Abstract
Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed in many neuroendocrine tumors (NETs). SSTRs can be efficiently targeted with octreotide, a cyclic octapeptide that is derived from native somatostatin. The conjugation of cargoes to octreotide represents an attractive approach for effective tumor targeting. In this study, we conjugated octreotide to cryptophycin, which is a highly cytotoxic depsipeptide, through the protease cleavable Val-Cit dipeptide linker using two different self-immolative moieties. The biological activity was investigated in vitro and the self-immolative part largely influenced the stability of the conjugates. Replacement of cryptophycin by the infrared cyanine dye Cy5.5 was exploited to elucidate the tumor targeting properties of the conjugates in vitro and in vivo. The compound efficiently and selectively internalized in cells overexpressing SSTR2 and accumulated in xenografts for a prolonged time. Our results on the in vivo properties indicate that octreotide may serve as an efficient delivery vehicle for tumor targeting.
Highlights
Cancer therapy has experienced several paradigm changes during the last decade from small molecule drugs over targeted therapy with antibody-drug conjugates (ADCs) to approaches in immuno-oncology
These findings demonstrate that efficient tumor delivery can be achieved with small molecules, such as octreotide, and that cryptophycin is a valid payload for targeted tumor therapy
Cryptophycin-55 glycinate was selected as the payload and octreotide as the targeting moiety to develop cryptophycin conjugates that targeted SSTR2
Summary
Cancer therapy has experienced several paradigm changes during the last decade from small molecule drugs over targeted therapy with antibody-drug conjugates (ADCs) to approaches in immuno-oncology. Tumor therapy was based on cytotoxic drugs as mono or combination therapy (alkylating agents like cisplatin, chlorambucil, procarbazine, carmustine; antimetabolites like methotrexate, cytarabine, gemcitabine; microtubule-binding agents like vinblastine, paclitaxel, or topoisomerase inhibitors). Targeted therapy with antibody-drug conjugates (ADCs) and, more recently, small molecule-drug conjugates (SMDCs), has emerged as a viable alternative to enlarging the therapeutic window [2,3,4,5,6]. When compared to classical cytotoxic drugs, ADCs have the benefit of higher specificity towards tumor cells and controllable release mechanisms at the site of action. Small molecule ligands have been used to efficiently target tumors expressing the folate receptor [7], prostate-specific membrane antigen (PSMA) [8], carbonic anhydrase IX (CAIX) [9,10,11], and somatostatin receptors (SSTRs) [12]
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