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  3. A Physiologically Responsive Nanocomposite Hydrogel for Treatment of Head and Neck Squamous Cell Carcinoma via Proteolysis-targeting Chimeras Enhanced Immunotherapy

A Physiologically Responsive Nanocomposite Hydrogel for Treatment of Head and Neck Squamous Cell Carcinoma via Proteolysis-targeting Chimeras Enhanced Immunotherapy

  • Adv Mater. 2023 Jan 19;e2210787. doi: 10.1002/adma.202210787.
Yaping Wu 1,  Xiaowei Chang 2,  Guizhu Yang 1,  Li Chen 2,  Qi Wu 1,  Jiamin Gao 1,  Ran Tian 2,  Wenyun Mu 2,  John Justin Gooding 3,  Xin Chen 2,  Shuyang Sun 1
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, P. R. China.
  • 2 Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, P. R. China.
  • 3 School of Chemistry, Australian Centre for Nano-Medicine and ARC Australian Centre of Excellence in Convergent Bio-Nano Science and Technology, University of New South Wales, Sydney, 2052, Australia.
PMID: 36656993 DOI: 10.1002/adma.202210787
Abstract

Although immunotherapy has revolutionized oncotherapy, only ∼15% of head and neck squamous cell carcinoma (HNSCC) patients benefit from the current therapies. An immunosuppressive tumor microenvironment (TME) and dysregulation of the polycomb ring finger oncogene BMI1 are potential reasons for the failure. Herein, to promote immunotherapeutic efficacy against HNSCC, we developed an injectable nanocomposite hydrogel with a polymer framework (PLGA-PEG-PLGA) that is loaded with both imiquimod encapsulated CaCO3 nanoparticles (RC) and Cancer cell membrane (CCM) coated mesoporous silica nanoparticles containing a peptide-based proteolysis-targeting chimeras (PROTAC) for BMI1 and paclitaxel (PepM@PacC). Upon injection, this nanocomposite hydrogel undergoes in situ gelation, after which it degrades in the TME over time, releasing RC and PepM@PacC nanoparticles to respectively perform immunotherapy and chemotherapy. Specifically, the RC particles selectively manipulate tumor-associated macrophages and dendritic cells to activate a T-cell immune response, while CCM-mediated homologous targeting and endocytosis delivers the PepM@PacC particles into Cancer cells, where endogenous glutathione promotes disulfide bond cleavage to release the PROTAC peptide for BMI1 degradation and frees the paclitaxel from the particle pores to elicit Apoptosis meanwhile enhance immunotherapy. Thus, our nanocomposite hydrogel, which was designed to exploit multiple known vulnerabilities of HNSCC, succeeds in suppressing both growth and metastasis of HNSCC. This article is protected by copyright. All rights reserved.

Keywords

injectable nanocomposite hydrogel; integrative inhibition of tumor growth and metastasis; manipulation of tumor microenvironment; proteolysis-targeting chimeras enhanced immunotherapy; stimuli-responsive cargos delivery.

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