Synthesis, drug release, and biological evaluation of new anticancer drug-bioconjugates containing somatostatin backbone cyclic analog as a targeting moiety

Boris Redko, Elena Ragozin, Bazylevich Andreii, Tuchinsky Helena, Albeck Amnon, Shekhter Zahavi Talia, Oron Herman Mor, Kostenich Genady, Gellerman Gary

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Peptide conjugates containing somatostatin (SST) cyclic analogs as a targeting moiety are able to deliver chemotherapeutic agents specifically to cancer cells expressing SST receptors (SSTRs), and hence increasing their local efficacy while limiting the peripheral toxicity. Here, we report on the synthesis and biochemical characterization of new SSTR-specific anticancer peptide conjugates, with different anticancer payloads acting through different oncogenic mechanisms to evaluate their biological activities and to provide a comparative study of their drug release profiles. The SSTR2-specific backbone cyclic peptide 3207-86 was chosen for the synthesis of a variety of novel anticancer drug conjugates with a broad drug release capabilities. The N-terminus of 3207-86 was equipped with GABA to generate free amino group available for the conjugation of chlorambucil, Camptothecin (CPT), Combretastatin 4A, ABT-751, and Amonafide through the formation of various biodegradable bonds. The chemo- A nd biostability/drug release of all the synthetic compounds was investigated at various pHs and in the presence of mouse liver homogenate, respectively. Their selective cytotoxic effect was evaluated on several human cancer cell lines that overexpress SSTR2. Compared with the free drugs, our peptide-drug conjugates exhibited considerable cytotoxic effect on cancer cell lines versus low SSTR2-expressed human embryonic kidney cells. Functional versatility of the conjugates was reflected in the variability of their drug release profiles, whereas the conserved sequence of a selective binding to the SSTR2 likely preserved their binding to the receptor and consequently their favorable toxicity toward targeted cancer cells.

Original languageEnglish
Pages (from-to)743-752
Number of pages10
JournalBiopolymers
Volume104
Issue number6
DOIs
StatePublished - 1 Nov 2015

Keywords

  • SPPS
  • SSTR
  • cancer
  • conjugate
  • stability profile
  • targeted drug delivery

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