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Porphyria is a group of genetic photodermatoses that cause too much porphyrin to accumulate in the blood, skin, and liver, resulting in skin photosensitivity and damage, liver disease, or potential liver failure. Conventional detection methods include high-performance liquid chromatography and fluorescence spectrometry. However, these methods usually require complicated pretreatment and time-consuming processes. Therefore, efficient and fast detection of porphyria is urgently needed. Herein, we develop a molecular afterglow reporter-based sensing scheme for the detection of porphyrins in whole blood. The afterglow reporter can respond to the production of singlet oxygen (1O2) of porphyrins after light excitation, and the detection signals can be amplified through adjusting the amount of singlet oxygen and afterglow reporter molecules. Moreover, without the use of a real-time excitation source, afterglow signals can avoid the scattering and autofluorescence interference in biological samples, thereby reducing background noise. More importantly, we prove the applicability of the afterglow reporter in the quantitative detection of porphyrins in whole blood and demonstrate its great clinical potential.

Purpose Cutaneous melanoma is among the fastest growing malignancies in Norway and ultraviolet radiation (UVR) exposure is the primary environmental risk factor. Immunomodulating drugs can increase skin photosensitivity and suppress immune responses, and by such mechanisms influence melanoma risk. We, therefore, aimed to examine the associations between use of immunomodulating drugs and melanoma risk, at a nationwide population level. Patients and methods In the Cancer Registry of Norway, we identified all cases aged 18-85 with a first primary cutaneous melanoma diagnosed in 2007-2015 (n=12,106). These were matched to population controls from the Norwegian National Registry 1:10 (n=118,564), on sex and year of birth using risk set sampling. Information on prescribed drugs (2004-2015) was obtained by linkage to the Norwegian Prescription Database (NorPD). Conditional logistic regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for associations between use of immunomodulating drugs (immunosuppressants and corticosteroids) and melanoma risk, adjusted for ambient UVR and other drug use. Results Compared with ≤1 prescription, use of ≥8 prescriptions of immunosuppressants was associated with increased risk of melanoma (RR 1.50, 95% CI 1.27, 1.77). Similar associations were found for subgroups of immunosuppressants: drugs typically prescribed to organ transplant recipients (OTRs) (RR 2.02, 95% CI 1.35, 3.03) and methotrexate (RR 1.27, 95% CI 1.04, 1.55). Similar results were found for high levels of cumulative doses and across all histological subtypes. Use of corticosteroids was not associated with melanoma risk. Conclusion We found a positive association between use of immunosuppressants and melanoma risk, with the highest risk seen for drugs prescribed to OTRs. Knowledge about this risk increase is important for physicians and users of these drugs, for intensified surveillance, awareness and cautious sun exposure.

Whether skin photosensitivity modulates sun exposure behaviours, consequent vitamin D status and skeletal health outcomes independently of constitutive pigmentation have not been systematically investigated. 1072 community-dwelling adults aged 50-80 years had skin photosensitivity quantified by questionnaire and melanin density by spectrophotometry. Bone mineral density (BMD), falls risk and 25-hydroxyvitamin D (25OHD) were measured using DXA, short form physiological profile assessment and radioimmunoassay, respectively. Sun exposure and symptomatic fractures were assessed by questionnaire. Participants were followed up at 2.5 (n = 879), 5 (n = 767) and 10 (n = 571) years. Higher resistance to sunburn and greater ability to tan were associated with reduced sun protection behaviours (RR 0.87, p < 0.001 & RR 0.88, p < 0.001), higher lifetime discretionary sun exposure in summer (RR 1.05, p = 0.001 & RR 1.07, p = 0.001) and winter (RR 1.07, p = 0.001 & RR 1.08, p = 0.02) and fewer lifetime sunburns (RR 0.86, p < 0.001 & RR 0.91, p = 0.001). Higher resistance to sunburn was associated with lower total body (β = - 0.006, p = 0.047) and femoral neck (β = - 0.006, p = 0.038) BMD, but paradoxically, fewer prevalent fractures (RR 0.94, p = 0.042). Greater ability to tan was associated with higher 25OHD (β = 1.43, p = 0.04), lumbar spine (β = 0.014, p = 0.046) and total body (β = 0.013, p = 0.006) BMD, but not fracture or falls risk. These associations were independent of constitutive melanin density. Cutaneous photosensitivity was associated with sun exposure behaviours, cutaneous sequelae and, consequently, 25OHD and BMD in older Caucasian adults independent of constitutive melanin density. There was no consistent association with fracture outcomes, suggesting environmental factors are at least as important.

