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Background: Phakomatosis pigmentovascularis (PPV) is a rare congenital syndrome. Only a few studies have reported the treatment of PPV, including a case using photodynamic therapy (PDT) to treat PPV-associated port-wine stains (PWS)., Objective: To investigating the efficacy and adverse effects of hemoporfin-PDT in PPV-associated PWS., Methods: The efficacy and adverse effects in patients with PPV who underwent two sessions of hemoporfin-PDT from January 2019 to December 2022 were retrospectively analyzed., Results: Twenty patients were included (13 females, 7 males, age range: 2-31 years; mean: 8.20 ± 8.92 years). Two, nine, seven, and two patients had PPV types Ia, IIa, IIb, and IIIa, respectively. After two treatments, the visual evaluation indicated the color of the PWS in 4, 5, 6, and 5 patients showed poor, fair, good, and excellent improvements, respectively. The combined good and excellent improvement rates in patients with PWS and pigmentary nevus overlapping in the same treatment area and in patients with PWS in the treatment areas only were 33.3% versus 87.5%, respectively, and were significantly different (p = 0.02). Minor side effects, such as edema, scabbing, hyperpigmentation, and blistering, were observed in some patients after PDT., Conclusion: Hemoporfin-PDT is an effective treatment for PPV-associated PWS. Patients with PWS and pigmentary nevus overlapping in the same treatment area showed poorer efficacy than patients with PWS in the treatment areas only., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Sonodynamic therapy (SDT) has emerged as a useful approach for tumor treatment. However, its widespread application is impeded by poor pharmacokinetics of existing sonosensitizers. Here we developed a metal-organic nanoplatform, wherein a small-molecule sonosensitizer (hematoporphyrin monomethyl ether, HMME) was ingeniously coordinated with zirconium, resulting in a multifunctional nanosonosensitizer termed Zr-HMME. Through post-synthetic modifications involving PEGylation and tumor-targeting peptide (F3) linkage, a nanoplatform capable of homing on melanoma was produced, which could elicit robust immune responses to suppress tumor lung metastasis in the host organism. Importantly, after seamless incorporation of positron-emitting 89 Zr into this nanosonosensitizer, positron emission tomography (PET) could be used to monitor its in vivo pharmacokinetics. PET imaging studies revealed that this nanoplatform exhibited potent tumor accumulation and strong in vivo stability. Using intrinsic fluorescence from HMME, a dual-modal diagnostic capability (fluorescence and PET) was confirmed for this nanosonosensitizer. In addition, the mechanisms of how this nanoplatform interacted with immune system were also investigated. The collective data proved that the coordination structure between small-molecule drug cargos and metals may enhance the functions of each other while mitigating their weaknesses. This straightforward approach can expand the potential applications of suitable drug molecules., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Port-wine stains occur in 0.3-0.5% newborns, mainly on the face and neck. Pulsed dye laser is recognized as the gold standard treatment; nevertheless, it is associated with a low cure rate and a high recurrence rate., Aims: This study aims to evaluate the efficacy of hemoporfin photodynamic therapy for pulsed dye laser-resistant port-wine stains in children., Methods: We studied 107 children who received hemoporfin photodynamic therapy for port-wine stains on the face and neck that were resistant to pulsed dye laser. After intravenous injection of 5 mg/kg hemoporfin, the local lesion was irradiated with 532 nm LED green light for 20 min with a power density of 80-100 mW/cm2. A total of 65 patients were given a second treatment after eight weeks. The efficacy and therapeutic responses were recorded at four days and eight weeks after each treatment., Results: The efficacy was positively correlated with the number of treatments received; two treatment sessions yielded significantly better results compared to a single treatment with a response rate of 96.9%, a significant response rate of 50.8% and a cure rate of 21.5%, respectively (P < 0.001). After two treatment sessions, the efficacy was negatively correlated with age (P = 0.04). The efficacy for port-wine stains located on the lateral part was better than that of the central face (P = 0.04). The efficacy for the pink type was better than that for the red and purple types (P = 0.03). No allergic or systematic adverse reactions were reported., Limitations: No objective measurement data were available., Conclusion: Hemoporfin photodynamic therapy is effective and safe for pulsed dye laser-resistant facial port-wine stains in children.

Elevating intratumoral levels of highly toxic reactive oxygen species (ROS) by nanocatalytic medicine for tumor-specific therapy without using conventional toxic chemodrugs is recently of considerable interest, which, however, still suffers from less satisfactory therapeutic efficacy due to the relatively poor accumulation at the tumor site and largely blocked intratumoral infiltration of nanomedicines. Herein, an ultrasound (US)-triggered dual size/charge-switchable nanocatalytic medicine, designated as Cu-LDH/HMME@Lips, is constructed for deep solid tumor therapy via catalytic ROS generations. The negatively charged liposome outer-layer of the nanomedicine enables much-prolonged blood circulation for significantly enhanced tumoral accumulation, while the positively charged Fenton-like catalyst Cu-LDH released from the liposome under the US stimulation demonstrates much enhanced intratumoral penetration via transcytosis. In the meantime, the co-released sonosensitizer hematoporphyrin monomethyl ether (HMME) catalyze the singlet oxygen ( 1 O 2 ) generation upon the US irradiation, and deep-tumoral infiltrated Cu-LDH catalyzes the H 2 O 2 decomposition to produce highly toxic hydroxyl radical (·OH) specifically within the mildly acidic tumor microenvironment (TME). The efficient intratumoral accumulation and penetration via the dual size/charge switching mechanism, and the ROS generations by both sonosensitization and Fenton-like reactions, ensures the high therapeutic efficacy for the deep tumor therapy by the nanocatalytic medicine., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

To improve water solubility, reduce phototoxicity and increase the tumor-targeting ability of hematoporphyrin (Hp) as a sonosensitizer for sonodynamic therapy under ultrasonic conditions, a novel folate receptor (FR)-targeted, folate-conjugated ethylenediamine-β-cyclodextrin (FA-EN-β-CD) containing Hp (FA-EN-β-CD-Hp) was constructed. β-Cyclodextrin containing Hp (β-CD-Hp) was also established as a nontargeted control. The inclusion efficiencies of Hp in FA-EN-β-CD-Hp and β-CD-Hp were determined to be 90.4 ± 2.7% (wt/wt) and 92.5 ± 3.4% (wt/wt), respectively. Growth inhibition rates in HepG-2 cells in vitro were assessed upon ultrasound exposure. The results indicated that the growth inhibition rates of FA-EN-β-CD-Hp, β-CD-Hp, and F-Hp (Hp: 150 μg/ml) reached 96.4 ± 3.6%, 53.4 ± 3.4%, and 48.2 ± 2.8%, respectively. These results indicated that FA-EN-β-CD-Hp is a promising drug delivery system in the field of sonodynamic cancer therapy., (© 2020 Wiley Periodicals, Inc.)

