Clinical Photodynamic Therapy Review and the Brazilian Experience

Kate C Blanco, Natalia M Inada, Ana Gabriela Salvio, José Dirceu Vollet-Filho, Vanderlei S Bagnato

Kate C Blanco, Natalia M Inada, José Dirceu Vollet-Filho, Vanderlei S Bagnato, University of São Paulo, São Carlos Institute of Physics, São Paulo, Brazil
Ana Gabriela Salvio, Skin Department, Amaral Carvalho Hospital, Brazil, Jahu, São Paulo, Brazil

Correspondingauthor: Kate Cristina Blanco, CEPOF, Av. Trabalhador São-carlense, 400, São Carlos 13566-590, SP, Brazil.
Email: vander@ifsc.usp.br
Received: June 28, 2015
Revised: July 24, 2015
Accepted: July 29, 2015
Published online: April 18, 2016


Photodynamic therapy (PDT) is a simple and promising technique indicated for the treatment of non-melanoma skin cancer. Although multicenter research trials have proved its success, PDT is not as much disseminated as surgery andcryotherapy approaches are.A light-activated substance (a photosensitizer) is usually topically administered. By irradiating the sensitized region with specific wavelengths and appropriated light dose, reactive oxygen species take place, which oxidize molecules and destroy tumor cells. This review article presents not only the base principles of PDT, but also a unique experience Brazil-wide, which reached other countries in Latin America. This initiative was funded by the Brazilian government via the Brazilian Development Bank (BNDES), involving private companies and academia in a validation study of the treatment of both pre-malignant and malignant skin cancer lesions.PDT protocol evolution is presented, including details that made the technique highly efficient and placed this experiencein a larger context.

© 2016 The Authors. Published by ACT Publishing Group Ltd.

Key words: Photodynamic therapy (PDT); Non-melanoma skin cancer; Photodynamic Therapy; Brazilian

Blanco KC, Inada NM, Salvio AG, Vollet-Filho JD, Bagnato VS. Clinical Photodynamic Therapy Review and the Brazilian Experience. Journal of Tumor 2016; 4(2): 386-392 Available from: URL: http://www.ghrnet.org/index.php/jt/article/view/1669


PDT is a non-systemic therapy, which has been successful in treating a number of diseases[1-4]. However, despite favourable results, it has not been the first option to date in the treatment of non-melanoma skin cancer and pre-malignant lesions[5,6]. This might be associated to the number of variables involved in PDT (photosensitizer, oxygen, light, anatomical site and depth of lesions, as well as other inherent, patient-dependent aspects), which might contribute to variations of the cure rates. Another possible factor is cost, since PDT drugs are not available in variability enough to make prices affordable and, in most cases, the light devices for treatment that are made available for acquisition only by tied sale with drugs.Skin cancer in Brazil is recognized as a public health problem, and at the same time it is considered a social and infrastructural problem, because it affects a great number of people, with important impact in morbidity, mortality, and economy.

A national program (entitled “Photodynamic Therapy Brazil”) was started in Brazil in 2012, thanks to the joint efforts of universities, research centers, hospitals, private medical clinics, private companies and research funding agencies. This program made skin cancer treatment available to the Brazilian (including the public health system) and other twelve other Latin America countries’ population[7] in a simple and fast way, resulting in the improvement of patients welfare through the fostering and application of advanced technology, by creating several PDT treatment centers.The program provides photosensitizer, treatment device and training to the upcoming partner centers, making diagnosis and treatment of lesions possible with low cost and shorter time spans when compared to lesions referred to surgery.

One hundred treatment centers were created under this initiative (Figure 1), and approximately 90% of the lesions treated since 2012 were completely cured. When results are assessed by centers, this cure rate is increased when the health professional taking part in the treatment had previous experience with PDT, due to two main factors: the expertise in referringto PDT treatment lesions that are more appropriate for this approach, and a more adequate preparation of the lesion for the procedure, such as sufficient curettage and administration of the methyl aminolevulinate (MAL) photosensitization cream (Figure 2). The results showed that a large-scale program for the treatment of small skin cancer lesions is viable; these results are so positive that new centers are continuously being added to the program, and treatment follow-up data are still being collected for future, more comprehensive analysis. A core result from this approach is that the involved countries currently start to face a new reality concerning skin cancer treatment due to this program[7].

Photodynamic Therapy

Although light has been used as a curative tool for thousands of years, the first report of the photodynamic effect in cell destruction of protozoa (paramecium) was presented by Oscar Raab in 1900[8] However, the first tumor treatment by PDTwas reported only in 1903 by von Tappeiner[8] Currently, tumor treatment has been the main application of PDT[9-13], although it is also effective in treating infections by promoting the death of microorganisms[14-17].

Tumor treatment by PDT is achieved by the interaction of light with the photosensitizer, which promotes the generation of reactive oxygen species that destroytumor cells. This process takes place when the photosensitizer molecules, which lead molecules from what is called a “fundamental energy state “to a so-called” excited state, absorb light of appropriate wavelength.