Background and objective The minimal erythema dose (MED), an essential measurement in studies of skin photosensitivity, requires establishing MED values for specific populations, given genetic variation. Different ways to assess erythema are also relevant. We aimed to determine MED values in a sample of Colombian patients and correlations between MED and Fitzpatrick skin type. We also studied concordance correlation between MEDs and two alternative ways to assess erythema. Patients and methods Cross-sectional study of 113 individuals in Bogota, Colombia. We used a solar simulator to measure UV-A radiation and combined UV-A and UV-B (UVA + UVB) radiation, for MED calculation. Narrowband UV-B (NBUVB) radiation was measured in a phototherapy cabin. Erythema was assessed visually and with a Mexameter MX 18 device. Results The median MEDs of UVA + UVB radiation were 22 mJ/cm2 for Fitzpatrick skin types I and II, and 33 and 43 mJ/cm2, respectively, for skin types III and IV. The MEDs of UV-A radiation were 22, 42, 86, and 100 J/cm2 for skin types I, II, III, and IV, respectively. The MEDs of NBUVB radiation were 390, 550, 770, and 885 mJ/cm2 for the 4 skin types. The correlation between MEDs and skin types ranged from 0.5 to 0.69. Lin's concordance correlation coefficients between visual and Mexameter assessments of erythema were greater than 0.8 in all cases. Conclusion This study allowed us to understand MED values for UV-A, UVA + UVB, and NBUVB according to different skin types in the Colombian population. Concordance correlation coefficients between the different methods of erythema assessment were very good. Correlations between MEDs and skin types were moderate to good.

Colorectal cancer (CRC) involving a malignant tumour remains one of the greatest contributing causes of fatal mortality and has become the third globally ranked malignancy in terms of cancer-associated deaths. Conventional CRC treatment approaches such as surgery, radiation, and chemotherapy are the most utilized approaches to treat this disease. However, they are limited by low selectivity and systemic toxicity, so they cannot completely eradicate this disease. Photodynamic therapy (PDT) is an emerging therapeutic modality that exerts selective cytotoxicity to cancerous cells through the activation of photosensitizers (PSs) under light irradiation to produce cytotoxic reactive oxygen species (ROS), which then cause cancer cell death. Cumulative research findings have highlighted the significant role of traditional PDT in CRC treatment; however, the therapeutic efficacy of the classical PDT strategy is restricted due to skin photosensitivity, poor cancerous tissue specificity, and limited penetration of light. The application of nanoparticles in PDT can mitigate some of these shortcomings and enhance the targeting ability of PS in order to effectively use PDT against CRC as well as to reduce systemic side effects. Although 2D culture models are widely used in cancer research, they have some limitations. Therefore, 3D models in CRC PDT, particularly multicellular tumour spheroids (MCTS), have attracted researchers. This review summarizes several photosensitizers that are currently used in CRC PDT and gives an overview of recent advances in nanoparticle application for enhanced CRC PDT. In addition, the progress of 3D-model applications in CRC PDT is discussed.

What is known and objective Knowledge regarding the association between photosensitivity and pirfenidone is based mainly on case reports. The purpose of this article was to evaluate the clinical characteristics of photosensitivity associated with pirfenidone. Methods We collected studies on photosensitivity induced by pirfenidone published from 2008 to 31 August 2021 in Chinese and English for a retrospective analysis. Results and discussion The median age was 70 years (range 57-80) in 22 patients with pirfenidone-induced photosensitivity. The dose at the onset of symptoms ranged from 600 to 2403 mg for the treatment of idiopathic pulmonary fibrosis. Pirfenidone-induced photosensitivity occurred within 1 week in some patients and up to 8 months in others. The most common clinical manifestation of photosensitivity caused by pirfenidone was itching on body parts exposed to sunlight (back of hands, face, neck, and limbs) in 15 patients followed by erythema in 13 patients. Histopathological examination revealed necrotic keratinocytes, lymphocytic inflammatory cell infiltrate, hyperkeratosis and liquefaction degeneration in 5 patients. The photosensitivity test showed a markedly decreased minimum erythema dose (MED) of 7-228 mJ/cm2 UV-B in 4 patients and 4.86-12 J/cm2 UV-A in 5 patients. The clinical symptoms were significantly improved or completely relieved with a median time of 4 weeks (range 1-8) after drug withdrawal, dose reduction or systemic and topical glucocorticoid therapy. What is new and conclusion Clinicians should be aware of the potential phototoxic effects of pirfenidone and should inform patients to take pirfenidone during (or after) a meal, avoid sun exposure, wear protective clothing, and apply broad-spectrum sunscreen with high ultraviolet UVA and UVB protection.

Photodynamic therapy (PDT) is a promising and clinically approved method for the treatment of cancer. However, the efficacy of PDT is often limited by the poor selectivity and distribution of the photosensitizers (PS) toward the malignant tumors, resulting in prolonged periods of skin photosensitivity. In this work, we present a simple and straightforward strategy to increase the tumor distribution, selectivity, and efficacy of lipophilic PS zinc phthalocyanine (ZnPc) in colon cancer by their stabilization in purified, naturally secreted extracellular vesicles (EVs). The PS ZnPc was incorporated in EVs (EV-ZnPc) by a direct incubation strategy that did not affect size distribution or surface charge. By using co-culture models simulating a tumor microenvironment, we determined the preferential uptake of EV-ZnPc toward colon cancer cells when compared with macrophages and dendritic cells. We observed that PDT promoted total tumor cell death in normal and immune cells, but showed selectivity against cancer cells in co-culture models. In vivo assays showed that after a single intravenous or intratumoral injection, EV-ZnPc were able to target the tumor cells and strongly reduce tumor growth over 15 days. These data expose opportunities to enhance the potential and efficacy of PDT using simple non-synthetic strategies that might facilitate translation into clinical practice.

Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated the effects of vitamin E supplementation in six SLOS patients already receiving dietary cholesterol treatment. Plasma vitamin A and E concentrations were determined by the high-performance liquid chromatography (HPLC) method. At baseline, plasma 7-DHC, 8-dehydrocholesterol (8-DHC) and cholesterol levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The clinical effect of the supplementation was assessed by performing structured parental interviews. At baseline, patients were characterized by low or low-normal plasma vitamin E concentrations (7.19-15.68 μmol/L), while vitamin A concentrations were found to be normal or high (1.26-2.68 μmol/L). Vitamin E supplementation resulted in correction or significant elevation of plasma vitamin E concentration in all patients. We observed reduced aggression, self-injury, irritability, hyperactivity, attention deficit, repetitive behavior, sleep disturbance, skin photosensitivity and/or eczema in 3/6 patients, with notable individual variability. Clinical response to therapy was associated with a low baseline 7-DHC + 8-DHC/cholesterol ratio (0.2-0.4). We suggest that determination of vitamin E status is important in SLOS patients. Supplementation of vitamin E should be considered and might be beneficial.

All-trans retinoic acid is a natural retinoid and the physiologically active metabolite of vitamin A. The aim of the present study is to develop and optimize a nanostructured lipid carrier formulation to enhance the photostability of all-trans retinoic acid and alleviate its skin photosensitivity. Box–Behnken design was used for optimizing dependent variables such as particle size, zeta potential and viscosity. The total lipid (%), liquid lipid (%) and total surfactant (%) were selected as independent variables. The optimized formulation was characterized by particle size of 151 nm, zeta potential of −31 mV and viscosity of 2064 cps. In vitro photoprotection effect of the optimized formulation containing different types and concentrations of inorganic sunscreens was evaluated employing Transpore® tape assay. Sun protection factor and other spectroscopic indices revealed that 6% titanium dioxide was the best choice to be combined with the optimized formulation. After 6 h of ultraviolet A exposure, the optimized formulation and the optimized formulation combined with 6% titanium dioxide enhanced the photostability of all-trans retinoic acid by about 1.5 and 2 times, respectively, compared to its methanolic solution. In vivo photoprotection effect of the developed formulations was conducted on mice exposed to direct sun light for 4 days. Photographs of the mice's skin, biochemical analysis of the pro-inflammatory cytokines in the skin as well as histopathological examination, depicted that the optimized formulation promoted an obvious alleviation of the all-trans retinoic acid-induced photosensitivity, which was further potentiated by the addition of 6% titanium dioxide, compared to the marketed product.

Combinatory modulation of the physical and biochemical characteristics of nanocarrier delivery systems is an emergent topic in the field of nanomedicine. Here, we studied the combined effects of incorporation of active targeting moieties into nanocarriers and their morphology affecting the enhanced permeation and retention effect for nanomedicine cancer therapy. Self-assembled lipid discoidal and vesicular nanoparticles with low-polydispersity sub-50 nm size range and identical chemical compositions were synthesized, characterized, and correlated with in vitro cancer cellular internalization, in vivo tumor accumulation and cancer treatments. The fact that folate-associated bicelle yields the best outcome is indicative of the preference for discoidal carriers over spherical carriers and the improved targeting efficacy due to the targeting ligand/receptor binding. The approach is successfully adopted to design the nanocarriers for photodynamic therapy, which yields a consistent trend in in vitro and in vivo efficacy: folate nanodiscs > folate vesicles > nonfolate nanodiscs > nonfolate vesicles. Folate discs not only have shown a higher tumor uptake and photothermal therapeutic efficiency, but also minimize skin photosensitivity side effects. The advantages of nanodiscoidal bicelles as nanocarriers, including well-defined size, robust formation, easy encapsulation of hydrophobic molecules (therapeutics and/or diagnostics), easy incorporation of targeting molecules, and low toxicity, enable the scalable manufacturing of a generalized in vivo multimodal delivery platform.

