Reactive oxygen species (ROS)-responsive polymersomes with site-specific chemotherapeutic delivery into tumors via spacer design chemistry

0523881 - ÚMCH 2021 RIV US eng J - Journal Article
Jäger, Eliezer - Sincari, Vladimir - Albuquerque, L. J. C. - Jäger, Alessandro - Humajová, J. - Kučka, Jan - Pankrác, J. - Páral, P. - Heizer, T. - Janoušková, Olga - Konefal, Rafal - Pavlova, Ewa - Sedláček, Ondřej - Giacomelli, F. C. - Poučková, P. - Šefc, L. - Štěpánek, Petr - Hrubý, Martin
Reactive oxygen species (ROS)-responsive polymersomes with site-specific chemotherapeutic delivery into tumors via spacer design chemistry.
Biomacromolecules. Roč. 21, č. 4 (2020), s. 1437-1449. ISSN 1525-7797. E-ISSN 1526-4602
R&D Projects: GA ČR(CZ) GA17-09998S; GA MŠMT(CZ) 8J18FR038; GA MŠMT(CZ) LM2015064; GA MŠMT(CZ) LO1507; GA MZd(CZ) NV16-30544A; GA TA ČR(CZ) TN01000008
Research Infrastructure: Czech-BioImaging - 90062
Institutional support: RVO:61389013
Keywords : polyredoxomes * block copolymer * reactive oxygen species
OECD category: Polymer science
Impact factor: 6.988, year: 2020
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acs.biomac.9b01748

The lack of cellular and tissue specificities in conventional chemotherapies along with the generation of a complex tumor microenvironment (TME) limits the dosage of active agents that reaches tumor sites, thereby resulting in ineffective responses and side effects. Therefore, the development of selective TME-responsive nanomedicines is of due relevance toward successful chemotherapies, albeit challenging. In this framework, we have synthesized novel, ready-to-use ROS-responsive amphiphilic block copolymers (BCs) with two different spacer chemistry designs to connect a hydrophobic boronic ester-based ROS sensor to the polymer backbone. Hydrodynamic flow focusing nanoprecipitation microfluidics (MF) was used in the preparation of well-defined ROS-responsive PSs. These were further characterized by a combination of techniques [1H NMR, dynamic light scattering (DLS), static light scattering (SLS), transmission electron microscopy (TEM), and cryogenic TEM (cryo-TEM)]. The reaction with hydrogen peroxide releases an amphiphilic phenol or a hydrophilic carboxylic acid, which affects polymersome (PS) stability and cargo release. Therefore, the importance of the spacer chemistry in BC deprotection and PS stability and cargo release is herein highlighted. We have also evaluated the impact of spacer chemistry on the PS-specific release of the chemotherapeutic drug doxorubicin (DOX) into tumors in vitro and in vivo. We demonstrate that by spacer chemistry design one can enhance the efficacy of DOX treatments (decrease in tumor growth and prolonged animal survival) in mice bearing EL4 T cell lymphoma. Side effects (weight loss and cardiotoxicity) were also reduced compared to free DOX administration, highlighting the potential of the well-defined ROS-responsive PSs as TME-selective nanomedicines. The PSs could also find applications in other environments with high ROS levels, such as chronic inflammations, aging, diabetes, cardiovascular diseases, and obesity.
Permanent Link: http://hdl.handle.net/11104/0308402