Development of multi-drug loaded PEGylated nanodiamonds to inhibit tumor growth and metastasis in genetically engineered mouse models of pancreatic cancer

• Published in: Nanoscale 2019-11, Vol.11 (45), p.226-2218
• Main Authors: Madamsetty, Vijay Sagar, Pal, Krishnendu, Keshavan, Sandeep, Caulfield, Thomas R, Dutta, Shamit Kumar, Wang, Enfeng, Fadeel, Bengt, Mukhopadhyay, Debabrata
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Cancer; Cell Line, Tumor; Computer simulation; Curcumin - chemistry; Curcumin - pharmacokinetics; Curcumin - pharmacology; Diamonds; Drug Carriers - chemistry; Drug Carriers - pharmacokinetics; Drug Carriers - pharmacology; Drug delivery systems; Genetic engineering; Humans; Mice; Mice, Mutant Strains; Nanodiamonds - chemistry; Nanodiamonds - therapeutic use; Nanostructure; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Polyethylene glycol; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 2040-3364; 2040-3372
• DOI: 10.1039/c9nr05478b

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Nanomedicine, however, offers new opportunities to facilitate drug delivery in PDAC. Our previous work has shown that poly(ethylene glycol)-functionalized nanodiamond (ND) mediated drug delivery offered a considerable improvement over free drug in PDAC. Inspired by this result and guided by molecular simulations, we opted for simultaneous loading of irinotecan and curcumin in ultra-small PEGylated NDs (ND-IRT + CUR). We observed that ND-IRT + CUR was more efficacious in killing AsPC-1 and PANC-1 cells than NDs with single drugs. Using NDs functionalized with a near-infrared (NIR) dye, we demonstrated the preferential localization of the NDs in tumors and metastatic lesions. We further demonstrate that ND-IRT + CUR is capable of producing pronounced anti-tumor effects in two different clinically relevant, immune-competent genetic models of PDAC. Cytokine profiling indicated that NDs with or without drugs downregulated the expression of IL-10, a key modulator of the tumor microenvironment. Thus, using a combination of in silico , in vitro , and in vivo approaches, we show for the first time the remarkable anti-tumor efficacy of PEGylated NDs carrying a dual payload of irinotecan plus curcumin. These results highlight the potential use of such nano-carriers in the treatment of patients with pancreatic cancer. Schematic representation demonstrating the fabrication and in vivo evaluation of an immune-modulatory nano-formulation consisting of irinotecan and curcumin in immune-competent mouse models of pancreatic adenocarcinoma.