Biologically activatable azobenzene polymers targeted at drug delivery and imaging applications

Taejun Eom, Wonjae Yoo, Sehoon Kim, Anzar Khan

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)

Abstract

Molecular design concepts are described for the preparation of azobenzene polymers capable of showing a tunable response to the rat liver microsome-induced side-chain self-immolation process under hypoxic conditions. It is shown that azobenzene nuclei carrying a donor/acceptor substitution pattern are the most active system towards the enzymatically triggered azobenzene cleavage reaction (half-life = t1/2 = 6 min). Their activity is followed by azobenzene nuclei carrying donor/donor (t1/2 = 20 min), electronically non-substituted (t1/2 = 72 min), and acceptor (t1/2 = 78 min) systems. This trend is preserved when a chemical stimulus, sodium dithionite, replaces the biological reducing conditions and demonstrates generality of the findings, and their potential in proteomics procedures. Furthermore, the established design concepts also permit for variation in polymer structure and topology while still maintaining the electronic substitution pattern. The steric constraints or the inherent character (hydrophilic/hydrophobic) of the azobenzene, however, does not alter the fate of the scission reaction. In all cases, the self-immolation process allows the polymer chain to convert from a chemically neutral to a cationic state. This structural transformation can be used as an activation mechanism (in vitro) to gain entry into cells through electrostatic interactions with the oppositely charged cell membrane and to deliver an anticancer drug. Interestingly, polymer structure now plays a role and bottlebrush-like copolymer show higher selectivity and faster cellular uptake. Finally, the best performing polymer allows for structural modulation into a fluorescent imaging probe. In vivo application to mice suffering from colitis confirms accumulation of the imaging probe in the diseased colon and cecum parts of the body where the endogenous microbial flora is known to produce the activation enzyme. This work, therefore, establishes general principles for the molecular design of biologically activatable and cleavable azobenzene-based polymeric scaffolds applicable to delivery and imaging applications.

Original languageEnglish
Pages (from-to)333-347
Number of pages15
JournalBiomaterials
Volume185
DOIs
Publication statusPublished - 2018 Dec

Bibliographical note

Funding Information:
AK acknowledges National Research Foundation of Korea grant funded by the Korean government (MSIP) ( NRF-2015R1D1A1A01057796 and NRF-18R1D1A1B07048527 ). SK acknowledges National Research Foundation of Korea ( 2017M3A9D8029942 and 2014M3C1A3054141 ) and the Development of Platform Technology for Innovative Medical Measurements Program from Korea Research Institute of Standards and Science ( KRISS–2017– GP2017-0020 ).

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

  • Activatable polymers
  • Enzymatic reduction
  • Polymer synthesis
  • Redox active
  • Reductive cleavage
  • Self-immolative

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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