MMP-9 responsive PEG cleavable nanovesicles for efficient delivery of chemotherapeutics to pancreatic cancer

Prajakta S. Kulkarni, Manas K. Haldar, Rahul R. Nahire, Preeya Katti, Avinash H. Ambre, Wallace W. Muhonen, John B. Shabb, Sathish K.R. Padi, Raushan K. Singh, Pawel P. Borowicz, D. K. Shrivastava, Kalpana S. Katti, Katie Reindl, Bin Guo, Sanku Mallik

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Significant differences in biochemical parameters between normal and tumor tissues offer an opportunity to chemically design drug carriers which respond to these changes and deliver the drugs at the desired site. For example, overexpression of the matrix metalloproteinase-9 (MMP-9) enzyme in the extracellular matrix of tumor tissues can act as a trigger to chemically modulate the drug delivery from the carriers. In this study, we have synthesized an MMP-9-cleavable, collagen mimetic lipopeptide which forms nanosized vesicles with the POPC, POPE-SS-PEG, and cholesteryl-hemisuccinate lipids. The lipopeptide retains the triple-helical conformation when incorporated into these nanovesicles. The PEG groups shield the substrate lipopeptides from hydrolysis by MMP-9. However, in the presence of elevated glutathione levels, the PEG groups are reductively removed, exposing the lipopeptides to MMP-9. The resultant peptide-bond cleavage disturbs the vesicles lipid bilayer, leading to the release of encapsulated contents. These PEGylated nanovesicles are capable of encapsulating the anticancer drug gemcitabine with 50% efficiency. They were stable in physiological conditions and in human serum. Effective drug release was demonstrated using the pancreatic ductal carcinoma cells (PANC-1 and MIAPaCa-2) in two-dimensional and three-dimensional "tumor-like" spheroid cultures. A reduction in tumor growth was observed after intravenous administration of the gemcitabine-encapsulated nanovesicles in the xenograft model of athymic, female nude mice.

Original languageEnglish (US)
Pages (from-to)2390-2399
Number of pages10
JournalMolecular Pharmaceutics
Volume11
Issue number7
DOIs
StatePublished - Jul 7 2014

Keywords

  • drug delivery
  • drug release
  • matrix metalloproteinase-9
  • nanoparticle
  • pancreatic cancer cell spheroids
  • peptide

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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    Kulkarni, P. S., Haldar, M. K., Nahire, R. R., Katti, P., Ambre, A. H., Muhonen, W. W., Shabb, J. B., Padi, S. K. R., Singh, R. K., Borowicz, P. P., Shrivastava, D. K., Katti, K. S., Reindl, K., Guo, B., & Mallik, S. (2014). MMP-9 responsive PEG cleavable nanovesicles for efficient delivery of chemotherapeutics to pancreatic cancer. Molecular Pharmaceutics, 11(7), 2390-2399. https://doi.org/10.1021/mp500108p