Enhanced Photodynamic Therapy Efficacy Research Articles

An Aged Tree with a New Bloom: A Simple Spatiotemporal Programming Strategy Enables Carbon Dot Photosensitizers to Regulate Cell Pyroptosis for Enhanced Tumor Photodynamic-Immunotherapy.

Pyroptosis induced by photodynamic therapy (PDT) is a promising field in both PDT and immunotherapy for tumors. However, effectively inducing tumor cell pyroptosis while triggering a strong immune response using current photosensitizers remains challenging. Herein, the developed positively charged carbon dots (PCDs) nanoPSs were utilized to modulate tumor cell pyroptosis for the first time through a simple spatiotemporal programming strategy. Briefly, PCDs enabled precisely time-dependent targeting of the cell membrane or lysosome. Upon light irradiation, in vitro studies revealed that lysosome-targeted PDT primarily induced apoptosis, while membrane-targeted PDT triggered pyroptosis, resulting in enhanced PDT efficacy and robust activation of the immune response. Conclusively, in vivo studies demonstrated that PCDs could serve as a novel pyroptosis nanotuner for enhanced photodynamic-immunotherapy, thereby simultaneously eliminating primary tumors and inhibiting distant tumor growth and metastases. This spatiotemporal programming strategy unprecedentedly offers a rejuvenation of aged PSs and expands the biomedical use of CDs in immunotherapy.

Zinc phthalocyanine-bridged periodic mesoporous organosilica nanoparticle as biodegradable photosensitizer for photodynamic therapy

The development of efficient photosensitizers is vital for advancing photodynamic therapy (PDT), a non-invasive cancer treatment. Although zinc phthalocyanine (ZnPc) has garnered significant attention as a photosensitizer in preclinical studies, its clinical application is hindered by poor solubility and a tendency to aggregate, despite its high absorption coefficient and low dark toxicity. To address these challenges, we developed a novel ZnPc-conjugated periodic mesoporous organosilica (PMO) nanoparticle, which enhances the photosensitizer's solubility, photostability, and biodegradability. The PMO nanoparticles retained the characteristic mesoporous structure, exhibited strong fluorescence emission, and effectively generated singlet oxygen. In vitro studies using 4T1 cells, along with in vivo experiments on a tumor-bearing mouse model, demonstrated that under 675 nm laser irradiation, the ZnPc-PMO nanophotosensitizer induced reactive oxygen species, leading to significant inhibition of tumor growth. This ZnPc-bridged PMO nanophotosensitizer holds great promise for enhancing PDT efficacy and biocompatibility, offering a potential platform for multimodal phototherapeutic strategies.

Ultrasmall iridium-encapsulated porphyrin metal-organic frameworks for enhanced photodynamic/catalytic therapy by producing reactive oxygen species storm

Transition metal-coordinated porphyrin metal-organic frameworks (MOFs) were perspective in photodynamic therapy (PDT) and catalytic therapy. However, the tumor hypoxia and the insufficient endogenous hydrogen peroxide (H2O2) seriously limited their efficacies. Herein, by encapsulating ultrasmall iridium (Ir) and modifying glucose oxidase (GOx), an iron-coordinated porphyrin MOF (Fe-MOF) nanoplatform (Fe-MOF@Ir/GOx) was designed to strengthen PDT/catalytic therapy by producing reactive oxygen species (ROS) storm. In this nanoplatform, Fe-MOF showed glutathione (GSH)-responsive degradation, by which porphyrin, GOx and ultrasmall Ir were released. Moreover, ultrasmall Ir possessed dual-activities of catalase (CAT)-like and peroxidase (POD)-like, which provided sufficient oxygen (O2) to enhance PDT efficacy, and hydroxyl radical (·OH) production was also improved by combining Fenton reaction of Fe2+. Further, GOx catalyzed endogenous glucose produced H2O2, also reduced pH value, which accelerated Fenton reaction and resulted in generation of ROS storm. Therefore, the developed Fe-MOF@Ir/GOx nanoplatform demonstrated enhanced PDT/catalytic therapy by producing ROS storm, and also provided a promising strategy to promote degradation/metabolism of inorganic nanoplatforms.

In Vitro Effect of Epigallocatechin Gallate on Heme Synthesis Pathway and Protoporphyrin IX Production.

