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  3. Enhanced Antitumor Efficacy through an "AND gate" Reactive Oxygen-Species-Dependent pH-Responsive Nanomedicine Approach

Enhanced Antitumor Efficacy through an "AND gate" Reactive Oxygen-Species-Dependent pH-Responsive Nanomedicine Approach

  • Adv Healthc Mater. 2021 Jul;10(13):e2100304. doi: 10.1002/adhm.202100304.
Eliézer Jäger 1 2,  Jana Humajová 3,  Yusuf Dölen 2,  Jan Kučka 1,  Alessandro Jäger 1,  Rafał Konefał 1,  Jan Pankrác 4,  Ewa Pavlova 1,  Tomáš Heizer 4,  Luděk Šefc 4,  Martin Hrubý 1,  Carl G Figdor 2 5 6,  Martijn Verdoes 2 6
Affiliations

Affiliations

  • 1 Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky Sq. 2, Prague, 162 06, Czech Republic.
  • 2 Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26, Nijmegen, 6525 GA, The Netherlands.
  • 3 Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University, Salmovska 1, Prague, 120 00, Czech Republic.
  • 4 Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine, Charles University, Salmovská 3, Prague, 120 00, Czech Republic.
  • 5 Oncode Institute, Geert Grooteplein Zuid 26, Nijmegen, 6525 GA, The Netherlands.
  • 6 Institute for Chemical Immunology, Geert Grooteplein Zuid 26, Nijmegen, 6525 GA, The Netherlands.
PMID: 34050625 DOI: 10.1002/adhm.202100304
Abstract

Anticancer drug delivery strategies are designed to take advantage of the differential chemical environment in solid tumors independently, or to high levels of Reactive Oxygen Species (ROS) or to low pH, compared to healthy tissue. Here, the design and thorough characterization of two functionalizable "AND gate" multiresponsive (MR) block amphiphilic copolymers are reported, aimed to take full advantage of the coexistence of two chemical cues-ROS and low pH-present in the tumor microenvironment. The hydrophobic blocks contain masked pH-responsive side chains, which are exposed exclusively in response to ROS. Hence, the hydrophobic polymer side chains will undergo a charge shift in a very relevant pH window present in the extracellular milieu in most solid tumors (pH 5.6-7.2) after demasking by ROS. Doxorubicin (DOX)-loaded nanosized "AND gate" MR polymersomes (MRPs) are fabricated via microfluidic self-assembly. Chemical characterization reveals ROS-dependent pH sensitivity and accelerated DOX release under influence of both ROS and low pH. Treatment of tumor-bearing mice with DOX-loaded nonresponsive and "AND gate" MRPs dramatically decreases cardiac toxicity. The most optimal "AND gate" MRPs outperform free DOX in terms of tumor growth inhibition and survival, shedding LIGHT on chemical requirements for successful Cancer nanomedicine.

Keywords

cancer therapy; drug delivery; functional materials; multiresponsive polymers; nanomedicine.

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