Presentation Authors: Gregory Barton*, Yang Liu, Paolo Maccarini, Gregory Palmer, Wiguins Etienne, Wei Phin Tan, Tuan Vo-Dinh, Brant Inman, Durham, NC
Introduction: We developed a novel treatment for bladder cancer (BC): a combination of gold nanoparticle-based immune- and photothermal therapy called SYMPHONY, which ablates primary tumors, induces potent anti-tumor immunity, and abscopally destroys distant metastases. Here we analyzed toxicity and biodistribution of SYMPHONY gold nanostars in murine BC models.
Methods: MB49 syngeneic bladder tumors were grown in C57BL/6 mice to 100 mm2. Tumors were treated with SYMPHONY and tissues obtained from lung, liver, brain, spleen, kidney, heart, and intestine at selected timepoints from minutes to months post-therapy. Gold nanostars (GNS) were given via tail vein injection, dosed at 20mg/kg or 80 mg/kg. We assessed toxicity multiply. First, with histopathology on necropsied tissue to assess for organ injury. Second, blood chemistries and body weight were measured longitudinally. Third, F4/80 immunohistochemistry staining for macrophages was done in spleen and liver. Fourth, tissues were digested with aqua regia for inductively coupled plasma mass spectrometry (ICP-MS) to quantify gold mass within organ sites. GNS uptake was calculated as % injection dose (ID)/g tissue. Last, we labeled GNS with I-124, injected via tail vein at 20mg/kg and obtained positron emission tomography (PET) images at 0h, 4h, 24h, 48h, and 120h with an animal microPET scanner.
Results: H&E examination showed healthy and intact tissue. There was no significant difference between control and GNS-treated animals on pathology, nor in blood chemistry results, and no evidence of biochemical toxicity. F4/80 IHC staining showed GNS within macrophages but no inflammatory response triggered by the GNS. GNS uptake (%ID/g) was highest in the spleen (median 105%), then liver (40%), with remaining organs < 20%. No brain uptake was noted. I-124 labeled GNS PET imaging showed that GNS travelled to the liver and spleen after 24 hours, and that free I-124 leached into the thyroid (Figure).
Conclusions: SYMPHONY treatment using gold nanostars shows no evidence of significant toxicity in BC models; this therapy should be safe to translate to humans. Biodistribution studies show gold metabolism with the splenic and hepatic reticuloendothelial system as the primary method of disposal. SYMPHONY provides local and distant BC control and is an exciting new therapy for BC.
Source of Funding: DOD grant WXWH-17-1-0567