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A Facile and Efficient Approach for the Production of Reversible Disulfide Cross-linked Micelles
Published on: December 23, 2016
ROS-responsive and triple-synergistic mitochondria-targeted polymer micelles for efficient induction of ICD in tumor
Xiaoxiao Hu1, Mo Zhang1, Cuilu Quan1
1School of Pharmacy, Key Laboratory of Innovative Drug Development and Evaluation, Hebei Medical University, No.361 Zhongshan East Road, Shijiazhuang, 050017, PR China.
Abstract:
Immunogenic cell death (ICD) represents a modality of apoptosis distinguished by the emanation of an array of damage-related molecular signals. This mechanism introduces a novel concept in the field of contemporary tumor immunotherapy. The inception of reactive oxygen species (ROS) within tumor cells stands as the essential prerequisite and foundation for ICD induction. The formulation of highly efficacious photodynamic therapy (PDT) nanomedicines for the successful induction of ICD is an area of significant scientific inquiry. In this work, we devised a ROS-responsive and triple-synergistic mitochondria-targeted polymer micelle (CAT/CPT-TPP/PEG-Ce6, CTC) that operates with multistage amplification of ROS to achieve the potent induction of ICD. Utilizing an "all-in-one" strategy, we direct both the PDT and chemotherapeutic units to the mitochondria. Concurrently, a multistage cyclical amplification that caused by triple synergy strategy stimulates continuous, stable, and adequate ROS generation (domino effect) within the mitochondria of cells. Conclusively, influenced by ROS, tumor cell-induced ICD is effectively activated, remodeling immunogenicity, and enhancing the therapeutic impact of PDT when synergized with chemotherapy. Empirical evidence from in vitro study substantiates that CTC micelles can efficiently provoke ICD, catalyzing CRT translocation, the liberation of HMGB1 and ATP. Furthermore, animal trials corroborate that polymer micelles, following tail vein injection, can induce ICD, accumulate effectively within tumor tissues, and markedly inhibit tumor growth subsequent to laser irradiation. Finally, transcriptome analysis was carried out to evaluate the changes in tumor genome induced by CTC micelles. This work demonstrates a novel strategy to improve combination immunotherapy using nanotechnology.
Insights
This study introduces a novel nanomedicine that triggers immunogenic cell death (ICD) by amplifying reactive oxygen species (ROS) in cancer cells. This approach enhances photodynamic therapy and chemotherapy, significantly inhibiting tumor growth and improving immunotherapy outcomes.
Area of Science:
- Nanotechnology
- Immunotherapy
- Cancer Research
Background:
- Immunogenic cell death (ICD) is a crucial mechanism in tumor immunotherapy, characterized by damage-associated molecular patterns.
- Reactive oxygen species (ROS) generation is fundamental for inducing ICD.
- Developing effective nanomedicines for ROS-mediated ICD induction via photodynamic therapy (PDT) is a key research area.
Purpose of the Study:
- To design and evaluate a novel ROS-responsive, mitochondria-targeted polymer micelle (CTC) for synergistic PDT and chemotherapy-induced ICD.
- To investigate the multistage amplification of ROS generation within tumor cells for potent ICD induction.
- To explore the potential of this nanomedicine in enhancing anti-tumor immunity and therapeutic efficacy.
Main Methods:
- Development of a "all-in-one" polymer micelle (CTC) encapsulating PDT and chemotherapeutic agents, targeted to mitochondria.
- Utilizing a triple-synergistic strategy for multistage cyclical amplification of ROS generation.
- In vitro studies to assess ICD induction markers (CRT, HMGB1, ATP) and in vivo animal trials for tumor inhibition and biodistribution.
- Transcriptome analysis to evaluate genomic changes induced by the nanomedicine.
Main Results:
- CTC micelles effectively induced ICD in vitro, evidenced by increased CRT translocation, HMGB1, and ATP release.
- In vivo studies demonstrated efficient tumor accumulation, significant tumor growth inhibition following laser irradiation, and ICD induction.
- The triple-synergistic strategy led to continuous and adequate ROS generation, amplifying the ICD effect.
- Transcriptome analysis revealed significant changes in the tumor genome, indicating modulation of anti-tumor immunity.
Conclusions:
- The developed CTC nanomedicine offers a novel strategy for potent ICD induction through ROS amplification and synergistic therapy.
- This approach enhances the immunogenicity of tumor cells, improving the therapeutic outcome of combined PDT and chemotherapy.
- The findings highlight the potential of nanotechnology in advancing combination immunotherapy for cancer treatment.