This study aims at exploring the clinical efficacy and sonographic changes of photodynamic therapy (PDT) using Hematoporphyrin Monomethyl Ether (HMME) for the treatment of port-wine stains (PWS). Forty-five patients with PWS were recruited between March 2017 and June 2018 from the Department of Dermatology of The Third Affiliated Hospital of Soochow University. Five cases were of the pink type, thirty-nine cases were of the purple-red type, and one case was of the thickened type. All patients received three treatment sessions of PDT. After covering normal skin outside the treated area, patients received an intravenous injection of 5 mg/kg HMME within 20 minutes. The affected areas were exposed to a 532 nm LED light and were kept vertically at a distance of 10 cm. The irradiation energy density was set between 80 and 110 J/cm 2 in 15-minute sessions. Intermittent power density adjustment was performed at a rate of 5 mW/cm 2 , and the treatment was withheld when the endpoint reaction appeared. Three follow-ups were performed before and after treatment, respectively, and the efficacy, thickness, and density of skin before and after treatment were evaluated with high-frequency ultrasound. The overall efficacy rate was 97.78% in forty-five cases after treatment for three sessions. Efficacy was related to age ( P = 0.029) and lesion severity ( P < 0.001). There were significant differences in the efficacy between the groups of <18 years old, 18-29 years old, and >29 years old ( P = 0.029). A marked decrease in the numbers of distorted enlarged blood vessels per unit of the lesion was observed under high-frequency ultrasound. There were significant differences in skin thickness and skin density before and after treatment ( F = 14.528, 5.428, P < 0.001). The swelling was reported to varying degrees in the treated areas in 23 patients with cheek lesion and in 6 frontal lesions. Hyperpigmentation after inflammation was observed in four patients that faded spontaneously after two months. In conclusion, photodynamic therapy for the treatment of PWS using HMME is effective and safe with few adverse reactions. Moreover, monitoring the changes in skin thickness and density of lesion tissue using high-frequency ultrasound can objectively evaluate the clinical efficacy of HMME photodynamic therapy and provide the basis for the formulation of individualized photodynamic therapy., Competing Interests: All authors declared that they had no conflicts of interest., (Copyright © 2020 Ahmad Taha Khalaf et al.)

Pulsed dye laser-resistant port-wine stains present a therapeutic challenge. The aim of this study was to evaluate the efficacy and safety of photodynamic therapy for treating these lesions. A total of 67 patients with pulsed dye laser-resistant cervicofacial port-wine stains were retrospectively assessed after undergoing photodynamic therapy mediated with a combination of hemoporfin and 532-nm light. For objective evaluation of photodynamic therapy efficacy, first, the colorimetric changes in the port-wine stain lesions were evaluated according to the L*a*b* color coordinate system, then the values of color changes (ΔE) and blanching rate were calculated. For subjective evaluation of improvement, photographs taken before and after photodynamic therapy were evaluated by three independent assessors blindly. Patient satisfaction was also used as a factor in the subjective evaluation. Adverse events were recorded after treatment. The median ΔE decreased significantly from the pretreatment value of 13.42 to 9.90 at the 2-month follow up (P < 0.001). The median blanching rate of port-wine stains was 28.04% after an average of 1.21 sessions of photodynamic therapy. Based on the overall visual assessment, 46.2% patients showed excellent or good levels of improvement (>50% color blanching). Adverse events were minimal, transient and self-limiting. In conclusion, photodynamic therapy serves as an alternative means to treat pulsed dye laser-resistant port-wine stains., (© 2020 Japanese Dermatological Association.)

Objective: To observe the efficiency and safety of hematoporphyrin mono-methylether photodynamic therapy (HMME-PDT) in treating port-wine stains (PWS) with Chinese patients, and to evaluate the advantage of photograph,VISIA Complexion Analysis System, and dermoscopy in efficacy evaluation.Analyzing changes of pain during treatment and related adverse reactions., Method: 62 patients were treated in our department during2017-2019 with HMME-PDT, among which, 20 cases were pink type, 32 cases were purple type and remain 11 cases were nodular thickening type. Initially, all patients received an intravenous injection of 5 mg/kg HMME, and then the lesion areas of the patients were exposed to 532 nm LED green light after 10 min. The irradiation power density was range between 80-100 mW/cm2. By utilization of photograph,VISIA system, and dermoscopy to evaluate the clearance after treatments, and then informing the patients to value the pain level during the treatment via visual analogue scale(VAS), and recording the adverse reactions., Result: After 2 times treatments, 11 of the 62 cases were cured (17.74 %), 17 cases showed a good efficacy (27.42 %), 20 cases indicated alleviation (32.26 %), while 14 cases displayed no efficacy (22.58 %).By observation, The VISIA system combined with image analysis software is an excellent technique in assessing efficacy. Dermoscopy helps to classify PWS types.It showed that the pain level each patient could endure was distinct, and it's remarkable that when receiving consecutive 12.09 ± 3.74 min of treatment, most of patients have showed severe pain.Patients with severe pain except young children who couldn't value the pain, had better efficacy.The side effects after treatment mainly displayed with edema, crust, hyperpigmentation. No recurrence within 2 years., Conclusion: It shows that after treating with HMME-PDTt efficacy is remarkable, with advantage of safety and fewer side effects. HMME&#95;PDT should undergo further research and promotion. VISIA system combined with image analysis software and dermoscopy are excellent techniques for evaluating efficacy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The tumor microenvironment (TME) affects not only tumor growth and metastasis, but also therapy efficacy. In the present study, an oxygen self-supplying delivery system for a photosensitizer (O 2 -PDS), with an oxygen source of calcium peroxide (CPO), has been designed to induce multi-path tumor apoptosis through interactive effects with the TME. In anti-tumor experiments, the CPO decomposition and O 2 released from the O 2 -PDS are site-activated and accelerated by high interstitial pressure and low pH level of the TME. The CPO decomposition products of O 2 and Ca 2+ lead to direct tumor apoptosis by irradiation generated singlet oxygen and mitochondrial calcium overload. The decomposition products of OH - and O 2 relieves the acid and hypoxic state of TME, inducing a decrease in tumor proliferation and metastasis. This multi-path tumor apoptosis leads to a positive therapeutic effect on an animal tumor model and nontoxicity in normal tissue., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of drug delivery is to increase therapeutic efficacy. Externally triggered drug delivery systems enable site-specific and time-controlled drug release. To achieve this goal, our strategy was based on ultrasound-triggered release of an anticancer agent from sonosensitive liposomes (SL). To realize the ultrasound-triggered drug release, a lipophilic sonosensitizer, hematoporphyrin monomethyl ether (HMME) was incorporated into the lipid bilayer of liposomes. Once irradiated by the ultrasound in tumor tissues, the sonodynamic effect generated by HMME could lead to an efficient disruption of the lipid bilayer in the SL. After encapsulating vincristine bitartrate (VIN) as the model drug, the ultrasound-triggered lipid bilayer breakdown can trigger the instant release of VIN, enabling ultrasound-controlled chemotherapy with great specificity. In the in vitro and in vivo studies, by integrating tumor-specific targeting and stimuli-responsive controlled release into one system, VIN-loaded SL showed excellent antitumor efficacy. The SL could potentially produce viable clinical strategies for improved targeting efficiency of VIN for the treatment of related cancer. More importantly, this report provides an example of controlled release by means of a novel class of ultrasound triggering system.

Background: Hemoporfin is a porphyrin-based photosensitizer and has been used for photodynamic therapy of port wine stain birthmarks in China. This study assessed the pharmacokinetics and cutaneous photosensitization of Hemoporfin in healthy volunteers., Methods: Sixteen healthy subjects received a single intravenous infusion injection of Hemoporfin (5 mg/kg). The concentrations of Hemoporfin (MHD) and its metabolite Haematoporphyrin (HP) in plasma, urine and faeces were determined. The pharmacokinetic parameters were calculated. In addition, the cutaneous photosensitization was evaluated under the irradiation of solar simulator, 532 nm laser, and sunlight., Results: The C max of MHD and HP were 46.7 ± 8.41 and 1.04 ± 0.265 μg/ml, respectively. The t 1/2 of MHD and HP were 5.09 ± 0.945 and 5.71 ± 2.65 h, respectively. The AUC 0-24h of MHD and HP were 29.8 ± 6.19 and 0.757 ± 0.285 h·μg/ml, respectively. The AUC 0-∞ of MHD and HP were 29.8 ± 6.2 and 0.792 ± 0.308 h·μg/ml, respectively. The cumulative fecal excretion rate of MHD and HP were 45.3% and 1.05% at 96 h, respectively. Whereas, the cumulative urinary excretion rate of MHD was only 0.132% at 96 h. The concentration of HP in urine was less than 10% of MHD. After 52 h of administration, the cutaneous photosensitization associated with the exposure to various light sources was minimal., Conclusion: MHD and HP were excreted mainly through the faeces after intravenous infusion. Hemoporfin associated cutaneous photosensitization was insignificant., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Combined checkpoint blockade (e.g., PD1/PD-L1) with traditional clinical therapies can be hampered by side effects and low tumour-therapeutic outcome, hindering broad clinical translation. Here we report a combined tumour-therapeutic modality based on integrating nanosonosensitizers-augmented noninvasive sonodynamic therapy (SDT) with checkpoint-blockade immunotherapy. All components of the nanosonosensitizers (HMME/R837@Lip) are clinically approved, wherein liposomes act as carriers to co-encapsulate sonosensitizers (hematoporphyrin monomethyl ether (HMME)) and immune adjuvant (imiquimod (R837)). Using multiple tumour models, we demonstrate that combining nanosonosensitizers-augmented SDT with anti-PD-L1 induces an anti-tumour response, which not only arrests primary tumour progression, but also prevents lung metastasis. Furthermore, the combined treatment strategy offers a long-term immunological memory function, which can protect against tumour rechallenge after elimination of the initial tumours. Therefore, this work represents a proof-of-concept combinatorial tumour therapeutics based on noninvasive tumours-therapeutic modality with immunotherapy.

