An Ethylenediamine‐based Switch to Render the Polyzwitterion Cationic at Tumorous pH for Effective Tumor Accumulation of Coated Nanomaterials

• Published in: Angewandte Chemie International Edition 2018-04, Vol.57 (18), p.5057-5061
• Main Authors: Ranneh, Abdul‐Hackam, Takemoto, Hiroyasu, Sakuma, Shunya, Awaad, Aziz, Nomoto, Takahiro, Mochida, Yuki, Matsui, Makoto, Tomoda, Keishiro, Naito, Mitsuru, Nishiyama, Nobuhiro
• Format: Article
• Language: English
• Subjects: Accumulation; Antifouling coatings; Antifouling substances; Betaine; betaines; Biomaterials; Biomedical materials; Cations; Cations - chemistry; Coating effects; Coatings; Constituents; Ethylenediamine; Ethylenediamines - chemistry; Humans; Hydrogen-Ion Concentration; Molecular Structure; Nanomaterials; Nanostructures - chemistry; Nanotechnology; Neoplasms - chemistry; net charge; pH effects; pH-responsiveness; Polymers; Polymers - chemistry; Protonation; Quantum dots; Quantum Dots - chemistry; Surface Properties; Switches; targeted delivery; Tumors
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201801641

Polyzwitterions are employed as coating polymers for biomaterials to induce an antifouling property on the surface. Fine‐tuning the betaine structure switches the antifouling property to be interactive with anionic tissue constituents in response to a tumorous pH gradient. The ethylenediamine moiety in the carboxybetaine enabled stepwise protonation and initiated the di‐protonation process around tumorous pH (6.5). The net charge of the developed polyzwitterion (PGlu(DET‐Car)) was thus neutral at pH 7.4 for antifouling, but was cationic at pH 6.5 for interaction with anionic constituents. Quantum dots coated with PGlu(DET‐Car) exhibited comparable stealth and enhanced tumor accumulation relative to the PEG system. The present study provides a novel design of smart switchable polyzwitterion based on a precise control of the net charge. The unique protonation behavior of an ethylenediamine‐based carboxybetaine generates a smart polyzwitterion, which switches its antifouling property to become tissue‐interactive by the recognition of the small pH window between physiological and tumorous conditions. Nanomaterials coated with the polyzwitterion achieved similar blood circulation, and enhanced tumor accumulation, relative to a conventional antifouling system.