Influence of the Topology of Poly(<span style="font-variant: small-caps">L</span>-Cysteine) on the Self-Assembly, Encapsulation and Release Profile of Doxorubicin on Dual-Responsive Hybrid Polypeptides
Dimitra Stavroulaki,
Iro Kyroglou,
Dimitrios Skourtis,
Varvara Athanasiou,
Pandora Thimi,
Sosanna Sofianopoulou,
Diana Kazaryan,
Panagiota G. Fragouli,
Andromahi Labrianidou,
Konstantinos Dimas,
Georgios Patias,
David M. Haddleton,
Hermis Iatrou
Affiliations
Dimitra Stavroulaki
Industrial Chemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, GR-15771 Athens, Greece
Iro Kyroglou
Industrial Chemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, GR-15771 Athens, Greece
Dimitrios Skourtis
Industrial Chemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, GR-15771 Athens, Greece
Varvara Athanasiou
Industrial Chemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, GR-15771 Athens, Greece
Pandora Thimi
Industrial Chemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, GR-15771 Athens, Greece
Sosanna Sofianopoulou
Hellenic Police Headquarters, Forensic Science Division, Chemical and Physical Examinations Department, GR-10442 Athens, Greece
Diana Kazaryan
Industrial Chemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, GR-15771 Athens, Greece
Panagiota G. Fragouli
DIDPE, Dyeing, Finishing, Dyestuffs and Advanced Polymers Laboratory, University of West Attica, 250 Thevon Street, GR-12241 Athens, Greece
Andromahi Labrianidou
Laboratory of Pharmacology, Faculty of Medicine, University of Thessaly, Viopolis, GR-41500 Larissa, Greece
Konstantinos Dimas
Laboratory of Pharmacology, Faculty of Medicine, University of Thessaly, Viopolis, GR-41500 Larissa, Greece
Georgios Patias
Department of Chemistry, University of Warwick, Gibbet Hill, Coventry CV4 7AL, UK
David M. Haddleton
Department of Chemistry, University of Warwick, Gibbet Hill, Coventry CV4 7AL, UK
Hermis Iatrou
Industrial Chemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, GR-15771 Athens, Greece
Τhe synthesis of a series of novel hybrid block copolypeptides based on poly(ethylene oxide) (PEO), poly(l-histidine) (PHis) and poly(l-cysteine) (PCys) is presented. The synthesis of the terpolymers was achieved through a ring-opening polymerization (ROP) of the corresponding protected N-carboxy anhydrides of Nim-Trityl-l-histidine and S-tert-butyl-l-cysteine, using an end-amine-functionalized poly(ethylene oxide) (mPEO-NH2) as macroinitiator, followed by the deprotection of the polypeptidic blocks. The topology of PCys was either the middle block, the end block or was randomly distributed along the PHis chain. These amphiphilic hybrid copolypeptides assemble in aqueous media to form micellar structures, comprised of an outer hydrophilic corona of PEO chains, and a pH- and redox-responsive hydrophobic layer based on PHis and PCys. Due to the presence of the thiol groups of PCys, a crosslinking process was achieved further stabilizing the nanoparticles (NPs) formed. Dynamic light scattering (DLS), static light scattering (SLS) and transmission electron microscopy (TEM) were utilized to obtain the structure of the NPs. Moreover, the pH and redox responsiveness in the presence of the reductive tripeptide of glutathione (GSH) was investigated at the empty as well as the loaded NPs. The ability of the synthesized polymers to mimic natural proteins was examined by Circular Dichroism (CD), while the study of zeta potential revealed the “stealth” properties of NPs. The anticancer drug doxorubicin (DOX) was efficiently encapsulated in the hydrophobic core of the nanostructures and released under pH and redox conditions that simulate the healthy and cancer tissue environment. It was found that the topology of PCys significantly altered the structure as well as the release profile of the NPs. Finally, in vitro cytotoxicity assay of the DOX-loaded NPs against three different breast cancer cell lines showed that the nanocarriers exhibited similar or slightly better activity as compared to the free drug, rendering these novel NPs very promising materials for drug delivery applications.