Prostate cancer is one of the leading causes of death in men worldwide. Photodynamic therapy (PDT) is a new emerging and promising strategy for the treatment of prostate cancer. PDT uses a combination of light and a photosensitizer (PS) to kill cancer cells. However, most photosensitizers (PS) accumulate in normal tissues, in particular the skin and eyes, and can be activated by sunlight, causing severe side effects such as prolonged skin photosensitivity that have limited the clinical application of PDT. Herein, a novel strategy is presented to overcome these limitations using Indocyanine green (ICG) as an activatable PDT agent. We developed a human serum albumin (HSA)-based nanoplatform loaded with Chlorin e6 (Ce6) and ICG. In vitro and in vivo studies showed that ICG effectively turned "OFF" the phototoxicity of Ce6, and the degradation of ICG by laser irradiation at 808 nm turned "ON" the phototoxicity of Ce6. In addition, ICG produced heat upon NIR irradiation to kill cancer cells, which could be used as a photothermal therapy (PTT). Therapeutic efficacy of HSA-ICG-Ce6 NPs in a prostate cancer model showed that tumors were completely damaged in mice treated by combined PTT with activated PDT. Our designed HSA nanoparticles containing ICG and Ce6 could be used as an activatable PDT combined with PTT for the treatment of prostate cancer.

Congenital erythropoietic porphyria (CEP) is an inborn error of heme synthesis resulting from uroporphyrinogen III synthase (UROS) deficiency and the accumulation of nonphysiological porphyrin isomer I metabolites. Clinical features are heterogeneous among patients with CEP but usually combine skin photosensitivity and chronic hemolytic anemia, the severity of which is related to porphyrin overload. Therapeutic options include symptomatic strategies only and are unsatisfactory. One promising approach to treating CEP is to reduce the erythroid production of porphyrins through substrate reduction therapy by inhibiting 5-aminolevulinate synthase 2 (ALAS2), the first and rate-limiting enzyme in the heme biosynthetic pathway. We efficiently reduced porphyrin accumulation after RNA interference–mediated downregulation of ALAS2 in human erythroid cellular models of CEP disease. Taking advantage of the physiological iron-dependent posttranscriptional regulation of ALAS2, we evaluated whether iron chelation with deferiprone could decrease ALAS2 expression and subsequent porphyrin production in vitro and in vivo in a CEP murine model. Treatment with deferiprone of UROS-deficient erythroid cell lines and peripheral blood CD34+-derived erythroid cultures from a patient with CEP inhibited iron-dependent protein ALAS2 and iron-responsive element–binding protein 2 expression and reduced porphyrin production. Furthermore, porphyrin accumulation progressively decreased in red blood cells and urine, and skin photosensitivity in CEP mice treated with deferiprone (1 or 3 mg/mL in drinking water) for 26 weeks was reversed. Hemolysis and iron overload improved upon iron chelation with full correction of anemia in CEP mice treated at the highest dose of deferiprone. Our findings highlight, in both mouse and human models, the therapeutic potential of iron restriction to modulate the phenotype in CEP.

Photodynamic therapy (PDT) is a promising cancer treatment which involves a photosensitizer (PS), light at a specific wavelength for PS activation and oxygen, which combine to elicit cell death. While the illumination required to activate a PS imparts a certain amount of selectivity to PDT treatments, poor tumor accumulation and cell internalization are still inherent properties of most intravenously administered PSs. As a result, common consequences of PDT include skin photosensitivity. To overcome the mentioned issues, PSs may be tailored to specifically target overexpressed biomarkers of tumors. This active targeting can be achieved by direct conjugation of the PS to a ligand with enhanced affinity for a target overexpressed on cancer cells and/or other cells of the tumor microenvironment. Alternatively, PSs may be incorporated into ligand-targeted nanocarriers, which may also encompass multi-functionalities, including diagnosis and therapy. In this review, we highlight the major advances in active targeting of PSs, either by means of ligand-derived bioconjugates or by exploiting ligand-targeting nanocarriers.

A thriving 4-month-old boy was referred to paediatric dermatology for ‘persistent ringworm’ since 2 weeks of life refractory to topical antifungals. During pregnancy, his mother, who had no known rheumatological diseases, reported skin photosensitivity and non-specific joint pains; antenatal scans were normal. At 2 weeks of life, an annular facial and upper-chest rash developed with an erythematous ring and central clearing without scaling (figure 1). Management with multiple …

Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disease derived from a deficient activity in the fourth enzyme of the heme biosynthetic pathway, uroporphyrinogen III synthase (UROIIIS). The impossibility of a correct heme production results in the accumulation of intermediate metabolites known as uroporhyrins, leading to pathological consequences such as skin photosensitivity and phototoxic cutaneous injuries. In this chapter, we discuss the importance of protein homeostasis in the heme pathway and its regulation, as well as how many of the CEP-causing mutations impair UROIIIS homeostasis, affecting thermodynamic stability but preserving normal or near-normal activity. As a proof of concept, we show how UROIIIS proteostasis can be restored by use of a proteasomal inhibitor in animal models. Finally, a new line of therapeutic intervention against CEP is presented, which involves the use of a pharmacological chaperone known as ciclopirox (CPX) to improve UROIIIS stability, reverting most of the CEP symptoms in mice models.