Eventually, the excited molecules undergo a relaxation process (which is a very fast process, about 10-12 s), releasing energy by vibration processes up to the lowest excited state before the fundamental one.At this point, for photosensitizer molecules, part of them release energy by molecule-molecule interaction, and part emitting a photon (i.e., light), which will have lower energy than the absorbed ones. This processes is usually fast (about 10-8 s), and is called fluorescence - which can be used for diagnosis[18] Part of the molecules, though, during relaxation, undergoes “intersystem crossing” (a change initsspin configuration), which leads the excited molecule to a triplet electronic spin configuration, producing a meta-stable (i.e., long-lived, minimum of 10-3 s) excited state.

When at this meta-stable state, the photosensitizer molecule may also emit light (and emission is then called phosphorescence), or may follow two different pathways: interacting with substrate molecules, producing free radicals by the transfer of electronic charges, or interacting with molecular oxygen by energy transfer and producing a special species called singlet oxygen, which is very reactive and, thus, very cytotoxic. One of those processes is usually dominant for each photosensitizer molecule; if free radicals production is dominant, it is called a type-I reaction; if singlet oxygen is more expressive, it is called a type-II reaction.

The wavelengths able to promote the excitation of the photosensitizer molecules are usually within the spectral regions of near ultraviolet[19,20], visible light[1,21] or near infrared[22-24] - these wavelengths avoid the spectral regions able to ionize molecules by ultraviolet and shorter wavelengths, and water absorption of infrared wavelengths. An efficient PDT application requires enough light penetration in biological tissues, determining the choice of wavelengths and photosensitizers. For cancer treatment, efficient photosensitizers must also have a stable formulation[25], physiological pH[26], high absorption in wavelengths that favor light penetration at the aimed biological tissue (usually between 600 and 850 nm for most applications)[27], and show selectivity for malignant cells[28,29], high quantum yield for reactive oxygen species production[30,31], no mutagenic effects[32] low cytotoxicity in the absence of light[33,34], and fast metabolization - in order to reduce side effects[35].

The main photosensitizers currently used are haematoporphyrin derivatives, which show efficacy for the treatment of non-melanoma skin cancer[36]. Among them, the similar first generation drugsPhotofrin®[37,38], Photogem® and Photosan® show unique characteristics, such as differences in toxicity, which make each of them ideally indicated to specific applications.

The second generation of photosensitizers includebenzoporphyrin derivatives[39,40], which are rapidly metabolized and show selective accumulation by endothelial cells[41], chlorins[42,43], texaphyrins[44,45] and dyes[46,47].

The third generation of photosensitizers conjugate characteristics of the first and second generation molecules, and are not commercially available. The main modifications made to them are related to the use of antibodies and nanoparticles[48,49].

Photosensitizers can also be endogenous, such as riboflavin (vitamin B12)[50,51] and protoporphyrin IX (PpIX)[52,53]. The 5-aminolaevulinic acid (ALA) and its derivatives (such as MAL) can be administered as a pre-drug, converting to PpIX inside cells[54,55].

Light sources for tumor treatment range from conventional lamp bulbs either with or without optical filters[56] to light-emitting diodes (LED)[16,57,58] andlasers[21,59,60]. The latter ones are the most versatile and thus the most used ones, due to the possibility of coupling optical fibbers to provide light delivery to treatment spots difficult to reach. Lasers are not ideal, though, due to the usual high cost; additionally, less monochromatic light sources may provide multiple excitation of a single absorption band of the photosensitizer molecules. LED devices, on the other hand, are currently largely applied to PDT since they provide an increasing availability of wavelengths with high power output and affordable cost. PDT efficacy has been proved for several applications and our research group currently works toward the development and optimization of protocols and dosimetry[61], drugs[62] and instrumentation[63].


Basal cell carcinoma

“PDT Brazil” program happened as a partnership of the clinical centers with the Sao Carlos Institute of Physics at University of Sao Paulo (IFSC/USP), the device- and drug-manufacturing companies (MMOptics® and PDT Pharma®, respectively) and funded by BNDES. The program provided skin cancer treatment, improving public health system patients’ welfare by making available health treatment with the latest technology[64,65]. Since then, more than 2 000 lesions have been treated at about 100 treatment centers established by this program, in Brazil - (distribution by country region: North: 1.8%, Central-West: 5.6%, Northeast: 13.2%, South: 30.6%; Southeast 48.8%) - and Latin America (5.2% of them), and particularly by the Phototherapy and Photodiagnosis center at the AmaralCarvalhoHospital Foundation (Jahu-SP, Brazil), a region reference hospital which treats usually more than 70 000 cancer patients a year, and which is a main training center for upcoming treatment centerswith the national devices and drug provided under the program[66-69]. The pharmaceutical ingredient is methyl aminolevulinate (MAL, PDTPharma, Cravinhos-SP, Brazil), which was used throughout the research and approved for clinical trials by ANVISA (the Brazilian Health Surveillance Agency). The drug approval (a cream containing 20% MAL, by PDT Pharma®) is in progress by ANVISA, after the end of the Phase II Trial including 600 patients,wich compared the efficacy of this drug with surgery, the gold standard method of treatment for non-melanoma skin cancer. The device provided to the centers by the program for the treatments, LINCE® (MMOptics LTDA, São Carlos-SP, Brazil. Figure 3), is composed by a portable console connected to a treatment probe and to a fluorescence imaging probe for visualization of the produced PpIX and the lesions’ endogenous fluorescence. This visualization probe allows for wide field fluorescence imaging and PpIX photobleaching monitoring.Light intensities between 50 and 150 mW/cm² and irradiation periods up to 90 min are available, and can be set up by the console control panel.

