Chemical conjugations of Sgc8-c with the lymphoma drug dasatinib to generate selective biotherapeutics

RESEARCH ARTICLE

OpenAccess

ISSN: 2514-3247
Aptamers 
(2021), Vol 5, in press

Published online: 18 October 2021

Full Text (Sicco ~855kb) | (Sicco Supplementary Data ~1108kb) (PubMed Central Record HTML) | (PubMed) | (References)

Estefanía Sicco 1, Lucía Almeida 1, María Moreno 2, Victoria Calzada 1,*, Hugo Cerecetto 1,*

Área de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, 11400 Montevideo, Uruguay

Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, 11600 Montevideo, Uruguay


*Correspondence to: Victoria Calzada, Email: vcalzada@cin.edu.uy; Hugo Cerecetto, Email: hcerecetto@cin.edu.uy


Received: 16 July 2021 | Revised: 13 October 2021 | Accepted: 18 October 2021


© Copyright The Author(s). This is an open access article, published under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0). This license permits non-commercial use, distribution and reproduction of this article, provided the original work is appropriately acknowledged, with correct citation details.


ABSTRACT

The conjugation of drugs to target therapeutics has become a promising method that could improve the efficacy of therapy and reduce side effects. Herein, we describe the efforts to covalently link the anti-lymphoma agent dasatinib to the truncated aptamer Sgc8-c, expecting the new hybrids to specifically damage lymphoma cells but with minimal toxicity towards non-target cells. Two linkages, ester and carbamate, with variable pH labilities were used to connect Sgc8-c with dasatinib. Different reaction conditions were studied by varying the solvent, time, temperature, heat source, pH and counter-ions. Each product from the reaction mixture was analysed by qualitative electrospray ionization time-of-flight mass spectrometry, identifying the nucleic acid modifications formed under the different experimental conditions. Among the reactions, depurinations from the 3´-extreme mainly occurred as lateral processes. Preparation of the carbamate-linked Sgc8-c–dasatinib hybrid Sgc8-c-carb-da was successful but the ester-linked hybrid only produced lateral undesired products. The potential biotherapeutic Sgc8-c-carb-da displayed the ability to trigger dasatinib at endosomal pH, which is optimal because this could be the aptamer’s cellular uptake route.

KEYWORDS: biotherapeutics, Sgc8-c, dasatinib, drug delivery, synthesis, depurination