Photodynamic therapy (PDT) treats nonmelanoma skin cancer. PDT kills cells through reactive oxygen species (ROS), generated by interaction among cellular O2, photosensitizer and specific light. Protoporphyrin IX (PpIX) is a photosensitizer produced from methyl aminolevulinate (MAL) by heme group synthesis (HGS) pathway. In PDT-resistant cells, PDT efficacy has been improved by addition of epigallocatechin gallate (EGCG). Therefore, the aim of this work is to evaluate the effect of EGCG properties over MAL-TFD and PpIX production on A-431 cell line. EGCG's role over cell proliferation (flow cytometry and wound healing assay) and clonogenic capability (clonogenic assay) was evaluated in A-431 cell line, while the effect of EGCG over MAL-PDT was determined by cell viability assay (MTT), PpIX and ROS detection (flow cytometry), intracellular iron quantification and gene expression of HGS enzymes (RT-qPCR). Low concentrations of EGCG (<50 µM) did not have an antiproliferative effect over A-431 cells; however, EGCG inhibited clonogenic cell capability. Furthermore, EGCG (<50 µM) improved MAL-PDT cytotoxicity, increasing PpIX and ROS levels, exerting a positive influence on PpIX synthesis, decreasing intracellular iron concentration and modifying HGS enzyme gene expression such as PGB (upregulated) and FECH (downregulated). EGCG inhibits clonogenic capability and modulates PpIX synthesis, enhancing PDT efficacy in resistant cells.

Multifunctional single-component photosensitizers as metal-free ferroptosis inducers for enhanced photodynamic immunotherapy

Immunotherapy can enhance primary tumor efficacy, restrict distant growth, and combat lung metastasis. Unfortunately, it remains challenging to effectively activate the immune response. Here, tertiary butyl, methoxy, and triphenylamine (TPA) were utilized as electron donors to develop multifunctional photosensitizers (PSs). CNTPA-TPA, featuring TPA as the donor (D) and cyano as the acceptor (A), excelled in reactive oxygen species (ROS) generation due to its smaller singlet-triplet energy gap (ΔES-T) and larger spin-orbit coupling constant (SOC). Additionally, cyano groups reacted with glutamate (Glu) and glutathione (GSH), reducing intracellular GSH levels. This not only enhanced PDT efficacy but also triggered redox dyshomeostasis-mediated ferroptosis. The positive effects of photodynamic therapy (PDT) and ferroptosis promoted immunogenic cell death (ICD) and immune activation. By further combining anti-programmed cell death protein ligand-1 (anti-PD-L1) antibody, the powerful treatments of ferroptosis-assisted photodynamic immunotherapy significantly eradicated the primary tumors, inhibited the growth of distant tumors, and suppressed lung metastasis. In this study, a three-pronged approach was realized by single-component CNTPA-TPA, which simultaneously served as metal-free ferroptosis inducers, type-I photosensitizers, and immunologic adjuvants for near-infrared fluorescence imaging (NIR FLI)-guided multimodal phototheranostics of tumor. Statement of significance(1) CNTPA-TPA shared the smallest singlet-triplet energy gap and the largest spin-orbit coupling constant, which boosted intersystem crossing for efficient type-I photodynamic therapy (PDT);(2) Special reactions between cyano groups with glutamate and glutathione in mild conditions restricted the biosynthesis of intracellular GSH. GSH-depletion efficiently induced glutathione peroxidase 4 inactivation and lipid peroxide, resulting in ferroptosis of tumor cells;(3) The combination treatments of ferroptosis-assisted photodynamic immunotherapy induced by single-component CNTPA-TPA with the participation of anti-PD-L1 antibody resulted in increased T-cell infiltration and profound suppression of both primary and distant tumor growth, as well as lung metastasis.

Enhancing PDT efficacy in NMIBC: Efflux inhibitor mediated improvement of PpIX levels and efficacy of the combination of PpIX-PDT and SO-cleavable prodrugs.