Lesions treated under PDT Brazil program are exclusively non-melanoma skin cancer, either superficial or nodular basal cell carcinoma (BCC) type, up to 2 cm in diameter and up to 6 mm infiltration, with histopathology confirmation (Figure 4). Highest incidence among the treated lesions was in elderly patients (60+ years old), in the face - probably due to the accumulative effect of sunlight UV radiation on skin over the years.To increase the cream penetration and favor light absorption into the lesion, a curettage procedure was introduced to the standard protocol, aiming to increase the volume of tissue treated. The three-hours time interval between the cream administration and the illumination is necessary for the PpIX production by the ALA in the cream[7]. ALA, which is a precursor of PpIX (and a direct by-product of MAL), is a hydrophilic agent that penetrates cells by active transport and depends on pH and temperature to be metabolized[70].

The fluorescence induced at photosensitized cells is related to PpIX accumulation and its increase to the accumulation time, and can provide evidence about the treatment response[71]. Due to this, such fluorescence is suggested as a monitoring tool for PDT applications. The main factors associated to the treatment response are MAL absorption, PpIX formation and consumption, adequacy of the curettage andavoidance or proper management of its resulting bleeding (clotting reduces light penetration), the adequate administration of the cream, the photosensitizer incubation time, adequate occlusion of the photosensitized lesion (to avoid premature irradiation), and uniformity of the light delivery to tissue[72-75].

The energy surface density that is delivered during the application is called light dose, which for this PDT initiative was 150 J/cm2. Different light doses can be used, however, since a balance between intensity (which is the light dose delivery rate, and is equivalent to output light power of the device delivered per irradiated area) and the time spent during irradiation; the balance is given mostly by empirical experience and by dosimetry models applied to preclinical and clinical trials[76]. Thelight source of choice (lasers, light-emitting diodes, lamp devices) is also not standardized for PDT, because different applications may require different sources.

Among the program results, light penetration was found to be a very important aspect concerning PDT outcome; since nodular BCC show geometrical differences when compared to superficial BCC, lesions thickness may challenge light penetration in PDT. Concerning pigmented BCC, melanin absorbs light, preventing it from being delivered to the full extension of the lesion. In all those cases, geometry and pigmentation is obstacles to light penetration end up reducing PpIX consumption, and thus prevent sufficient photodynamic effect.

Results showed a linear correlation between lesion size and cure rate. Lesions larger than 2-3 cm in diameter which were treated did not show the same cure rate, probably due to the difficulty in light penetration for larger lesions - those lesions demand more light and drug to undergo sufficient PDT effect[77,78]. The superficial extension of lesions can receive enough cream to suffice adequate sensitization but, since the LINCE® device was aimed for small lesions, the original device was improved during the program development, adapting consoles to the irradiation necessities of larger lesions, up to 10 × 12 cm.

Over the clinical trial, the observed PDT side effects were the report of pain during irradiation and cicatrizationmodifications. Pain is the main expected reaction to the photodynamic effect, due to the PDT-induced inflammatory response. Hyperchromia and hypochromia were observed as cicatrization modifications, but both showed a low rate of incidence, and are both reversible.

The complete response to treatment is greater than 80% and has 1.22% recurrence rate after 6 months from the first PDT session.Patients showed 83% normal healing and 17% abnormal healing (atrophic, hypertrophic, hypochromic and hyperchromic) in the cosmetic results of PDT. The session number and lesion localization influenced in painful intensity during PDT. Patients reported a higher intensity of pain in lesions on the head and neck than on the trunk and limbs in second session[79].

Premalignant lesions of skin

The use of PDT for the treatment of premalignant lesions such as actin keratosis (AK), including field cancerization, has been approved clinically in several countries[80,81]. A number of studies showed the efficacy of this treatment modality for field cancerization, since it provides the treatment of subclinical lesions[82-84].

Our research group also performed trials aiming premalignant lesions[85], showing that PDT using MAL is efficient in those cases, producing excellent aesthetical results in the treatment of AK using a LED light source named KeratoPDT, developed by the Optics Group at IFSC/USP, by members of the Biophotonics and Technology Support (LAT) laboratories (Patent PI: 1000413-0).KeratoPDT was especially designed to anatomically fit the upper limbs, for the treatment of widespread actin keratosis (DSAP)[86]. The prototype allows for uniform and simultaneous illumination of the upper limbs, providing treatment of widespread actin keratosis with relevant cosmetic results, with tolerable pain for the patient[67,68,86].

Another relevant response to PDT is observed for actinic cheilitis. Actin cheilitisis also called lip actinic keratosis, which is an inflammatory pathological condition of the lips that may be caused by the chronic, excessive exposure to sunlight ultraviolet radiation, with potential to become a malignant lesion. Since non-surgical therapeutic protocols are preferable for the treatment of this type of lesion, PDT is a natural candidate as non-invasive treatment option, due to the excellent outcome and aesthetic results. Thus, clinical trials are currently in progress by our research group at IFSC/USP, aiming to define an optimum treatment protocol[87].

