Dark Cytotoxicity Research Articles

Dark cytotoxicity of submicrometer vaterite particles loaded with photosensitizer Fotoditazin and the vaterite-based core – shells structures

Photodynamic therapy (PDT) is based on the use of photosensitizers together with a light at the wavelength corresponding to its absorption maximum. Photosensitizers are able to generate reactive oxygen species under the visible or infrared light irradiation. They are broadly used for the treatment of cancer and infections due to their physical and chemical properties. Dose-dependent light induced cytotoxicity of photosensitizers shows the strong relation between its concentration in the treatment area and PDT efficiency. With this regard, the development of novel carriers for targeted delivery of photosensitizers is a very prospective research direction, as allows for the enhancement of the local drug concentration in the treatment area and the reduction of the incidental dark toxicity in healthy tissue associated with a classic PDT. Mesoporous vaterite particles are considered as a promising tool for biomedical application due to their biodegradability, high payload ability, as well as to the simplicity and cheapness of their fabrication. The efficiency of vaterite carrier application for a PDT delivery system design has been previously demonstrated. With this regard, the current study was aimed at the evaluation of dark cytotoxicity of the submicron vaterite particles and the vaterite-based core-shells, both loaded with Fotoditazin photosensitizer.

In Vitro Low-Fluence Photodynamic Therapy Parameter Screening Using 3D Tumor Spheroids Shows that Fractionated Light Treatments Enhance Phototoxicity.

The evaluation of novel photosensitizers (PSs) for photodynamic therapy (PDT) is difficult due to the limitations of two-dimensional cell culture and multiple parameters (dose, light intensity, uptake time), which complicate progression to in vivo experiments and clinical translation. Three-dimensional (3D) cell culture models like multicellular cancer tumor spheroids (MCTS) show great similarities to in vivo avascular tumor conditions, improving the speed and accuracy of screening novel compounds with various treatment combinations. In this study, we utilize C8161 human melanoma spheroids to screen PDT treatment combinations using protoporphyrin IX (PpIX) and drug-loaded carbon dot (CD) conjugates PpIX-CD and PpIX@CD at ultralow fluence values (<10 J/cm2). Conjugates show equivalent light-induced damage to PpIX from 1 μg/mL with significantly less dark cytotoxicity up to 72 h after exposure, shown by LDH release and dsDNA content. Fractionated treatments, carried out by dividing light exposure with 24 h intervals, demonstrate an enhanced PDT effect compared to single exposure at equal concentrations. Light sheet fluorescence microscopy combined with live/dead staining demonstrates that spheroids sustain extensive damage after PDT, with PpIX and PpIX-CD showing improved uptake compared to PpIX@CD. We show that PDT parameter screening can be carried out using a low-cost and convenient combination of assays to improve the efficiency of evaluating novel compounds.

Isolation and Characterization of Stigmasterol and β-sitosterol from Plectranthus scutellarioides var. color blaze dark star and Cytotoxicity of Its Fraction

Plectranthus scutellarioides is one of medicinal plants in Indonesia, traditionally known as iler/miana/jawer kotok. Due to a large number of varieties, certain varieties of P. scutellarioides have not been extensively studied. This study focused on the isolations of two phytosterols, stigmasterol and β-sitosterol, which were characterized by various 1D and 2D NMR analyses, from the ethyl acetate extract of P. scutellarioides var. color blaze dark star. Cytotoxicity of the ethyl acetate extract and some selected fractions were evaluated against A549, MDA-MB-231, MCF-7, KB, and KB-Vin cell lines using SRB (Sulforhodamine B) method. Among all tested sample, fractions 15 and 17 have significantly inhibited cell growth with IC50 of 14.3-24.3 µg/mL and 7.3-14.1 µg/mL, respectively.

Photodynamic therapy of prostate cancer using porphyrinic formulations.