Trichophyton rubrum is one of the most common dermatophytes, which can cause fungal nail and ringworm infections. Infections associated with T. rubrum have become a global phenomenon. Herein, we report the antifungal photodynamic inactivation of T. rubrum (ATCC 28188) using the mesoporous silica-coated silver nanoparticle-based hybrid photosensitizers without involving antifungal drugs. Results show that the hybrid photosensitizers display low cytotoxicity under the experimental conditions where significant killing (∼3 orders of magnitude) against T. rubrum is observed. These results demonstrate the potential applications of the nanoparticle-based hybrid photosensitizers in antifungal photodynamic therapy against T. rubrum., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background/purpose: Previous studies have shown that hemoporfin-mediated photodynamic therapy (PDT) was a treatment for port-wine stain (PWS). Our current study aimed to identify optimal hemoporfin dose., Methods: A prospective, multicenter, double-blind, randomized clinical trial was conducted. Patients were assigned into low- or high-dose hemoporfin (2.5 mg/kg and 5 mg/kg intravenously, respectively), or control (placebo) group, at a rate of 2:2:1. Treatment efficacy was evaluated at week 8. Then, patients in control group were randomly assigned into either high- or low-dose hemoporfin group. Treatment reactions and adverse events were analyzed at week 16., Results: A total of 100 patients (40, 40, 20 in low-, high-dose hemoporfin, and control group, respectively) were enrolled. Compared to low dose (40%) and control group (15%), a higher proportion of patients in high-dose group (75%) had achieved skin lesion improvements. Treatment satisfactions were graded highest in high-dose group. Compared to low-dose group (14.3%), high-dose group (46.0%) had more frequent skin hyperpigmentation, which disappeared 3-6 months after treatment. Other treatment reactions and adverse events were comparable between two groups., Conclusions: Photodynamic therapy with 5 mg/kg hemoporfin could be an effective and safe treatment for PWS., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To report our observations from a trial of the effectiveness and safety of hematoporphyrin monomethyl ether photodynamic therapy (HMME-PDT) in treating Chinese Pediatric patients port-wine stains (PWS)., Method: From October 2017 to December 2017, the study recruited 82 patients of PWS with negative HMME skin test results. The patients received an intravenous injection of 5 mg/kg HMME and the affected areas were exposed to 532 nm LED green light, with the irradiation power density between 80-85 mW/cm 2 . Each light spot was irradiated for 20-25 min. After two treatments, the clinical efficacy and posttreatment reactions at each treated area were observed., Result: The patient age between 1 and 14 years old. 24 of the 82 cases were cured (29.27%) after two HMME-PDT treatment, 34 cases indicates a good efficacy (41.46%), 16 cases showed alleviation (19.51%), while 8 cases displayed no efficacy (9.76%). Pain was observed during treatment, and post-treatment edema was observed at the treated areas. No other obvious systematic adverse reaction were reported., Conclusion: HMME-PDT is an effective and safe treatment for pediatric patients with PWS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Stimuli-responsive nanomedicine (NM) with an on-demand drug release property has demonstrated promising utility toward cancer therapy. However, sensitivity and cancer selectivity still remain critical challenges for intelligent NM, which will compromise its therapeutic efficacy and lead to undesired toxicity to normal tissues. Herein, we report a convenient and universal approach to spatiotemporally control the chemodrug release via the photodynamic therapy (PDT)-mediated alteration of the tumor microenvironment. An arylboronic ester (BE)-modified amphiphilic copolymer (mPEG-PBAM) was designed to form micelles and encapsulate doxorubicin (Dox) and hematoporphyrin (Hp). The Dox/Hp co-encapsulated micelles (PB-DH) were stable under normal physiological environment with a uniform size distribution (∼100 nm). In contrast, under tumor-specific light irradiation, extensive reactive oxygen species (ROS) will be generated from Hp in the tumor sites, thus quickly dissociating the micelles and selectively releasing the chemodrug Dox as a consequence of the ROS-mediated cleavage of the hydrophobic BE moieties on the polymers. As such, synergistic anti-cancer efficacy was achieved between the Dox-mediated chemotherapy and the Hp-mediated PDT. This study therefore provides a useful approach to realize the precise and selective control over chemodrug delivery, and it renders promising utilities for the programmable combination of PDT and chemotherapy.

Background: Cell membranes have been identified as an important intracellular cancer treatment target, since the glycoconjugates present on the cell surface are involved in numerous cell functions. Photodynamic therapy (PDT) is a therapeutic modality employed in the treatment of tumors that uses visible light to activate a photosensitizer., Objective: This study analyzed the expression of surface carbohydrates after PDT with two different photosensitizers, 5-aminolevulinic acid (ALA) and Photosan-3., Methods: Mice were injected subcutaneously with 2 × 10 5 B16 cells. After 7-10 days, the presence of a tumor with a diameter of 3.6 mm was observed. Photosan-3 ® and 5-aminolevulinic acid-ALA were used in the PDT treatment. Control animals (not submitted to either laser treatment or photosensitizer injection) and treated animals were euthanized 15 days post-treatment. The tumors were irradiated with a red diode laser, λ = 655 nm, energy density of 10 J.cm -2 , and power density of 45 mW.cm -2 . After 2 weeks of treatment with PDT, the mice were euthanized, the tumors were collected, and the cell surfaces were labeled with lectins concanavalin A (ConA) and wheat germ agglutinin (WGA)., Results: Fluorescence microscopy analysis of the cell surfaces with lectins ConA and WGA showed the presence of α-mannose and α-glucose., Conclusions: The combined effects of either Photosan-3 or ALA and red laser light on melanoma suggest an inhibitory glycosylation action from PDT on the surface of B16-F10 cells.

Photodynamic therapy (PDT), combining the laser and photosensitizers to kill tumor cells, has the potential to address many current medical requirements. In this study, magnetic Fe 3 O 4 nanoparticles were first employed as cores and modified with oleic acid (OA) and 3-triethoxysilyl-1-propanamine. Then, the photosensitizers phycocyanin (PC) and hematoporphyrin monomethyl ether (HMME), which might be able to stimulate the cell release of reactive oxygen species after the irradiation of a near-infrared (NIR) laser, were grafted on the surface of such nanoparticles. Our results revealed the high-efficiency inhibition of breast cancer MCF-7 cells growing upon near-infrared irradiation both in vitro and in vivo. Furthermore, it was the synergy between the natural photosensitizers PC and the synthetic photosensitizers HMME that deeply influenced such inhibition compared to the groups that used either of these medicines alone. To utilize the combination of different photosensitive agents, our study thus provides a new strategy for breast cancer treatment.