Extensive lesions of skin cancer

One of the great advantages offered by the PDT Brazil program was the opportunity to use PDT for the treatment of both large superficial BCC lesions and Bowen’s disease occurring in elderly patients with comorbidities that would prevent treatment involving surgical procedures. Lesions of up to 8 cm in diameter were treated during the program course, with total response observed for more than 70% of the treated lesions. That made possible to provide treatment to patients for which surgery procedures would present risk of death. Even in those cases for which partial response was obtained, lesions showed improvement that reduced surgical complexity and, thus, risk[69].

Since treating large lesions is a limit due to the cream penetration in bulky skin lesions, large lesions were also treated using Photogem as anintravenously administered photosensitizer, with incubation time of 24 hours and light dose between 200 and 300 J/cm²[88,89]. Results for this lesions showed improvement of lesions, by reducing them, showing that systemic photosensitization for PDT is a viable alternative for the treatment of bulky lesions.

Finally, one of the most important limitations of PDT - light penetration into biological tissues, which limits the photosensitizer activation - may be actually considered an advantage in some clinical skin cancer situations, in which preserving healthy tissues beyond skin is a must, or at least desirable.


Although currently PDT is not the standard method for the treatment of tumors that are responsive to the photodynamic effect, PDT is gaining space among the therapy possibilities for lesions such as skin cancer. Thanks to the opportunity created by the joint public and private funding, and to the partnership between research institutions and hospitals, a well-defined protocol for PDT is made available to patients all over Latin America, which include making available both photosensitizing drug and irradiation devices that make possible to diagnose and to treat premalignant and malignant skin cancer lesions. Our research group iscontinuously increasing the number of treated lesions, and fostering the improvement of in vitro tests, pre-clinical tests, and clinical trials, seek for new possibilities for PDT application and understanding.


Funding for this study was provided by the Brazilian Development Bank (BNDES n° 09.2.1458.1), the Center for Research inOptics and Photonics (CEPOF - FAPESP CePID programgrant 2013/07276-1), and the Brazilian Innovation Agency (FINEP).


There are no conflicts of interest with regard to the present study.


1Bozzini G, Colin P, Betrouni N et al. Efficiency of 5-ALA mediated photodynamic therapy on hypoxic prostate cancer: a preclinical study on the Dunning R3327-AT2 rat tumor model. [Internet]. Photodiagnosis Photodyn Ther 2013: 10: 296-303. [cited 2013 Dec 16] DOI: http://www.ncbi.nlm.nih.gov/pubmed/23993856

2Ortner ME, Caca K, Berr F et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study [Internet]. Gastroenterology 2003: 125: 1355-1363. DOI: http://www.sciencedirect.com/science/article/pii/S0016508503013623

3 Koudinova NV, Pinthus JH, Brandis A et al. Photodynamic therapy with Pd-bacteriopheophorbide (TOOKAD): Successfulin vivo treatment of human prostatic small cell carcinoma xenografts [Internet]. Int J Cancer 2003: 104: 782-789. DOI: http://doi.wiley.com/10.1002/ijc.11002

4Dummer R, Green A. Skin cancer - A world-wide perspective. In: Dummer R, Pittelkow MR, Iwatsuki K, Green A, Elwan NM, editors. Berlin, Heidelberg: Springer Berlin Heidelberg, 2

5Hendren SK, Hahn SM, Spitz FR et al. Phase II trial of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. [Internet]. Ann Surg Oncol 2001: 8: 65-71. DOI: http://www.ncbi.nlm.nih.gov/pubmed/11206227

6Witzigmann H, Berr F, Ringel U et al. Surgical and Palliative Management and Outcome in 184 Patients With Hilar Cholangiocarcinoma [Internet]. Ann Surg 2006: 244: 230-239. DOI: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00000658-200608000-00009

7Ramirez D P, Kurachi C, Inada N M et al. Experience and BCC subtypes as determinants of MAL-PDT response: Preliminary results of a national Brazilian project. Photodiagnosis Photodyn Ther 2014:: 22-26.

8Daniell MD, Hill JS. A history of photodynamic therapy [Internet]. Aust N Z J Surg 1991: 61: 340-348. DOI: http://dx.doi.org/10.1111/j.1445-2197.1991.tb00230.x

9Kim J Y, Choi W Il, Kim M et al. Tumor-targeting nanogel that can function independently for both photodynamic and photothermal therapy and its synergy from the procedure of PDT followed by PTT. J Control Release 2013: 171: 113-121.

10Sanovic R, Verwanger T, Hartl A et al. Low dose hypericin-PDT induces complete tumor regression in BALB/c mice bearing CT26 colon carcinoma [Internet]. Photodiagnosis Photodyn Ther 2011: 8: 291-296. DOI: http://dx.doi.org/10.1016/j.pdpdt.2011.04.003

11Fei B, Wang H, Wu C et al. Choline PET for monitoring early tumor response to photodynamic therapy. [Internet]. J Nucl Med 2010: 51: 130-138. DOI: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2999358&tool=pmcentrez&rendertype=abstract

12Mroz P, Hashmi JT, Huang YY et al. Stimulation of anti-tumor immunity by photodynamic therapy. Expert Rev Clin Immunol 2011: 7: 75-91.

