Problem: Drug delivery to solid cancers via intravenous or oral infusion is generally inefficient, resulting in poor treatment outcomes for these cancers. An emerging strategy for overcoming this dilemma is the use of image- guided intratumoral drug infusion techniques. Yet, with this infusion route, achieving a homogeneous intratumoral drug distribution is challenging. When therapeutic radionuclides are used in place of drugs, homogeneity of the intratumoral therapy is improved due to the cross-fire of beta emissions. Purpose: The long-term goals of this research are: 1) to develop an image-guided interventional cancer liposomal radionuclide therapy system, which includes the use of image-guidance and dose planning for effective tumor therapy, and the performance of interventional intratumoral therapy;and 2) to develop an optimal therapeutic radiopharmaceutical for this therapy. The hypothesis of this proposal is that ideal liposome radiopharmaceutical formulations will be discovered for optimized image-guided interventional cancer radionuclide therapy.
Specific Aims are: 1) to determine intratumoral distribution and retention of liposomes of various liposome surface charges / sizes and with / without specific targeting to epidermal growth factor receptor (EGFR) after intratumoral infusion;2) to determine the therapeutic effectiveness of rhenium-186 (Re-186)-liposomes in tumor xenografts in nude rats;and 3) to determine radiation absorbed dose distribution using dosimetry for liposomes carrying therapeutic radionuclides. Methods: Liposome formulations will be tested in head and neck squamous cell carcinoma (HNSCC) xenograft model in nude rats. Non-invasive nuclear imaging with technetium-99m (Tc-99m)-labeled liposomes will be used to determine intratumoral retention and the distribution of liposomes within the tumor. Therapeutic efficiency of optimal liposome formulations carrying the therapeutic radionuclide, Re-186 will also be determined. Tumor pathology/histochemistry will be correlated with caliper measured therapy response and its potential influence on drug delivery. As a crucial component for development of an effective Re-186-liposome radiopharmaceutical, dosimetry of Re-186 liposomes in tumors and normal organs will also be studied. Outcomes: A better understanding of the optimal liposome characteristics for intratumoral retention and distribution following intratumoral infusion will be determined. The relationship between intratumoral retention and distribution and tumor response will also be determined. This will provide a crucial step for translation of this solid tumor therapy into humans. Benefits: This project will advance the use of this new interventional cancer therapy technique to benefit patients with solid cancers. Public Health Relevance: Solid cancer therapy is greatly compromised by insufficient drug delivery to tumors to ensure tumor eradication. The proposed new solid cancer therapy technique uses advanced medical imaging to guide the direct delivery of therapeutic radionuclides to the solid cancer. This method will potentially benefit cancer patients by enhancing tumor drug concentrations and thereby improving tumor therapy while decreasing damage to normal tissue.
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