Prostate cancer (PCa) is the second most frequent cancer diagnosed in men worldwide. Among the common treatment options, photodynamic therapy (PDT) is being considered a promising local therapy to treat this cancer. Although PDT is an established treatment modality approved for several types of cancer, the low solubility, the reduced tumor selectivity, the absorption in the therapeutic window and the poor clearance from the body of the currently approved photosensitizers (PS) hampers its wide clinical application. In this regard, herein we synthesized three fluorinated porphyrinoid derivatives and entrapped them into polyvinylpyrrolidone (PVP) to prevent their aggregation and preserve their desirable photophysical properties under the physiological environment. In vitro studies revealed the negligible dark cytotoxicity of all PVP formulations (PS1@PVP, PS2@PVP and PS3@PVP) at the tested concentrations (5.0 to 20μM), but also confirmed the significant photodynamic effect of PS2@PVP and PS3@PVP towards the PCa cell line PC-3, upon red light irradiation at an irradiance of 17.6mW.cm-2. To provide insight into the underlying mechanisms of cell death under PDT treatment induced by PS2@PVP and PS3@PVP, their intracellular localization in PC-3 cells was firstly investigated by confocal microscopy. Since both PS2@PVP and PS3@PVP nanoparticles were mainly localized in mitochondria, the involvement of this organelle in PDT-induced apoptosis mediated by both formulations was further explored. Western blot analysis revealed that PDT treatment of PC-3 cells with either PS2@PVP or PS3@PVP resulted in the reduction of the expression level of the anti-apoptotic protein Bcl-2. As the photodamage to Bcl-2 after PDT with PS2@PVP and PS3@PVP was accompanied by the further activation of pro-caspase-3, we assumed that upon irradiation the photogenerated reactive oxygen species (ROS) were able to activate a caspase-dependent apoptotic response as a consequence of a post-mitochondrial event. Taken together, these findings demonstrate that among the tested fluorinated porphyrinoids, PS2@PVP and, particularly, PS3@PVP, are significantly more effective in overall PC-3 cell killing than PS1@PVP, thus highlighting their great potential as therapeutic agents for PCa.

Improved Photophysical Properties of Ionic Material-Based Combination Chemo/PDT Nanomedicine.

Herein, a cost-effective and prompt approach to develop ionic material-based combination nanodrugs for cancer therapy is presented. A chemotherapeutic (phosphonium) cation and photodynamic therapeutic (porphyrin) anion are combined using a single step ion exchange reaction. Afterward, a nanomedicine is prepared from this ionic materials-based combination drug using a simplistic strategy of reprecipitation. Improved photophysical characteristics such as a slower nonradiative rate constant, an enhanced phosphorescence emission, a longer lifetime, and a bathochromic shift in absorbance spectra of porphyrin are observed in the presence of a chemotherapeutic countercation. The photodynamic therapeutic activity of nanomedicines is investigated by measuring the singlet oxygen quantum yield using two probes. As compared to the parent porphyrin compound, the synthesized combination material showed a 2-fold increase in the reactive oxygen species quantum yield, due to inhibition of face-to-face aggregation of porphyrin units in the presence of bulky chemotherapeutic ions. The dark cytotoxicity of combination therapy nanomedicines in the MCF-7 (cancerous breast) cell line is also increased as compared to their corresponding parent compounds in vitro. This is due to the high cellular uptake of the combination nanomedicines as compared to that of the free drug. Further, selective toxicity toward cancer cells was acquired by functionalizing nanomedicine with folic acid followed by incubation with MCF-7 and MCF-10A (noncancerous breast). Light toxicity experiments indicate that the synthesized ionic nanomedicine shows a greater cell death than either parent drug due to the improved photophysical properties and effective combination effect. This facile and economical strategy can easily be utilized in the future to develop many other combination ionic nanomedicines with improved photodynamics.

Modulation of fluorescent protein chromophore for photodynamic therapy and two-photon fluorescent imaging in living cells

The green fluorescent protein (GFP) chromophore has been widely applied as a biological marker or viscosity sensor. However, modulation of GFP chromophore for photodynamic therapy (PDT) has rarely been reported. Inspired by this, through the unique phenothiazine-anchored strategy, a near-infrared emission photosensitizer Lys-PtzFP was designed and synthesized to achieve this process. The maximum absorption wavelength of Lys-PtzFP was 460 nm and the corresponding molar extinction coefficient was 6.60 × 104 M−1 cm−1 in MeOH. The maximum emission wavelengths of Lys-PtzFP was at 725 nm. The photosensitizer Lys-PtzFP showed a high singlet oxygen quantum yield (ΦΔ = 0.42) and low fluorescence quantum yield (φF = 0.002) in MeOH. Besides, Lys-PtzFP possessed high specificity for lysosomes with negligible dark cytotoxicity (MTT assay >94.6%), good photostability and low half-maximal inhibitory concentration (IC50) of 0.93 μM. Finally, the intracellular photodynamic therapy experiments revealed that Lys-PtzFP can produce singlet oxygen in lysosomes and induce apoptosis under irradiation. In conclusion, Lys-PtzFP could be a promising photosensitizer for PDT and two-photon imaging applications. This type of photosensitizer can inspire the development of new photosensitizers for further explore highly efficient PDT.