Protoporphyrin IX (PpIX)-based photodynamic therapy (PDT) has shown limited efficacy in nonmuscle-invasive bladder cancer (NMIBC). To improve PDT efficacy, we developed singlet oxygen-cleavable prodrugs. These prodrugs, when combined with PpIX-PDT, induce cancer cell death through both PDT and drug release mechanisms. Inhibition of PpIX efflux was reported to be an effective strategy to improve PpIX-PDT in certain cancer cells. Our main goal was to investigate whether adding an efflux inhibitor to the combination of PpIX and prodrugs can improve the PpIX levels in bladder cancer cells and the release of active drugs, thus improving the overall efficacy of the treatment. We treated bladder cancer cell lines with lapatinib and evaluated intracellular PpIX fluorescence, finding significantly increased accumulation. Combining lapatinib with prodrugs led to significantly reduced cell viability compared to prodrugs or PpIX-PDT alone. The effect of lapatinib depended on the expression level of the efflux pump in bladder cancer cells. Interestingly, lapatinib increased paclitaxel (PTX) prodrug uptake by threefold compared to prodrug alone. Adding an efflux inhibitor (e.g., lapatinib) into bladder instillation solutions could be a straightforward and effective strategy for NMIBC treatment, particularly in tumors expressing efflux pumps, with the potential for clinical translation.

Enhancing Surface Hydroxyl Group Modulation on Carbon Nitride Boosts the Effectiveness of Photodynamic Treatment for Brain Glioma.

The effectiveness of photodynamic therapy (PDT) in treating brain gliomas is limited by the solubility of photosensitizers and the production of reactive oxygen species (ROS), both of which are influenced by the concentration of photosensitizers and catalyst active sites. In this study, we developed a controllable surface hydroxyl concentration for the photosensitizer CN11 to address its poor water solubility issue and enhance PDT efficacy in tumor treatment. Compared to pure g-C3N4 (CN), CN11 exhibited 4.6 times higher hydrogen peroxide production under visible light, increased incidence of the n → π* electron transition, and provided more available reaction sites for cytotoxic ROS generation. These findings resulted in a 2.43-fold increase in photodynamic treatment efficacy against brain glioma cells. Furthermore, in vivo experiments conducted on mice demonstrated that CN11 could be excreted through normal cell metabolism with low cytotoxicity and high biosafety, effectively achieving complete eradication of tumor cells.

Step-by-step guided photo-chemotherapy nanoplatforms for efficiently suppressing cervical carcinoma metastasis by hijacking intracellular metabolism

Intracellular energy metabolism, particularly in the mitochondria, can effectively modulate the epithelial to mesenchymal transition (EMT) to promote cervical carcinoma metastasis, which contributes to a much worse prognosis in the clinic. Notably, mitochondria are more vulnerable to hyperthermia and oxidative damage, thereby mitochondria-targeting photothermal therapy (PTT) and photodynamic therapy (PDT) appear to be promising strategies against EMT. Herein, we developed step-by-step guided photo-chemotherapy nanoplatforms (CS@ATO/CHC/T780 NPs) to reprogram intracellular metabolism for efficiently suppressing cervical carcinoma metastasis. Mechanistically, chondroitin sulfate (CS) and triphenylphosphine (TPP)-tailored phototherapeutic agent IR780 (T780) achieved step-by-step delivery to cancer cells and mitochondria, respectively. Subsequently, the atovaquone (ATO) disturbed mitochondrial electron transport chain complex III to efficiently induce mitochondrial dysfunction, which reversed the thermo-resistance associated with PTT by the down-regulation of ATP-dependent heat shock protein 70 (HSP 70) expression. Simultaneously, α-cyano-4-hydroxycinnamate (CHC) efficiently reduced the internalization of lactate (LA) to conserve oxygen consumption for enhancing PDT efficacy. Furthermore, the decrease in intracellular LA also inhibited the process of EMT. As expected, the enhanced phototherapy significantly induced mitochondrial impairment to suppress the proliferation and metastasis of cervical cancer in vitro and in vivo, offering a promising strategy for the treatment of cervical cancer by hijacking intracellular metabolism.

