Haixia Qiu

Twenty Years of Clinical Experience with a New Modality of Vascular‐Targeted Photodynamic Therapy for Port Wine Stains

BACKGROUND Port wine stains (PWS) are congenital capillary malformations of the skin and are difficult to treat without scarring. Since January 1991, our group has performed a new modality of vascular‐targeted photodynamic therapy (PDT) for PWS treatment. OBJECTIVE To summarize our clinical experiences with vascular‐targeted PDT for PWS at Chinese PLA General Hospital. METHODS AND MATERIALS Our group has collected and reviewed retrospective clinical research data of vascular‐targeted PDT for treating PWS since January 1991. RESULTS Clinical studies showed that vascular‐targeted PDT is an effective treatment for all types of PWS. Repetitive treatment sessions were usually needed to obtain a better cosmetic effect. No recurrence was seen in patients followed up for longer than 19 years. There were no significant side effects or adverse reactions. CONCLUSION This new PDT is an effective, safe, and noninvasive modality with no recurrence for PWS, although the protocol for PDT requires further optimization. The authors have indicated no significant interest with commercial supporters.

Monitoring Microcirculation Changes in Port Wine Stains During Vascular Targeted Photodynamic Therapy by Laser Speckle Imaging

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 5u2003min 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 (4–5u2003mgu2003kg−1). A 532u2003nm laser was used for irradiation (power density: 80–100u2003mWu2003cm−2, exposure time: 20–50u2003min). Before V‐PDT, all 24 PWS patients demonstrated a significant difference in perfusion between the PWS lesion and the contralateral healthy control skin (1132u2003±u2003724 and 619u2003±u2003478 PU, respectively, Pu2003<u20030.01). Five minutes after V‐PDT, the mean perfusion value of the 24 PWS lesions was 1246u2003±u2003754 PU. There was no significant difference compared to the perfusion before V‐PDT (Pu2003>u20030.05). During V‐PDT, the perfusion of seven PWS patients increased rapidly after initiation of V‐PDT, reached a maximum within 10u2003min, 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.

Novel Surfactant-like Hypocrellin Derivatives to Achieve Simultaneous Drug Delivery in Blood Plasma and Cell Uptake

Water‐soluble derivatives of hypocrellins can be safely delivered in blood plasma but lose their photodynamic activity in vivo due to poor cell uptake, while hydrophobic derivatives retaining their activity may aggregate in the blood plasma and block vascular networks. Considering both drug delivery and biological activity, surfactant‐like hypocrellin B (HB) derivatives, sodium 12‐2‐HB‐aminododecanoate (SAHB) and sodium 11,11′‐5,8‐HB‐dimercaptoundecanoate (DMHB), were first designed and then synthesized in the current work. Both SAHB and DMHB were photoactive, generating free radicals and reactive oxygen species, as confirmed by EPR and chemical measurements. Most importantly, DMHB was not only readily soluble, allowing preparation of an intravenous injection solution at a clinically acceptable concentration, but it was also more photodynamic therapy (PDT) active to human breast carcinoma MCF‐7 cells than its parent HB under irradiation. The photodynamic activity was exactly identical to the 1O2 quantum yield and was not reduced by the improved water solubility, suggesting an independent hydrophilicity or lipophilicity. To our knowledge, this is a new strategy that possesses general significance for converting hydrophobic photosensitizers into clinically usable PDT drugs.

In vitro and in vivo antitumor activity of a novel hypocrellin B derivative for photodynamic therapy

BACKGROUNDnPhotodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by irradiating photosensitizers with light exposure to produce reactive oxygen species (ROS). An ideal photosensitizer is a crucial element to PDT. In the current study, we evaluated the photodynamic activity of a novel photosensitizer, the derivative of hypocrellin B (HB), 17-(3-amino-1-pentanesulfonic acid)-substituted hypocrellin B Schiff-base (PENSHB), both in vitro and in vivo.nnnMETHODSnPhysicochemical characteristics of the novel photosensitizer were compared with that of its parent HB. The intracellular distribution of photosensitizers and mitochondrial membrane potential were detected with laser scanning confocal microscopy. The pathway of cell death was analyzed by flow cytometry. The release of proapoptotic proteins was evaluated by Western blot. S180 tumor model was used to evaluate the antitumor effects of PENHB-mediated PDT.nnnRESULTSnCompared with its parent HB, water solubility of the derivative was improved enormously (6.6 mg/ml vs. 4.6 μg/ml), rendering its intravenous injection feasible without auxiliary solvent. The derivative had better PDT effect than HB in vitro under similar dark cytotoxicity. Moreover, PENSHB-mediated PDT was able to induce mitochondrial inner membrane permeabilisation, cytochrome c release, caspase-3 activation and subsequent apoptotic death. In vivo study showed that more than half of tumor bearing mice were cured by PENSHB-mediated PDT.nnnCONCLUSIONSnIn vitro and in vivo studies suggest that PENSHB is an effective photosensitizer for PDT to tumors. Therefore, PENSHB as a novel photosensitizer has a good prospect of clinical application.