Methylene blue-mediated Photodynamic Therapy in human retinoblastoma cell lines

Retinoblastoma is a malignant tumor of the retinal precursor cells and one of the rarest types of pediatric tumor, often occurring in the earliest years of life. Symptoms are conditioned by tumor size and location; one of the most recurrent symptoms is a white reflex in the pupillary area, called leukocoria or cat's eye reflex. In the present work, we studied the in vitro effectiveness of Photodynamic treatment (Pdt) in two types of human retinoblastoma, Y79 and WERI-Rb cell lines, using methylene blue (MB), a photosensitizer (PS) from the phenothiazine group. The two cell lines were incubated with varying concentrations of MB (3, 7, 10, 15, 20, 25, 30, 40, and 50μM), in the absence of light (dark cytotoxicity) and, in the presence of 664nm laser light (phototoxicity) with fluences of 1, 1.5, 3, 5, 7, 10, and 15J/cm2. The Y79 cell line showed higher cellular uptake values for MB than the WERI-Rb cell line. After three hours of incubation, the Y79 and WERI-Rb took up 48% and 34% of the total photosensitizer present in the medium, respectively. Using MTT assay, the results showed that the Y79 cell line was more affected by the photo treatment as demonstrated by the combination of MB concentration and light doses compared with WERI-Rb cell line. The results were correlated with the more pronounced singlet oxygen emission observed in Y79 cells. While MB does show efficacy for eradication of retinoblastoma in vitro, only studies in appropriate animal models will reveal whether the selectivity of photokilling at tolerable drug and light doses is sufficient to suggest clinical trials.

Multifunctional AIE iridium (III) photosensitizer nanoparticles for two-photon-activated imaging and mitochondria targeting photodynamic therapy

Developing novel photosensitizers for deep tissue imaging and efficient photodynamic therapy (PDT) remains a challenge because of the poor water solubility, low reactive oxygen species (ROS) generation efficiency, serve dark cytotoxicity, and weak absorption in the NIR region of conventional photosensitizers. Herein, cyclometalated iridium (III) complexes (Ir) with aggregation-induced emission (AIE) feature, high photoinduced ROS generation efficiency, two-photon excitation, and mitochondria-targeting capability were designed and further encapsulated into biocompatible nanoparticles (NPs). The Ir-NPs can be used to disturb redox homeostasis in vitro, result in mitochondrial dysfunction and cell apoptosis. Importantly, in vivo experiments demonstrated that the Ir-NPs presented obviously tumor-targeting ability, excellent antitumor effect, and low systematic dark-toxicity. Moreover, the Ir-NPs could serve as a two-photon imaging agent for deep tissue bioimaging with a penetration depth of up to 300 μm. This work presents a promising strategy for designing a clinical application of multifunctional Ir-NPs toward bioimaging and PDT.

Rational Design of Near‐Infrared Aza‐Platinum‐Dipyrromethene‐Based Nanophototherapy Agent with Multistage Enhancement for Synergistic Antitumor Therapeutics

The development of innovative synergistic phototherapy (SPT) agent with excellent photodynamic therapy (PDT) and photothermal therapy (PTT) effects for efficient antitumor is of great significance. However, the low photothermal conversion efficiency or low singlet oxygen yield of SPT agent during the phototherapy process will result in inefficient tumor therapy. Herein, a new near‐infrared (NIR) SPT agent based on aza‐platinum‐dipyrromethene dye (D‐3) with synergistic PDT and PTT effects is rationally designed and synthesized by the metallization and halogenation of aza‐dipyrromethene simultaneously. The introduction of iodine atoms and Pt(II) ion to aza‐dipyrromethene skeleton can not only effectively promote the excited electrons to undergo intersystem crossing process for improving singlet oxygen (1O2) generation capability, but also inhibit radiative transition process for boosting photothermal conversion properties. For biological exploration, the biocompatible D‐3 nanomaterials (APIDNs) with excellent concentration‐dependent photoacoustic and photothermal properties are prepared, thus visibly guiding synergetic PDT and PTT effects for inhibiting the growth of tumor cells in vivo. This work demonstrates the superior therapy effects of APIDNs and its negligible dark cytotoxicity. The novel strategy reported in this work will offer a new way to design new‐generation NIR aza‐metal‐dipyrromethene‐based dyes for developing superior SPT agents.

