BIODISTRIBUTION OF DENDRIMER NANOCOMPOSITES FOR NANO-RADIATION THERAPY OF CANCER

摘要

Multifunctional nanocomposites have an enormous scientific and practical future in medicine, especially in biomedical imaging and targeted delivery. Multifunctional composite nanodevices (CND) possess chemical and physical properties of all components, while interactions with the environment of the nanoparticle are dominated by the contact surface of the host molecule. Thus, if the surface is dominated by the organic component of a nanosized organic-inorganic composite particle, an inorganic particle property can be manipulated in a biologic environment as if it belonged to an organic macromolecule. Composition, charge, and size of are critical in determining nanoparticle trafficking and uptake by organs, and therefore this knowledge is crucial for the development of cancer imaging and therapies. Specific biokinetics and biodistribution then can be influenced by correctly selecting size, and modifying surface characteristics, such as covalently attaching various targeting moieties to the surface forming biohybrids, regulating the surface charge, etc. Dendrimer nanocomposites are recently developed nearly monodisperse hybrid nanoparticles composed of macromolecular hosts and very small, uniformly dispersed inorganic guest domains combining desirable properties of the components. The surface groups control the interaction of these nanodevices with the biological environment. As a result of various synthetic options, the interior and/or the exterior of the host can be cationic, anionic, or non-ionic, depending on their termini and interior functionalities and the pH, and may involve multiple targeting moieties. We have synthesized gold/dendrimer nanocomposites to carry payload radiation and/or diagnostic moiety to specific targets. We examined the biodistribution of the templates and the corresponding gold/dendrimer nanocomposites. We employed the same dendrimer template and systematically varied the size, the surface charge and the composition. Biodistribution of {Au} gold/dendrimer nanodevices of various size (5, 12 and 22 nm) and surface charge (positive, negative) was investigated in mice models (B16 melanoma and DU145 human prostate cancer). Isotope neutron activation analysis (INAA) was used to measure the presence of Au (0) in the tissue sample. All {Au} gold/dendrimer-nanocomposites were assayed for their quantitative short-term (1hr), intermediate (1 day) and long-term (4 days) biodistribution throughout organs for clinical toxicity. Delivery of radiation dose was achieved by radioactive {{sup}198Au} composites in a mice model. We have shown that modulating surface charge and composition will greatly change the biodistribution characteristics of the nanodevices. Rigorous testing of the principles that govern nanoparticle interactions with the complex environment of biological systems will be critical for an understanding of how these nanodevices will behave in vivo.