Photodynamic effect of indocyanine green and its application to hepatocellular carcinoma treatment

Hepatocellular carcinoma (HCC) stands as the primary cause of liver cancers, with limited treatment options outside of surgical resection or transplant. Photodynamic therapy (PDT) using indocyanine green (ICG) as a photosensitizer offers a promising therapeutic option for HCC. ICG PDT has demonstrated efficacy in vitro and in vivo , providing a safe treatment option for patients ineligible for resection or transplant. Challenges in PDT optimization include limited light delivery, poor photosensitizer optimization, and low oxygen generation. Innovative solutions, such as ICG incorporation into nanostructures and direct administration for HCC cases, show promise. Combining ICG PDT with Lentinula edodes mycelia (LEM) and hydrogen gas inhalation may address oxygen production limitations. Utilizing a combination of therapeutic approaches and therapies may increase the efficacy of ICG PDT, making it the safer and more effective treatment option for patients. ICG’s proven clinical safety may expedite potential approval for its use in PDT. Advancements in photosensitizer technology, such as aggregation-induced emission photosensitizers (AIE-PSs), and combination therapies will enhance PDT efficacy shortly, as developments show promise for improved outcomes. For HCC patients, ICG PDT presents a valuable therapeutic option. This work is novel because it explores new combination therapy approaches, leveraging the benefits of PDT with ICG and the developments in photosensitizer technology, nanotechnology, and the combination of other treatments such as LEM and hydrogen gas, which could potentially revolutionize the treatment of HCC and offer a better prognosis for patients.

Natural-product-based, carrier-free, noncovalent nanoparticles for tumor chemo-photodynamic combination therapy

Cancer, with its diversity, heterogeneity, and complexity, is a significant contributor to global morbidity, disability, and mortality, highlighting the necessity for transformative treatment approaches. Photodynamic therapy (PDT) has aroused continuous interest as a viable alternative to conventional cancer treatments that encounter drug resistance. Nanotechnology has brought new advances in medicine and has shown great potential in drug delivery and cancer treatment. For precise and efficient therapeutic utilization of such a tumor therapeutic approach with high spatiotemporal selectivity and minimal invasiveness, the carrier-free noncovalent nanoparticles (NPs) based on chemo-photodynamic combination therapy is essential. Utilizing natural products as the foundation for nanodrug development offers unparalleled advantages, including exceptional pharmacological activity, easy functionalization/modification, and well biocompatibility. The natural-product-based, carrier-free, noncovalent NPs revealed excellent synergistic anticancer activity in comparison with free photosensitizers and free bioactive natural products, representing an alternative and favorable combination therapeutic avenue to improve therapeutic efficacy. Herein, a comprehensive summary of current strategies and representative application examples of carrier-free noncovalent NPs in the past decade based on natural products (such as paclitaxel, 10-hydroxycamptothecin, doxorubicin, etoposide, combretastatin A4, epigallocatechin gallate, and curcumin) for tumor chemo-photodynamic combination therapy. We highlight the insightful design and synthesis of the smart carrier-free NPs that aim to enhance PDT efficacy. Meanwhile, we discuss the future challenges and potential opportunities associated with these NPs to provide new enlightenment, spur innovative ideas, and facilitate PDT-mediated clinical transformation.

Engineering tumor-oxygenated nanomaterials: advancing photodynamic therapy for cancer treatment.

Photodynamic therapy (PDT), a promising treatment modality, employs photosensitizers to generate cytotoxic reactive oxygen species (ROS) within localized tumor regions. This technique involves administering a photosensitizer followed by light activation in the presence of oxygen (O2), resulting in cytotoxic ROS production. PDT's spatiotemporal selectivity, minimally invasive nature, and compatibility with other treatment modalities make it a compelling therapeutic approach. However, hypoxic tumor microenvironment (TME) poses a significant challenge to conventional PDT. To overcome this hurdle, various strategies have been devised, including in-situ O2 generation, targeted O2 delivery, tumor vasculature normalization, modulation of mitochondrial respiration, and photocatalytic O2 generation. This review aims to provide a comprehensive overview of recent developments in designing tumor-oxygenated nanomaterials to enhance PDT efficacy. Furthermore, we delineate ongoing challenges and propose strategies to improve PDT's clinical impact in cancer treatment.