Enhanced upconversion emission of Er3+-Yb3+ co-doped Ba5(PO4)3OH powder phosphor for application in photodynamic therapy

Er3+-Yb3+ co-doped Ba5(PO4)3OH nanoparticle powder phosphors were successfully synthesized by urea combustion method. The resulting powder phosphors were characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), high resolution scanning electron microscopy (HRSEM), energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS) and photoluminescence spectroscopy (PL). XRD data confirmed crystallization of pure hexagonal phase of Ba5(PO4)3OH and HRSEM images showed formation of ellipsoidal particles. XPS data combined with EDS analysis confirmed the materials composition that corresponds with identification of all the chemical elements constituting the materials. The in vitro dark cytotoxicity of the particles confirmed lack of cytocidal behaviour in the absence of light, but considerable photodynamic therapy (PDT) activity was observed upon illumination. Upon excitation using a 980 nm laser, multiple emission peaks in the green and red regions corresponding to the optical transitions of Er3+ ion were observed. Upon co-doping with Yb3+, upconverted red emission was detected and this was attributable to non-radiative energy transfer from Yb3+ to Er3+. The proposed mechanism of upconversion photoluminescence is discussed.

Mitochondrial Targeting Cationic Purpurinimide–Polyoxometalate Supramolecular Complexes for Enhanced Photodynamic Therapy with Reduced Dark Toxicity

AbstractPolyoxometalates (POMs), that are well‐defined metal‐oxygen cluster anions, are functional molecules extensively used in various research applications. The synthesis of neutral purpurinimides, followed by conversion to cationic purpurinimides (CPIs), formed CPI–POM supramolecular complexes via electrostatic interactions between each CPI and the polyanionic POM. The cellular uptake of purpurinimides, CPIs, and their CPI–POMs in A549 and HeLa cell lines was confirmed by confocal laser scanning microscopy. CPIs showed concentration‐dependent dark cytotoxicity; however, CPI–POMs exhibited reduced low dark cytotoxicity. After photoirradiation, CPIs and CPI–POMs revealed enhanced photodynamic therapy (PDT) compared to free purpurinimides against A549 and HeLa cells. The CPIs exhibit low cell viability by incorporating their PDT effect with intrinsic dark cytotoxicity; however, the CPI–POMs exhibited a POM delivery effect‐based enhanced PDT activity in the supramolecular complex system with low dark cytotoxicity. In particular, the clicked CPI–POM revealed two times higher PDT activity compared with the clicked free CPI, due to the good delivery effect of POM.

Controlled killing of human cervical cancer cells by combined action of blue light and C-doped TiO2 nanoparticles.

In this study, C-doped TiO2 nanoparticles (C-TiO2) were prepared and tested as a photosensitizer for visible-light-driven photodynamic therapy against cervical cancer cells (HeLa). X-ray diffraction and Transmission Electron Microscopy confirmed the anatase form of nanoparticles, spherical shape, and size distribution from 5 to 15nm. Ultraviolet-visible light spectroscopy showed that C doping of TiO2 enhances the optical absorption in the visible light range caused by a bandgap narrowing. The photo-cytotoxic activity of C-TiO2 was investigated in vitro against HeLa cells. The lack of dark cytotoxicity indicates good biocompatibility of C-TiO2. In contrast, a combination with blue light significantly reduced the survival of HeLa cells: illumination only decreased cell viability by 30% (15min of illumination, 120µW power), and 60% when HeLa cells were preincubated with C-TiO2. We have also confirmed blue light-induced C-TiO2-catalyzed generation of reactive oxygen species in vitro and intracellularly. Oxidative stress triggered by C-TiO2/blue light was the leading cause of HeLa cell death. Fluorescent labeling of treated HeLa cells showed distinct morphological changes after the C-TiO2/blue light treatment. Unlike blue light illumination, which caused the appearance of large necrotic cells with deformed nuclei, cytoplasm swelling, and membrane blebbing, a combination of C-TiO2/blue light leads to controlled cell death, thus providing a better outcome of local anticancer therapy.

