Within this proposal, we aim to investigate a novel concept of targeted cancer cell destruction by using magnetic vortices as mediators of cellular mechanotransduction. The importance of this work was recently highlighted by featuring our approach on the cover of Nature Materials. A unique material - lithographically defined, biocompatible, ferromagnetic microdisc - possessing a spin vortex ground state has been interfaced with cancer cells via incorporation of a tumor specific antibody. For GBM, our specific targeting of glioma cells was based on the selective expression of the IL13?2 receptor (IL13?2R) on malignant brain tumors. IL13?2R is expressed only on malignant glioma and not on normal, healthy astrocytes. In fact, the receptor is not expressed on other organ, with the exception of testis. Moreover, IL13?2R expression is associated with glial transformation and increased tumor grade. Our working hypothesis is that selective targeting of microdiscs conjugated with an antibody against IL13?2R will result in enhanced GBM cytotoxicity in the context of extremely low frequency and small amplitude magnetic field. The actuation of the magnetic vortices by an alternating magnetic field (AC) leads to oscillatory motion of the microdiscs and transduction of a magneto-mechanical stimulus directly to the cell membrane and into sub- cellular compartments. This results in membrane disturbance, and cellular signal transduction and amplification, causing initiation of cell death. Application of extraordinarily weak magnetic fields produces an extremely high degree of spin-vortex induced cytotoxicity. The concept, if successful, will open up the field for tremendous improvements in cancer therapy. Because the microdiscs target individual cells, the external power supplied to the cultures is at least ~100,000s times smaller than that employed by current best practice techniques for hyperthermia using superparamagnetic nanoparticles. The low operating field strength creates an opportunity for a multifunctional therapy platform with low cost, large working volume, and minimal invasiveness. Moreover, the most striking feature of this approach is that the energy is delivered directly to the individual cell. To further advance this strategy ito the preclinical setting, we now propose to complete the following specific aims:
Specific Aim 1 : Determine the in vivo therapeutic response of antibody conjugated ferromagnetic microdiscs in human xenograft murine glioma model as well as a transgenic model of murine glioma.
Specific Aim 2 : Evaluate the migration, engraftment, and long-term fate of antibody conjugated ferromagnetic microdiscs in animal models of glioma.
Specific Aim 3 : Examine the mechanism of cytotoxicity of microparticles and dynamics of triggered cell death.
Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the adult central nervous system (CNS). Recently, we have developed magnetic microdiscs which are capable of inducing high toxicity in the setting of this tumor. This proposal seeks to complete the preclinical and mechanistic studies necessary to advance this therapy to the clinical setting.
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