New somatostatin-drug conjugates for effective targeting pancreatic cancer

[Display omitted] •New cyclic peptide-drug conjugates for effective targeting pancreatic cancer were discovered.•These conjugates comprising cyclic peptides SSTp-58 and SSTp-86 that are based on the sandostatin motive.•The drug conjugates specifically accumulated in tumors in the animal xenograft mo...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry Vol. 26; no. 13; pp. 3825 - 3836
Main Authors:	Ragozin, E., Hesin, A., Bazylevich, A., Tuchinsky, H., Bovina, A., Shekhter Zahavi, T., Oron-Herman, M., Kostenich, G., Firer, M.A., Rubinek, T., Wolf, I., Luboshits, G., Sherman, M.Y., Gellerman, G.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 30-07-2018
Subjects:	Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Camptothecin - chemistry Cell Line, Tumor Cell Survival - drug effects Humans Indoles - chemistry Kidney - metabolism Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Peptide conjugate Peptides, Cyclic - chemical synthesis Peptides, Cyclic - chemistry Receptors, Somatostatin - antagonists & inhibitors Receptors, Somatostatin - genetics Receptors, Somatostatin - metabolism Somatostatin - chemistry SPPS SSTR Stability profiles Stilbenes - chemistry Targeted drug delivery Tissue Distribution Xenograft Model Antitumor Assays DMSO PyBOP MALDI SPPS DIPEA DMBA Stability profiles ACN cAMP rpm TFA DCM LC-MS Targeted drug delivery SST Pancreatic cancer DMAP SSTR XTT Fmoc DMF Peptide conjugate HPLC TIPS
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Summary:	[Display omitted] •New cyclic peptide-drug conjugates for effective targeting pancreatic cancer were discovered.•These conjugates comprising cyclic peptides SSTp-58 and SSTp-86 that are based on the sandostatin motive.•The drug conjugates specifically accumulated in tumors in the animal xenograft model. Pancreatic cancer poorly responds to available drugs, and finding novel approaches to target this cancer type is of high significance. Here, based on a common property of pancreatic cancer cells to express somatostatin receptors (SSTR), we designed drug conjugates with novel somatostatin-derived cyclic peptides (SSTp) with broad selectivity towards SSTR types to facilitate drug targeting of the pancreatic cancer cells specifically. Uptake of our newly designed SSTps was facilitated by SSTRs expressed in the pancreatic cancers, including SSTR2, SSTR3, SSTR4 and SSTR5. Three major drugs were conjugated to our best SSTps that served as delivery vehicles, including Camptothecin (CPT), Combretastatin-4A (COMB) and Azatoxin (AZA). All designed drug conjugates demonstrated penetration to pancreatic cancer cell lines, and significant toxicity towards them. Furthermore, the drug conjugates specifically accumulated in tumors in the animal xenograft model, though some accumulation was also seen in kidney. Overall these findings lay the basis for development of novel drug series that could target the fatal pancreatic cancer.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2018.06.032