Excited-State-Guided Molecular Design System for Type I Photosensitizers.

Nanotechnology offers unique advantages over small-molecule drugs by delivering a high payload of photosensitizers to the target tissue, providing flexibility in the excitation wavelengths, enabling longer retention in the target tissue, possessing regenerative reactive oxygen speciesproducing capability and stimulating the immune system.

Photoinduced Carbene for Effective Photodynamic Therapy Against Hypoxic Cancer Cells

Aggregation Turns BODIPY Fluorophores into Photosensitizers: Reversibly Switching Intersystem Crossing On and Off for Smart Photodynamic Therapy

Emerging Designs of Aggregation-Induced Emission Agents for Enhanced Phototherapy Applications

As an emerging clinical modality for cancer treatment, photodynamic therapy (PDT) takes advantage of the cytotoxic activity of reactive oxygen species (ROS) that are generated by light irradiating photosensitizers (PSs) in the presence of oxygen (O2 ). However, further advancements including tumor selectivity and ROS generation efficiency are still required. Substantial efforts are devoted to design and synthesize smart PSs with optimized properties for achieving a desirable therapeutic efficacy. This review summarizes the recent progress in developing intelligent PSs for efficient PDT, ranging from single molecules to delicate nanomaterials. The strategies to improve ROS generation through optimizing photoinduced electron transfer and energy transfer processes of PSs are highlighted. Moreover, the approaches that combine PDT with other therapeutics (e.g., chemotherapy, photothermal therapy, and radiotherapy) and the targeted delivery in cancer cells or tumor tissue are introduced. The main challenges for the clinical application of PSs are also discussed.

Objective To investigate the anti carcinoma role of integrin targeted photodynamic therapy (PDT) on pancreatic carcinoma cells in vitro.Methods Pancreatic carcinoma cells SW1990 were divided into four groups:cells without quantum dots (QDs) and light-treated as blank control group,pure light-treated group,photosensitizer group and PDT group.The targeting of QDs-arginine,glycine,aspartic acid (RGD) and integrin probe was confirmed by laser confocal microscopy.And as a photosensitizer for photodynamic therapy,after treated for 48 hours the morphology changes of pancreatic carcinoma cells of each group were observed.After 48 hours,the cell proliferation,apoptosis and cell cycle changes were detected by methyl thiazolyl tetrazolium (MTT) assay and flow cytometry (FCM).The expressions of myeloid cell leukemia-1 (Mcl-1),protein kinase B(Akt) and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) were detected by reverse transcriptase polymerase chain reaction(RT-PCR).The amount of reactive oxygen species (ROS) of each group were evaluated by fluorescence probe.One-way ANOVA was performed for comparison between groups to analyze the treatment effects of PDT group.Results The QDs RGD probe could effectively targeting pancreatic carcinoma cells.The MTT results indicated that the relative inhibition rate of pancreatic carcinoma cells proliferation of PDT group was statistically higher than that of the other groups at 24,48,72 h (F=73.00,85.10,126.58; all P＜0.01).The FCM results revealed that the cell apoptosis rate of PDT group (17.860％ ±1.230％) was higher than that of the other groups (F=130.617,P＜0.01) and cell cycle G0/G1 phase (69.14％±2.63％) and S phase (24.41％ ± 2.67 ％) retardance was also significant (all P＜0.05).The expression of proliferation and apoptosis related gene Mcl-1 and Akt at mRNA level was lower than that of the other groups however the expression of apoptosis-inducing ligand TRAIL at mRNA level was higher than that of the other groups (F=567.456,446.817,145.238; all P＜0.05).The ROS level of PDT group was higher than that of the other groups (F=3262.559,P＜0.01).Conclusion PDT with a QDs-RGD probe could significantly inhibit pancreatic carcinoma cell proliferation and promote cell apoptosis. Key words: Pancreatic neoplasms; Integrins; Molecular probes; Photochemotherapy; Apoptosis

Photodynamic therapy (PDT) is attracting widespread attention as a promising strategy for tumor treatment. However, the efficacy of PDT is severely limited by the insufficient tissue penetration depth of the light source and low reactive oxygen species (ROS) generation efficiency. Herein, the metal doping strategy is reported to construct a series of defect-rich M-doped amorphous CoMo-layered double hydroxide (a-M-CoMo-LDH, M = Mn, Cu, Al, Ni, Mg, Zn) photosensitizers (PSs) for NIR-II PDT. Especially, M-doped CoMo-LDH nanosheets are synthesized through a simple hydrothermal method and then etched by acid treatment to prepare defect-rich a-M-CoMo-LDH nanosheets. Under NIR-II 1270 nm laser irradiation, the defect-rich a-Zn-CoMo-LDH nanosheets exhibit the optimal PDT performance compared with other a-M-CoMo-LDH nanosheets, and also possess much higher ROS production activity (3.9 times) than that of the pristine a-CoMo-LDH, with a singlet oxygen quantum yield up to 1.86, which is the highest among all the reported PSs. After polyethylene glycol (PEG) modification, the a-Zn-CoMo-LDH-PEG nanosheets can function as an effective inorganic PS for PDT, effectively inducing cell apoptosis in vitro and eradicating tumors in vivo. Notably, transcriptome sequencing analysis and further molecular validation highlight the critical role of the apoptotic/p53/AMPK/oxidative phosphorylation signaling pathways in a-Zn-CoMo-LDH-PEG-induced cancer cell apoptosis.

