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

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.

MnO2 nanoflowers as a multifunctional nano-platform for enhanced photothermal/photodynamic therapy and MR imaging.

Photodynamic therapy (PDT) has been regarded as a promising strategy for tumor therapy. However, heterogeneous tumor microenvironments severely limit the efficacy of photodynamic therapy. In this work, a multifunctional theranostic platform (MnO2-SiO2-APTES&Ce6 (MSA&C)) was fabricated based on MnO2 nanoflowers, which afforded MRI-guided synergistic therapy incorporating PDT and second near-infrared window (NIR-II) photothermal therapy (PTT). Herein, MnO2 nanoflowers are first proposed as a NIR-II photothermal agent. In the MSA&C system, MnO2 nanoflowers were employed for effective photosensitizer loading, relieving tumor hypoxia, and NIR-II PTT and tumor-specific imaging. The large amount of photosensitizer, reduced tumor hypoxia, and hyperthermia all contributed to the improvement of PDT. The quantity of reactive oxygen species (ROS) generated during PDT in turn down-regulated the expression of heat shock proteins (HSP 70), thereby improving photothermal performance. Positively charged (3-aminopropyl)triethoxysilane (APTES) was used to promote cellular uptake, further improving treatment efficiency. In this system, the MSA&C nanoflowers can not only alleviate tumor hypoxia, but they also obviously induce cell apoptosis under laser irradiation through a ROS- and hyperthermia-mediated mechanism, thereby leading to remarkable tumor growth inhibition. Furthermore, the Mn2+ ions generated during treatment can be explored for MR imaging, and this could be used to finally realize MRI-guided enhanced PDT/PTT.