Targeted-Lymphoma Drug Delivery System Based on the Sgc8-c Aptamer

SIMPLE SUMMARY: Aptamers are oligonucleotides that recognise their target with high specificity and affinity, having properties comparable to those of antibodies; however, they present important advantages in terms of their size, production, and modification. These characteristics make them excellent candidates for the development of new biotechnological platforms and their application as imaging or therapy agents. The Sgc8-c aptamer binds to PTK7, allowing the recognition of haemato-oncological malignancies, among others. Thus, we have developed aptamer-drug conjugates by chemical synthesis, hybridizing Sgc8-c and dasatinib, a drug proposed for lymphoma chemotherapy. Here, we demonstrated that the aptamer-drug conjugate, Sgc8-c-carb-da, specifically inhibited lymphocyte growth, produced cell death, caused cell proliferation arrest, and affected mitochondrial potential. In addition, Sgc8-c-carb-da showed higher (2.5-fold) cytotoxic effects than dasatinib in an in vitro cell-directed assay that mimics in vivo conditions. These findings provide proof-of-concept of the therapeutic value of Sgc8-c-carb-da for lymphoma, creating new opportunities for the chemical synthesis of novel targeted biotherapeutics. ABSTRACT: Aptamers are emerging as a promising new class of functional nucleic acids because they can specifically bind to any target with high affinity and be easily modified chemically with different pharmacophoric subunits for therapy. The truncated aptamer, Sgc8-c, binds to tyrosine-protein kinase-like 7 receptor, a promising cancer therapeutic target, allowing the recognition of haemato-oncological malignancies, among others. We have previously developed aptamer-drug conjugates by chemical synthesis, hybridizing Sgc8-c and dasatinib, a drug proposed for lymphoma chemotherapy. One of the best-characterised Sgc8-c-dasatinib hybrids, namely Sgc8-c-carb-da, was capable of releasing dasatinib at an endosomal-pH. Herein, we probed the therapeutic potential of this aptamer-drug conjugate. Sgc8-c-carb-da specifically inhibited murine A20 B lymphocyte growth and produced cell death, mainly by late apoptosis and necrosis. In addition, Sgc8-c-carb-da generated an arrest in cell proliferation, with a cell cycle arrest in the Sub-G1-peak. The mitochondrial potential was altered accordingly to these pathways. Moreover, using an in vitro cell-targeting assay that mimics in vivo conditions, we showed that Sgc8-c-carb-da displayed higher (2.5-fold) cytotoxic effects than dasatinib. These findings provide proof-of-concept of the therapeutic value of Sgc8-c-carb-da for lymphoma, creating new opportunities for the chemical synthesis of targeted biotherapeutics.