Porphyrins are endogenous photosensitizers, which are widely present in living systems. Endogenous porphyrins in the human body are mainly the precursors for heam biosynthesis. However, excessive porphyrins can lead to syndrome porphyria, causing skin photosensitivity and damage, anemia, hepatotoxicity, or organ failure. Traditional detection techniques include spectrometry and high performance liquid chromatography (HPLC). Without any pretreatment, they can hardly determine the level of porphyrins in whole blood. Therefore, it's significantly important to realize highly efficient detection of porphyrins. In this work, we proposed a superlong afterglow reporter to realize easy and rapid detection for porphyria. The molecular afterglow reporters can respond to singlet oxygen (1O2) produced by porphyrins, and the detection signals can be received by the emission of afterglow reporters. During the detection process, afterglow signals can avoid the autofluorescence and scattering of complex biological system to reduce the interference of background noise. Our study demonstrates that superlong afterglow reporter is a promising technique for efficient and accurate detection of porphyria and has a great potential in clinical detection.

Background/Purpose: Recent GWAS studies, mostly performed in populations of North European origin, have identified the genetic loci associated with pigmentation, sun sensitivity, freckling and skin cancer susceptibility. Here, we aimed at addressing the genetic determinants of sunlight sensitivity in Spain, a southern European population.Methods: Nine SNPs located in 8 pigmentation- related genes (IRF4,TYR,ASP,HERC2,OCA2,BNC2,SLC24A4 and SLC45A2) were genotyped in 456 Spaniards. Additionally, the complete sequence of the MC1R gene was obtained, testing each nonsynony-mous mutation supported by the classification as R or r alleles. A standardised ques-tionnaire was used to collect demographic characteristics, pigmentation and sun sensitivity traits, as well as sun exposure habits.Results: MC1R R alleles and IRF4 rs12203592 were significantly associated with sun-light sensitivity at the Bonferroni-corrected level (P- value < 4.54 × 10−3). Genetic variants in SLC45A2 (rs16891982) and HERC2 (rs12913832) were also found to be significantly associated with skin photosensitivity in our Spanish sample. Interaction analysis using the MDR method revealed epistatic effects when these four variants were considered together.Conclusion: MC1R, IRF4,HERC2 and SLC45A2 play a significant role in skin sensitivity to sunlight in the Spanish population. Moreover, interaction among these four loci seems to modulate the ability of the skin to respond to UV radiation.

Phthalocyanines are promising photosensitizers for photodynamic therapy (PDT). A novel zinc 1,8(11),15(18),22(25)-tetraiodo-3,10(9),17(16),24(23)-tetra-tert-butylphthalocyanine has been synthesized and characterized. The synthesis of iodinated phthalocyanine was achieved through templated cyclotetramerization of 6-tert-butyl-4-iodo-1,3-diiminoisoindoline around zinc ions (Zn2+). A six step route leading to 6-tert-butyl-4-iodo-1,3-diiminoisoindoline was proposed. The synthesis started with a regiospecific iodination of 4-tert-butyl-o-xylene to 5-tert-butyl-2,3-dimethyl-iodobenzene, followed by oxidation of the methyl groups to phthalic acid, conversion of phthalic acid to phthalimide, hydrolysis of phthalimide to phthalamide, conversion of phthalamide to phthalonitrile, followed by conversion of phthalonitrile to a more reactive 6-tert-butyl-4-iodo-1,3-diiminoisoindoline. Highly desirable photophysical and photochemical properties were induced in zinc phthalocyanine by iodination of the aromatic rings, while the presence of tert-butyl groups rendered the compound non-aggregating in solution. The photosensitizer studied exhibits absorption band within the so-called “therapeutic window”, with λmax at 689 nm and very high molar absorption coefficient of 295 000 [M−1 cm−1] in DMF. Transient absorption experiment revealed T1 → Tn absorption spanning from ca. 400 nm to ca. 600 nm and allowed determination of the excited triplet state lifetime (τT). The estimated τT in THF equaled 3.3 μs. The phosphorescence maximum was found to be located at λP 1103 nm and the excited triplet state energy (ET) equaled 1.12 eV in 2-methyltetrahydrofuran at 77 K. The photosensitizer studied is characterized by a high value of singlet oxygen quantum yield (ΦΔ) of ca. 0.76 and the photooxygenation process proceeds via Type II mechanism under the experimental conditions applied. The photodegradation studies revealed that the iodinated phthalocyanine was moderately stable in the presence of oxygen with quantum yield of photodegradation (Φd) equaled 4.01 × 10−4. Moderate photostability of photosensitizer is advantageous from a PDT point of view where rapid breakdown and fast clearance from the patient’s system is necessary to avoid prolonged skin photosensitivity following treatment.

The development of activatable nanoplatforms to simultaneously improve diagnostic and therapeutic performances while reducing side effects is highly attractive for precision cancer medicine. Herein, we develop a one-pot, dopamine-mediated biomineralization method using a gas diffusion procedure to prepare calcium carbonate-polydopamine (CaCO3–PDA) composite hollow nanoparticles as a multifunctional theranostic nanoplatform. Because of the high sensitivity of such nanoparticles to pH, with rapid degradation under a slightly acidic environment, the photoactivity of the loaded photosensitizer, i.e., chlorin e6 (Ce6), which is quenched by PDA, is therefore increased within the tumor under reduced pH, showing recovered fluorescence and enhanced singlet oxygen generation. In addition, due to the strong affinity between metal ions and PDA, our nanoparticles can bind with various types of metal ions, conferring them with multimodal imaging capability. By utilizing pH-responsive multifunctional nanocarriers, effec...

