This application aims to develop composite magnetic nanoparticles with controlled surface functionalization and stability in physiological conditions for applications in targeted delivery of platin-like anticancer molecules to tumor cells, and, specifically to study the effectiveness of the platin nanoparticles in elimination of the glioma cells. The work is based on our preliminary research on the synthesis and surface functionalization of monodisperse magnetic iron-based nanoparticles, including Fe3O4, core/shell Fe/Fe3O4, and dumbbell-like Au-Fe3O4 nanoparticles, and may lead to a solution for highly efficient platin-based cancer therapy in the near future. The multifunctional nanostructures proposed here are illustrative of the exciting possibilities that can emerge from the union of nanoscience and medicine. The selective delivery of therapeutic drugs to malignant tissues constitutes one of the greatest challenges in cancer research. We propose that carefully designed bifunctional nanoparticles may provide an exciting practical vehicle to achieve selective and efficacious platin drug delivery. The composite nanoparticles, as shown in Figure 1, have both magnetic iron oxide and optically active noble metal of Au (or Ag) nanoparticle units. The different surface chemistry offered by this composite structure will facilitate the simultaneous attachment of special peptides and cisplatin-like anticancer drugs for the target specific cell recognition and cell entry. The detailed surface functionalization of the composite nanoparticles is also shown in Figure 1, in which the Fe3O4 particles are coated with a monoclonal antibody (Ab) or peptides via polyethylene glycol (PEG) and dopamine and the Au nanoparticles are linked to a TAT-like peptide (Nuclear Localization signal, NLS) through a platin complex and PEG unit. The monoclonal antibody will be used to target an antigen on the surface of tumor cells, while the NLS is to induce nanoparticle penetration through nuclear membrane. When the functionalized nanoparticles are within the tumor cell nucleus, an alternating magnetic field will be applied to remotely heat the magnetic nanoparticles, and the resultant heat will break the Pt-O bond in the structure and induce the formation of an active Pt coordination site that can readily attach to DNA strands, leading to the interruption of the DNA excision repair system and consequent cell death. The composite nanoparticles can also serve as highly sensitive multifunctional labels for the detection of trajectories of the particles within the cells by either magnetic resonance image (MRI) on iron oxide nanoparticles or electron/optical microscopic image on Au (or Ag), facilitating quantification of transporter-conjugate uptake in tumor cells. The ultimate goal of this application is to provide nanoparticle based therapeutics for successful cancer therapy. ? ? ?
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