We report pronounced and specific antiglioblastoma cell phototoxicity of 5 nm TiO2 particles covalently tethered to an antibody via a dihydroxybenzene bivalent linker. The linker application enables absorption of a visible part of the solar spectrum by the nanobio hybrid. The phototoxicity is mediated by reactive oxygen species (ROS) that initiate programmed death of the cancer cell. Synchrotron X-ray fluorescence microscopy (XFM) was applied for direct visualization of the nanobioconjugate distribution through a single brain cancer cell at the submicrometer scale.
The vibrant development of modern nanotechnology and nanobiotechnology opens novel horizons for diagnosis, imaging, and therapy of diseases that have traditionally been recognized as incurable via basic therapies or surgical methods. Malignant glioma, in particular, glioblastoma multiforme (GBM), represents a devastating form of primary brain cancer characterized by resistance to conventional adjuvant therapies. Despite surgery, radiation, and chemo- therapy treatments the median survival is measured in months rather than years. Cases of primary malignant brain and other nervous system tumors were estimated at ∼23,000 annually, and about 13,000 people die of malignant brain tumors each year in the United States.3 In light of this prognosis, innovative adjuvant technologies include gene and immuno-therapy, and nanotechnology platforms. The ability to integrate the advanced properties of nanoscaled materials with the unique recognition capability of biomolecules to achieve active transport, imaging, and, finally, specific elimination of malignancies, makes emerging nanoplatforms attractive for the development of rationally designed modali- ties for neuro-oncology. Semiconductor TiO2 is well known as a photocatalyst in the degradation of organic substrates and the deactivation of microorganisms and viruses. Under ultraviolet light (UV) excitation, TiO2 nanoparticles of various sizes and morphologies have been reported to exhibit cytotoxicity toward some tumors. Although nanomaterials tend to passively accumulate in tumors due to the so-called enhanced “permeability and retention effect” and often serve as “nanocarriers” for chemotherapeutics, this passive strategy has limitations because of its random delivery mode. In this work, we propose a technique to overcome the passive transport drawbacks by integrating the hard inorganic nanomaterial with a biological soft material, an antibody that is able to recognize GBM cells. The interleukin-13R2 receptor domain (IL13R2R) has been widely studied because of its importance in tumor biology. It binds to interleukin-13 (IL13), a key signaling molecule in malignancy and inflammation, with consequent internal-ization of the ligand-receptor complex inside the tumor cell. IL13R2R has been reported to be exclusively overexpressed on the surface of certain tumors, including GBM. Therefore IL13R2R is an ideal candidate to serve as a marker and a glioma-targeting vehicle for cytotox- ic elements, such as toxins, viruses, and immunonano- shells. We focus on the development of a polychromatic visible-light inducible nanobio hybrid system based on 5 nm TiO2 nanocrystals covalently tethered to a biological vehicle capable of selective recognition of the GBM (Figure 1). Like photodynamic therapy (PDT), our approach includes three main components: light, oxygen, and a photoreactive ma- terial. The hybrid semiconductor particles absorb energy from light, which is then transferred to molecular oxygen, produc- ing cytotoxic reactive oxygen species (ROS). While brain tumors can not be exposed to light directly, even the deepest brain tumors may become accessible during surgery, and light-based techniques may serve as an excellent intraop- erative adjuvant therapy. The advantages of nanoscale photosensitization compared to “classical” PDT are the result of a synergistic combination of advanced physical properties of inorganic materials with the targeting abilities of biomol- ecules and the multiple functions of drugs and imaging payloads in one ideal therapeutic system. Furthermore, nanoparticles may overcome biological barriers, including the blood-brain barrier (BBB).
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- Elena A. Rozhkova; Ilya Ulasov; Barry Lai; Nada M. Dimitrijevic; Maciej S. Lesniak; Tijana Rajh
- 2 : Technology concept and/or application formulated
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