This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have developed immunoliposome technology as a powerful and versatile nanoscale system for tumor-targeted intracellular delivery. Immunoliposomes were designed to provide a stable, long-circulating, non-immunogenic carrier system that efficiently delivers drugs or probes to the cell interior via receptor-targeting. The modular organization of immunoliposome constructs makes possible a combinatorial strategy for the generation of new agents: monoclonal antibody fragments selected from our phage antibody libraries can be coupled to an appropriate liposomal drug, chosen from a repertoire of liposomal drugs. This delivery platform can also readily accommodate in vivo reporters for targeted imaging, including attached radionuclides for tumor localization and encapsulated paramagnetic probes sensitive to tumor cell internalization. This highly innovative system features truly multifunctional capabilities for targeted delivery of anticancer drugs in conjunction with nuclear medicine- and MRI-based reporters for integrated therapy and imaging of cancer. We have constructed immunoliposomes directed against HER2 and other oncogenic receptor tyrosine kinases, including EGFR. Radionuclides (In-111 isotope and Ga-67 isotope) were attached to immunoliposomes using analogous methodology developed for capture of MAb fragments, enabling imaging of agent/target localization. Gd-based probes have been encapsulated in the liposome interior in a non-signaling configuration to enable signal generation upon tumor cell internalization. These modifications have been readily combined within a multifunctional immunoliposome reporter having both surface-linked radionuclides and interior-encapsulated Gd. Because this immunoliposome reporter is based upon the same modular structure and targeting technology as our immunoliposome drugs, the two can be co-developed for use in a closely integrated strategy for imaging, treatment, and treatment monitoring. Mass spectrometry is critical to the characterization of these complex nanoparticles and has been used successfully to positively identify many novel high molecular weight lipid-anchored 111In-chelators, and pH or enzyme-sensitive Gd-chelators. Several lipopolymer-anchored antibody fragments and novel intraliposomal trapping agents are also important components of this delivery system and will be characterized more fully in the upcoming year. The structures of these agents must be first elucidated using several spectroscopic techniques, and then their stability examined. Mass spectrometry provides a powerful tool for accomplishing these goals.
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