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

Vijay Sagar Madamsetty, Krishnendu Pal, Sandeep Keshavan, Thomas R. Caulfield, Shamit Kumar Dutta, Enfeng Wang, Bengt Fadeel, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)22006-22018
Number of pages13
JournalNanoscale
Volume11
Issue number45
DOIs
StatePublished - Dec 7 2019

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Nanodiamonds
irinotecan
Tumors
Curcumin
Drug delivery
Pharmaceutical Preparations
Medical nanotechnology
Interleukin-10
Modulators
Polyethylene glycols
Coloring Agents
Dyes
Cytokines
Infrared radiation

ASJC Scopus subject areas

  • Materials Science(all)

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Development of multi-drug loaded PEGylated nanodiamonds to inhibit tumor growth and metastasis in genetically engineered mouse models of pancreatic cancer. / Madamsetty, Vijay Sagar; Pal, Krishnendu; Keshavan, Sandeep; Caulfield, Thomas R.; Dutta, Shamit Kumar; Wang, Enfeng; Fadeel, Bengt; Mukhopadhyay, Debabrata.

In: Nanoscale, Vol. 11, No. 45, 07.12.2019, p. 22006-22018.

Research output: Contribution to journalArticle

Madamsetty, Vijay Sagar ; Pal, Krishnendu ; Keshavan, Sandeep ; Caulfield, Thomas R. ; Dutta, Shamit Kumar ; Wang, Enfeng ; Fadeel, Bengt ; Mukhopadhyay, Debabrata. / Development of multi-drug loaded PEGylated nanodiamonds to inhibit tumor growth and metastasis in genetically engineered mouse models of pancreatic cancer. In: Nanoscale. 2019 ; Vol. 11, No. 45. pp. 22006-22018.
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