Background: Research has focused on treatment efficiency and/or treatment reactions of photodynamic therapy (PDT) on port-wine stain (PWS). But few studies reported the association between them. Hence, here we investigated the association between the treatment efficiency and treatment reactions after Hemoporfin (HMME) mediated photodynamic therapy (PDT) on PWS through a prospective study., Methods: Patients (n=50) with PWS were randomly assigned to the HMME group or the placebo group. Three quit after the first treatment, and forty-seven received two sessions of treatment at an 8-week interval. They were given the treatment at day 1 and evaluations were performed at day 1, day 4 and week 8 in each session. HMME group was treated with HMME while the placebo group was given normal saline instead in the first session, double-blindly. While in the second session, both groups received HMME-PDT treatment., Results: After a single treatment, swelling was more severe in younger patients (p<0.05) and the lesion far from centro-facial showed more severe pruritus and scab. Compared with a single treatment, burning sensation had a higher occurrence rate, while burning sensation and scab were less severe in the second treatment. Importantly, severity of scab and pain (5min after irradiation) were found possibly correlated with the treatment efficiency., Conclusion: HMME-PDT on PWS induces several treatment reactions, including pruritus, burning sensation, pain, swelling, blisters and scab. Two sessions of treatments do not have any accumulation effects on treatment reactions. And there might be a positive correlation between treatment efficiency and the severity of scab or pain (at early stage of the therapy), which might help in regulating treatment modalities., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We evaluated the potential utility of hydrogels for delivery of the photosensitizing agents 5-aminolevulinic acid (ALA) and hematoporphyrin monomethyl ether (HMME) to rectal tumors. Hydrogel suppositories containing ALA or HMME were administered to the rectal cavity of BALB/c mice bearing subcutaneous tumors of SW837 rectal carcinoma cells. For comparison, ALA and HMME were also administered by three common photosensitizer delivery routes; local administration to the skin and intratumoral or intravenous injection. The concentration of ALA-induced protoporphyrin IX or HMME in the rectal wall, skin, and subcutaneous tumor was measured by fluorescence spectrophotometry, and their distribution in vertical sections of the tumor was measured using a fluorescence spectroscopy system. The concentration of ALA-induced protoporphyrin IX in the rectal wall after local administration of suppositories to the rectal cavity was 9.76-fold (1 h) and 5.8-fold (3 h) higher than in the skin after cutaneous administration. The maximal depth of ALA penetration in the tumor was ~3-6 mm at 2 h after cutaneous administration. Much lower levels of HMME were observed in the rectal wall after administration as a hydrogel suppository, and the maximal depth of tumor penetration was <2 mm after cutaneous administration. These data show that ALA more readily penetrates the mucosal barrier than the skin. Administration of ALA as an intrarectal hydrogel suppository is thus a potential delivery route for photodynamic therapy of rectal cancer.

Objectives: The aim of this study was to perform a histological evaluation of sonodynamic therapy (SDT) of hematoporphyrin monomethyl ether (HMME) on artificially induced periodontal disease in rats., Methods: Submerging ligatures were placed at the subgingival region of the first maxillary molar in rats. Eighty rats were randomly assigned into four groups: group 1 received no treatment; group 2 was subjected to 50 μg/mL HMME alone; group 3 was treated with low-intensity ultrasound alone (1 W/cm(2)); and group 4 was treated with 50 μg/mL HMME plus ultrasound irradiation (1 MHz, 30 minutes). Ten rats in each group were euthanized at 7 and 15 days, and periodontal tissue samples were taken for histological examination., Results: The animals treated by SDT showed less bone loss (P<0.05) at all experimental periods than the other three groups. No significant differences were found between the control and HMME groups (P>0.05)., Conclusion: Our results suggest that HMME-mediated SDT can effectively alleviate the periodontal tissue destruction in artificially induced periodontitis in rats. Hence, SDT may have good clinic potential as a noninvasive treatment of periodontal diseases.

Background: For glioma, temozolomide (TMZ) is a commonly used chemotherapy drug and photodynamic therapy (PDT) is an important adjuvant therapy. The aim of this study was to evaluate the effect of their combination for the treatment of glioma., Methods: A rat C6 glioma model using male Wistar rats (n=180) weighing 280-300 g was established. Glioma-bearing rats (n=100) were treated with mock, hematoporphyrin monomethyl ether (HMME), laser or PDT. The expression of P-glycoprotein (P-gp) in endothelial cells of the blood-tumor-barrier and in glioma tissues was detected using immunohistochemistry and western blot, respectively. Glioma-bearing rats (n=40) were treated with normal saline, TMZ (60 mg/m(2) for five consecutive days), PDT (630 nm for 10 min) or a combination of TMZ and PDT. TMZ concentration in glioma tissues was detected using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and cell death was observed using transmission microscopy. Concurrently, another batch of 40 glioma-bearing rats was subjected to the same treatment, and the survival of these rats was estimated using Kaplan-Meier analysis., Results: PDT significantly decreased the expression of P-gp in endothelial cells comprising the blood-tumor-barrier and in glioma tissues. The combination of TMZ with PDT significantly increased TMZ concentration in glioma tissues, enhanced glioma cell apoptosis and prolonged the median survival of glioma-bearing rats., Conclusion: The combination of PDT with TMZ shows synergistic effect in rat C6 glioma model, indicating its potential clinical use in glioma treatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: In radiotherapy, temporary translocations of the internal organs and tumor induced by respiratory and cardiac activities can undesirably lead to significantly lower radiation dose on the targeted tumor but more harmful radiation on surrounding healthy tissues. Respiratory and cardiac gated radiotherapy offers a potential solution for the treatment of tumors located in the upper thorax. The present study focuses on the design and development of simultaneous acquisition of respiratory and cardiac signal using electrical impedance technology for use in dual gated radiotherapy., Methods: An electronic circuitry was developed for monitoring the bio-impedance change due to respiratory and cardiac motions and extracting the cardiogenic ECG signal. The system was analyzed in terms of reliability of signal acquisition, time delay, and functionality in a high energy radiation environment. The resulting signal of the system developed was also compared with the output of the commercially available Real-time Position Management™ (RPM) system in both time and frequency domains., Results: The results demonstrate that the bioimpedance-based method can potentially provide reliable tracking of respiratory and cardiac motion in humans, alternative to currently available methods. When compared with the RPM system, the impedance-based system developed in the present study shows similar output pattern but different sensitivities in monitoring different respiratory rates. The tracking of cardiac motion was more susceptible to interference from other sources than respiratory motion but also provided synchronous output compared with the ECG signal extracted. The proposed hardware-based implementation was observed to have a worst-case time delay of approximately 33 ms for respiratory monitoring and 45 ms for cardiac monitoring. No significant effect on the functionality of the system was observed when it was tested in a radiation environment with the electrode lead wires directly exposed to high-energy X-Rays., Conclusion: The developed system capable of rendering quality signals for tracking both respiratory and cardiac motions can potentially provide a solution for simultaneous dual-gated radiotherapy.