Luminescent Neutral Cyclometalated Iridium(III) Complexes Featuring a Cubic Polyhedral Oligomeric Silsesquioxane for Lipid Droplet Imaging and Photocytotoxic Applications

New neutral iridium(III) complexes featuring a cubic polyhedral oligomeric silsesquioxane (POSS) unit, [Ir(N∧C)2(L1-POSS)] [HN∧C = 2-phenylpyridine (Hppy; 1), 2-phenylbenzothioazole (Hbt; 2), and 2-(1-naphthyl)benzothiazole (Hbsn; 3); L1-POSS = (E)-4-[(2-hydroxybenzylidene)amino]benzyl 3-heptakis(isobutyl)POSS-propyl carbamate], were designed and synthesized. Their POSS-free counterparts, [Ir(N∧C)2(L1)] [L1 = (E)-N-(4-hydroxymethylphenyl)-1-(2-hydroxyphenyl)methanimine; HN∧C = Hppy (1a), Hbt (2a), and Hbsn (3a)], and the poly(ethylene glycol) (PEG) derivatives [Ir(N∧C)2(L1-PEG)] [L1-PEG = (E)-4-[(2-hydroxybenzylidene)amino]benzyl 3-[2-[ω-methoxypoly(1-oxapropyl)]ethyl]carbamate; HN∧C = Hppy (1b), Hbt (2b), and Hbsn (3b)] were also prepared. The photophysical, photochemical, and biological properties of the POSS complexes were compared with those of their POSS-free and PEG-modified counterparts. Upon irradiation, all of these complexes displayed orange-to-red emission and long emission lifetimes under ambient conditions. The bsn complexes 3, 3a, and 3b exhibited the highest singlet oxygen (1O2) generation quantum yields (ΦΔ = 0.85-0.86) in aerated CH3CN. Laser-scanning confocal microscopy images revealed that complexes 1-3 and 1a-3a showed exclusive lipid-droplet staining upon cellular uptake, while the PEG derivatives 1b-3b displayed lysosomal localization. Complex 3 was utilized to study various lipid-droplet-related biological events including lipid-droplet accumulation under oleic acid stimulation, the movement of lipid droplets, and preadipocyte differentiation. Notably, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays indicated that the ppy complexes 1 and 1b and the bt complexes 2 and 2b were noncytotoxic both in the dark and upon irradiation at 450 nm for 5 min (IC50 > 200 μM), while the bsn complexes 3, 3a, and 3b showed low dark cytotoxicity (IC50 = 52.9 to >200 μM) and high photocytotoxicity (IC50 = 1.1-5.3 μM). The cellular uptake, internalization mechanisms, and cell death pathways of these complexes were also investigated. This work not only offers promising luminescent probes for lipid droplets through the structural modification of iridium(III) complexes but also paves the way to the construction of new reagents for theranostics.

Nitric oxide release activated near-Infrared photothermal agent for synergistic tumor treatment

Activatable phototherapeutic agents (PTA) in one system with synergistic gas therapy (GT) and photothermal therapy (PTT) hold great promise for highly efficient tumor treatments. In this study, an activatable multifunctional platform with photothermal conversion “turn on” features via nitric oxide (NO) release for synergistic GT and PTT was rationally designed using an aryl N-nitrosamine (NO-donating unit) functionalized aza-BODIPY framework (S–NO). As expected, after NO release from S–NO, the product (Red-S) showed obviously enhanced heat production performance under a longer excited wavelength via improved near-infrared light absorption and decreased fluorescence emission. Furthermore, water-soluble and biocompatible S–NO nanoparticles (S–NO NPs) with negligible dark cytotoxicity successfully suppressed tumor growth and enhanced the survival rate of mice via synergistic GT and PTT under the guidance of multimode imaging. The study offered rational guidance to design better platforms for synergistic tumor treatments and validated that S–NO NPs can act as potential PTAs in biological applications.