13 Olivo M, Bhuvaneswari R, Lucky SS et al. Targeted therapy of cancer using photodynamic therapy in combination with multi-faceted anti-tumor modalities. Pharmaceuticals 2010: 3: 1507-529.

14Longo JPF, Leal SC, Simioni AR et al. Photodynamic therapy disinfection of carious tissue mediated by aluminum-chloride-phthalocyanine entrapped in cationic liposomes: an in vitro and clinical study. [Internet]. Lasers Med Sci 2012: 27: 575-584.[cited 2013 Dec 16] DOI: http://www.ncbi.nlm.nih.gov/pubmed/21809069

15Rolim JPML, de-Melo MaS, Guedes SF et al. The antimicrobial activity of photodynamic therapy against Streptococcus mutans using different photosensitizers. [Internet]. J Photochem Photobiol B 2012: 106: 40-46. [cited 2013 Dec 16] DOI: http://www.ncbi.nlm.nih.gov/pubmed/22070899

16Paschoal MA, Tonon CC, Spolidório DMP et al. Photodynamic potential of curcumin and blue LED against Streptococcus mutans in a planktonic culture. [Internet]. Photodiagnosis Photodyn Ther 2013: 10: 313-319. [cited 2013 Dec 16] DOI: http://www.ncbi.nlm.nih.gov/pubmed/23993858

17Kharkwal GB, Sharma SK, Huang YY et al. Photodynamic Therapy for Infections: Clinical Applications. Laser Surg Med 2011: 43: 755-767.

18Moghissi K, Stringer M R, Dixon K. Fluorescence photodiagnosis in clinical practice. Photodiagnosis Photodyn Ther 2008: 5: 235-237.

19Smith RC, Baker KS. Optical properties of the clearest natural waters (200--800\,nm). Appl Opt 1981: 20: 177-184./span>

20Hale GM, Querry MR. Optical Constants of Water in the 200-nm to 200-microm Wavelength Region. Appl Opt 1973: 12: 555-563

21Wang Y, Chen R, Zuo Z et al. New optional photodynamic therapy laser wavelength for infantile port wine stains : 457 nm for infantile port wine stains: 457 nm [Internet]. J Biomed Opt 2012: 17: 068003. DOI: http://www.ncbi.nlm.nih.gov/pubmed/22734789

22Bozkulak O, Yamaci RF, Tabakoglu O et al. Photo-toxic effects of 809-nm diode laser and indocyanine green on MDA-MB231 breast cancer cells. [Internet]. Photodiagnosis Photodyn Ther 2009: 6: 117-21. DOI: http://www.sciencedirect.com/science/article/pii/S157210000900060X

23Chen WR, Adams RL, Higgins AK et al. Photothermal effects on murine mammary tumors using indocyanine green and an 808-nm diode laser: An in vivo efficacy study. Cancer Lett 1996: 98: 169-173.

24Liu V G, Cowan T M, Jeong S W et al. Selective photothermal interaction using an 805-nm diode laser and indocyanine green in gel phantom and chicken breast tissue. Lasers Med Sci 2002: 17: 272-279.

25Shi Z, Ren W, Gong A et al. Stability enhanced polyelectrolyte-coated gold nanorod-photosensitizer complexes for high/low power density photodynamic therapy [Internet]. Biomaterials 2014: 35: 7058-7067. DOI: http://dx.doi.org/10.1016/j.biomaterials.2014.04.105

26Taillefer J, Jones M C, Brasseur N et al. Preparation and characterization of pH-responsive polymeric micelles for the delivery of photosensitizing anticancer drugs. [Internet]. J Pharm Sci 2000: 89: 52-62. DOI: http://www.ncbi.nlm.nih.gov/pubmed/10664538

27Yogo T, Urano Y, Ishitsuka Y et al. Highly efficient and photostable photosensitizer based on BODIPY chromophore. J Am Chem Soc 2005: 127: 12162-12163.

28Jori G. Tumour photosensitizers: Approaches to enhance the selectivity and efficiency of photodynamic therapy. J Photochem Photobiol B Biol 1996: 36: 87-93.

29Rosenkranz aa, Jans Da, Sobolev aS. Targeted intracellular delivery of photosensitizers to enhance photodynamic efficiency. [Internet]. Immunol Cell Biol 2000: 78: 452-64. DOI: http://www.ncbi.nlm.nih.gov/pubmed/10947873

30Belfield KD, Bondar MV, Przhonska OV. Singlet oxygen quantum yield determination for a fluorene-based two-photon photosensitizer. J Fluoresc 2006: 16: 111-117.

31Wang KK, Choi KH, Shin HW et al. Photophysics of a new photosensitizer with high quantum yield of singlet oxygen generation and its application to stereo-selective synthesis of (+)-deoxoartemisinin [Internet]. Chem Phys Lett 2009: 482: 81-86. DOI: http://linkinghub.elsevier.com/retrieve/pii/S0009261409012020

32Evans HH, Rerko RM, Mencl J EtAl. Cytotoxic And Mutagenic Effects Of The Photodynamic Action Of ChloroaluminumPhthalocyanine And Visible Light In L5178y Cells [Internet]. Photochem Photobiol 1989: 49: 43-47. DOI: http://dx.doi.org/10.1111/j.1751-1097.1989.tb04075.x.

