Nanoparticle-based Targeting Tumor Neoangiogenesis to Improve Surgical Resection of PrimaryTtumor and Lung Metastasis in Advanced Osteosarcoma
Although the prognosis of osteosarcoma has greatly improved over the last two decades, overall survival remains dependant upon optimal local and metastatic tumor control. Tumor size and location along with efficacy of pre-operative imaging are limiting factors for optimal surgical excision. We have developed a highly selective αvß3 integrin-targeting system based on the multivalent presentation of cRGD4 by our patented RAFT (Regioselectively Addressable Functionalized Template) nanoparticle. This system provides strong binding on αvß3 integrin-rich osteosarcoma neoangiogenesis followed by receptor-mediated endocytosis. Using RAFT-cRGD4 combined with ICG’ fluorescent molecule, we showed improved tumor and lung metastasis margin detection in an orthotopic osteosarcoma model in rats. We now propose a phase 1-2 study in patients with relapsed/refractory osteosarcoma. Main objectives are: Aim 1. Assessing the safety of diagnostic nanoparticles. We will determine the safety and potency of clinical-grade RAFT-cRGD4-ICG’ administered intravenously in a dose-escalation fashion. Aim 2. Comparing the sensitivity of tumor margin detection using RAFT-cRGD4-ICG’ or conventional histopathology coloration. We will administer clinical-grade RAFT-cRGD4-ICG’ prior to surgery and subsequently compare tumor margins in the surgically-excised tumor/metastasis using conventional histopathology and fluorescence. We hypothesize that neoangiogenesis detection in tumor/metastasis using RAFT-cRGD4-ICG’ will delineate tumor margins similarly to conventional histopathology coloration. Aim 3. To assess the sensitivity of intra operative surgical margin detection using RAFT-cRGD4-ICG’ and a portable near-infrared camera. In a subsequent patient cohort, we will verify that clinical-grade RAFT-cRGD4-ICG’ administered intravenously prior to surgery correctly delineate tumor/metastasis extension upon in situ near-infrared illumination. After removing tumor/metastasis under near-infrared guidance, we will evaluate tumor margin control on histopathology samples using conventional histopathology and fluorescence. We hypothesize that in situ RAFT-cRGD4-ICG’-guided will improve tumor/metastasis excision and provide safe and efficient margin control compared to classical de visu surgery. At the end of this phase 1-2 study, we will have determined: i) the safety and optimal doses of RAFT-cRGD4-ICG’ in osteosarcoma patients; ii) the potency of intra operative tumor margin detection using RAFT-cRGD4-ICG’ and a portable near-infrared camera. Ultimately, we believe that this approach of tumor-margin optimization may improve both functional outcome of orthopedic limb reconstruction and overall survival of patients after tumor/metastasis excision