A pH‐responsive polymer linked with immunomodulatory drugs: synthesis, characteristics and in vitro biocompatibility

Abstract

Cancer immunotherapy is a promising method for cancer therapy. Imiquimod (R837) is a molecule that could activate immune systems for cancer immunotherapy, but an easily manufactured biocompatible carrier to deliver R837 may be needed to overcome the disadvantages of R837. Micelles formed by biocompatible copolymers have been widely used to deliver chemotherapeutic drugs but not immunotherapeutic drugs. In this study, R837 was linked to an amphiphilic biodegradable copolymer mPEG‐b‐PLA via acid‐sensitive Schiff bases. The molecular structures were investigated by 1H nuclear magnetic resonance, gel permeation chromatography and Fourier transform infrared spectroscopy. The product could be self‐assembled into micelles with R837 content as high as 22.4%. Owing to acid‐cleavable Schiff bases, the release of R837 from micelles was markedly accelerated under acidic media. Consequently, the micelles linked with R837 stimulated the expression of major histocompatibility complex II‐stimulating molecules on the surface of RAW 264.7 macrophages at pH 6.5 but not pH 7.4. By using human umbilical vein endothelial cells as the in vitro model, it was shown that the polymer carriers and R837‐linked micelles were minimally cytotoxic and did not induce the activation of endothelial cells under physiological pH, which suggested the relatively high biocompatibility. In conclusion, this study successfully developed pH‐responsive immunotherapeutic drug‐loaded micelles that could activate macrophages at acidic pH in vitro. The high biocompatibility of the micelles to endothelial cells also indicated the potential uses under in vivo conditions.

Comparison of cytotoxicity of Ag/ZnO and Ag@ZnO nanocomplexes to human umbilical vein endothelial cells in vitro

“…This is also consistent with previous studies that showed that the presence of metal‐based NPs or metal ions alleviated the toxicity of other NPs (Hackenberg et al, 2017; Hernández‐Moreno et al, 2016; Hu, Hu, Li, & Zhao, 2016; Sun et al, 2020). However, we noticed that compared with soft materials such as liposomes (L. Shi, Wang, et al, 2020), polymers (Li et al, 2021; Zhou et al, 2020), chitosan (W. Han et al, 2019), lipids (Wan et al, 2018; Xie, Wan, Chen, Han, & Wang, 2020), soluble supramolecular NPs (X. Chen, Hu, et al, 2020), and proteins (An et al, 2020), the cytotoxicity of Ag–ZnO nanocomplexes was still relatively high. Nevertheless, the results from this study suggested that development of novel nanocomplexes might be a plausible way to reduce the toxicity of ZnO NPs.…”

Smart Polymeric Nanoparticles in Cancer Immunotherapy

“…Under acidic conditions, an accelerated release of R837 from micelles was observed. In RAW264.7 macrophages, R837-loaded micelles stimulate the expression of MHC II-stimulating molecules at pH 6.5, but not at physiologic pH [ 71 ].…”

Construction of pH/reduction dual responsive MSN-HAgel containing HApt for tumor targeting carriers

“…2,3 Chemotherapy, as one of the three main therapies, is limited by toxic and side effects to normal cells and drug resistance of cancer cells [4][5][6] because of the low concentration of effective drugs in the tumor area. 7 Therefore, effectively improving the targeting of anti-tumor drugs to tumor tissues and controlling the release of drugs have become the focus of contemporary medical research. 8 Smart drug-loaded nanocarriers, also called stimulusresponsive or environment-responsive drug-loaded nanocarriers, have attracted widespread attention and research.…”