Chemical structure of Rapamycin. 

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... C for irreversible vessel coagulation and destruction. Although several vascular specific lasers have been used for the treatment of PWS, PDL has largely replaced other lasers and become a standard therapy in the treatment of PWS. Currently, several devices (585 - 600 nm) are commercially available. Figure 1 shows a child PWS case treated with a 585 nm PDL. Newer models have been developed with longer pulse durations which better match the 1- to 10-ms thermal relaxation times of PWS vessels. Longer wavelengths of 595 nm and 600 nm penetrate more deeply, enhancing effectiveness. However, these wavelengths are slightly longer than the hemoglobin absorption peak (577 nm), so higher fluences are required. These higher fluences can potentially damage epidermal tissue. Subsequently, surface cooling devices have been developed to protect the epidermis. Photodynamic therapy is a site-specific treatment modality. It involves the local or systemic administration of a photosensitizer followed by irradiating the targeted site with non-thermal visible light of appropriate wavelength(s) at a specific drug to light interval (DLI). In the presence of oxygen, the light irradiation of photosensitizer can lead to a series of photochemical reactions and generation of various cytotoxic species (e.g. singlet oxygen and other reactive oxygen species), and consequently induce various therapeutic effects. Photodynamic therapy can be performed in various forms in non-invasive or minimally invasive fashion [12]. Vascular-targeted PDT is characterized by a short DLI (e.g. 0 – 30 minutes) and is by far the most successful PDT application. Under this unique setup, light irradiation takes place while the photosensitizer is circulating in the vascular compartment and therefore causes selective vascular damages through the low-density lipoprotein receptor-mediated endocytosis pathways which lead to thrombosis and vessel occlusion [13]. Vascular PDT has been used primarily for the management of wet age-related macular degeneration (AMD) in the western world [12]. Vascular PDT-mediated with domestically produced photosensitisers has been used for the treatment of PWS in China since the early 1990’s [14]. Chinese data suggest that vascular-targeted PDT can selectively eliminate abnormal PWS vessels and provide a promising alternative modality for treating PWS of various severities. Early Chinese trials mainly used Photocarinorin (mixture of porphyrins, also known as PSD-007) and various light sources [15]. The wavelengths of laser ranged from 488, 510, 532 to 578 nm (single wavelength or their combination) and that of non-coherent light 600 to 700 nm [14,16]. Although Photocarinorin continues to be used in many clinics in China, more recently, Photocarinorin has been gradually replaced by hematoporphyrin monomethyl ether (HMME) (one of the active ingredients of Photocarinorin), which has several absorption peaks (401, 500, 533, 569 and 613 nm). Figure 2 shows an adult PWS case treated with HMME-mediated PDT. In a recent article, we reported our retrospective analysis of medical records of 306 patients treated with a combination of HMME and copper vapour laser [17]. Immediately after HMME injection (3.5 mg/kg for children and 4.0 – 5.0 mg/kg for adults), light (80 – 100 mW/cm 2 ) was delivered to PWS lesion at dose levels of 140 - 240 J/cm 2 . The laser emits two peak wavelengths (510.6 and 578.2 nm) at a frequency of 10 KHz and pulse width of 50 ns. Irradiation lasted 20 – 40 min. The children group (3 – 10 years old) included 98 patients with pink flat PWS located in the cheek region. The overall fair to excellent response was 88.8%. The excellent response rate of PDT group (23.5%) was higher than that of PDL group (16.1%). The adult group (18 – 30 years old) included 208 patients with purple flat PWS located in the temple, cheek or neck region. The overall fair to excellent response was 94.2%. The excellent response rate of PDT group (37.5%) was significantly higher than that of PDL group (3.1%). The complication rate (pigmentary or textural change) in PDT group (10.2%) was lower than that in PDL group (24.7%). PDL thermal treatment of PWS blood vessels induces a visible purpuric reaction, which is associated with various degrees of inflammation, edema, and hypoxia in the upper layers of the skin. Vascular wall necrosis can take place 2–3 mm below the skin surface. These reactions can initiate wound healing responses and trigger the body to repair the laser-induced damage. This process can result in reformation of PWS blood vessels within 1 month after laser exposure. Due to the reformation of PWS blood vessels, in some cases PWS can become darker and redder after PDL treatment [5]. Therefore, it is important to modulate the skin wound healing response by inhibiting the reformation of blood vessels caused by PDL. Recently, the potentials of Rapamycin and Imiqimod as a modulator have been