title: Synthesis, drug release, and biological evaluation of new anticancer drug-bioconjugates containing somatostatin backbone cyclic analog as a targeting moiety.
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- and 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.
authors.affiliation: Department of Biological Chemistry, Ariel University, Ariel 40700, Israel.|Department of Chemistry, The Julius Spokojny Bioorganic Chemistry Laboratory, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Boris
authors.initials: B
authors.lastname: Redko
authors.affiliation: Department of Biological Chemistry, Ariel University, Ariel 40700, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Ragozin
authors.affiliation: Department of Biological Chemistry, Ariel University, Ariel 40700, Israel.
authors.forename: Bazylevich
authors.initials: B
authors.lastname: Andreii
authors.affiliation: Department of Molecular Biology, Ariel University, Ariel 40700, Israel.
authors.forename: Tuchinsky
authors.initials: T
authors.lastname: Helena
authors.affiliation: Department of Chemistry, The Julius Spokojny Bioorganic Chemistry Laboratory, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Albeck
authors.initials: A
authors.lastname: Amnon
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Shekhter Zahavi
authors.initials: SZ
authors.lastname: Talia
authors.affiliation: The Advanced Technologies Center, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Oron-Herman
authors.initials: OH
authors.lastname: Mor
authors.affiliation: The Advanced Technologies Center, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Kostenich
authors.initials: K
authors.lastname: Genady
authors.affiliation: Department of Biological Chemistry, Ariel University, Ariel 40700, Israel.
authors.forename: Gellerman
authors.initials: G
authors.lastname: Gary
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D016503:Drug Delivery Systems; D006801:Humans; D051379:Mice; D013004:Somatostatin / Q000737:chemistry* / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000970:Antineoplastic Agents; D013004:Somatostatin
keywords: SPPS; SSTR; cancer; conjugate; stability profile; targeted drug delivery