Congenital erythropoietic porphyria, also called Gunther's disease, is a very rare genetic autosomal recessive diseaseaffecting less than 1 per 1,000,000 children. Pathogenesis involves genetic mutation encoding uroporphyrinogen-III cosynthase which leads to accumulation of porphyrin in many tissues, leading to extreme skin photosensitivity, red cell lysis, splenomegaly and reduced life expectancy. Herein, we report a 12-year mentally challenged girl with multiple blisters and scars on sun exposed sites since birth. She had hepatomegaly, erythrodontia, severe anaemia with haemolytic blood picture and mildly elevated liver enzymes. Skin biopsy showed deposition of amorphous eosinophilic porphyrins in the dermis, thus confirming a diagnosis of congenital erythropoietic porphyria.

Photodynamic therapy (PDT) uses a photosensitizer, molecular oxygen, and visible light as an alternative clinical protocol against located malignant tumors and other diseases. More recently, PDT has been combined to immunotherapy as a promising option to treat metastatic cancer. However, previous generations of photosensitizers (PSs) revealed clinical difficulties such as long-term skin photosensitivity (first generation), the need for drug delivery vehicles (second generation), and intracellular self-aggregation (third generation), which have generated a somewhat confusing scenario in PDT approaches and evolution. Recently, metal-organic frameworks (MOFs) with exceptionally high PS loading as a building unit of MOF framework have emerged as fourth-generation PS and presented outstanding outcomes under pre-clinical studies. For PS-based MOFs, the inorganic building unit (metal ions/clusters) plays an important role as a coadjuvant in PDT to alleviate hypoxia, to decrease antioxidant species, to yield ROS, or to act as a contrast agent for imaging-guided therapy. In this review, we intend to carry out a broad update on the recent history and the characteristics of PS-based MOFs from basic chemistry to the structure relationship with biological application in PDT. The details and variables that result in different photophysics, size, and morphology, are discussed. Also, we present an overview of the achievements on the pre-clinical assays in combination with other strategies, including alleviating hypoxia in solid tumors, chemotherapy, and the most recent immunotherapy for cancer.

Objectives The goal of this study was to compare tumor response to Photofrin® photodynamic therapy using intravenous and intratumoral injection of photosensitizer. Systemic skin photosensitivity and photosensitizer distribution were also compared between the two delivery methods. Methods SCCVII tumors were initiated in the hind legs of female C3H mice and grown to a volume of ∼1,000 mm3 . Photofrin® was delivered intravenously via the tail vein at a concentration of 2 mg/kg or intratumorally at concentrations ranging from 0.5-2 mg/kg. A 630 nm laser illumination was delivered via interstitial diffuser placement at a fluence rate of 400 mW/cm and fluence of 100 J/cm. Mice were maintained under normal room lighting for 24 hours after treatment, at which point photographs were captured for assessment of skin photosensitivity. Animals were then sacrificed, and their tumors were excised, sectioned, imaged, and stained with hematoxylin and eosin (H&E). H&E slides were imaged to assess necrosis post-PDT, and skin photographs were evaluated by two blinded reviewers for quantification of skin photosensitivity. Whole-body fluorescence imaging was performed before and after photodynamic therapy. Results Tumor necrosis was not significantly different based on treatment group (P = 0.33), while skin photosensitivity was significantly reduced in animals that received Photofrin® intratumorally (P = 0.0005). Fluorescence imaging revealed similar photosensitizer fluorescence in excised tumors for intratumor and intravenous injection of Photofrin® (P = 0.48), although fluorescence decreased significantly with decreasing intratumor injection concentration (P= 0.01). Conclusions This pilot study shows that intratumoral administration of Photofrin® has the potential to produce similar tumor outcomes, while reducing systemic skin photosensitivity. Further studies are warranted to characterize and optimize intratumor delivery. Lasers Surg. 50:476-482, 2018. © 2017 Wiley Periodicals, Inc.

