Targeted radiotherapies maximize cytotoxicty to cancer cells. In vivo α-generator targeted radiotherapies can deliver multiple α particles to a receptor site dramatically amplifying the radiation dose delivered to the target. The major challenge with α-generator radiotherapies is that traditional chelating moieties are unable to sequester the radioactive daughters in the bioconjugate which is critical to minimize toxicity to healthy, non-target tissue. The recoil energy of the 225Ac daughters following α decay will sever any metal-ligand bond used to form the bioconjugate. This work demonstrates that an engineered multilayered nanoparticle-antibody conjugate can deliver multiple α radiations and contain the decay daughters of 225Ac while targeting biologically relevant receptors in a female BALB/c mouse model. These multi-shell nanoparticles combine the radiation resistance of lanthanide phosphate to contain 225Ac and its radioactive decay daughters, the magnetic properties of gadolinium phosphate for easy separation, and established gold chemistry for attachment of targeting moieties.
Radioactive cadmium telluride/zinc sulfide (Cd125mTe/ZnS) nanoparticles were targeted to mouse lung with antibody to mouse lung endothelium and quantified using radiological histology in order to test the in vivo targeting efficacy of a nanoparticle–antibody (NP–mAb) system. The nanoparticles were linked to either a monoclonal antibody to mouse lung thrombomodulin (mAb 201B) or a control antibody (mAb 33), and injected into groups of 6-week-old Balb/C female mice. Animals were sacrificed at 1, 4, 24, 72 and 144 h post-injection, and biodistribution in major organs was determined. Full body microSPECT/CT imaging was performed on a pair of mice (experimental and control) providing visual confirmation of the biodistribution. The Cd125mTe/ZnS NPs conjugated to mAb 201B principally target the lungs while the nanoparticles coupled to mAb 33 accumulate in the liver and spleen. These data provide, for the first time, a quantitative measurement of the in vivo targeting efficacy of an inorganic nanoparticle–mAb system.
Radionuclides with specific emission properties can be incorporated into metalchalcogenide and metal-oxide nanoparticles. Coupled to antibodies, these conjugates could be injected into the bloodstream to target and destroy non-solid tumors or target organs for radioimaging. In the first year of this project, two types of radioactive nanoparticles, CdTe:125m Te and Y 2 O 3 : 170Tm were synthesized and coupled to antibodies specific to murine epithelial lung tissue. The nanoparticles successfully target the lung tissue in vivo. Some leaching of the radioisotope was observed. The coming year will explore other types of nanoparticles (other crystal chemistries) in order to minimize leaching. Body of ReportNanoparticles have been shown to couple to proteins and the resulting conjugates may find applications as targeted drug delivery systems or medical imaging diagnostic tools (Tiefenauer, Kuhne et al. 1993;Frey, Mantis et al. 1999;Akerman, Chan et al. 2002;Wang, Mamedova et al. 2002;Gao, Cui et al. 2004). These conjugates could be injected into the bloodstream to target and destroy non-solid tumors or target organs for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) imaging (for a review of small molecule analogs see (Goldenberg 2002)). The nanoparticle based drugs may also mitigate unintentional radiotoxic effects by effectively sequestering and retaining the radionuclides and daughter products.CdTe nanoparticles were selected for the first experiments because the techniques for synthesizing CdTe nanoparticles are well-developed and the surfaces can be easily modified to allow for protein coupling. The CdTe nanoparticles can be doped with small quantities of the radioisotope 125m Te (t 1/2 = 58 days) which emits low energy 35.5 keVrays with no complicating beta or alpha emission thus allowing for verification of antibody performance and nanoparticle fate within the test mice.Cadmium telluride nanoparticles doped with 125m Te were prepared based on the Peng method (Peng and Peng 2001) in which CdO reacts with 125m Te metal within trioctylphosphine micelles at 250 ºC. A reaction time of 5 min affords homogeneous and unaggregated 5 nm diameter nanoparticles. The CdTe nanoparticle surfaces were derivatized by mercaptoacetic acid (Wuister, Swart et al. 2003).
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