2. Academic Validation
  3. Sequence modification of heptapeptide selected by phage display as homing device for HT-29 colon cancer cells to improve the anti-tumour activity of drug delivery systems

Sequence modification of heptapeptide selected by phage display as homing device for HT-29 colon cancer cells to improve the anti-tumour activity of drug delivery systems

  • Eur J Med Chem. 2019 Aug 15:176:105-116. doi: 10.1016/j.ejmech.2019.05.016.
Krisztina Kiss 1,  Beáta Biri-Kovács 1,  Rita Szabó 2,  Ivan Ranđelović 3,  Kata Nóra Enyedi 1,  Gitta Schlosser 1,  Ádám Orosz 4,  Bence Kapuvári 3,  József Tóvári 3,  Gábor Mező 5
Affiliations

Affiliations

  • 1 MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, 1117, Budapest, Hungary; Institute of Chemistry, Eötvös L. University, 1117, Budapest, Hungary.
  • 2 MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, 1117, Budapest, Hungary.
  • 3 Department of Experimental Pharmacology, National Institute of Oncology, 1122, Budapest, Hungary.
  • 4 Institute of Biophysics and Radiation Biology, Semmelweis University, 1444, Budapest, Hungary.
  • 5 MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, 1117, Budapest, Hungary; Institute of Chemistry, Eötvös L. University, 1117, Budapest, Hungary. Electronic address: gmezo@elte.hu.
PMID: 31100648 DOI: 10.1016/j.ejmech.2019.05.016
Abstract

Development of peptide-based conjugates for targeted tumour therapy is a current research topic providing new possibilities in Cancer treatment. In this study, VHLGYAT heptapeptide selected by phage display technique for HT-29 human colon Cancer was investigated as homing peptide for drug delivery. Daunomycin was conjugated to the N-terminus of the peptide directly or through Cathepsin B cleavable spacers. Conjugates showed moderate in vitro cytostatic effect. Therefore, sequence modifications were performed by Ala-scan and positional scanning resulting in conjugates with much higher bioactivity. Conjugates in which Gly was replaced by Amino acids with bulky apolaric side chains provided the best efficacy. The influence of the cellular uptake, stability and drug release on the anti-tumour activity was investigated. It was found that mainly the difference in the cellular uptake of the conjugates generated the distinct effect on cell viability. One of the most efficient conjugate Dau = Aoa-LRRY-VHLFYAT-NH2 showed tumour growth inhibition on orthotopically developed HT-29 colon Cancer in mice with negligible toxic side effect compared to the free drug. We also indicate that this sequence is not specific to HT-29 cells, but it has a remarkable effect on many other Cancer cells. Nevertheless, the Phe-containing conjugate was more active in all cases compared to the conjugate with the parent sequence. The literature data suggested that this sequence is highly overlapped with Peptides that recognize HSP70 membrane bound protein overexpressed in many types of tumours.

Keywords

Daunomycin; Drug delivery system; Drug release; Phage display; Small molecule drug conjugate; Targeted cancer therapy.

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