Injectable alginate hydrogels for synergistic tumor combination therapy through repolarization of tumor-associated macrophages

Tingting Xiao, Jianzhi Zhu, Liang Jia, Hailong Che, Jie Liu, J. Deckers, Jan C.M. van Hest (Corresponding author), Xiangyang Shi (Corresponding author)

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20 Citations (Scopus)
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Abstract

Locally administered drug delivery systems are promising as they allow to circumvent the side effects associated with systematic administration. In this study, we constructed multifunctional hydrogels by simply mixing commercial alginate (ALG) sols with glucose oxidase (GOx)-conjugated polyacrylic acid-stabilized iron oxide nanoparticles (GPI NPs) and Toll-like receptor 7/8 agonist resiquimod (R848). The injectable sols were able to transform into hydrogels (GPI/R848@ALG) by the ionic cross-linking between ALG and physiological Ca2+ to trap the therapeutic components within the hydrogel framework. Upon intratumoral injection, the hydrogels were employed for starvation therapy, promoted chemodynamic therapy and tumor-associated macrophages (TAMs) repolarization. The energy supply was blocked by consuming the intratumoral glucose via the GOx-catalyzed conversion of glucose into gluconic acid and hydrogen peroxide (H2O2). In vitro results showed that the generated H2O2 could be further converted into highly cytotoxic hydroxyl radicals (·HO) by the Fenton reaction to induce enhanced chemodynamic therapy. The TAMs repolarization studies in vitro exhibited that the GPI/R848@ALG hydrogels up-regulated the expression of CD86 by 63% and down-regulated the proportion of CD206 by 14% with a synergistic effect of the presence of Fe3O4 and R848, suggesting that the multifunctional hydrogels exert functions to direct the remodeling of TAMs from the tumor supportive M2-like phenotype to the tumor destructive M1-like phenotype to further contribute to the antitumor effect. Moreover, both in vitro and in vivo experiments demonstrate that the multifunctional hydrogels exhibit admirable antitumor performance towards 4T1 tumors. This work thereby provides a promising multifunctional nanoplatform for synergistic cancer starvation therapy, chemodynamic therapy and TAMs repolarization.

Original languageEnglish
Pages (from-to)239-249
Number of pages11
JournalJournal of Controlled Release
Volume348
DOIs
Publication statusPublished - Aug 2022

Bibliographical note

Funding Information:
This study was financially supported by the Netherlands Ministry of Education, Culture and Science (Gravitation Program 024.001.035), the Sino-German Center for Research Promotion (GZ1505) and the National Natural Science Foundation of China (81761148028).

Publisher Copyright:
© 2022 The Authors

Keywords

  • Combination therapy
  • Ferromagnetic nanoparticles
  • Glucose oxidase
  • Injectable hydrogels
  • Resiquimod
  • Tumor-associated macrophages repolarization

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