Photosensitizer-encapsulated amphiphilic sodium alginate derivative (Photosan-CSAD) nanoparticles were prepared because of their ability to enhance phototoxicity in the photodynamic therapy of pancreatic cancer. These nanoparticles are spherical, 150-250 nm in size as determined by transmission electron microscopy, and have negative zeta potentials. Upon incubation with human pancreatic cancer cells, the Photosan-CSAD nanoparticles showed high fluorescence activity and reactive oxygen species generation, resulting in strong phototoxicity. However, no dark toxicity was observed. Apoptosis played a leading role in the cell death process induced by the Photosan phototoxicity. These results demonstrate that the Photosan-CSAD nanoparticles are a candidate for the photodynamic therapy of pancreatic cancer., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: In the present study, the effectiveness of Photodynamic Antimicrobial Chemotherapy (PACT) was evaluated on planktonic cells and biofilms of five Enterococcus faecalis clinical isolates., Methods: Planktonic cells and biofilms of E. faecalis E2, E3, ER3/2s, OS16 and AA-OR34 were grown in SDMY medium plus 0.4% glucose. Approximately 5.0×10(7)CFU planktonic cells and 24h biofilms were subjected to PACT using the combination of Light Emitting Diodes (LEDs, Biotable(®)) and Photogem(®). The metabolic activity of bacterial cells was evaluated by a resazurin assay. Biomass values of the biofilms were determined by a crystal violet assay., Results: Compared to the water-treated control group, gradual increases of light energy led to greater reduction of metabolic activity of planktonic cells and biofilms of E. faecalis when the combination of LEDs and Photogem(®) was applied. Photogem(®) alone significantly reduced the metabolic activity of planktonic cells, whereas LEDs or Photogem(®) alone did not result in biofilm viability changes. PACT yielded similar antimicrobial outcomes on planktonic cells of all tested E. faecalis strains, whereas biofilms of E. faecalis E3, ER3/2s and OS16 were more resistant to PACT than biofilms of E. faecalis E2 and AA-OR34., Conclusions: The efficacy of PACT on E. faecalis biofilms was strain dependent. PACT demonstrated its potential as an adjuvant antimicrobial treatment by killing of E. faecalis planktonic and biofilm cells., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Photodynamic therapy (PDT) has been shown to inactivate blood-borne pathogenic microorganisms in vitro. The method may be used to purify blood in the body, kill pathogenic microorganisms, and treat difficult diseases. Our aim was to investigate the safety of photodynamic blood purification (PBP) therapy using an in vivo blood circulation experiment in an animal model. Twenty-four New Zealand rabbits were used as experimental subjects; 12 received PDT and 12 served as negative controls. Extracorporeal blood bypass was established using the femoral artery and vein. A sterile disposable irradiation chamber was connected in the bypass pathway. Hematoporphyrin monomethyl ether was injected intravenously as a photosensitizer with an initial bolus of 3.7 mg, followed by a continuous infusion at 24 mg/h during PDT administration. Five minutes after initial injection, a laser beam was vertically focused on the irradiation chamber side wall, with a 9.5 cm(2) spot area, 1 h exposure time, and 20 mW/cm(2) power density. Six animals received a single PDT application, and six received PDT every other day for three applications. The 12 control group animals underwent extracorporeal blood circulation but did not receive the photosensitizer or light treatment. Blood samples were taken 20 min, 1 day, 4 days, and 7 days after PDT treatment for analysis of cell counts, coagulation, liver and renal function, and other biochemical changes. On the 7th day, animals were sacrificed, and parenchymal organs were evaluated for morphological changes. There were no significant differences in white blood cells, red blood cells, or destroyingplatelets after PDT compared with the control group. There was a little significant difference in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, uric acid, blood urea nitrogen, and creatinine in the PDT group compared with the control group, except at individual time points. We found no significant damage in the heart, liver, spleen, lungs, kidneys, or other organs after PDT. This short-duration, fixed-strength PBP method did not cause changes in blood parameters or in the structure or function of major organs in an animal model. These findings suggest that PBP is safe in vivo and has potential as a new therapy for inactivating blood-borne microorganisms., (Copyright © 2013 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Recently, fullerene and fullerene derivatives owning to their highly enriched physical and chemical properties have been widely explored for applications in many different fields including biomedicine. In this study, iron oxide nanoparticles (IONPs) were decorated onto the surface of fullerene (C60), and then PEGylation was performed to improve the solubility and biocompatibility of C60-IONP, obtaining a multi-functional C60-IONP-PEG nanocomposite with strong superparamagnetism and powerful photodynamic therapy capacity. Hematoporphyrin monomethyl ether (HMME), a new photodynamic anti-cancer drug, was conjugated to C60-IONP-PEG, forming a C60-IONP-PEG/HMME drug delivery system, which demonstrated an excellent magnetic targeting ability in cancer therapy. Compared with free HMME, remarkably enhanced photodynamic cancer cell killing effect using C60-IONP-PEG/HMME was realized not only in a cultured B16-F10 cells in vitro but also in an in vivo murine tumor model due to 23-fold higher HMME uptake of tumor and strong photodynamic activity of C60-IONP-PEG. Moreover, C60-IONP-PEG could be further used as a T2-contrast agent for in vivo magnetic resonance imaging. Our work showed C60-IONP-PEG/HMME had a great potential for cancer theranostic applications., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

It is well established that both hematoporphyrin monomethyl ether-sonodynamic therapy (HMME-SDT) and doxorubicin (DOX) can induce cell apoptosis but each alone has its own limitations. To date, the combined effects of HMME-SDT and DOX on inducing cell apoptosis are little known and the mechanism for the combined effects remains poorly understood. In the present study, we reported the synergistic effects of HMME-SDT and DOX on inhibiting the proliferation of human cholangiocarcinoma QBC939 cells and investigated the mechanism of this synergy. The data from MTT assay, flow cytometer, Hoechst staining and cell arrest analysis showed that the combination of HMME-SDT and DOX exhibited higher inhibiting effects on proliferation of QBC939 cells than the sole application of HMME-SDT or DOX. In addition, the synergistic effects were shown to result from the DNA damage as demonstrated by single cell gel electrophoresis and DNA fragmentation. Furthermore, the expression of p53, Fas, Bax and activated caspase-3 protein was significantly upregulated in cells treated with HMME-SDT and DOX, whereas Bcl-2 protein was downregulated. Taken together, our data suggested that the application of HMME-SDT combined with DOX had better inhibiting effects on QBC939 cells and the effects were caused mainly by DNA damage., (Copyright © 2013 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Unlabelled: In research of the last decade, rhythmic (circadian) variations of vascular endothelial growth factor (VEGF) production by tumors were discovered. The present paper authors have earlier synthesized and characterized a new derivative photosensitizer - an immunoconjugate of hematoporphyrin with antiVEGF antibodies., Aim: To elaborate and to test a novel modification of the photodynamic therapy of tumors (PDT) method, founding upon a timed introduction of the immunoconjugated photosensitizer to tumor-bearing animals, so that this coincides with a maximum content of VEGF in tumor tissues., Methods: Circadian variations of VEGF contents in murine transplanted tumors, Lewis lung carcinoma and sarcoma 180, were determined by ELISA method. Immunoconjugated photosensitizer concentrations in tumors were estimated by spectrofluorometry. Photoirradiation of the tumors was carried out with a red light (wavelength of 635 nm) from a semiconductor laser. Light doses were chosen, calculating on a partial inhibition of tumor growth, in order that a dependence of PDT efficiency on a daily time-moment (circadian rhythm phase) of the treatment could be observed distinctly., Results: Circadian variations of the VEGF levels in Lewis lung carcinoma and sarcoma 180 were demonstrated with the maximum at 14:00 h and the minimum at 02:00 h. Intra-abdominal introduction into tumor-bearing mice of the immunoconjugated photosensitizer resulted in a greater accumulation of the immunoconjugate in tumors at 14:00 h than at 02:00 h. Laser irradiation of carcinomas and sarcomas at 14:00 h or 02:00 h after introduction of the immunoconjugated photosensitizer to mice the day before at the same time points, induced a significantly enhanced inhibition of tumor growth in animals treated at day-time versus those treated at night-time., Conclusion: The obtained results justify further attempts to transfer principles of tumor chronochemotherapy onto photodynamic therapy.

This study was conducted to test laser speckle perfusion imaging (LSPI) for imaging microcirculation and monitoring microcirculatory changes of port wine stains (PWS) during vascular targeted photodynamic therapy (V-PDT). Before and 5 min after V-PDT, PWS lesions and the corresponding contralateral healthy skins of 24 PWS patients were scanned, whereas seven PWS patients were scanned throughout V-PDT. V-PDT was conducted immediately after intravenous injection of photocarcinorin (4-5 mg kg(-1)). A 532 nm laser was used for irradiation (power density: 80-100 mW cm(-2), exposure time: 20-50 min). Before V-PDT, all 24 PWS patients demonstrated a significant difference in perfusion between the PWS lesion and the contralateral healthy control skin (1132 ± 724 and 619 ± 478 PU, respectively, P < 0.01). Five minutes after V-PDT, the mean perfusion value of the 24 PWS lesions was 1246 ± 754 PU. There was no significant difference compared to the perfusion before V-PDT (P > 0.05). During V-PDT, the perfusion of seven PWS patients increased rapidly after initiation of V-PDT, reached a maximum within 10 min, lasted for several minutes, and slowly returned to a relatively lower level at the end of V-PDT. On the basis of these results, LSPI is capable of imaging PWS microvasculature and monitoring microvascular reactivity to V-PDT., (© 2012 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2012 The American Society of Photobiology.)