Photococatalytic anticancer performance of naked Ag/AgCl nanoparticles

Ag/AgCl as a plasmonic photocatalyst has an excellent performance in dye degradation, but its photocatalytic ability in cancer therapy has not been well researched. Hence, we synthesized bio-compatible and surfactant-free Ag/AgCl nanoparticle to investigate their photocatalytic efficacy. AgCl can be oxidized by FeCl3 on the surface of Ag nanoparticles (NPs), which will naturally form a Schottky junction. Thus, Ag as a co-catalyst can easily trap the photo-generated charge carriers and then provide free electrons, which will decrease the influence of the recombination process and increase photocatalytic efficacy. Besides that, the light irradiation will stimulate the surface plasmon resonance of Ag nanoparticle, which can enhance visible light absorption by the material. Our photocatalyst can generate Reactive oxygen species (ROS) which generate oxidative stress to cellular systems and result in apoptosis. Compared to pure Ag nanoparticle, AgCl coated on Ag nanoparticle has a larger range of working wavelength and higher photocatalytic efficacy, moreover, it has less dark cytotoxicity than pure AgCl nanoparticle based on our results. The photocatalytic efficacy of Ag/AgCl nanoparticle can eliminate over 75% HeLa cells under 30 min of light irradiation.

The photodynamic activities of the gold nanoparticle conjugates of phosphorus(V) and gallium(III) A3meso-triarylcorroles

The synthesis and characterization of series of P(V) and Ga(III) A3 triarylcorrole complexes with 4-methylthiophenyl (2a, 3a), thien-3-yl (2b, 3b) and thien-2-yl (2c, 3c) meso-groups are reported along with the physicochemical and photodynamic activity properties of the dyes and their gold nanoparticle (AuNP) conjugates. The Ga(III) corrole series have lower fluorescence quantum yields and higher singlet oxygen quantum yields than the analogous P(V) complexes. Upon conjugation to AuNPs, the fluorescence quantum yields of the P(V) and Ga(III) corroles decrease, while the singlet oxygen quantum yields increase due to an external heavy atom effect. The P(V) and Ga(III) corroles exhibit relatively low in vitro dark cytotoxicity, which was further enhanced upon conjugation to AuNPs. The P(V) complexes and their AuNP conjugates display more favorable PDT activity properties upon illumination with a Thorlabs 625 nm light-emitting diode (288 J cm−2) with phototoxicity indices > 18.5 and 20.8, respectively, for the meso-thienyl-substituted 2b-AuNP and 2c-AuNP conjugates. Optical spectroscopy analyses demonstrate that this can be attributed to there being significantly less aggregation due to the presence of two trans-hydroxy axial ligands.

Structural property and risk assessment of loose deposits in drinking water distribution systems

Abstract Discoloration events caused by loose deposits resuspension in drinking water distribution systems (DWDS) are the main aspects of customer complaints across the world, but the understanding of the potential risks of loose deposits is insufficient. In this study, loose deposits in real DWDS were collected from regions frequently experiencing ‘yellow water’. Cytotoxicity of healthy human liver cells was used to evaluate the toxicity risks of the particle samples. The results showed that the loose deposits would have a realistic discoloration risk (turbidity &amp;gt; 10 NTU) when their concentrations were higher than 10 mg/L. The water sample containing 1,000 mg/L loose deposits had a dark yellow color (100–300 PCU) and cytotoxicity (viability of human liver cells during cytotoxicity tests 59.18–80.69%), while the water sample containing 1 mg/L loose deposits did not have obvious color (&amp;lt;15 PCU) and cytotoxicity (&amp;gt;97.00%). Particle size showed a stronger correlation with relative viability (r = 0.761) than other properties (specific area, metal content, contact angle, saturation magnetization and electron transfer number). However, it is interesting to note that both turbidity and color had a low correlation with relative viability, thus the toxicity of the particles could not be properly judged using turbidity or color. This study gives an important guidance that although the loose deposits could be visualized during water discoloration, its toxicity risks could not be evaluated through aesthetic indicators.

Highly Efficient Far-Red/NIR-Absorbing Neutral Ir(III) Complex Micelles for Potent Photodynamic/Photothermal Therapy.

