A Physiologically Responsive Nanocomposite Hydrogel for Treatment of Head and Neck Squamous Cell Carcinoma via Proteolysis-targeting Chimeras Enhanced Immunotherapy.
Yaping WuXiaowei ChangGuizhu YangLi ChenQi WuJiamin GaoRan TianWenyun MuJohn Justin GoodingXin ChenShuyang SunPublished in: Advanced materials (Deerfield Beach, Fla.) (2023)
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 CaCO 3 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.
Keyphrases
- drug delivery
- cancer therapy
- reduced graphene oxide
- dendritic cells
- immune response
- drug release
- body mass index
- hyaluronic acid
- quantum dots
- carbon nanotubes
- wound healing
- tissue engineering
- solid phase extraction
- ejection fraction
- weight gain
- end stage renal disease
- prognostic factors
- oxidative stress
- visible light
- regulatory t cells
- gold nanoparticles
- squamous cell carcinoma
- high resolution
- dna repair
- dna binding
- squamous cell
- signaling pathway
- walled carbon nanotubes
- endoplasmic reticulum stress
- radiation therapy
- physical activity
- aqueous solution
- patient reported outcomes
- mass spectrometry
- chemotherapy induced
- cell proliferation
- ultrasound guided
- cell cycle arrest
- combination therapy
- human health
- pi k akt