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Multifunctional Nanoparticles for Medical Imaging and Therapeutic Applications
Daniel Lee, M.D., Ph.D.
Targesome, Inc.
Palo Alto, CA
We describe a biocompatible nanoparticle-based system engineered to target cell surface receptors that are important in medical applications. The system is based on nanoparticles constructed with bipolar lipid subunits containing a polymerizable functional group. By incorporating modified subunits, specific targeting agents such as monoclonal antibodies (MAb) and synthetic ligands are multivalently presented on the nanoparticle surface. Chelators on the nanoparticle surface confer high-capacity metal binding sites for medical diagnostic and therapeutic functions.
In early pilot studies we have demonstrated the detection of cell surface receptors using conventional magnetic resonance (MR) and nuclear scintigraphy imaging techniques. Cell surface markers upregulated during pathological processes such as autoimmune inflammation and tumor-induced angiogenesis were directly imaged in experimental animal models. MR images were obtained using gadolinium-loaded nanoparticles conjugated to monoclonal antibodies directed against ICAM-1 or Integrin ?v?3. Targeted nanoparticles accumulated at anatomic sites of receptor upregulation as confirmed by immunohistochemical analysis. These MRI data were corroborated by whole body scans that were obtained using indium-111 loaded nanoparticle-MAb conjugates. Nuclear scintigraphy, an exceptionally sensitive imaging modality, also demonstrated pharmacologically favorable biodistribution of nanoparticles.
In more recent pilot studies we have investigated the therapeutic potential for this targeted nanoparticle-based approach. By loading nanoparticles with yttrium-90 and conjugating with an anti-integrin (?v?3) MAb, a radiotherapeutic complex was evaluated for antitumor activity in an animal cancer model. With a single intravenous administration of the radiotherapeutic nanoparticle, significant tumor growth inhibition and complete tumor regression were observed in the rabbit Vx2 carcinoma model. Interestingly, the radiotherapeutic nanoparticle was directed at receptors highly expressed on tumor-induced angiogenic blood vessels but only weakly expressed on tumor cells. Similar observations have been reproduced in a murine model of malignant melanoma using a synthetic ligand conjugated nanoparticle that targets integrins.
This multifunctional and versatile platform technology has broad diagnostic and therapeutic applications. Targeted nanoparticles are ideally suited to detect phenomena that occur at the vascular endothelial surface including atherosclerosis, apoptosis, inflammation, and angiogenesis. Such nanoparticles may ultimately improve our ability to visualize and diagnose disease processes in vivo and in real time. With this powerful targeting ability and high-capacity payload, nanoparticles can dramatically enhance the efficacy of conventional pharmaceuticals and may accelerate the development of other therapeutic approaches. Nanoparticles offer a new class of rationally designed therapeutics with exciting future potential...
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