Combination of gemcitabine with cell-penetrating peptides: A pharmacokinetic approach using in silico tools

Gemcitabine is an anticancer drug used to treat a wide range of solid tumors and is a first line treatment for pancreatic cancer. Our group has previously developed novel conjugates of gemcitabine with cell-penetrating peptides (CPP), and here we report some preliminary data regarding the pharmacokinetics of gemcitabine, two gemcitabine-CPP conjugates and respective CPP gathered from GastroPlus™, and analyze these results considering our previous evaluation of gemcitabine release and conjugates’ bioactivity. Additionally, seeking to shed some light on the relation between the penetration ability of CPP and their physicochemical properties, chemical descriptors for the 20 natural amino acids were calculated, a new principal property scale (z-scale) was created and CPP prediction models were developed, establishing quantitative structure-activity relationships (QSAR). The z-scores of the peptides conjugated with gemcitabine are presented and analyzed with the aforementioned data. ; This work has been financed by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI) and Portugal 2020, and Portuguese funds through Fundação para a Ciência e a Tecnologia (FCT, Portugal), in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274), and through grant UID/QUI/50006/2019 (LAQV-REQUIMTE). NV also acknowledges support from FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004. AF thanks FCT for a doctoral fellowship (PD/BD/135120/2017).