INTRODUCTION: Standard-of-care systemic chemotherapies for pancreatic ductal adenocarcinoma (PDAC) currently have limited clinical benefits, in addition to causing adverse side effects in many patients. One factor known to contribute to the poor chemotherapy response is the poor drug diffusion into PDAC tumors. Novel treatment methods are therefore drastically needed to improve targeted delivery of treatments. Here, we evaluated the efficacy of the 3DNA® Nanocarrier (3DNA) platform to direct delivery of therapeutics to PDAC tumors in vivo.
MATERIALS AND METHODS: A panel of PDAC cell lines and a patient tissue microarray were screened for established tumor-specific proteins to identify targeting moieties for active targeting of the 3DNA. NRG mice with or without orthotopic MIA PaCa-2-luciferase PDAC tumors were treated intraperitoneally with 100 μl of fluorescently labeled 3DNA.
RESULTS: Folic acid and transferrin receptors were significantly elevated in PDAC compared to normal pancreas. Accordingly, both folic acid- and transferrin-conjugated 3DNA treatments significantly increased delivery of 3DNA specifically to tumors in comparison to unconjugated 3DNA treatment. In the absence of tumors, there was an increased clearance of both folic acid-conjugated 3DNA and unconjugated 3DNA, compared to the clearance rate in tumor-bearing mice. Lastly, delivery of siLuciferase by folic acid-conjugated 3DNA in an orthotopic model of luciferase-expressing PDAC showed significant and prolonged suppression of luciferase protein expression and activity.
CONCLUSION: Our study progresses the 3DNA technology as a reliable and effective treatment delivery platform for targeted therapeutic approaches in PDAC.
McCarthy, Grace A; Jain, Aditi; Di Niro, Roberto; Schultz, Christopher W.; Jiang, Wei; Yeo, Charles; Bowers, Jessica; Finan, Jennifer; Rhodes, Kelly; Casta, Lou; Hou, Vivi; Stefanoni, Anthony; Brown, Samantha Z; Nevler, Avinoam; Agostini, Lebaron C.; Getts, Lori; Getts, Robert; and Brody, Jonathan R, "A Novel 3DNA® Nanocarrier Effectively Delivers Payloads to Pancreatic Tumors" (2023). Department of Surgery Faculty Papers. Paper 240.
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