Background The second-generation photosensitizer NPe6 has strong anti-tumor effects with a much shorter photosensitive period than the first-generation photosensitizer Photofrin. Although photosensitive period has been reduced, skin photosensitivity is still a major side effect of photodynamic therapy (PDT). Therefore, we conducted a prospective study to investigate whether the NPe6 fluorescence intensity in skin after PDT could be measured effectively in human patients to improve the management of a patient's photosensitive period. Methods The NPe6 fluorescence measurements using a constructed fluorescence sensing system at the inside of the arm were acquired prior to and 5 and 10 min after NPe6 administration as well as at the time of PDT (4–5 h after administration), at discharge (2 or 3 days after PDT), and at 1 or 2 weeks after PDT. Participants were interviewed as to whether they had any complications at 2 weeks after PDT. Results Nine male patients and one female patient entered this study. Nine patients were inpatients and one patient was an outpatient. All of the measurements of NPe6 fluorescence in the skin could be obtained without any complications. The spectral peak was detected at the time of discharge (2–3 days after administration) in most cases and it decreased at 1 or 2 weeks after PDT. Conclusions The fluorescence of NPe6 in the skin could be detected feasibly using the fluorescence sensing system in human patients. Measuring the relative concentration of NPe6 in the skin indirectly by measuring fluorescence intensity might be useful to predict the period of skin photosensitivity after PDT.

Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly used as an antipyretic analgesic owing to its strong anti-inflammatory action in clinical treatment. However, diclofenac can cause injury, with gastrointestinal mucosal lesions and skin photosensitivity as the main side effects. In general, photosensitive drugs contain photosensitive chemical sites, and form free radicals under ultraviolet irradiation, leading to phototoxic reactions. Therefore, this study focuses on free radical production in photosensitive reactions of diclofenac. The free radical production mechanism of diclofenac under ultraviolet irradiation, which might result in photo-toxicity, was clarified using a direct electron spin resonance method. When diclofenac was irradiated with ultraviolet light (254 nm), diclofenac radicals were generated depending on the ultraviolet irradiation time and stably present for 30 min at room temperature. Diclofenac radicals were produced by the ultraviolet irradiation system depending on the dose of diclofenac until 2 mM. Therefore, diclofenac radicals might directly or indirectly react with various biomolecules to cause phototoxicity, other side effects, and new diclofenac pharmacology owing to its stability of diclofenac radicals.

A 16 month old toddler presented with global developmental delay, truncal hypotonia and microcephaly. Her background history was significant for bilateral developmental dysplasia of the hip, recurrent upper respiratory tract infections, conductive hearing loss and a scalp haemangioma. Development had been apparently normal up until 6 months of age. Over the course of her follow-up she developed signs of cerebellar dysfunction including intention tremor and broad based ataxia, chronic feeding difficulties, pigmentary retinopathy and skin photosensitivity. MRI brain at age 2.5 years showed delayed myelination and cerebellar atrophy. A skeletal muscle biopsy revealed reduced activities for the respiratory chain complexes I, II and IV, in particular, in keeping with a mitochondrial condition. After extensive genetic investigations failed to identify the underlying aetiology, an exome sequencing study was carried out and revealed a mutation in the ERCC6 DNA repair gene, consistent with Cockayne syndrome (OMIM # 133540). This is a rare autosomal recessive genetic condition which causes microcephaly, developmental delay and failure to thrive, along with sun sensitivity, tooth decay, bone abnormalities, hearing and vision loss and other symptoms. The patient has been managed with multidisciplinary care and symptomatic treatment, including skin protection, as well as nutritional and multivitamin supplements. She is wheelchair bound and non-verbal but otherwise medically well at age 7 yrs. Many clinical signs seen in patients with Cockayne syndrome are also found in patients with a primary mitochondrial disease. Conversely, secondary dysfunctional mitochondria may also contribute to the phenotype of patients with Cockayne syndrome. Taken together, this case demonstrates the value of exome sequencing in diagnosing and differentiating rare disorders with diverse and overlapping phenotypes, including primary and secondary mitochondrial conditions, which are less likely to be diagnosed on clinical grounds and biochemical investigations alone.

Background Skin cancers have a complex disease mechanism, involving both genetic and non-genetic risk factors. Numerous meta-analyses have been published claiming statistically significant associations between non-genetic risk factors and skin cancers without applying a thorough methodological assessment. Objective The present study maps the literature on the non-genetic risk factors of skin cancers, assesses the presence of statistical biases and identifies the associations with robust evidence. Methods We searched PubMed up to January 20, 2016 to identify systematic reviews and meta-analyses of observational studies that examined associations between non-genetic factors and skin cancers. For each meta-analysis, we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We also assessed the between-study heterogeneity (I 2 metric), evidence for small-study effects and excess significance bias. Results Forty-four eligible papers were identified and included a total of 85 associations. Twenty-one associations were significant at P −6 . Fifty-two associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in fifteen and thirteen associations, respectively. Overall, thirteen associations (actinic keratosis, serum vitamin D, sunburns, and hair color for basal cell carcinoma and density of freckles, eye color, hair color, history of melanoma, skin type, sunburns, premalignant skin lesions, common and atypical nevi for melanoma) presented high level of credibility. Conclusion The majority of meta-analyses on non-genetic risk factors for skin cancers suffered from large between-study heterogeneity and small-study effects or excess significance bias. The associations with convincing and highly suggestive evidence were mainly focused on skin photosensitivity and phenotypic characteristics.