A critical issue in photodynamic therapy (PDT) is inadequate reactive oxygen species (ROS) generation in tumors, causing inevitable survival of tumor cells that usually results in tumor recurrence and metastasis. Existing photosensitizers frequently suffer from relatively low light-to-ROS conversion efficiency with far-red/near-infrared (NIR) light excitation due to low-lying excited states that lead to rapid non-radiative decays. Here, a neutral Ir(III) complex bearing distyryl boron dipyrromethene (BODIPY-Ir) is reported to efficiently produce both ROS and hyperthermia upon far-red light activation for potentiating in vivo tumor suppression through micellization of BODIPY-Ir to form "Micelle-Ir". BODIPY-Ir absorbs strongly at 550-750nm with a band maximum at 685nm, and possesses a long-lived triplet excited state with sufficient non-radiative decays. Upon micellization, BODIPY-Ir forms J-type aggregates within Micelle-Ir, which boosts both singlet oxygen generation and the photothermal effect through the high molar extinction coefficient and amplification of light-to-ROS/heat conversion, causing severe cell apoptosis. Bifunctional Micelle-Ir that accumulates in tumors completely destroys orthotopic 4T1 breast tumors via synergistic PDT/photothermal therapy (PTT) damage under light irradiation, and enables remarkable suppression of metastatic nodules in the lungs, together without significant dark cytotoxicity. The present study offers an emerging approach to develop far-red/NIR photosensitizers toward potent cancer therapy.

Co-Encapsulation of Methylene Blue and PARP-Inhibitor into Poly(Lactic-Co-Glycolic Acid) Nanoparticles for Enhanced PDT of Cancer.

The development of resistance against photodamage triggered by photodynamic therapy (PDT) is ascribed mainly to the cellular redox defenses and repair. If the tumor tissue is not promptly eliminated by the first few PDT sessions, PDT-resistance can be favored, challenging the efficacy of the treatment. Although the mechanism of PDT resistance is still unclear, in vitro assays have evidenced that it can be developed through the PARP damage-repair signaling pathway. Therefore, inhibition of poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) has the potential to increase PDT efficacy. This work reports on the synthesis of a controlled release system of a photosensitizer, methylene blue (MB) and a PARP-inhibitor, the veliparib. MB and veliparib were co-encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (VMB-NPs). A colloidal stable aqueous suspension of nanoparticles was obtained. The average hydrodynamic diameter was 90 nm and a narrow size distribution was obtained, with a polydispersity index (PDI) of 0.08. The release kinetics of MB and veliparib from VMB-NPs showed an initial burst of 8.7% and 58.3% release of the total amounts of MB and veliparib respectively, in the first 6 h, and a delayed release of up to 11.3% and 70%, in 19 days, for MB and veliparib, respectively. The VMB-NPs showed no cytotoxicity in the dark but the viability of B16F10-Nex2 cells decreased by 36% when the cells were irradiated (102 J/cm2, 660 nm) and treated with VMB-NPs containing 1.0 µM of MB and 8.3 µM of veliparib. Considering the increased photoactivity even at low MB and veliparib concentrations and the absence of cytotoxicity in dark, the co-encapsulation of MB and veliparib was shown to be a promising strategy to improve the PDT efficacy.

DNA-Intercalative Platinum Anticancer Complexes Photoactivated by Visible Light.

Photoactivatable agents offer the prospect of highly selective cancer therapy with low side effects and novel mechanisms of action that can combat current drug resistance. 1,8‐Naphthalimides with their extended π system can behave as light‐harvesting groups, fluorescent probes and DNA intercalators. We conjugated N‐(carboxymethyl)‐1,8‐naphthalimide (gly‐R‐Nap) with an R substituent on the naphthyl group to photoactive diazido PtIV complexes to form t,t,t‐[Pt(py)2(N3)2(OH)(gly‐R‐Nap)], R=H (1), 3‐NO2 (2) or 4‐NMe2 (3). They show enhanced photo‐oxidation, cellular accumulation and promising photo‐cytotoxicity in human A2780 ovarian, A549 lung and PC3 prostate cancer cells with visible light activation, and low dark cytotoxicity. Complexes 1 and 2 exhibit pre‐intercalation into DNA, resulting in enhanced photo‐induced DNA crosslinking. Complex 3 has a red‐shifted absorption band at 450 nm, allowing photoactivation and photo‐cytotoxicity with green light.