Effects of Photodynamic Therapy Using Hematoporphyrin Monomethyl Ether on Experimental Choroidal Neovascularization

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 20u2003min 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 1000u2003mWu2003cm−2 corresponding to a fluence of 36, 54, 90u2003Ju2003cm−2 in PDT plan I (15u2003mgu2003kg−1 HMME). In PDT plan II (30u2003mgu2003kg−1 HMME), the laser had a constant irradiance of 600u2003mWu2003cm−2, which was delivered for 60, 90 or 150u2003s, to also achieve total energy doses of 36, 54 or 90u2003Ju2003cm−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 (Pu2003<u20030.01). 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.

A randomized, double-blind, placebo-controlled study of oral oxycodone plus acetaminophen for the treatment of pain in photodynamic therapy on port wine stains

BACKGROUNDnThe major side-effect of photodynamic therapy (PDT) on port wine stains (PWS) is pain during the treatment. Although several strategies for controlling the pain during topical PDT achieve a reduction in the levels of pain, none were completely effective and convenient. This randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of an oral analgesic for the treatment of pain in PDT on PWS.nnnMETHODSnFifty-eight patients with PWS on the face were included. The treatment and placebo groups were selected by computer randomization. The patients, doctor and statistician were blinded to the patients groups. The analgesic contained 5mg of oxycodone in combination with 325 mg of acetaminophen. The patient took the tablet orally 30 min before PDT. The patient was injected intravenously with 4-5mg/kg photosensitizer PSD-007 within 5 min, and then the lesion was exposed to a 532 nm laser immediately for 30-60 min at 100 mW/cm(2). The intensity of the pain during irradiation, the characteristic and beginning time of pain, and adverse effects were recorded. A visual analog scale (VAS) was used to assess the pain.nnnRESULTS AND CONCLUSIONSnThe time of the pain beginning was 8.31 ± 4.58 min in the treatment group and 7.10 ± 3.54 min in the placebo group, which was not significantly different (P=0.266). The VAS score in the treatment group was 7.88 ± 1.52 compared with 8.17 ± 1.12 in the placebo group, with no significant difference (P=0.422). The subgroup of age, gender, lesion location and classification between two groups had similar VAS score (P>0.05). No serious adverse events were reported. This study found that oral oxycodone 5mg/acetaminophen 325 mg was completely ineffective for pain relief, and age, gender, lesion location and classification did not influence the pain perception and the analgesic effect. The challenge of controlling pain during PDT on PWS remains.

Influence of laser wavelength on the damage of comb's vasculature by photodynamic therapy--simulation and validation of mathematical models.

Lasers of different wavelengths have been used as a photodynamic therapy (PDT) light source in the treatment of port-wine stains. This study attempts to investigate the influence of wavelength on depth of vascular damage using a cock comb model and mathematical modeling/simulation. Monte Carlo simulation was used to calculate the distribution of laser light in skin tissue. A series of equations including the diffusion equation for modeling the distribution of photosensitizers and oxygen, and the photobleaching equation were established to calculate the singlet oxygen generation in PDT. The singlet oxygen generation in comb tissue model with vasculature was simulated with 532- and 627.8-nm laser, respectively. In the animal experiment, the comb was treated using hematoporphyrin monomethyl ether (HMME) (10xa0mg/kg dose) as a photosensitizer and lasers of two different wavelengths (532 and 627.8xa0nm) at an identical power density (100 mW/cm2, fluence 120 J/cm2). The simulation results showed that the 627.8-nm laser was more effective in generating singlet oxygen in blood vessels at deep dermis. The animal experiments showed that the average depth of thrombosis was 1,012.5u2009±u2009647.06xa0μm with the 532-nm laser, and 2,204.2u2009±u2009410.35 μm with the 627.8-nm laser. The results showed that the laser wavelength had a strong effect on the depth of thrombosis in PDT treatment for the comb model. The simulation results were consistent with the animal experimental results.