studied. Rapamycin (C 51 H 79 NO 13 , M.W. 914.19; Figure 3) is a specific inhibitor of mammalian target of rapamycin (mTOR) and has been used as an immunosuppressive and anticancer agent. Its anti-angiogenic function is attributed to the downregulation of hypoxiainducible factor (HIF-1a) synthesis, which in turn acts as a transcriptional factor that regulates VEGF expression [18,19]. The effects of Rapamycin as a topical agent to modulate the skin wound healing response by inhibiting the reformation of blood vessels after light induced photothermolysis has been investigated in an animal model and normal human skin [5]. Initial animal data demonstrate that following laser irradiation, the topical application of Rapamycin daily for two weeks can suppress the reformation and reperfusion of blood vessels previously disrupted by photothermolysis. These results may be attributed in part to an inhibition of endothelial cell proliferation, leading to a decrease in the overall blood vessel density. Studies on normal human skin showed that combined laser and topical Rapamycin significantly inhibited the regrowth of new blood vessels in the skin and vascular leak and dermal edema. Limited human data also suggest that the combined procedure appears safe for human use. Nonetheless, the topical use of anti-angiogenic therapy to inhibit revascularization following laser photothermolysis of blood vessels may be extended beyond RPM to include other angiogenesis inhibitors such as VEGF inhibitors and inhibitors of the VEGF receptor signaling pathway [5]. Imiquimod (C 14 H 16 N 4 , M.W. 240.3; Figure 4) is a topical immune response modifier agent that can also inhibit neovascularization [20-22]. Its antiangiogenic mechanisms can be summarized as: (1) induction of cytokines (interferons, IFN- α, β, γ , IL-10, IL-12, IL-18) that inhibit angiogenesis; (2) up-regulation of endogenous angiogenesis inhibitors (IFNs, IP10, TIMP, TSP-1); (3) down-regulation of pro-angiogenic factors (bFGF, MMP-9); and (4) promotion of endothelial apoptosis [23]. The effects of Imiquimod as a topical agent to modulate the skin wound healing response by inhibiting the reformation of blood vessels after light induced photothermolysis has been investigated in a pilot study of 20 Asian PWS patients [6]. In this study, three sites on each subject were randomly assigned to the following regimens: (1) PDL + Imiquimod; (2) PDL alone; and (3) Imiquimod alone. PDL test sites received a single PDL treatment. For the PDL + Imiquimod and Imiquimod alone test sites, Imiquimod was topically applied once daily for 1 month after PDL exposure. Subjects were followed-up for 12 months. Based on paired analysis, there were clinically and statistically significant differences in blanching responses between PDL + Imiquimod group and PDL or Imiquimod alone group. Although the regimens of this study were not designed for complete blanching, there was some evidence of redarkening of PWS in PDL + Imiquimod and PDL alone groups at 12 months. This is presumably due to revascularization of blood vessels. However, based on the comparison of the hemoglobin-indices determined at 1 and 12 months, there was less revascularization of PWS at test sites treated with PDL + Imiquimod as compared to PDL alone. Although the preliminary studies suggest that the combined use of PDL and a topical application of Rapamycin and Imiquimod is promising, clinical trials in large PWS patient populations is required to assess the true value such combination modality. Nonetheless, these studies also confirm the involvement of skin wound healing response and blood vessel reformations in redarkening and recurrence of PWS lesions after PDL treatment. Vascular damage and inflammation development are well recognized as acute responses of solid tumor to PDT treatment. On one hand, these effects can cause tumor hypoxia and generate anti-tumor immune response, thereby contributing to long-term tumor control. On the other hand, these effects might initiate the proliferation of blood vessels through various pathways. Similar responses have been well characterized for ocular PDT. PDT with verteporfin (benzoporphyrin derivative monoacid ring A, BPD-MA) has been approved worldwide since 2000 as a first-line therapy for the treatment of patients with predominantly classic subfoveal choroidal neovascularization (CNV) due to AMD, pathologic myopia or presumed ocular histoplasmosis. PDT with verteporfin has to be carried out while the photosensitizer is in the general circulation in order to maximize anti-vascular effect and ultimately to achieve complete occlusion of CNV lesions, stabilize vessel leakage and gain visual acuity or limit visual loss. However, PDT itself could induce (i) acute inflammatory response which might cause a transient visual disturbance and (ii) proliferation of vessels which might cause treatment failure. Anti-inflammatory adjuvant therapy might have the potential to counteract some of these adverse effects associated with PDT. ...