Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancer

Welley S. Loc, Samuel S. Linton, Zachary R. Wilczynski, Gail Matters, Christopher O. McGovern, Thomas Abraham, Todd Fox, Christopher M. Gigliotti, Xiaomeng Tang, Amra Tabakovic, Jo Ann Martin, Gary Clawson, Jill P. Smith, Peter J. Butler, Mark Kester, James Hansell Adair

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Drug resistant cancers like pancreatic ductal adenocarcinoma (PDAC) are difficult to treat, and nanoparticle drug delivery systems can overcome some of the limitations of conventional systemic chemotherapy. In this study, we demonstrate that FdUMP and dFdCMP, the bioactive, phosphorylated metabolites of the chemotherapy drugs 5-FU and gemcitabine, can be encapsulated into calcium phosphosilicate nanoparticles (CPSNPs). The non-phosphorylated drug analogs were not well encapsulated by CPSNPs, suggesting the phosphate modification is essential for effective encapsulation. In vitro proliferation assays, cell cycle analyses and/or thymidylate synthase inhibition assays verified that CPSNP-encapsulated phospho-drugs retained biological activity. Analysis of orthotopic tumors from mice treated systemically with tumor-targeted FdUMP-CPSNPs confirmed the in vivo up take of these particles by PDAC tumor cells and release of active drug cargos intracellularly. These findings demonstrate a novel methodology to efficiently encapsulate chemotherapeutic agents into the CPSNPs and to effectively deliver them to pancreatic tumor cells.

Original languageEnglish (US)
Pages (from-to)2313-2324
Number of pages12
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume13
Issue number7
DOIs
StatePublished - Oct 1 2017

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Bioactivity
Pancreatic Neoplasms
Encapsulation
Nanoparticles
Calcium
Tumors
Fluorodeoxyuridylate
Chemotherapy
Pharmaceutical Preparations
Cells
gemcitabine
Assays
Neoplasms
Adenocarcinoma
Therapeutics
Drug Therapy
Thymidylate Synthase
Drug Delivery Systems
Metabolites
Fluorouracil

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

Cite this

Loc, Welley S. ; Linton, Samuel S. ; Wilczynski, Zachary R. ; Matters, Gail ; McGovern, Christopher O. ; Abraham, Thomas ; Fox, Todd ; Gigliotti, Christopher M. ; Tang, Xiaomeng ; Tabakovic, Amra ; Martin, Jo Ann ; Clawson, Gary ; Smith, Jill P. ; Butler, Peter J. ; Kester, Mark ; Adair, James Hansell. / Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancer. In: Nanomedicine: Nanotechnology, Biology, and Medicine. 2017 ; Vol. 13, No. 7. pp. 2313-2324.
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abstract = "Drug resistant cancers like pancreatic ductal adenocarcinoma (PDAC) are difficult to treat, and nanoparticle drug delivery systems can overcome some of the limitations of conventional systemic chemotherapy. In this study, we demonstrate that FdUMP and dFdCMP, the bioactive, phosphorylated metabolites of the chemotherapy drugs 5-FU and gemcitabine, can be encapsulated into calcium phosphosilicate nanoparticles (CPSNPs). The non-phosphorylated drug analogs were not well encapsulated by CPSNPs, suggesting the phosphate modification is essential for effective encapsulation. In vitro proliferation assays, cell cycle analyses and/or thymidylate synthase inhibition assays verified that CPSNP-encapsulated phospho-drugs retained biological activity. Analysis of orthotopic tumors from mice treated systemically with tumor-targeted FdUMP-CPSNPs confirmed the in vivo up take of these particles by PDAC tumor cells and release of active drug cargos intracellularly. These findings demonstrate a novel methodology to efficiently encapsulate chemotherapeutic agents into the CPSNPs and to effectively deliver them to pancreatic tumor cells.",
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Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancer. / Loc, Welley S.; Linton, Samuel S.; Wilczynski, Zachary R.; Matters, Gail; McGovern, Christopher O.; Abraham, Thomas; Fox, Todd; Gigliotti, Christopher M.; Tang, Xiaomeng; Tabakovic, Amra; Martin, Jo Ann; Clawson, Gary; Smith, Jill P.; Butler, Peter J.; Kester, Mark; Adair, James Hansell.

In: Nanomedicine: Nanotechnology, Biology, and Medicine, Vol. 13, No. 7, 01.10.2017, p. 2313-2324.

Research output: Contribution to journalArticle

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AU - Loc, Welley S.

AU - Linton, Samuel S.

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AU - Matters, Gail

AU - McGovern, Christopher O.

AU - Abraham, Thomas

AU - Fox, Todd

AU - Gigliotti, Christopher M.

AU - Tang, Xiaomeng

AU - Tabakovic, Amra

AU - Martin, Jo Ann

AU - Clawson, Gary

AU - Smith, Jill P.

AU - Butler, Peter J.

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AU - Adair, James Hansell

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