Colloidal gold, a sol comprised of nanoparticles of Au 0 , has been used as a therapeutic for the treatment of cancer as well as an indicator for immunodiagnostics. However, the use of these gold nanoparticles for in vivo drug delivery has never been described. This communication outlines the development of a colloidal gold (cAu) nanoparticle vector that targets the delivery of tumor necrosis factor (TNF) to a solid tumor growing in mice.The optimal vector, designated PT-cAu-TNF, consists of molecules of thiol-derivatized PEG (PT) and recombinant human TNF that are directly bound onto the surface of the gold nanoparticles. Following intravenous administration, PT-cAu-TNF rapidly accumulates in MC-38 colon carcinoma tumors and shows little to no accumulation in the livers, spleens (i.e., the RES) or other healthy organs of the animals. The tumor accumulation was evidenced by a marked change in the color of the tumor as it acquired the bright red/purple color of the colloidal gold sol and was co-

The synthesis of a series of thiolated paclitaxel analogs is described as part of a novel nanomedicine program aimed at developing formulations of paclitaxel that will bind to gold nanoparticles for tumor targeted drug delivery. Preliminary evaluation of the new nanomedicine comprised of 27 nm gold nanoparticles, tumor necrosis factor alpha (TNFα), thiolated polyethylene glycol (PEG-Thiol) and one of several thiolated paclitaxel analogs is presented.

3586 Background: CYT-6091 is the first tumor-targeted nanomedicine formulation designed to safely deliver an API that itself is not approved for systemic administration due to unacceptable toxicity. CYT-6091, consisting of tumor necrosis factor-α (TNF) covalently linked to pegylated colloidal gold nanoparticles, has been safely administered in preclinical models, demonstrating an increased T1/2 compared to native TNF, a documented trafficking of nanoparticles to tumor, and no hypotension, the known DLT for TNF. Methods: CYT-6091 was tested in a phase I open label trial in solid tumor, advanced stage patients. Patients (n = 3/dose), admitted to the NIH Clinical Center ICU, received two IV injections of CYT-6091 on day 0 and 14. Dosing started at 50 μg/m2 of TNF, up to 600 μg/m2. Vital signs were monitored and blood samples were drawn over 48 h. The primary endpoint of the study was to determine the MTD for CYT-6091. Secondary endpoints included PK, disease response (staged 45 days post treatment by RECIST), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Twenty-nine patients were treated. Even at the lowest dose (50 μg/m2), patients exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the 29 patients treated with doses of 50–600 μg/m2 showed a DLT hypotensive response, and in fact, no DLT was seen. T1/2 estimates for TNF, administered as CYT-6091, are 120, 131, 127, 146, 112, 113, 266, 371, and 160 minutes for 50, 100, 150, 200, 250, 300, 400, 500, 600 μg/m2, respectively (published T1/2 for native TNF is ∼27 minutes). In the 28 patients eligible for response assessment, there was 1 PR (100 μg/m2 dose, 7 months duration) and 3 SD (2, 2, and 3 months duration). Electron micrographs show gold nanoparticles in tumor biopsies. Conclusions: CYT-6091 is well tolerated at doses up to 600 μg/m2 of TNF, levels 3-times greater than the published MTD for native TNF. CYT-6091 targets tumors in humans. Efficacy studies in combination with chemotherapy are planned. [Table: see text]

No abstract

Triple negative breast cancer (TNBC) patients are insensitive to hormonal or anti-HER2 therapy and have a higher recurrence rate among all breast cancer subtypes. There is a lack of common therapeutic targets in TNBC due to its six distinct molecular characteristics. Recently, ~50% of TNBC cases were found to express the folate receptor alpha (FRα) on tumor cells. FRα is a GPI-anchored membrane glycoprotein capable of bringing folate-targeted small-molecule drug conjugates (SMDCs) inside the cell. EC1456 is a folic acid-tubulysin B hydrazide (TubBH) SMDC that specifically binds to the membrane FRα and is internalized by endocytosis. While encapsulated within the early endosome, EC1456 releases TubBH into the cytosol where it inhibits the polymerization of tubulin into microtubules, thus blocking spindle formation to arrest cells in metaphase which ultimately induces apoptosis. EC1456 is currently under Phase 1 clinical investigation in patients with common solid tumors [IND# 118,859]. The purpose of this study is to evaluate EC1456 activity in Champions TumorGraftTM TNBC patient-derived xenograft (PDX) models to help guide our drug development strategies. These PDX models were derived from patients who were treated with multiple lines of standard-of-care agents. A total of six low-passage, FR-positive TNBC models were tested against two different treatment regimens of EC1456 (once or twice a week for 2 weeks only). Plasma and tumor drug concentrations were quantified by LC-MS/MS using satellite study animals. The tumor-bearing animals were monitored for up to 60 days to assess both short-term (i.e. % TGI) and long-term (%PR, CR, TFS) anti-tumor responses. Using a stringent efficacy criteria (≥60% CR/TFS), 3 of the 6 TNBC models were found highly sensitive to EC1456 and 3 were found resistant. To identify potential gene signatures of EC1456 response, bioinformatics analysis was performed using existing RNA-seq data and compared across a broad panel of TumorGraftTM TNBC models, regardless of FR expression status. Specific biomarkers of interest were further analyzed by qRT-PCR using control tumors from the current study. Together, our analysis revealed potential resistance mechanisms associated with microtubule dynamics as well as a cancer cell’s ability to undergo apoptosis. Citation Format: Yingjuan Lu, Nikki L. Parker, Haiyan Chu, Michael R. Pugh, Satish I. Rao, Patrick J. Klein, Michael F. Ritchie, Lonnie D. Myer, Jennifer Jaskowiak, Christopher P. Leamon. Evaluation of anti-tumor efficacy of EC1456 in low-passage and pre-treated patient-derived xenograft models of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2057. doi:10.1158/1538-7445.AM2017-2057