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Breast Cancer Brachytherapy Using Nanoparticle-Carried Therapeutic Radionuclides
Brachytherapy after breast conserving surgery to remove an early stage breast tumor may be greatly improved by using new approaches. Current clinical breast cancer brachytherapy mainly uses the MammoSite® balloon applicator to deliver the radiation doses from gamma emission iridium-192 (192Ir) sealed sources. This current brachytherapy method has the following limitations: 1) There is a less rapid dose decrease from cavity wall to further distant normal breast tissue, thus a radiation absorbed dose delivered to normal breast tissue is still relatively high; 2) Sealed radioactive sources have no mechanism for treating lymph nodes where metastasized tumor cells may be residing. By using beta-emission therapeutic radionuclides encapsulated within nanoparticles, the above limitations can potentially be overcome. The goal of this project is to study the feasibility of using beta-emission therapeutic radionuclides encapsulated inside nanoparticles to perform breast cancer brachytherapy after breast-conserving surgery. Beta particles have a path length of a few mm, which enables a high radiation dose to the surgical bed and a very low dose to normal breast tissue located a few mm beyond the bed area. By encapsulating these radionuclides inside nanoparticles, and administering them in the cavity after surgery, these radionuclides can be retained in the surgical cavity for an extended period and provide effective radiation dose to the area. In addition, nanoparticles have the potential to accumulate in lymph nodes after local administration. This therapy strategy enables the concurrent treatment of lymph nodes to eradicate tumor cells which may reside in lymph nodes. Furthermore, chemotherapeutic agents can be co-loaded into nanoparticles, making it possible to combine both radiation and chemotherapy to enhance the therapeutic efficacy of breast cancer brachytherapy. A method of loading technetium-99m (99mTc) and rhenium-186 / 188 (186Re / 188Re) into lipid nanoparticles (liposomes) with high specific activity and high efficiency has been developed. 99mTc is the most widely used diagnostic radionuclide. 186Re and 188Re are beta emitters with great physical characteristics. The in vivo behavior of 186Re and 188Re can also be imaged with a gamma camera. In the current project, we intend to achieve the following three specific aims: 1) Determine the best nanoparticle size for breast cancer brachytherapy based on both the retention of the nanoparticles in the surgical region and their retention in lymph nodes; 2) Investigate tumor specific targeting efficiency of 99mTc-immuno-liposomes which have epidermal growth factor receptor (EGFR) antibody attached to the liposome surface; 3) Compare the in vivo distribution of 99mTc-liposomes and 186Re-liposomes in animals. Use these distribution results to calculate the radiation absorbed dose distribution of 186Re / 188Re-liposomes in tumors and normal tissues for future use in human breast cancer brachytherapy.
A newly conceived approach for locally treating cancer with short range radionuclides has the potential to prevent the reoccurrence of breast cancer following initial treatment. This new approach could increase the likelihood of complete tumor cell eradication while reducing damage to normal breast tissue. Frequently, following surgery to remove breast cancer, additional therapies are performed to ensure complete eradication of tumor cells which may reside in the surgical area and decrease the probability of tumor recurrence. One treatment option used after breast conserving surgery is known as brachytherapy. Compared with another strategy where external beams of radiation are delivered from outside of the body after surgery, brachytherapy has an advantage of causing less radiation damage to normal breast tissue. However, the current brachytherapy method still induces a relatively high radiation absorbed dose to normal tissue due to the high penetration of gamma rays. This limits the radiation dose that can be applied to kill the tumor cells during treatment and decreases the probability of complete eradication of tumor cells in surgical area. In addition, this brachytherapy method cannot treat nearby lymph nodes where tumor cells may have migrated. We propose a new brachytherapy strategy which delivers lipid nanoparticles (liposomes) that contain the therapeutic beta emitting radionuclide, rhenium-186, (high energy electrons) directly into the surgical area. Since the beta radiation from rhenium-186 has a shorter penetration distance (a few millimeters), the radioactivity applied to surgical area will result in a much lower radiation dose to normal breast tissue. This liposome carrier system will protect the rhenium-186 from rapidly leaving the surgical area, thus leading to a higher radiation dose delivered to the surgical area compared with normal tissues. In addition, a fraction of rhenium-186-liposomes will migrate to lymph nodes and accumulate there, which will enable the concurrent killing of tumor cells that may have migrated to lymph nodes. Another advantage of this brachytherapy strategy is that specific targeting molecules can be easily attached to the surface of the nanoparticles. These modified nanoparticles carrying rhenium-186 can specifically target the tumor cells and thereby achieve a more specific tumor cell eradication. Specific aims related to this proposal will determine if the proposed breast cancer brachytherapy technique is efficacious and practical in clinical use by answering the following questions: 1) What is the best nanoparticle size for this brachytherapy method? 2) Is there a significant enhancement in tumor cell eradication when the nanoparticles have specific tumor cell targeting capability? 3) What is the radiation dose distribution in surgical cavity, lymph nodes, normal breast tissue, and other normal tissues, when nanoparticles containing rhenium-186 are administered to the surgical area?