Photodynamic therapy (PDT) is the combination of light and photosensitizer (PS) to kill tumor cells, which has the potential to meet many currently unmet medical needs. However, the whole body distribution and activatability by sunlight of photosensitizers to induce skin photosensitivity have limited the extensive clinic application of PDT. Herein, a novel strategy is presented to overcome these limitations by using a hydrophobic Near-infared (NIR) dye IR-780 iodide (IR780) to induce the self-assembly of albumin-PS conjugates, as a switchable PDT (Switch-PDT) agent. The PDT effect of PS is effectively inhibited by IR780 and recovered by NIR light irradiation in vitro. This quench/recovery strategy dose not sacrifice the anti-tumor ability in vivo, and the combined PDT and PTT (photothermal) effect contributes a very effective tumor inhibition rate of 100%. More importantly, the PDT effect is significantly suppressed after intravenous administration in mice or subcutaneous administration in rabbits as exhibited by the negligible skin response, while traditional PDT agent arouses severe skin erythema and edema. To the best of our knowledge, the switchable PDT is the first time to be used to eradicate the skin photosensitization of PS in vivo.

Photodynamic therapy (PDT) is a light-activated photochemical reaction that induces localized tissue damage for the treatments of cancers and other nonmalignant conditions through the generation of reactive oxygen species. In the clinic, patients treated with PDT reveal strong skin photosensitivity and thus should be kept away from direct sunlight. In our previous study, we demonstrated that the skin phototoxicity of meta-tetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in the clinic, can be significantly reduced after micellar encapsulation. In this present work, m-THPC was loaded into artificial oil bodies (AOBs) to improve its biocompatibility with self-aggregation. Our results show that the m-THPC-loaded oil bodies with particle size around 100 nm significantly enhanced the nuclear localization of m-THPC, whereas m-THPC-loaded Pluronic® F68 micelles were only observed in the cytosol. In addition, m-THPC-loaded oil bodies had better PDT efficacy than those m-THPC-loaded polymeric mi...

In recent years, cancer has been one of the leading causes of death in the world. Much effort has been devoted to developing cancer treatments. Photodynamic therapy (PDT) is a noninvasive therapeutic modality by combining the light of a specific wavelength, a photosensitizer (PS) and oxygen, which has been widely applied for the treatment of cancers. However, the application of PDT in clinic is greatly limited due to lack of tumor selectivity and often causing skin photosensitivity. The use of organic nanoparticles (NPs) as an advanced technology in the field of PDT shows a great promise to overcome these shortcomings. Therefore, in this review, we summarize several functional organic NPs as PS carriers that have been developed to enhance the efficacy of PDT against cancers.

Since the discovery of photodynamic therapy, scientists have constantly been searching for more effective and ideal photosensitizers (PSs). As part of our ongoing interest in the development of more potent photosensitizers, quinoline-8-yloxy-substituted zinc(II) phthalocyanine (ZnPc-Q1) has been identified as a promising photosensitizers in tumor cells. This study aims to explore the photodynamic mechanism and in vivo photodynamic efficacy of ZnPc-Q1, and further evaluate its potential in clinical photodynamic therapy application. The single crystal structure of ZnPc-Q1 enables the easy control of clinical quality standards. In comparison with Photofrin, ZnPc-Q1 exhibits considerably higher in vitro anticancer activity by dual dose-related mechanisms (antiproliferative and apoptosis). In addition, the in vivo results demonstrate that ZnPc-Q1 exhibits significant tumor regression with less skin photosensitivity by both direct killing and apoptosis anticancer mechanisms. In conclusion, ZnPc-Q1 can be considered to be a promising ideal PS for clinical application owing to its defined chemical structure without phthalocyanine isomerization, good absorption of tissue-penetrating red light, improved photodynamic therapy efficacy, and reduced skin phototoxicity.

Photodynamic therapy (PDT) can destroy local tumor cells and induce effective antitumor immune responses, and has been applied in the treatment of patients with superficial solid tumors. Numerous systemic side effects of PDT, such as pain and skin photosensitivity, however, limit this therapeutic option. In addition, the immunosuppressive tumor microenvironment has been found to be another critical barrier for the antitumor immunity induced by PDT. Therefore, effectively enhancing the cytotoxicity to tumor cells of low-dose PDT and inhibiting the tumor immunosuppressive tumor microenvironment may be a feasible strategy to overcome these drawbacks of PDT. Here, a sorafenib and chlorin e6 co-loaded reactive oxygen species (ROS)-responsive nanoparticle (NP-sfb/ce6) is developed to improve antitumor responses by intratumoral release of sorafenib at the time of PDT. Under 660-nm laser irradiation, ROS produced by chlorin e6 (ce6) destruct the nanoparticles, resulting in boosted sorafenib cascade release. The rapidly released sorafenib acts synergistically with the low-dose PDT to inhibit tumor growth by inducing strong T cell-dependent local and systemic antitumor immune responses, reprograming the tumor immune microenvironment, and limiting the interaction between cytotoxic CD8+ T cells and immunosuppressive cells. This study provides new avenues for cascade-amplifying antitumor effects of photodynamic therapy.