The second generation photosensitizer Hemoporfin (7(12)-(1-methoxyethyl) -12(7)-(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid) is a porphyrin derivative which processes a stable structure, high singlet oxygen yield, high photoactivity, low dark toxicity and fast clearance rate. Hemoporfin, also known as hematoporphyrin monomethyl ether (HMME) has been studied and used in photodynamic therapy (PDT) in China since 1989. This series of reports will provide an overview on the preclinical and clinical studies of this PDT photosensitizer. The first part of this series will highlight the results of preclinical studies that focused on the compound's optical characteristics, mechanism of the activities, pharmacological and toxicological properties., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Previous studies found that topical photodynamic therapy (PDT) is very effective for human oral precancerous lesions., Methods: This study evaluated whether topical photosan-mediated PDT (topical photosan-PDT), using a 640-nm light-emitting diode (LED) light, is an effective treatment modality for hamster buccal pouch precancerous lesions. Fourteen 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch precancerous lesions were treated with topical photosan-PDT using the 640-nm LED light twice a week., Results: All 14 of the precancerous lesions showed a complete histologically confirmed response to the lesions after an average of 3.79 (range, 3-5) PDT treatments. Normal and precancerous pouch mucosae in the other 4 hamsters received 17 or 19 treatments of topical photosan-PDT showed no cumulative side effects. No recurrence of the lesions was found in these 18 PDT-treated hamsters after a follow-up period of 50 weeks., Conclusion: Our findings indicate that topical photosan-PDT is a very effective treatment modality for DMBA-induced hamster buccal pouch precancerous lesions., (Copyright © 2011 Wiley Periodicals, Inc.)

Background and Objective: To evaluate the usefulness and feasibility of fluorescence examination and photodynamic therapy (PDT) for facial squamous cell carcinoma., Methods: A 68-year-old male patient underwent 3 courses of PDT. The first treatment was carried out using topically applied 5-aminolevulinic acid (ALA) to the affected area (5.0 cm × 2.5 cm) 3h before light irradiation. ALA/PpIX-mediated fluorescence was used to visualize the lesion and its margin. The lesion was illuminated with a 630 nm laser at 120 J/cm². Thirty days later, the residual lesion received the second treatment at the same light dose after topical use of ALA. Despite the tumor was treated with two courses of PDT, The lesion was not cleared completely yet. At last we used topical ALA and intravenous injection of HiPorfin, with the same light dose, then the lesion was cured and the patient was tumor-free followed up for over 15 months., Results: ALA/PpIX-mediated fluorescence visualized the lesion location. Complete cure was achieved after the third course of ALA/Hiporfin PDT. During the 15 months of followed up, no recurrence was noticed., Conclusion: ALA assisted fluorescence examination can be a useful tool to visualize the malignant lesion and determine its margin. ALA-PDT is effective for superficial lesions, but for thicker and deeper lesions, systemic administration of photosensitizer is indispensable., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

The purpose of this study was to develop a sonosensitizer-loaded multi-functional ultrasound (US) contrast agent for both tumour therapy and imaging. The hematoporphyrin (HP)-encapsulated poly(lactic-co-glycolic acid) microbubbles (HP-PLGA-MBs) were prepared and filled with perfluorocarbon gases. The enhancement of US imaging and its sonodynamically induced anti-tumour effect were evaluated by both in vitro and in vivo experiments. The HP-PLGA-MBs have a narrow size distribution and smooth surface with a mean diameter of 702.6 ± 56.8 nm and HP encapsulation efficiency of 63.50 ± 1.26% and drug-loading efficiency of 2.15 ± 0.13%. The HP-PLGA-MBs could well enhance the ultrasound imaging both in vitro and in vivo. A significant anti-tumour effect was obtained by HP-PLGA-MBs mediated sonodynamic therapy. The tumour growth rate and the tumour proliferation index were the lowest in the HP-PLGA-MBs plus sonication group. And the tumour cell apoptotic index was the biggest in the HP-PLGA-MBs plus sonication group. In conclusion, a sonosensitizer-loaded multi-functional contrast agent was constructed and the feasibility was demonstrated, which might provide a novel strategy for tumour imaging and therapy.

Aim: To investigate the safety, tolerability and pharmacokinetics of intravenous hemoporfin, a novel photosensitive drug for the treatment of port-wine stain (PWS), in healthy Chinese volunteers following single-dose administration., Methods: Thirty-six healthy Chinese subjects were enrolled. The subjects were administered hemoporfin (2.5, 5, 7.5 or 10 mg/kg) via single-dose intravenous infusion. Pharmacokinetics of the drug were studied in the groups with doses of 2.5, 5 and 7.5 mg/kg, and tolerability was studied in all the 4 groups. Safety and tolerance were evaluated by monitoring adverse events and laboratory parameters, and pharmacokinetics were assessed by determining hemoporfin content with a validated high-performance liquid chromatography with fluorescence detection (HPLC/FLD) method., Results: Mild and transient adverse events occurred in the trial (n=10), but none were serious, and no subjects were withdrawn from the trial. The gastrointestinal tract adverse events, such as nausea, stomach upset, abdominal pain and vomiting, were observed in the groups with doses of 7.5 and 10 mg/kg. Increased alanine aminotransferase (ALT) concentration was found in 3 subjects, and increased alkaline phosphatase (ALP) concentration in one subject. The half-life of hemoporfin for doses of 2.5, 5, and 7.5 mg/kg was 1.26 h, 1.31 h, and 1.70 h, respectively. C(max) and AUC increased with dose for intravenous single-dose administration of hemoporfin in the 2.5, 5, and 7.5 mg/kg groups. Urinary excretion of hemoporfin within 12 h was less than 0.2%., Conclusion: Hemoporfin is safe and well-tolerated in healthy Chinese volunteers at a single intravenous dose of up to 10 mg/kg. It was rapidly cleared from the blood and had a short half-life, which insures a short light-avoidance period.

Photodynamic therapy (PDT) is a minimally invasive cancer therapy that depends on the buildup of a photosensitizing drug within targeted tissue. The photosensitizer is subsequently activated by light of a specific wavelength, resulting in destruction of the targeted tissue by free radicals or singlet oxygen. Successful treatment requires delivery of critical amounts of drug into the cancerous tissue. This frequently demands high doses of the drug in the circulatory system that could lead to side effects in normal daylight due to accumulation of photodrug in normal tissue. To reduce drug load we explored the possibility of targeting cancer with antibody conjugated with photosensitizer. As a model we used LnCAP human prostate cancer cells targeted by antibody (against prostate-specific membrane antigen) which was conjugated with hematoporphyrin (HP). Our results show clearly that mAb/HP conjugates can deliver HP to the tumor cells which would result in considerably less HP in the circulation and, therefore, lower the delivery of HP to normal tissue, resulting in fewer side effects.

