Implication of linker length on cell cytotoxicity, pharmacokinetic and toxicity profile of gemcitabine-docetaxel combinatorial dual drug conjugate

Abstract

The present study investigates effect of linkers [zero length (without linker), short length linker (glycine and lysine) and long length linker (PEG1000, PEG2000 and PEG3500)] on pharmacokinetics and toxicity of docetaxel (DTX) and gemcitabine (GEM) bio-conjugates. Conjugates were synthesized via carbodiimide chemistry and characterized by 1H NMR and FTIR. Conjugation of DTX and GEM via linkers showed diverse physiochemical and plasma stability profile. Cellular uptake mechanism in MCF-7 and MDA-MB-231 cell lines revealed clathrin mediated internalization of bio-conjugates developed by using long length linkers, leading to higher cytotoxicity compared with free drug congeners. DTX-PEG3500-GEM and DTX-PEG2000-GEM demonstrated 4.21 and 3.81-fold higher AUC(0-∞) of GEM in comparison with GEM alone. DTX-PEG2000-GEM and DTX-PEG3500-GEM exhibited reduced hepato-, nephro- and haemolytic toxicity as evident via histopathology, biochemical markers and SEM analysis of RBCs. Conclusively, PEG2000 and PEG3500 significantly improved pharmacokinetics without any sign of toxicity and hence can be explored further for the development of dual-drug conjugates for better therapeutic efficacy. © 2018 Elsevier B.V.