Improving the photosensitization efficiency represents a critical challenge in photodynamic therapy (PDT) research. While cyanines exhibit potential as photosensitizers (PSs) due to their large extinction coefficients and excellent biocompatibility, the inherent limitations in intersystem crossing severely affect therapeutic efficacy. Herein, we proposed a bottom-up magnetically enhanced photodynamic therapy (magneto-PDT) paradigm employing fluorobenzene-substituted pentamethine cyanine as type-I reactive oxygen species generators. Based on the radical pair mechanism and magnetic field effect, the notable difference in g-factors (Δg) between PSs and oxyradicals enabled magnetically responsive amplification of Cy5-3,4,5-3F-mediated hydroxyl radical (•OH) and superoxide anion radical (O2•-) production, achieving maximum yield enhancements of 66.9 and 28.0% respectively at 500 mT. This magnetically augmented oxyradicals generation exhibited universal cytotoxicity superiority over conventional PDT protocols in various cancer cell models. Notably, the semi-inhibitory concentration (IC50) of murine mammary carcinoma 4T1 cells demonstrated a remarkable reduction under both normoxic and hypoxic conditions, with the most pronounced decrease observed in normoxia from 0.91 μM (PDT alone) to 0.38 μM (magneto-PDT). The significantly magneto-enhanced therapeutic performance effectively inhibited orthotopic tumor growth. This magneto-PDT paradigm established a novel strategy for manipulating spin-dependent photosensitization processes in biological applications.

Photodynamic therapy (PDT) has emerged as an effective and minimally invasive cancer treatment modality. In the present study, two novel phthalocyanines, tetra‑triethyleneoxysulfonyl substituted zinc phthalocyanine (ZnPc) and dihydroxy‑2,9(10),16(17),23(24)‑tetrakis(4,7,10‑trioxaundecan‑1‑sulfonyl) silicon phthalocyanine (Pc32), were investigated as photosensitizers (PS) for PDT of cholangiocarcinoma(CC). ZnPc showed a pronounced dose‑dependent and predominantly cytoplasmic accumulation in EGI‑1 and TFK‑1 CC cell lines. Pc32 also accumulated in the CC cells, but this was less pronounced. Without photoactivation, the PS did not exhibit any antiproliferative or cytotoxic effects. Upon photoactivation, ZnPc induced the formation of reactive oxygen species (ROS) and immediate phototoxicity, leading to a dose‑dependent decrease in cell proliferation, and an induction of mitochondria‑driven apoptosis and cell cycle arrest of EGI‑1 and TFK‑1 cells. Although photoactivated Pc32 also induced ROS formation in the two cell lines, the extent was less marked, compared with that induced by ZnPc‑PDT, and pronounced antipoliferative effects occurred only in the less differentiated EGI‑1 cells, whereas the more differentiated TFK‑1 cells did not show sustained growth inhibition upon Pc32‑PDT induction. Invivo examinations on the antiangiogenic potency of the novel PS were performed using chorioallantoic membrane(CAM) assays, which revealed reduced angiogenic sprouting with a concomitant increase in nonperfused regions and degeneration of the vascular network of the CAM following induction with ZnPc‑PDT only. The study demonstrated the pronounced antiproliferative and antiangiogenic potency of ZnPc as a novel PS for PDT, meriting further elucidation as a promising PS for the photodynamic treatment of CC.

There is a current surge of interest in the development of novel photosensitizers (PSs) for photodynamic therapy (PDT), as those currently approved are not completely ideal. Among the tested compounds, we have previously investigated the use of RuII polypyridyl complexes with a [Ru(bipy)2(dppz)]2+ and [Ru(phen)2(dppz)]2+ scaffold (bipy=2,2′‐bipyridine; dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine; phen=1,10‐phenanthroline). These complexes selectively target DNA. However, because DNA is ubiquitous, it would be of great interest to increase the selectivity of our PDT PSs by linking them to a targeting vector in view of targeted PDT. Herein, we present the synthesis, characterization, and in‐depth photophysical evaluation of a nanobody‐containing RuII polypyridyl conjugate selective for the epidermal growth factor receptor (EGFR) in view of targeted PDT. Using ICP‐MS and confocal microscopy, we could demonstrate that our conjugate has high selectivity for the EGFR receptor, which is a crucial oncological target because it is overexpressed and/or deregulated in a variety of solid tumors. However, in contrast to expectations, this conjugate was found to not produce reactive oxygen species (ROS) in cancer cells and is therefore not phototoxic.