Endoscopic lithotripsy for gastric bezoars by Nd:YAG laser-ignited mini-explosive technique

Until now, there still has no standard treatment option to deal with gastric bezoars. This respective study was conducted to evaluate the safety and efficiency of Nd:YAG laser-ignited mini-explosive technique for the treatment of gastric bezoars. Two hundred sixty patients with 285 gastric bezoars were treated by endoscopic lithotripsy with Nd:YAG laser-ignited mini-explosive technique. Among the 260 patients, the 284 gastric bezoars of the 259 patients completely disappeared, with the cure rate of 99.6xa0% after 1–2 treatments at 2–4xa0weeks follow-up. Only one patient, who was cured by surgery, had gastric perforation during the explosion. No intraoperative or delayed complications was found in the other 259 patients. The endoscopic lithotripsy with Nd:YAG laser-ignited mini-explosive technique is an effective, safe, and promising alternative for gastric bezoars.

Vascular targeted photodynamic therapy for bleeding gastrointestinal mucosal vascular lesions: A preliminary study

BACKGROUNDnVascular-targeted photodynamic therapy (V-PDT) has shown good selectivity and efficacy in the treatment of certain types of vascular disease, including port wine stains, age-related macular degeneration, and esophageal varices. This study was conducted to test the efficacy and safety of V-PDT in the treatment of gastrointestinal (GI) bleeding caused by the abnormal dilatation of capillaries.nnnMETHODSnPatients with bleeding GI mucosal vascular lesions treated with V-PDT were included in this retrospective study. The efficiency of V-PDT was analyzed by comparing the documented endoscopy results, hemoglobin levels, and transfusion requirements before and at 6 months after the last V-PDT. Side effects during and after V-PDT and follow-up results were also analyzed.nnnRESULTSnSeven patients with bleeding GI mucosal vascular lesions were treated with V-PDT. After 1-4 V-PDT sessions, all patients no longer needed transfusions to maintain a stable hemoglobin level during the follow-up period of 6 months. The mean hemoglobin level of the seven patients improved from 6.21±1.48 g/dl to 11.66±1.21 g/dl (p<0.001), and the GI bleeding and melena of all the patients disappeared. No perforations, strictures, scars, or episodes of photosensitization occurred in the seven patients, and there were no recurrences of GI bleeding during the 1-21 months of further follow-up.nnnCONCLUSIONSnThis preliminary study indicated that V-PDT is a highly selective, safe, well-tolerated, and effective treatment modality for bleeding GI mucosal vascular lesions. However, prospective studies with larger sample sizes are needed to confirm this finding.

In vitro photodynamic inactivation effects of benzylidene cyclopentanone photosensitizers on clinical fluconazole-resistant Candida albicans

BACKGROUNDnThe incidence of Candida infections has increased for various reasons, including, the more frequent use of immunosuppresants or broad-spectrum antibiotics. Photodynamic inactivation (PDI) is a promising approach for treating localized Candida infections.nnnMETHODSnThe PDI efficacies of three benzylidene cyclopentanone-based (BCB) photosensitizers (PSs: P1, P2 and Y1) against three fluconazole-resistant C. albicans (cal-1, cal-2, and cal-3) and one control C. albicans (ATCC 90028), respectively, were evaluated using an established plate dilution method. The binding of PSs to C. albicans was determined by fluorescence spectroscopy. The mechanism of antifungal PDI was investigated using confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM).nnnRESULTSnThree BCB PSs all bound rapidly to C. albicans. After incubation with PSs for 30u202fmin and irradiation with a 532u202fnm laser for 10u202fmin (40u202fmWu202fcm-2, 24u202fJu202fcm-2), the fungicidal activity was achieved as 7.5u202fμM for P1 and P2, and 25u202fμM for Y1. CLSM confirmed that P1 and Y1 were located in intracellular components, including mitochondria, while P2 bound to the protoplast exterior and failed to enter the cells. TEM revealed the damage of mitochondria ultrastructures after P1- or Y1-mediated PDI, consistenting with the CLSM results. However, most cells became edematous, enlarged or deformation after P2-mediated PDI.nnnCONCLUSIONSnThe three BCB PSs all have remarkable PDI effects on C. albicans. The best effect is obtained by P1, which has one cationic charge with a proper lipophilicity. The respective subcellular localization of the three PSs led to different PDI mechanisms.