Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for cardiovascular toxicity

Jason H. Gill, Paul M. Loadman, Steven D. Shnyder, Patricia Cooper, Jennifer Xavier, Goreti Ribeiro Morais, Laurence H. Patterson, Robert A. Falconer

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Development of therapeutic strategies for tumor-selective delivery of therapeutics through exploitation of the proteolytic tumor phenotype has significant scope for improvement of cancer treatment. ICT2588 is a peptide-conjugated prodrug of the vascular disrupting agent (VDA) azademethylcolchicine developed to be selectively hydrolyzed by matrix metalloproteinase-14 (MMP-14) within the tumor. In this report, we extend our previous proof-of-concept studies and demonstrate the therapeutic potential of this agent against models of human colorectal, lung, breast, and prostate cancer. In all tumor types, ICT2588 was superior to azademethylcolchicine and was greater or comparable to standard clinically used agents for the respective tumor type. Prodrug activation in clinical human lung tumor homogenates relative to stability in human plasma and liver was observed, supporting clinical translation potential. A major limiting factor to the clinical value of VDAs is their inherent cardiovascular toxicity. No increase in plasma von Willebrand factor (vWF) levels, an indicator of systemic vascular dysfunction and acute cardiovascular toxicity, was detected with ICT2588, thereby supporting the tumor-selective activation and reduced potential of ICT2588 to cause cardiovascular toxicity. Our findings reinforce the improved therapeutic index and tumor-selective approach offered by ICT2588 and this nanotherapeutic approach.

Original languageEnglish (US)
Pages (from-to)1294-1300
Number of pages7
JournalMolecular Pharmaceutics
Volume11
Issue number4
DOIs
StatePublished - Apr 7 2014

Fingerprint

Prodrugs
Neoplasms
Therapeutics
Blood Vessels
Matrix Metalloproteinase 14
ICT2588
von Willebrand Factor
Colorectal Neoplasms
Lung Neoplasms
Prostatic Neoplasms
Breast Neoplasms
Phenotype
Lung
Peptides
Liver

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery
  • Medicine(all)

Cite this

Gill, J. H., Loadman, P. M., Shnyder, S. D., Cooper, P., Xavier, J., Ribeiro Morais, G., ... Falconer, R. A. (2014). Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for cardiovascular toxicity. Molecular Pharmaceutics, 11(4), 1294-1300. https://doi.org/10.1021/mp400760b
Gill, Jason H. ; Loadman, Paul M. ; Shnyder, Steven D. ; Cooper, Patricia ; Xavier, Jennifer ; Ribeiro Morais, Goreti ; Patterson, Laurence H. ; Falconer, Robert A. / Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for cardiovascular toxicity. In: Molecular Pharmaceutics. 2014 ; Vol. 11, No. 4. pp. 1294-1300.
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Gill, JH, Loadman, PM, Shnyder, SD, Cooper, P, Xavier, J, Ribeiro Morais, G, Patterson, LH & Falconer, RA 2014, 'Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for cardiovascular toxicity', Molecular Pharmaceutics, vol. 11, no. 4, pp. 1294-1300. https://doi.org/10.1021/mp400760b

Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for cardiovascular toxicity. / Gill, Jason H.; Loadman, Paul M.; Shnyder, Steven D.; Cooper, Patricia; Xavier, Jennifer; Ribeiro Morais, Goreti; Patterson, Laurence H.; Falconer, Robert A.

In: Molecular Pharmaceutics, Vol. 11, No. 4, 07.04.2014, p. 1294-1300.

Research output: Contribution to journalArticle

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AU - Loadman, Paul M.

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AU - Cooper, Patricia

AU - Xavier, Jennifer

AU - Ribeiro Morais, Goreti

AU - Patterson, Laurence H.

AU - Falconer, Robert A.

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Y1 - 2014/4/7

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