This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Current clinical practice for diagnosis, prognosis and deciding on treatment options for deeply invading cutaneous melanomas involves a process called sentinel lymph node biopsy, which entails injecting a dye and radioistope at the site of the primary lesion and allowing it to drain to the surrounding lymphatics. An agent is urgently needed to add to the dye for imaging, to halt invasion and to kill melanoma cells by targeting key genes regulating these processes, which has potential to halt spread at its very earliest stages. Therefore, the central hypothesis for the proposed research is that melanoma lymphatic invasion can be imagined using antibody targeted iron oxide nanoparticles. The rationale is that no targeted agents exist to halt cutaneous spread and lymph node dissemination at the time of excision of a primary melanoma skin lesion, which could aid in diagnosis and treatment. The central hypothesis will be tested by creating nanoliposomes conjugated to antibody GD2, recognizing epitopes preferentially present on invasive melanoma cells, expressing tumor suppressor genes (CD82 and PTEN) and inhibiting oncogene (V600E)B-Raf to synergistically inhibit melanoma cell survival. Second, a novel nanotechnology capable of detecting and killing melanoma cells metastasizing through the lymphatic system of animals would be developed. This would involve creating antibody 9.2.27 conjugated iron oxide nanoparticles to detect melanoma cells invading through the lymphatic system using MRI and combining it with nanoliposomes conjugated to antibody GD2, containing plasmids for expressing suppressor genes CD82 and PTEN as well siRNA for targeting the key melanoma oncogene (V600E)B-Raf. These discoveries would be highly significant, providing a novel agent to detect and treat lymphatically invading melanoma, which has significant potential to decrease mortality rates.
SPECIFIC AIMS No targeted agents are available to halt invasive melanoma dissemination in the lymphatic system at the time of excision of a primary melanoma lesion. Agents to detect and synergistically target melanoma cells moving through the lymphatic system could be highly significant, enabling treatment while still invading the skin or lymphatic system, which has potential to decrease mortality rates resulting from metastatic dissemination. Currently, sentinel lymph node biopsy is used to determine disease staging, prognosis and treatment options for primary melanomas. A vital blue dye and radioactive isotope is injected at the site of the primary lesion, which drains through the lymphatic basin to the surrounding lymph nodes. Dye positive lymph nodes are then removed, sectioned and stained for metastatic cells. Presence of melanoma cells in lymph nodes is used for staging with presence of cancer cells in lymph nodes being a poor prognostic indicator. No agents are available that could be added to the dye that would synergistically halt invasion and kill melanoma cells. An agent of this type could prevent melanoma spread thereby reducing development of more aggressive disease, which would have significant clinical impact. Therefore, the central hypothesis for the proposed research is that melanoma lymph node invasion can be imagined using antibody targeted iron oxide nanoparticles. Furthermore, that these cells could be killed using antibody-targeted nanoliposomes carrying plasmids expressing CD82 and PTEN to halt invasion and trigger apoptosis respectively and liposomes delivering siRNA targeting B-Raf to halt melanoma cells'proliferative potential. This discovery would be highly significant, providing novel agents to treat lymphatically invading melanoma, which has potential to decrease mortality rates. The rationale for this approach is that no targeted agents are available to retard dissemination of invasive melanoma at the time of excision of a melanoma skin lesion, which could aid diagnosis and treatment.
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