Controlled Dissociation of Polymeric Micelles in Response to Oxidative Stress

Nanoparticle-based drug carriers that can respond to oxidative stress in tumor tissue have attracted attention for site-specific drug release. Taking advantage of the characteristic microenvironment in tumors, one of the attractive directions in drug delivery research is to design drug carriers that release drugs upon oxidation. A strategy to incorporate oxidation-sensitive thioether motifs such as thiomorpholine acrylamide (TMAM) to drug carriers has been often used to achieve oxidation-induced dissociation, thereby targeted drug release. However, those delivery systems often suffer from a slow dissociation rate due to the intrinsic hydrophobicity of the thioether structures. In this study, we aimed to enhance the dissociation rate of TMAM-based micelles upon oxidation. The random copolymers of N-isopropylacrylamide and TMAM (P(NIPAM/TMAM)) were designed as an oxidation-sensitive segment that showed a fast response to oxidative stress. We first synthesized P(NIPAM/TMAM) copolymers with different NIPAM:TMAM molar ratios. Those copolymers exhibited low critical solution temperatures (LCSTs) below 32 °C, which shifted to higher temperatures after oxidation. The changes in LCSTs depend on the NIPAM:TMAM molar ratios. At the NIPAM:TMAM molar ratio of 82:18, the LCSTs before and after oxidation were 17 and 54 °C, respectively. We then prepared micelles from the diblock copolymers of poly(N-acryloyl morpholine) (PAM) and P(NIPAM/TMAM). The micelles showed an accelerated dissociation rate upon oxidation compared to the micelles without NIPAM units. Furthermore, the doxorubicin (Dox)-loaded micelles showed enhanced relative toxicity in human colorectal cancer (HT29) cells over human umbilical vein endothelial cells (HUVECs). Our novel strategy to design an oxidation-sensitive micellar core comprising a P(NIPAM/TMAM) segment can be used as a chemotherapeutic delivery system that responds to an oxidative tumor microenvironment in an appropriate time scale.

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Work Title Controlled Dissociation of Polymeric Micelles in Response to Oxidative Stress
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Open Access
Creators
  1. Roujia Chang
  2. Binru Han
  3. Amira Ben Mabrouk
  4. Urara Hasegawa
License In Copyright (Rights Reserved)
Work Type Article
Publisher
  1. Biomacromolecules
Publication Date January 1, 2023
Publisher Identifier (DOI)
  1. https://doi.org/10.1021/acs.biomac.3c01156
Deposited March 31, 2024

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  • Created
  • Added Chang_et_al._Biomacromolecules_revised.pdf
  • Added Creator Roujia Chang
  • Added Creator Binru Han
  • Added Creator Amira Ben Mabrouk
  • Added Creator Urara Hasegawa
  • Published
  • Updated