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Enhanced Antitumor Efficacy through an “AND gate” Reactive Oxygen‐Species‐Dependent pH‐Responsive Nanomedicine Approach
Author(s) -
Jäger Eliézer,
Humajová Jana,
Dölen Yusuf,
Kučka Jan,
Jäger Alessandro,
Konefał Rafał,
Pankrác Jan,
Pavlova Ewa,
Heizer Tomáš,
Šefc Luděk,
Hrubý Martin,
Figdor Carl G.,
Verdoes Martijn
Publication year - 2021
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.202100304
Subject(s) - reactive oxygen species , nanomedicine , polymersome , doxorubicin , tumor microenvironment , chemistry , biophysics , amphiphile , nanoparticle , materials science , nanotechnology , combinatorial chemistry , polymer , copolymer , biochemistry , cancer research , chemotherapy , organic chemistry , biology , tumor cells , genetics
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.