33Fischer BB, Krieger-Liszkay A, Eggen RL. Photosensitizers neutral red (type I) and rose bengal (type II) cause light-dependent toxicity in Chlamydomonas reinhardtii and induce the Gpxh gene via increased singlet oxygen formation. [Internet]. Environ Sci Technol 2004: 38: 6307-6313. DOI: http://www.ncbi.nlm.nih.gov/pubmed/15597886

34Fischer BB, Krieger-Liszkay A, Eggen RIL. Oxidative stress induced by the photosensitizers neutral red (type I) or rose bengal (type II) in the light causes different molecular responses in Chlamydomonas reinhardtii [Internet]. Plant Sci 2005: 168: 747-759. DOI: http://www.sciencedirect.com/science/article/pii/S0168945204004418

35Knutson C, Benkö G, Rocheleau T et al. Metabolic photofragmentation kinetics for a minimal protocell: rate-limiting factors, efficiency, and implications for evolution. [Internet]. Artif Life 2008: 14: 189-201. DOI: http://www.ncbi.nlm.nih.gov/pubmed/18331190

36Lipson RL, Baldes EJ. The Photodynamic Properties of a Particular Hematoporphyrin Derivative [Internet]. Arch Dermatol 1960: 82: 508-516. DOI: ://A1960WG76100005

37Baas P, Mansom I Van, Tinteren H Van et al. Effect of N-acetylcysteine on photofrin-induced skin photosensitivity in patients. Lasers Surg Med 1995: 16: 359-367.

38 Jones LR, Grossweiner LI. Effects of Photofrin on in vivo skin reflectivity. [Internet]. J Photochem Photobiol B 1996: 33: 153-156. DOI: http://www.ncbi.nlm.nih.gov/pubmed/8691356

39Osaki T, Takagi S, Hoshino Y et al. Antitumor effects and blood flow dynamics after photodynamic therapy using benzoporphyrin derivative monoacid ring A in KLN205 and LM8 mouse tumor models. [Internet]. Cancer Lett 2007: 248: 47-57. DOI: http://www.ncbi.nlm.nih.gov/pubmed/16837129

40Osaki T, Takagi S, Hoshino Y et al. Intracellular localization and concentration as well as photodynamic effects of benzoporphyrin derivative monoacid ring A in four types of rodent tumor cells. [Internet]. Cancer Lett 2006: 243: 281-292. DOI: http://www.ncbi.nlm.nih.gov/pubmed/16412570

41Calzavara-Pinton P, Venturini M, Sala R. Photodynamic therapy: update 2006 Part 1: Photochemistry and photobiology [Internet]. J Eur Acad Dermatology Venereol 2007: 21: 293-302. DOI: http://doi.wiley.com/10.1111/j.1468-3083.2006.01902.x

42Sorkhdini P, Moslemi N, Jamshidi S et al. Effect of hydrosoluble chlorine-mediated antimicrobial photodynamic therapy on clinical parameters and cytokine profile in ligature-induced periodontitis in dogs. [Internet]. J Periodontol 2013: 84: 793-800. DOI: http://www.ncbi.nlm.nih.gov/pubmed/22813345

43Lee DJ, Park SY, Oh YT et al. Preparation of chlorine e6-conjugated single-wall carbon nanotube for photodynamic therapy. Macromol Res 2011: 19: 848-852.

44Sessler JL, Miller Ra. Texaphyrins: new drugs with diverse clinical applications in radiation and photodynamic therapy. [Internet]. Biochem Pharmacol 2000: 59: 733-739. DOI: http://www.ncbi.nlm.nih.gov/pubmed/10718331

45Wei W-H, Wang Z, Mizuno T et al. New polyethyleneglycol-functionalized texaphyrins: synthesis and in vitro biological studies. Dalton Trans 2006: 1934-1942.

46Ormond AB, Freeman HS. Dye sensitizers for photodynamic therapy. Materials (Basel) 2013: 6: 817-840.

47Araújo NC, Fontana CR, Gerbi MEM et al. Overall-Mouth Disinfection by Photodynamic Therapy Using Curcumin. Photomed Laser Surg 2012: 30: 96-101.

48Nafiujjaman M, Revuri V, Nurunnabi M et al. Photosensitizer conjugated iron oxide nanoparticles for simultaneous in vitro magneto-fluorescent imaging guided photodynamic therapy [Internet]. Chem Commun 2015: 51: 5687-5690. DOI: http://xlink.rsc.org/?DOI=C4CC10444G

49Lee SJ, Koo H, Jeong H et al. Comparative study of photosensitizer loaded and conjugated glycol chitosan nanoparticles for cancer therapy [Internet]. J Control Release 2011: 152: 21-29. DOI: http://dx.doi.org/10.1016/j.jconrel.2011.03.027

50Cardoso DR, Libardi SH, Skibsted LH. Riboflavin as a photosensitizer. Effects on human health and food quality. Food Funct 2012: 3: 487.

51Vanathi M, Bypareddy R, Panda A. Corneal collagen crosslinking using UVA light and riboflavin for keratoconus. Expert Rev Ophthalmol 2012: 7: 33-44.

