PDA-Based Glyconanomicelles for Hepatocellular Carcinoma Cells Active Targeting Via Mannose and Asialoglycoprotein Receptors

Hepatocellular carcinoma (HCC) is the sixth most common neoplasia and the fourth most common cause of cancer-related mortality worldwide. Sorafenib is the first-line molecular therapy for patients in an advanced stage of HCC. However, the recommended clinical dose of Sorafenib is associated with several complications, which derive from its lack of cell specificity and its very low water solubility. To circumvent these drawbacks, in the present study we developed two sugar-coated polydiacetylene-based nanomicelles-Sorafenib carriers targeting mannose and asialoglycoprotein receptors (MR and ASGPR, respectively). The strategies allowed the inducement of apoptosis and reduction of cell proliferation at a nanomolar, instead of micromolar, range in liver cancer cells. The study showed that, contrary to literature data, Sorafenib included into the pMicMan (Man = mannose) vector (targeting MR) is more efficient than pMicGal (Gal = galactose) (targeting ASGPR). Indeed, pMicMan increased the endosomal incorporation with an increased intracellular Sorafenib concentration that induced apoptosis and reduced cell proliferation at a low concentration range (10-20 nM).Financial support was provided by the Spanish Ministry of Economy and Competitiveness (CTQ2016-78580-C2-1-R to N.K.) and the Institute of Health Carlos III (ISCIII) (PI13/00021, PI16/00090, and PI19/01266 to J.M.) both cofinanced by the European Regional Development Fund (ERDF) from FEDER and the European Social Fund (ESF), as well by the Andalusian Ministry of Economy, Science and Innovation (P07-FQM-2774 to N.K., CV20-04221 to N.K. P20_00882 to N.K. and CTS-6264 to J.M.), the PAIDI Program from the Andalusian Government (FQM-313 to N.K., CV20-04221 to N.K., P20_00882 to N.K., P20_00882 to N.K., and CTS-0664 to J.M.), the Andalusian Ministry of Health (PI-00025-2013, and PI-0198-2016 to J.M.), and the CSIC (CSIC–COV19-047). We thank the Biomedical Research Network Center for Liver and Digestive Diseases founded by the ISCIII and cofinanced by FEDER “A way to achieve Europe” and ERDF for their financial support. The COST action CA-18132 “Functional Glyconanomaterials for the Development of Diagnostic and Targeted Therapeutic Probe” is also acknowledged. E.R.B., C.C.A., and P. de la C.-O. were supported by FPU predoctoral fellowship (FPU15/04267, FPU17/00190, and FPU17/00026) from Spanish Ministry of Education, Culture and Sports. E.N.-V. was supported by the predoctoral i-PFIS IIS-enterprise contract in science and technologies in health (IFI18/00014) from ISCiii.Peer reviewe