Enhancing photodynamic therapy efficacy through silica nanoparticle-mediated delivery of temoporfin for targeted in vitro breast cancer treatment

Photodynamic therapy (PDT), an approach to cancer treatment, relies fundamentally on two key elements: a light source and a photosensitizing agent. A primary challenge in PDT is the efficient delivery of photosensitizers to the target tissue, hindered by the bodyʼs reticuloendothelial system (RES). Silica nanoparticles (SiNPs), known for their unique properties, emerge as ideal carriers in this context. In this study, SiNPs are utilized to encapsulate Temoporfin, a photosensitizer, aiming to enhance its delivery and reduce toxicity, particularly for treating MCF-7 cancer cells in vitro. The synthesized SiNPs were meticulously characterized by their size and shape using Transmission Electron Microscopy (TEM). The study also involved evaluating the cytotoxicity of both encapsulated and naked Temoporfin across various concentrations. The objective was to determine the ideal concentration and exposure duration using red laser light (intensity approximately 110 mW/cm2) to effectively eradicate MCF-7 cells. The findings revealed that Temoporfin, when encapsulated in SiNPs, demonstrated significantly greater effectiveness compared to its naked form, with notable improvements in concentration efficiency (50 %) and exposure time efficiency (76.6 %). This research not only confirms the superior effectiveness of encapsulated Temoporfin in eliminating cancer cells but also highlights the potential of SiNPs as an efficient drug delivery system in photodynamic therapy. This sets the groundwork for more advanced strategies in cancer treatment.

Oxygen-supplying ROS-responsive prodrug for synergistic chemotherapy and photodynamic therapy of colon cancer.

Introduction: The synergistic treatment of chemotherapy and photodynamic therapy (PDT) has remarkable potential in cancer therapy. However, challenges remain, such as unstable chemotherapeutic drug release, suboptimal targeting, and reduced efficacy of PDT under hypoxic conditions commonly found in solid tumors. Methods: To address these issues, we use camptothecin (CPT) and pheophorbide a (Pa) incorporated through the functional thioketal, which serves as the reactive oxygen species (ROS)-responsive trigger, to construct a ROS-responsive prodrug (CPT-TK-Pa). Subsequently, we co-loaded it with a platinum nanozyme (PtNP) in distearylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) to obtain the ROS-responsive prodrug nanoparticle (CPT-TK-Pa/Pt NP). Results and Discussion: Specifically, the incorporated PtNP within CPT-TK-Pa/Pt NP positively catalyzes the conversion of hydrogen peroxide (H2O2) to oxygen, thereby ameliorating the hypoxic state of the tumor. This enhanced oxygen generation could replenish the oxygen that is consumed by Pa during 660nm exposure, enabling controlled CPT release and amplifying the photodynamic response. In vitro investigations reveal the potency of CPT-TK-Pa/Pt NPs in inhibiting colon tumor cells. Given its ROS-responsive release mechanism and enhanced PDT efficacy, CPT-TK-Pa/Pt NP has the potential to be a promising candidate for cancer therapy.

Molecular Nanoarchitectonics of Natural Photosensitizers and Their Derivatives Nanostructures for Improved Photodynamic Therapy.

Natural photosensitizers (PSs) and their derivatives have drawn ever-increasing attention in photodynamic therapy (PDT) for their wild range of sources, desirable biocompatibility, and good photosensitivity. Nevertheless, many factors such as poor solubility, high body clearance rate, limited tumor targeting ability, and short excitation wavelengths severely hinder their applications in efficient PDT. In recent years, fabricating nanostructures by utilizing molecular assembly technique is proposed to solve these problems. This technique is easy to put into effect, and the assembled nanostructures could improve the physical properties of the PSs so as to meet the requirement of PDT. In this concept, we focus on the construction of natural PSs and their derivatives nanostructures through molecular assembly technique to enhance PDT efficacy (Figure 1). Furthermore, current challenges and future perspectives of natural PSs and their derivatives for efficient PDT are discussed.

Amphiphilic Janus nanoparticles for nitric oxide synergistic photodynamic eradication of MRSA biofilms.