Non-invasive treatment techniques have drawn a lot of interest due to the rising need for precise and secure cancer treatment. One such treatment method is photodynamic therapy (PDT), which uses the light irradiation of photosensitizers (PSs) to produce reactive oxygen species (ROS), which kill cancer cells. Most of the conventional photosensitizers used in the PDT process rely on molecular oxygen to produce cytotoxic ROS, known by the name of type II PSs. Because type II PSs requires oxygen to produce ROS, their full potential is not realized in hypoxic tumor tissues. On the other hand, type I PSs can increase the effectiveness of PDT in hypoxic tumor tissues since they rely less on oxygen to produce ROS. Consequently, it has become increasingly crucial to develop type I PSs to treat hypoxic malignancies. Numerous type I PSs of inorganic origin have been developed so far. Nonetheless, certain issues like poor biodegradability and persistent toxicity exist. Type I PSs based on organic compounds were developed in response to these concerns since they are comparatively more biocompatible and biodegradable. Therefore, in this article, we describe recent developments in the development of organic type I PSs for the PDT.

pH-Sensitive star-shaped poly(glutamic acid) with a porphyrin core as highly efficient photosensitizers for photodynamic therapy and molecular imaging

Multilayer photodynamic therapy for highly effective and safe cancer treatment.

Photodynamic therapy (PDT) with an oxygen-dependent character is a noninvasive therapeutic method for cancer treatment. However, its clinical therapeutic effect is greatly restricted by tumor hypoxia. What's more, both PDT-mediated oxygen consumption and microvascular damage aggravate tumor hypoxia, thus, further impeding therapeutic outcomes. Compared to type II PDT with high oxygen dependence and high oxygen consumption, type I PDT with less oxygen consumption exhibits great potential to overcome the vicious hypoxic plight in solid tumors. Type I photosensitizers (PSs) are significantly important for determining the therapeutic efficacy of PDT, which performs an electron transfer photochemical reaction with the surrounding oxygen/substrates to generate highly cytotoxic free radicals such as superoxide radicals (˙O2-) as type I ROS. In particular, the primary precursor (˙O2-) would progressively undergo a superoxide dismutase (SOD)-mediated disproportionation reaction and a Haber-Weiss/Fenton reaction, yielding higher cytotoxic species (˙OH) with better anticancer effects. As a result, developing high-performance type I PSs to treat hypoxic tumors has become more and more important and urgent. Herein, the latest progress of organic type I PSs (such as AIE-active cationic/neutral PSs, cationic/neutral PSs, polymer-based PSs and supramolecular self-assembled PSs) for monotherapy or synergistic therapeutic modalities is summarized. The molecular design principles and strategies (donor-acceptor system, anion-π+ incorporation, polymerization and cationization) are highlighted. Furthermore, the future challenges and prospects of type I PSs in hypoxia-overcoming PDT are proposed.

Porphyrinic pigments are used as photosensitizers (PS) in photodynamic detection (PDD) and therapy (PDT) that is a minimally invasive modality in the fight against cancer. When the PS is activated by visible light at a given wavelength, reactive oxygen species (ROS) are generated, which cause cancer cells to undergo cell death. Despite significant advances, drawbacks of the PSs in clinical use include their non-selectivity in cellular-targeting causing cell death by necrosis leading to tissue inflammation. Nitric oxide (NO) has been shown to play a key role in modulating apoptotic cell death pathways and to react with reactive oxygen species to form additional lethal reactive nitrogen species (RNS). In our efforts to enhance the effectiveness of PDT, we set out to investigate the role of NO in PDT. We hypothesized that NO delivered to cancer cells at the time that the PS was administered would enhance the efficacy of PDT by promoting mitochondria-mediated apoptosis. To this end, we incubated androgen-sensitive human prostate adenocarcinoma (LNCaP) cells with both a PS and an NO releasing agent that was most effective in NO release as was spectrophotometrically determined by its oxidation of hemoglobin. Phototoxicity experiments were carried out at 37 OC with a noncoherent light source. Cell viability, damage and death were assessed in both illuminated and non-illuminated cells and were quantified by MTT staining as well as trypan blue and propidium iodide exclusion. To corroborate the cell viability results, we assayed clonogenic recovery in response to PDT in pigmented cells both in the presence and absence of NO. Our results indicate that the effectiveness of PDT in causing cell death depends on the NO concentration. PDT with NO alone was toxic to the cancer cells at high concentration of NO, whereas at low NO concentration no significant cell damage was observed after light illumination. PDT with the PS alone was not as effective in promoting cell death as PDT in the presence of both NO and the PS. Depending on the concentrations of the PS and NO, we observed that either necrosis or apoptosis were the prevailing modes of cell death after PDT. Our results indicate that the phototoxicity of the compounds is mainly determined by their intracellular concentration. Thus, understanding the combined effects of NO and the PSs in enhancing cell phototoxicity will aid in determining the roles that NO plays in improving the efficacy of PDT and may provide an alternate regimen to enhance PDT efficacy. Citation Format: Marco Monroy, Pooncharas Tipgunlakant, Ursula Simonis, Raymond Esquerra. Nitric oxide and its role in photodynamic therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5111. doi:10.1158/1538-7445.AM2014-5111