Background: Efficacy of photodynamic therapy can be enhanced by improving uptake, localization, and sub-cellular localization of sensitizers at the sensitive targets., Materials and Methods: Uptake, localization, and photodynamic effects of hematoporphyrin derivative (HpD, Photosan-3; PS-3) and disulfonated aluminum phthalocyanine (AlPcS₂) were studied either encapsulated in liposomes or conjugated to a monoclonal antibody to carcinoembryonic antigen (anti-CEA) in a brain glioma cell line, BMG-1., Results: Although the total uptake with encapsulated or conjugated sensitizers was less than the free sensitizers, photodynamic efficiency was higher due to the localization of the sensitizer at the sensitive targets. Biodistribution of intravenously administered technetium (⁹⁹m Tc)-labeled PS-3 analyzed by gamma camera imaging showed maximum accumulation in the liver followed by tumor. Tumor/muscle (T/N) ratio of free PS-3 was higher compared to encapsulated or conjugated PS-3 but the accumulation of PS-3 significantly reduced in brain and cutaneous tissue following modulated delivery. Pharmacokinetics suggested faster accumulation of encapsulated and conjugated PS-3 in the tumor., Conclusion: Localization of sensitizers at sensitive targets and reduced accumulation in normal tissues with liposome encapsulation and antibody conjugation suggest that these two delivery systems can potentially enhance the efficacy of photodynamic treatment.

Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.

Hematoporphyrin monomethyl ether (HMME) is a novel and promising second-generation porphyrin-related photosensitizer for photodynamic therapy (PDT). To study the effects of HMME PDT on choroidal neovascularization (CNV) in rats, the PDT was performed 20 min after HMME bolus injection, which was investigated prior to the PDT by fluorescence microscopy with laser-induced CNV, and delivered at an irradiance of 400, 600 and 1000 mW cm(-2) corresponding to a fluence of 36, 54, 90 J cm(-2) in PDT plan I (15 mg kg(-1) HMME). In PDT plan II (30 mg kg(-1) HMME), the laser had a constant irradiance of 600 mW cm(-2), which was delivered for 60, 90 or 150 s, to also achieve total energy doses of 36, 54 or 90 J cm(-2). CNV closure rates assessed by fluorescein angiography and histologic damage to treated areas of choroid and retina varied as a function of the dose of HMME and of the activating light energy fluence. Endothelial cell labeled by platelet/endothelial cell adhesion molecule-1 presented treated CNV lesions that were significantly reduced in size (P < 0.01). It can be concluded that PDT using HMME can effectively occlude CNV. HMME is a potentially useful photosensitizer for the reduction in CNV size of irradiated areas.

The purpose of this study was to examine the properties of a new pulmonary delivery platform of microparticles containing micelles in which a therapeutic photosensitizing drug, hematoporphyrin (Hp), was encapsulated. Different poloxamers were used to form micellar Hp, and one of these, Pluronic L122-Hp, was subsequently incorporated into lactose microparticles by spray-drying. Spectral and morphological analyses were performed on both micellar Hp, and lactose microparticles containing micellar Hp (lactose-micellar Hp) before and after dissolution of the microparticles in water. Photodynamic activity of the various Hp samples were evaluated in human lung epithelial carcinoma A549 cells using a light-emitting diode (LED) device at a wavelength of 630 +/- 5 nm. No significant difference was observed between micellar Hp and lactose-micellar Hp regarding the generation of singlet oxygen. The mean particle size of the microparticles was 2.3 +/- 0.7 microm which is within the size range for potential lung delivery. The cellular uptake of micellar Hp and lactose-micellar Hp measured on A549 cells was at least twofold higher than those obtained with the Hp at equivalent concentrations. Micellar Hp exhibited higher cytotoxicity than Hp due to reduced formation of Hp aggregates and increased cellar uptake. The spectral properties as well as the photodynamic activity of the micellar Hp was retained when formulated into microparticles by spray-drying. Microparticles containing micelles have the potential for delivering micelle-encapsulated hydrophobic drugs in targeted therapy of pulmonary diseases.

Objective: In vivo studies of antimicrobial PDT in animal models of oral candidosis are scarce and the association of porphyrin and LED light has not been evaluated for in vivo photoinactivation of Candida. In this study the effectiveness of photodynamic therapy (PDT) on the inactivation of Candida albicans in vivo was evaluated., Study Design: Seventy-one 6-week-old female Swiss mice were immunosuppressed, provided tetracycline to their drinking water, then orally swabbed with a suspension of C. albicans (10(7) CFU/mL). Four days after oral inoculation, PDT was performed on the dorsum of the tongue after topical administration of Photogem at 400, 500, or 1000 mg/L and followed 30 minutes later by illumination with LED light (305 J/cm(2)) at 455 or 630 nm (n = 5 each). After swabbing to recover yeast from the tongue, the number of surviving yeast cells was determined (CFU/mL) and analyzed by ANOVA and Holm-Sidak tests (P < .05). Animals were humanely killed, and the tongues surgically removed and processed for histological evaluation of presence of yeast and inflammatory reaction., Results: PDT resulted in a significant reduction in C. albicans recovered from the tongue (P < .001) when compared with mice from the positive control group. There was no difference between the concentrations of Photogem and LED light wavelengths used. Histological evaluation of the tongue revealed that PDT causes no significant adverse effects to the local mucosa., Conclusion: PDT promoted significant reduction in the viability of C. albicans biofilm without harming the tongue tissue., (Copyright 2010 Mosby, Inc. All rights reserved.)

Endoscopic biliary drainage is the mainstay of palliative treatment in patients with unresectable malignant hilar biliary obstruction. While self-expandable metal stents have shown significant advantages in distal tumors, bilateral hilar stenting is technically demanding. Moreover, ingrowth is a significant problem in uncovered stents. We evaluated the feasibility and efficacy of endoscopic bilateral JoStent SelfX deployment in patients with proximal malignant biliary obstruction in combination with photodynamic therapy (PDT) and/or chemotherapy. Twenty-one consecutive patients with malignant hilar biliary strictures were treated with transpapillary bilateral insertion of JoStentSelfX metal stents. Additional PDT was applied in 8 patients (PDT plus chemotherapy n = 4, only PDT n = 4). Solely chemotherapy was performed in 5 patients. Mean (+/- SD) stent patency was 173.9 +/- 201.8 days. The median estimated survival was 12.3 months (95 % CI: 8.5; 15.9). PDT was safely and efficaciously performed after endoscopic stent deployment (1.8 +/- 1.1 sessions/patient). There was a trend towards a longer stent patency in patients receiving additional therapy (202.2 +/- 197.6 vs. 128 vs. 213.2 days; p = 0.38). Furthermore, we observed a significantly longer survival in this cohort (16.5 [12.2; 20.1] vs. 12.3 [1.9; 8.5] months, p < 0.005). Additional therapy had no significant impact on cumulative hospitalization time (16.3 +/- 15.8 vs. 14.4 +/- 22.5 days; p = 0.54). Bilateral insertion of Jostent SelfX in patients with proximal cholangiocarcinoma is feasible and effective and can be safely combined with trans-stent photodynamic therapy.

Objectives: Osteosarcoma is one of the most common malignant cancers afflicting young adults. Ultrasound is a new therapeutic modality for controlling malignant cancers. Enhancing the efficacy of ultrasound treatment will improve clinical outcomes. The aim of this study was to investigate the killing action of ultrasound on osteosarcoma enhanced by hematoporphyrin monomethyl ether (HMME) in vivo., Methods: An animal model of an osteosarcoma xenograft was set up to investigate the inhibitory effect of sonoactivating HMME on osteosarcoma. High-performance liquid chromatography was used to analyze the time course of HMME in the osteosarcoma xenograft. Three hours after intravenous (IV) administration of HMME, ultrasound radiation was administered in the osteosarcoma xenograft. On day 7 after ultrasound radiation, the tumor volume and weight were measured and calculated for effect assessment, hematoxylin-eosin staining for histopathologic examination, immunohistochemical staining for proliferating cell nuclear antigen (PCNA) expression, and terminal deoxyuridine nick end-labeling (TUNEL) staining for apoptosis examinations., Results: The peak value of HMME in osteosarcoma tissues increased with time after IV administration of HMME and reached a plateau at 3 hours. The increasing rates of the tumor volume and weight in the control group were very fast, but the increasing rates in the ultrasound-alone group were slower, and those in the ultrasound-HMME group were the slowest throughout the observation period. There was a significant difference between the HMME-ultrasound, ultrasound-alone, and control groups (P < .01). Hematoxylin-eosin staining showed that some cells had typical cell death such as pyknosis and nuclear fragmentation after ultrasound radiation alone. More cells with pyknosis, nuclear fragmentation, and even karyolysis were found after HMME-ultrasound treatment. Immunohistochemical staining showed that the percentage of PCNA-positive cells decreased and that of TUNEL-positive cells increased after ultrasound treatment alone, and the changes in the PCNA- and TUNEL-positive percentages were significantly enhanced by pretreatment with HMME (20 mg/kg, IV) for 3 hours and ultrasound radiation (10.5 MHz) for 120 seconds at an intensity of 0.8 W/cm(2) (P < .05)., Conclusions: Hematoporphyrin monomethyl ether pretreatment could substantially enhance the growth inhibition of ultrasound on osteosarcoma, which suggests that HMME is an efficient sonosensitizer, and ultrasound radiation with HMME could be developed as a new modality for treating osteosarcoma.

