Dual Stimuli-Responsive Micelles for Imaging-Guided Mitochondrion-Targeted Photothermal/Photodynamic/Chemo Combination Therapy-Induced Immunogenic Cell Death

Abstract

Introduction

As the special modality of cell death, immunogenic cell death (ICD) could activate immune response. Phototherapy in combination with chemotherapy (CT) is a particularly efficient tumor ICD inducing method that could overcome the defects of monotherapies.

Methods

In this study, new dual stimuli-responsive micelles were designed and prepared for imaging-guided mitochondrion-targeted photothermal/photodynamic/CT combination therapy through inducing ICD. A dual-sensitive methoxy-polyethylene glycol-SS-poly(L-γ-glutamylglutamine)-SS-IR780 (mPEG-SS-PGG-SS-IR780) polymer was synthesized by grafting IR780 with biodegradable di-carboxyl PGG as the backbone, and mPEG-SS-PGG-SS-IR780/paclitaxel micelles (mPEG-SS-PGG-SS-IR780/PTXL MCs) were synthesized by encapsulating PTXL in the hydrophobic core.

Results

In-vivo and -vitro results demonstrated that the three-mode combination micelles inhibited tumor growth and enhanced the therapeutic efficacy of immunotherapy. The dual stimuli-responsive mPEG-SS-PGG-SS-IR780/PTXL MCs were able to facilitate tumor cell endocytosis of nanoparticles. They were also capable of promoting micelles disintegration and accelerating PTXL release. The mPEG-SS-PGG-SS-IR780/PTXL MCs induced mitochondrial dysfunction by directly targeting the mitochondria, considering the thermo- and reactive oxygen species (ROS) sensitivity of the mitochondria. Furthermore, the mPEG-SS-PGG-SS-IR780/PTXL MCs could play the diagnostic and therapeutic roles via imaging capabilities.

Conclusion

In summary, this study formulated a high-efficiency nanoscale platform with great potential in combined therapy for tumors through ICD.

Keywords:

• immunogenic cell death
• photothermal/photodynamic/chemo therapy
• dual-stimuli-responsive
• poly(amino acid)s micelles
• imaging-guided therapy
• mitochondria targeting

Acknowledgments

This work was financially supported by the Natural Science Fund of Shandong Province (No. ZR2019PH061, ZR2022LSW002, ZR2020KH015), the National Natural Science Foundation of China (No. 82002604, 81772281), the Shandong Province Taishan Scholar Project (No. ts201712067), the Support Plan for Youth Entrepreneurship and Technology of Colleges and Universities in Shandong (grant no. 2021KJ101), and Home for Researchers (www.home-for-researchers.com).

Disclosure

The authors report no conflicts of interest in this work.