52Warren CB, Lohser S, Wene LC et al. Noninvasive fluorescence monitoring of protoporphyrin IX production and clinical outcomes in actinic keratoses following short-contact application of 5-aminolevulinate. [Internet]. J Biomed Opt 2014: 15: 051607. [cited 2014 Oct 29] DOI: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2955723&tool=pmcentrez&rendertype=abstract

53Eshghi H, Sazgarnia A, Rahimizadeh M et al. Protoporphyrin IX-gold nanoparticle conjugates as an efficient photosensitizer in cervical cancer therapy [Internet]. Photodiagnosis Photodyn Ther 2013: 10: 304-312. DOI: http://dx.doi.org/10.1016/j.pdpdt.2013.02.003

54Menezes PFC, Requena MB, Bagnato VS. Optimization of Photodynamic Therapy Using Negative Pressure. [Internet]. Photomed Laser Surg 2014: 32: 1-6. DOI: http://www.ncbi.nlm.nih.gov/pubmed/24730611

55Liu B, Farrell TJ, Patterson MS. A dynamic model for ALA-PDT of skin: simulation of temporal and spatial distributions of ground-state oxygen, photosensitizer and singlet oxygen. [Internet]. Phys Med Biol 2010: 55: 5913-5932. [cited 2014 Oct 31] DOI: http://www.ncbi.nlm.nih.gov/pubmed/20844331

56Triesscheijn M, Baas P, Schellens JHM et al. Photodynamic therapy in oncology. Oncologist 2006: 11: 1034-1044.

57Tanaka M, Kinoshita M, Yoshihara Y et al. Optimal photosensitizers for photodynamic therapy of infections should kill bacteria but spare neutrophils. Photochem Photobiol 2012: 88: 227-232.

58Mattos LHL de, Álvarez LEC, Yamada ALM et al. Effect of phototherapy with light-emitting diodes (890 nm) on tendon repair: an experimental model in sheep [Internet]. Lasers Med Sci 2014: 30: 193-201. DOI: http://link.springer.com/10.1007/s10103-014-1641-1

59Ermertcan AT, Hellings PW, Cingi C. Nonmelanoma skin cancer of the head and neck: nonsurgical treatment. [Internet]. Facial Plast Surg Clin North Am 2012: 20: 445-454. [cited 2015 Jan 12] DOI: http://www.ncbi.nlm.nih.gov/pubmed/23084297

60Besner S, Kabashin A V, Winnik F M et al. Ultrafast laser based “green” synthesis of non-toxic nanoparticles in aqueous solutions [Internet]. Appl Phys A 2008: 93: 955-959. DOI: http://www.springerlink.com/index/10.1007/s00339-008-4773-y

61BVollet-Filho JD, Menezes PFC, Moriyama LT et al. Possibility for a full optical determination of photodynamic therapy outcome. J Appl Phys 2009: 105

62 Oliveira D, Souza D, Assis D et al. Conceitos Fundamentais e Aplicações de Fotossensibilizadores do Tipo Porfirinas, Clorinas e Ftalocianinas em Terapias Fotônicas Basic Concepts and Applications of Porphyrins, Chlorins Phthalocyanines as Photosensitizers in Photonic Therapies Resu. Photonic Therapies Resu 2015: 7: 310-335.

63Grecco C, Buzzá HH, Stringasci MD et al. Single LED-based device to perform widefield fluorescence imaging and photodynamic therapy [Internet]. Proc SPIE 2015: 9531: 953110-953121. DOI: http://dx.doi.org/10.1117/12.2185925

64Bagnato VS, Kurachi C, Ferreira J et al. PDT experience in Brazil: A regional profile [Internet]. Photodiagnosis Photodyn Ther 2005: 2: 107-118. [cited 2014 Mar 22] DOI: http://linkinghub.elsevier.com/retrieve/pii/S157210000500058X

65Ramirez DP, Kurachi C, Inada NM et al. Experience and BCC subtypes as determinants of MAL-PDT response: Preliminary results of a national Brazilian project. [Internet]. Photodiagnosis Photodyn Ther 2014: 11: 22-26. [cited 2014 Mar 24] DOI: http://www.ncbi.nlm.nih.gov/pubmed/24412582

66Buzzá HH, Silva AP Da, Filho JDV et al. Photodynamic Therapy: Progress toward a scientific and clinical network in Latin America [Internet]. Photodiagnosis Photodyn Ther 2015. DOI: http://linkinghub.elsevier.com/retrieve/pii/S157210001530020X

67Buzzá HH, Silva AP Da, Filho JDV et al. Photodynamic Therapy: Progress toward a scientific and clinical network in Latin America [Internet]. Photodiagnosis Photodyn Ther 2015. DOI: http://linkinghub.elsevier.com/retrieve/pii/S157210001530020X

68Oliveira ER de, Inada NM, Ramirez DP et al. Photodynamic therapy for widespread actinic keratosis of the upper limbs: comparison of pain and response using aminolevulinic acid 15% and methyl aminolevulinate 15% through a new light source device [Internet]. Photodiagnosis Photodyn Ther 2015: 12: 375. DOI: http://dx.doi.org/10.1016/j.pdpdt.2015.07.197