This investigation was made with regard to the influences of ultrasound combined with hematoporphyrin on the activities of antioxidative enzyme in ascites hepatoma 22 (H-22) tumor cells, and to a better understanding of the potential biological mechanism of sonodynamic therapy which involved the damage to cells. Combined with 100 microg/ml hematoporphyrin, high intensity focused ultrasound sonication at a frequency of 1.43 MHz and an intensity level of 2.0 W/cm2 was delivered to H-22 tumor cells for 1 min. The viability of cells was evaluated by typan-blue blue exclusion test. The intracellular reactive oxygen species (ROS) levels were determined by 2',7'-dichlorofluorescein diacetata (DCFH-DA). Enzymatic chemical methods were used to measure the activities of key antioxidative enzymes. The results indicated that the cell damage rate of ultrasound combined with hematoporphyrin was significantly higher than that of the treatment with ultrasound alone, and hematoporphyrin alone had no killing effect on H-22 cells. The level of ROS in cell suspension was significantly increased, and the key antioxidative enzyme activities were obviously decreased after treatment with the combined use of ultrasound and hematoporphyrin. We speculated that the decreased activities of key antioxidative enzymes in cells might be involved in mediating the killing effect on H22 cells in sonodynamic therapy.

Background and Objectives: Antimicrobial photodynamic inactivation (PDI) is a promising treatment modality for local infections. To increase the efficacy of photosensitizer, hematoporphyrin (Hp) was used as a model drug and encapsulated in liposomes and micelles. The bactericidal efficacy of the carrier-entrapped Hp was assessed against gram-positive bacteria., Study Design/materials and Methods: Hp was encapsulated in liposomes by a modified reversed-phase evaporation and extrusion method. Micelle-Hp was prepared by the reversed-phase evaporation method. Spectroscopic analysis was used to characterize the properties of Hp in PBS, liposome or micelle. The PDI efficacy was examined by using gram-positive pathogens including methicillin-susceptible, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pyogenes., Results: The absorption and fluorescence emission spectra indicated that Hp encapsulated in liposomes and micelles is less likely to exist in aggregated form compared to that generally seen in an aqueous medium. Liposome- or micelle-Hp can induce complete eradication of the bacteria above a critical Hp dose, which is significantly lower than the dose required when using the non-encapsulated Hp. Furthermore, the PDI effect of the Hp encapsulated in micelles was superior to the Hp encapsulated in liposomes at lower Hp doses. Similar PDI results were also found in S. epidermidis and S. pyogenes., Conclusions: Our results indicate that photosensitizer entrapped in micelle exert similar or better PDI efficacy than that of liposome, which indicates this formulation may be useful for the treatment of local infections in the future.

With limited treatment options, intraperitoneal spread of ovarian cancer is a common problem leading to high morbidity. Intraperitoneal photodynamic therapy combined with debulking surgery to treat residual disease is an alternative choice for clinicians. Hematoporphyrin monomethyl ether (HMME) is a promising second-generation photosensitizer developed in China. Our study was designed to investigate the phototoxicity of HMME on ovarian cancer. NuTu-19, a cell line derived from adenocarcinoma of Fischer 344 rat, and its allogeneic graft ascites tumor model was used in this study. HMME was confirmed to be localized in cytolysosome, and HMME-based photosensitization induced direct necrosis as well as mitochondria damage. The photocytotoxicity of HMME was both light- and drug dose-dependent and no significant dark cytotoxicity was observed in NuTu-19 cells. With the ascite tumor-bearing Fischer 344 rat model, HMME-based intraperitoneal photodynamic therapy was proved to be useful in improving the prognosis of ovarian cancer. Thus, this study provides evidence that HMME-based photodynamic therapy is an effective adjuvant therapy for ovarian cancer.

Background & Objective: Photodynamic therapy (PDT) is a new treatment choice for ovarian carcinoma. Hematoporphyrin monomethyl ether (HMME) is a novel photosensitive reagent developed in China. This study was to investigate the photodynamic effect of HMME-based PDT on human epithelial ovarian cancer cell line SKOV3., Methods: After an incubation with 30 microg/ml HMME for different time, the fluorescent image and intracellular location of HMME in SKOV3 cells were observed under a fluorescent microscope and laser scanning confocal microscope (LSCM). After being treated with different doses (5-50 microg/ml) of HMME and irradiated with different optical doses (1.5-12 J/cm(2)) of laser, the survival rate of SKOV3 cells was measured by MTT assay. Mechanisms of cell death during PDT was determined by Annexin V/PI double staining technique and analyzed by flow cytometry., Results: Red fluorescence appeared shortly after administration of HMME and localized in cytoplasm; intracellular fluorescence intensity reached the peak after 3 h. High concentrations of HMME alone had cytotoxicity to SKOV3 cells, while laser irradiation alone had no effect on cell survival. Survival rate of SKOV3 cells was gradually decreased along with the increase of HMME concentration and laser dose, but such a trend diminished when HMME concentration reached 40 microg/ml. After treatment of HMME, the dead cells were predominantly necrosis cells., Conclusion: HMME has a photodynamic effect on SKOV3 cells.

The uptake of two photosensitising agents (hematoporphyrin and chlorophyll a) by a highly pathogenic bacterium, namely methicillin-resistant Staphylococcus aureus (MRSA), has been studied by using unilamellar liposomes of different size, fluidity and electric charge as carriers. Optimal results are obtained by using hematoporphyrin embedded in fluid cationic vesicles composed by the monocationic lipid N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate (DOTAP), which yield an endocellular concentration of photosensitiser much higher than that obtained by incubation of the cells with the free porphyrin, yet promote a tighter binding and a more efficient photoinactivation of MRSA. Apparently, the photosensitiser is successfully transferred from the liposome to the bacterial cells when the presence of the tetrapyrrolic derivative does not appreciably perturb the native three-dimensional organisation of the lipid vesicle, such as it occurs with hematoporphyrin. On the other hand, chlorophyll, which causes a marked structural alteration of the DOTAP vesicles as shown by electron microscopy and fluorescence anisotropy measurements, does not show any detectable photocytotoxicity toward MRSA, contrary to what observed for the free dye.

We evaluated changes in hematology and chemical profile, and the tissue retention of hematoporphyrin derivative (HpD) following the intravenous injection in dogs. HpD at concentrations of 1, 5, 10, and 15 mg/kg was intravenously injected to 16 dogs (n=4 each) and complete blood count (CBC) and blood chemistry were performed on days 1, 3, 5, and 7 after the injection. To examine tissue retention, HpD (5 mg/kg) was administered to 15 dogs and 3 dogs were euthanized on days 1, 2, 7, 14, and 28 after the injection, respectively, to collect the skin, muscle, small intestine, spleen, kidney and liver as tissue samples. There were no significant changes in CBC and blood chemical profile except for an increase in LDH concentrations in dogs given 10 and 15 mg/kg of HpD at day 3. The levels of HpD retention in the tissues were ranked in the following order: liver > kidney > spleen > intestine > muscle > skin.