Biofilms pose significant threats to public health by causing persistent clinical infections. The development of innovative antibacterial approaches for eliminating biofilms is an urgent necessity. In this study, we developed amphiphilic Janus nanoparticles (JNPs), loaded with hydrophobic chlorin e6 (Ce6) and hydrophilic S-nitrosoglutathione (GSNO), denoted as Ce6-PDA/CaP-GSNO, with the aim to effectively eradicate biofilms and combat methicillin-resistant Staphylococcus aureus (MRSA) infections through nitric oxide (NO) synergistic photodynamic therapy (PDT). Ce6-PDA/CaP-GSNO demonstrated remarkable biofilm penetration ability, efficiently reaching the acidic inner layers, which triggered the rapid release of GSNO, resulting in the generation of an abundant supply of NO. NO not only exhibited potent bactericidal activity but also effectively lowered the GSH level of the biofilm, leading to enhanced efficacy of Ce6. Additionally, the interaction between NO and reactive oxygen species (ROS) resulted in the generation of reactive nitrogen species (RNS), further enhancing PDT efficacy both in vitro and in vivo. In summary, Ce6-PDA/CaP-GSNO demonstrated remarkable biofilm penetration capacity and effective reduction of the GSH level in the biofilms, leading to enhanced PDT efficacy at low photosensitizer doses and laser intensities, thereby minimizing adverse effects on normal tissues. These findings highlight the promising potential of our approach for combating biofilm-related infections.

Activable Photodynamic DNA Probe with an "AND" Logic Gate for Precision Skin Cancer Therapy.

Photodynamic therapy (PDT) has emerged as a promising approach for squamous cell carcinoma treatment but hindered by tumor hypoxia, acquired resistance, phototoxicity, and so on. To address these issues, we developed a smart strategy utilizing activable photosensitizers delivered by an aptamer-functionalized DNA probe (ADP). The ADP incorporated an AS1411 aptamer for tumor targeting and a linear antisense oligonucleotide (ASO) for recognition of Survivin mRNA. In the absence of the target, PDT remained quenched, thereby avoiding phototoxicity during circulation and nonselective distribution. With the aid of the aptamer, ADP achieved selective targeting of tumors. Upon internalization, ADP targeted recognized Survivin mRNA, triggering PDT activation, and releasing ASO to down-regulate Survivin expression and reverse tumor resistance. Consequently, the activable photosensitizers exhibited an "AND" logic gate, combining tumor-targeting delivery and tumor-related gene activation, thus enhancing its specificity. Additionally, the incorporation of hemin into the ADP provided catalase activity, converting tumor-abundant H2O2 into O2, thereby ameliorating tumor hypoxia. The resulting functionalized G-quadruplex/hemin-DNA probe complex demonstrated targeted delivery and activation, minimized side effects, and enhanced PDT efficacy in both xenograft tumor-bearing mice and patient-derived xenograft models. This study offers a unique and promising platform for efficient and safe PDT, thus holding great potential for future clinical translation and improved cancer therapy.

A Ru(II) complex-based COX-2 targeting type I photosensitizer evokes ferroptosis and apoptosis.

Photodynamic therapy (PDT) often faces challenges such as oxygen dependence and limited tumour specificity. We report a tumour-targeting photosensitizer (PS), RuCXB, which enhances uptake by cancer cells by targeting overexpressed cyclooxygenase-2 enzyme in tumours. RuCXB also reduces oxygen dependence via a type I PDT mechanism and achieves a strong therapeutic effect through the synergistic induction of ferroptosis and apoptosis. This work presents a reliable strategy for developing potent PSs with enhanced PDT efficacy, tumour selectivity, and diminished oxygen dependence.

The m-TORC1 inhibitor Sirolimus increases the effectiveness of Photodynamic therapy in the treatment of cutaneous Squamous Cell Carcinoma, impairing NRF2 antioxidant signaling.

Squamous Cell Carcinoma (SCC) is a subtype of Non-Melanoma Skin Cancer, the most common group of malignancies worldwide. Photodynamic therapy (PDT) is a non-invasive treatment approved for specific subtypes of SCC. Some malignancies resist PDT, forming more aggressive tumors and multiple relapses. Thus, new approaches aimed at optimizing the response to PDT are needed. The mTORC1 inhibitor rapamycin, also known as Sirolimus (SRL), interferes with protein synthesis and cell metabolism. The use of SRL as an immunosuppressant is associated to lower rates of SCC in kidney-transplanted patients, which are frequently affected by this pathology. We have evaluated SRL pre-treatment efficacy to enhance the damage induced by PDT with Methyl 5-aminolevulinate in two different cutaneous SCC established cell lines (SCC13 and A431) in vitro and therapy sensitization in PDT-resistant cell lines. We tested for the first time the SRL + PDT combination in a SKH-1 mouse model of photocarcinogenesis, diminishing the frequency of lesions and restraining tumor growth. Molecular studies revealed that protoporphyrin IX and reactive oxygen species production induced by PDT were promoted by SRL pre-treatment. Lastly, SRL modifies the expression and intracellular location of NRF2, interfering with the downstream antioxidant response modulated by NQO1 and HO-1. In conclusion, we propose SRL as a potential adjuvant to enhance PDT efficacy for SCC treatment.