69Salvio AG, Oliveira ER de, Ramirez DP et al. Long- term follow-up of nodular basal cell carcinoma after Photodynamic Therapy [Internet]. Photodiagnosis Photodyn Ther 2015: 12: 375. DOI: http://dx.doi.org/10.1016/j.pdpdt.2015.07.195

70Lopez RF, Bentley MV, Delgado-Charro MB et al. Iontophoretic delivery of 5-aminolevulinic acid (ALA): effect of pH. [Internet]. Pharm Res 2001: 18: 311-5. DOI: http://www.ncbi.nlm.nih.gov/pubmed/11442270

71Blanco KC, Moriyama LT, Inada NM et al. Fluorescence guided PDT for optimization of the outcome of skin cancer treatment [Internet]. Front Phys 2015: 3: 1-7. DOI: http://journal.frontiersin.org/article/10.3389/fphy.2015.00030/abstract

72Negosanti L, Pinto V, Sgarzani R et al. Photodynamic therapy with topical aminolevulinic acid. World Journal of Dermatology 2014; (2):6-14

73Allison RR, Downie GH, Cuenca R et al. Photosensitizers in clinical PDT. Photodiagnosis Photodyn Ther 2004: 1: 27-42..

74Zhou X, Pogue BW, Chen B et al. Pretreatment photosensitizer dosimetry reduces variation in tumor response. Int J Radiat Oncol Biol Phys 2006: 64: 1211-1220.

75Zhou X, Pogue BW, Chen B et al. Photosensitizer dosimetry controlled PDT treatment planning reduces inter-individual variability in response to PDT [Internet]. In: Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XV, January 21, 2006 - January 22, 2006. 2006: SPIE. DOI: http://dx.doi.org/10.1117/12.647439

76Patterson MS, Wilson BC, Graff R. In vivo tests of the concept of photodynamic threshold dose in normal rat liver photosensitized by aluminum chlorosulphonated phthalocyanine. Photochem Photobiol 1990: 51: 343-349.

77Schenk A. Lesion size, PDT and classical CNV. Effect of PDT in relation to lesion size. Spektrum der Augenheilkd 2007: 21: 183-186.

78 Szeimies R, Morton C. Photodynamic Therapy for Non-Melanoma Skin Cancer [Internet]. ACTA 2005. [cited 2014 Jul 2] DOI: http://medicaljournals.se/acta/content/download.php?doi=10.1080/00015550510044136

79 Kate Cristina Blanco, Natalia Mayumi Inada et al. Resultados Multicentros. In: Terapia Fotodinânica Dermatológica Programa TFD Brasil. São Carlos, 2015: 313.

80Passos S K, Souza P E de, Soares P K et al. Quantitative approach to skin field cancerization using a nanoencapsulated photodynamic therapy agent: a pilot study. [Internet]. Clin Cosmet Investig Dermatol 2013: 6: 51-59. DOI: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3581285&tool=pmcentrez&rendertype=abstract

81Braathen LR, Morton C a., Basset-Seguin N et al. Photodynamic therapy for skin field cancerization: An international consensus. International Society for Photodynamic Therapy in Dermatology. J Eur Acad Dermatology Venereol 2012: 26: 1063-1066

82Fenske NA, Spencer J, Adam F. Actinic keratoses: past, present and future. J Drugs Dermatol 2010: 9: s45-s49.

83Rigel DS, Stein Gold LF. The importance of early diagnosis and treatment of actinic keratosis. [Internet]. J Am Acad Dermatol 2013: 68: S20-S27. DOI: http://www.ncbi.nlm.nih.gov/pubmed/23228303

84Neto PD, Alchorne M, Michalany N et al. Reduced P53 Staining in Actinic Keratosis is Associated with Squamous Cell Carcinoma: A Preliminary Study. [Internet]. Indian J Dermatol 2013: 58: 325. DOI: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3726892&tool=pmcentrez&rendertype=abstract

85Andrade CT, Vollet-Filho JD, Salvio a G et al. Identification of skin lesions through aminolaevulinic acid-mediated photodynamic detection. [Internet]. Photodiagnosis Photodyn Ther 2014: 11: 409-15. DOI: http://www.ncbi.nlm.nih.gov/pubmed/24892509

86Dora Patricia Ramirez Angarita, Ana Gabriela Sálvio, et al. Lesões pré malignas. In: Terapia Fotodinânica Dermatológica Programa TFD Brasil. São Carlos: 2015: 313.

87 Fontes KBF da C, Leite TC, Miranda AMO et al. Clinical and histopathological outcomes of one session of photodynamic therapy with previous CO2 laser application for actinic cheilitis [Internet]. Photodiagnosis Photodyn Ther 2015: 12: 338. DOI: http://dx.doi.org/10.1016/j.pdpdt.2015.07.056

88 Daniel B, Vanderlei B. Terapia fotodinamica de lesões extensas com fotossensibilizador administrado sistemicamente. In: Terapia Fotodinânica Dermatológica Programa TFD Brasil. São Carlos: 2015: 313.

89Bagnato VS. Terapia Fotodinânica Dermatológica Programa TFD Brasil. 1st ed. São Carlos: 2015.

Peer reviewer:Cheng-Han Lee, MD, Division of Cardiology, Department of Medicine 138 Sheng-Li Road, Tainan, Taiwan.


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