into tumors and their subsequent heating in an alternating magnetic field (AMF) has been developed as a cancer treatment, resulting in direct tumor cell killing or making the cells more susceptible to radiation- or chemotherapy.[0004]Targeted hyperthermia has clinical potential because it is associated with fewer side effect...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61N2/10A61N5/10A61K49/06B82Y5/00
CPCA61K2035/124B82Y5/00C12N5/0663A61K49/1896A61N5/10A61K41/0052A61K49/1863C12N2529/00
Inventor OSTROVSKA, LYUBOV
Owner OSTROVSKA LYUBOV PHD
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