Osimertinib delivery using 660nm-activated polymeric nano-photosensitizer carriers for combined photodynamic and EGFR-targeted therapy of non-small cell lung cancer.

The recalcitrance of tumors to photodynamic therapy (PDT) has been linked to PDT-induced activation of survival pathways in sublethally afflicted cancer cells that modulate cellular responses to oxidative stress and damage. Survival signaling manifests in regions of the tumor where the tumor cells are insufficiently photosensitized or subjected to inadequate fluence rates. The survival signaling in these tumor regions is believed to account for tumor recurrence. Accordingly, PDT efficacy can be improved by intervening in these pathways using molecular inhibitors of key modulators of survival signaling, thereby increasing the number of lethally afflicted cancer cells and with it therapeutic efficacy. A promising target for pharmacological intervention is the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, which induces the antioxidant and xenobiotic stress response that helps cells cope with prolonged periods of hyperoxidative stress after PDT. This review outlines our current understanding of this pathway, how it is activated, and how it confers cytoprotective effects and ensures cell survival. Additional distinguishing features of the review are that (1) studies are addressed in which PDT activation of the NRF2 pathway has been demonstrated; (2) a non-exhaustive overview of NRF2 pathway inhibitors is presented that could serve as potential adjuvants in PDT regimens to augment therapeutic efficacy in treatment-resistant tumors and cancers that recur after PDT; (3) molecular docking analyses are included that show potential interactions between the NRF2 inhibitors and the redox sensor KEAP1; and (4) an elaborate account is provided of the potential bottlenecks and caveats that can be encountered when using NRF2 inhibitors in the development of fourth-generation photosensitizers for oncological PDT.

Multiple mitochondrial stress dysregulation represents an emergent mechanism for inducing tumor cell death. While photodynamic (PDT) and cuproptosis therapies can generate oxidative and proteotoxic stress respectively, their cooperativity and effects are hampered by the uncontrolled spatiotemporal interaction with glutathione (GSH) overexpressed in the tumor microenvironment. Here, we developed a GSH-depleting nanodrug for synergistic mitochondria-targeting PDT and cuproptosis, by co-loading mitochondria-targeting photosensitizer PpIX-TPP with copper ionophore elesclomol (ES) into GSH-responsive dextran-based nanoassemblies. The interaction between GSH in tumor cells and disulfide bonds in nanodrugs led to GSH depletion, thereby triggering the responsive release of the loaded drugs and reducing the limitation of GSH on therapeutic effectiveness. The released PpIX-TPP effectively targeted mitochondria, inducing PDT effects under laser irradiation, causing oxidative stress and further reducing GSH levels. ES carried copper ions into tumor cells and selectively released them in mitochondria, inducing proteotoxic stress through cuproptosis and generating hydroxyl radicals via a Fenton-like reaction to cause extra oxidative stress. The orchestration of multiple mitochondrial stress pathways led to mitochondrial dysfunction, immunogenic cell death, and subsequent immune activation both in vitro and in vivo. This study provides a strategy for enhanced antitumor efficacy through mitochondrial stress amplification and immune activation. STATEMENT OF SIGNIFICANCE: Combining light-activated photodynamic therapy (PDT) with copper-dependent cell death (cuproptosis) is promising for treating melanoma. However, tumors often overexpress glutathione (GSH), which neutralizes reactive oxygen species generated by PDT and blocks the cancer-killing effects of copper, thus compromising both therapeutic modalities. Poor targeting further impairs the treatment effectiveness. Herein, we developed a smart drug delivery system that combines mitochondria-targeting PDT with elesclomol-induced cuproptosis to improve the precision of treatment while depleting GSH to eliminate its negative impact on the therapeutic effect. Our nanodrugs induce abnormal amplification of mitochondrial stress in cancer cells, triggering their self-destruction and activating the immune system to attack tumors. This work provides a new strategy to enhance melanoma treatment through mitochondrial stress amplification and immune activation.

Photodynamic therapy remodels the prostate cancer microenvironment by suppressing cancer-associated fibroblast-mediated calcium signaling.

High-dose radiotherapy is known to enhance cuproptosis, and when combined with copper-coordinated delivery to tumors, it shows promise as a synergistic treatment mechanism. In this study, we present a simple method for synthesizing stimuli-responsive copper-iodide nanoparticles using a commercial, insoluble copper-iodide powder that emitted a strong radioluminescence matching the absorbance of the clinical dye indocyanine green. The copper-iodide nanoparticles efficiently absorbed and transferred radiation energy to ICG activating an X-ray-induced photodynamic therapy (X-PDT) mechanism. After accumulating in tumors, the low-dose X-PDT process first generated reactive oxygen species to induce cell death. The tumor microenvironment then caused the copper-iodide nanoparticles to decompose and release copper and iodide ions, which promoted cuproptosis. X-PDT followed by ion-induced cell death achieved 87.7% tumor regression in CT26 tumor-bearing mice without systemic toxicity. This work establishes a therapeutic paradigm that exploits metal metabolism dysregulation to potentiate radiation-based therapies. STATEMENT OF SIGNIFICANCE: Stimuli-responsive copper-iodide nanoparticles were synthesized and induced by X-ray-induced photodynamic therapy to decompose, releasing copper and iodide ions that caused tumor cell death. (1) Commercial copper-iodide powder exhibited strong radioluminescent properties and formed stable nanoparticles with the clinical dye indocyanine green, which realized X-ray-induced photodynamic therapy under X-ray irradiation. (2) After accumulating in tumors and following X-ray-induced photodynamic therapy, the decomposition of copper-iodide nanoparticles in the tumor tissue induced cell death.

Biomimetic and microenvironment-adaptive nanoplatform potentiates photodynamic therapy of rheumatoid arthritis via H2S-Modulated oxygen metabolism.

Metal ion-amplified phototherapy for tumors: Mechanisms, nanomaterial design, and synergistic strategies.

A meta-analysis of photodynamic therapy in the treatment of cervical intraepithelial neoplasia: Based on randomized controlled trials.

A core-shell upconversion nanoparticle@copper-porphyrin metal-organic framework for near-infrared light-triggered synergistic antibacterial treatment.

Endoplasmic reticulum targeted photosensitizer with high photostability and dual ROS generation for breast cancer PDT via apoptosis and pyroptosis.

Fe3O4/ZnTCPP heterojunction for rapid treatment of bacteria-infected wounds.

Lysosome-targeted copper-modulated carbon dots with near-infrared fluorescence imaging and enhanced photodynamic therapy effects.

Alkyl-chain engineering of berberine-based amphiphilic AIE photosensitizers for dual-model antifungal phototherapy.

Oxygen-sparing photodynamic therapy via dissolving microneedles for rheumatoid arthritis.

Long-acting multiple programmed cell death nanoinducers based on polyunsaturated fatty acid supplemented liposomal photosensitizers for enhanced photodynamic immunotherapy.

Optimized Talaporfin-Encapsulated by Silica Nanoparticles for In-Vitro Photodynamic Therapy Against MCF-7 Cancer Cells

Photodynamic therapy-assisted Mohs micrographic surgery for extramammary Paget's disease: A retrospective clinical study.

Injectable pH-responsive cross-linked chitosan hydrogel co-delivering methotrexate and diaminoperylene bisimide: Enhanced targeted chemo-photodynamic therapy for breast cancer cells with reduced systemic toxicity

A phthalocyanine-peptide conjugate for targeted photodynamic therapy of dental caries with concurrent tooth whitening effect.

Aptamer-guided upconversion nanoconstructs enable proximity-dependent and precise photodynamic therapy for MRSA-infected wounds.