S. Moeendarbari, R. Tekade, A. Mulgaonkar, P. Christensen, S. Ramezani, G. Hassan, R. Jiang, O.K. Oz, X. Sun, Y. Hao
University of Texas at Arlington,
Keywords: brachytherapy, gold nanoparticles, radiotherapy, biomedical imaging
Summary:A major class of internal radiation therapy of cancer is low-dose brachytherapy, in which radioactive seeds are permanently placed in tumor sites by an imaging-guided surgical procedure. Brachytherapy has been in clinical use for many different cancer sites as a sole modality or in conjunction with external beam radiotherapy for years. The major advantage is that it confines a low dose of therapeutic radiation to the tumor region while sparing normal tissues. However, the millimeter size of the current brachytherapy seeds and their associated implantation technologies not only cause many adverse side effects, but also limit its applications to large solid tumors. Reducing the seed size to nanoscale and making it injectable would avoid most adverse side effects, and also greatly expand the applications of brachytherapy to treat much smaller tumors and other diseases, to be intraoperatively applied in situations where optimal surgical resection is not possible, and to be used postoperatively to target potential regions of residual microscopic disease. However, some major challenges strictly hinder the development of nanoseeds; First, medical radioactive chemicals are usually prepared in solution with trace level concentration (~10-8M), which makes it impractical for the commonly used nanoparticle synthesis methods to incorporate sufficient radioactive dose into reasonable number of nanoparticles for therapeutic use. Second, the size of nanoseeds needs to be large enough to prevent these radioactive particles from diffusing into other areas. To overcome these challenges, here, we report a general, practical method to prepare nanoscale radiotherapeutic seeds (nanoseeds) for more efficacious brachytherapy with significant reduction of adverse side effects. The facile, inventive radiolabeling process reported here enables the incorporation of radioactive isotopes with therapeutic dose to monodispersed relatively large gold nanoparticles (>120nm). Accordingly, a Cu layer is first coated to Au nanoparticles by a simple, robust electroless deposition process. Then, the Cu layer is replaced by inerter metals through a galvanic replacement reaction. Using this method, a commonly used radioisotope for brachytherapy seeds, 103Pd, was incorporated onto hollow gold nanoparticles (~120 nm in diameter). The resulting 103Pd@Au nanoseeds were tested in vivo by intratumoral injection into prostate cancer xenograft mice models. Five weeks after a single dose treatment, an averaged tumor burden reduction of 80% was observed as compared to a control cohort administered with the corresponding Pd@Au nanoparticles. At the same time, toxicity of nanoseeds was assessed by complete blood analysis and animal body weight loss, which showed no noticeable side effects on liver, spleen and other organs. In addition, we were able to develop a practical single-photon emission computed tomography (SPECT) imaging method using the low energy emission of 103Pd to noninvasively monitor the tumor retention of 103Pd@Au nanoseeds, which was found to be virtually 95% over the entire course of our 5-week study. The reported preparation process can be easily adopted to produce other Au nanoparticle-based nanoseeds with various radioactive properties for different cancers and other diseases. This opens up many possible applications of nanoseed-based brachytherapy, as well as for other nanotechnology research areas.