Triple-function porphyrin in glycopolymeric photosensitizers: from photoATRP to targeted PDT.

Porphyrin derivatives serve as photocatalysts in reversible-deactivation radical polymerization and as photosensitizers in photodynamic therapy (PDT). Herein, a triple function porphyrin, ZnTPPC6Br, was synthesized as a photocatalyst and initiator for photoATRP. Oxygen-tolerant photoATRP produced fructose-based star-shaped glycopolymers as targeted photosensitizers for PDT. ZnTPPC6Br/CuII/PMDETA could synthesize polymer photosensitizers with predictable M n and low Đ. Mechanistic studies unveiled the transition of ZnTPPC6Br from a singlet excited state (1PC*) to a triplet excited state (3PC*), enabling the activator CuI/L generation and initiating photoATRP. The excess ligands facilitate return of the active species to the ground state, while the presence of DMSO assists in oxygen depletion. Three fructose-based monomers with different polymerizable groups (acrylated, methacrylated, and p-vinylbenzoated) were employed to scale up polymerization, yielding glycopolymeric photosensitizers post-deprotection. In vitro cellular studies showed enhanced PDT efficacy of glycopolymeric photosensitizers against MCF-7 cells, attributed to specific GLUT5 binding for targeted endocytosis, highlighting their potential for precise cancer treatment compared to L929 cells. The multifunctional capabilities of ZnTPPC6Br are anticipated to serve as a strategic avenue for the advancement of polymer photosensitizers with potential PDT applications.

Light-responsive smart nanocarriers for wirelessly controlled photodynamic therapy for prostate cancers.

Photodynamic therapy (PDT) is an effective non-invasive or minimally invasive treatment method against different tumors. Loading photosensitizers in nanocarriers can potentially increase their accumulation in tumor sites. However, the PDT efficacy may be hindered because of self-quenching of the encapsulated photosensitizer and the small diffusion radii of the generated reactive oxygen species (ROS). Herein, light responsive nano assemblies composed of (Polyethylene glycol)-block-poly(4,5-dimethoxy-2-nitrobenzylmethacrylate) (PEG-b-PNBMA) were designed and loaded with the photosensitizer, Rose Bengal lactone (RB), to act as a smart nanocarrier (RB-M) for the delivery of the photosensitizer. A wirelessly activated light-emitting diode (LED) implant was designed to programmatically induce the release of the loaded RB and activate PDT after diffusion of RB into the cytoplasm. The results showed that sequential '405-580 nm' irradiation of the RB-M treated 22RV1 cells resulted in the highest PDT outcome among different irradiation protocols. The combination of this smart nanocarrier and sequential '405-580 nm' irradiation strategy exhibited good PDT efficacy against 2D 22RV1 prostate cancer cells as well as 3D cancer cell spheroids. This platform overcome the light penetration limitations in PDT, and can potentially be applied in cancer bearing patients who are unfit for chemotherapy. STATEMENT OF SIGNIFICANCE: Nanocarriers for the delivery of photosensitizer in photodynamic therapy may result in relatively low therapeutic efficacy because of self-quenching of the encapsulated photosensitizer and the small diffusion radii of the generated reactive oxygen species (ROS). Light responsive smart nanocarriers can potentially overcome this challenge. In this study, a light responsive polymer (Polyethylene glycol)-block-poly(4,5-dimethoxy-2-nitrobenzylmethacrylate) (PEG-b-PNBMA) was synthesized and utilized to fabricate the smart nanocarrier. A wirelessly activated light-emitting diode (LED) implant was designed for light delivery in deep tissue. This new approach permits wirelessly and programmatically control of photosensitizer release and PDT activation under deep tissue, thus significantly enhancing PDT efficacy against prostate cancer cells as well as 3D cancer cell spheroids. This design should have a significant impact on controllable PDT under deep tissue.