RESUMO
Current treatment for prostate cancer is dependent on the stages of the cancer, recurrence, and genetic factors. Treatment varies from active surveillance or watchful waiting to prostatectomy, chemotherapy, and radiation therapy in combination or alone. Although radical prostate cancer therapy reduces the advancement of the disease and its mortality, the increased disease treatment associated morbidity, erectile dysfunction, and incontinence affect the quality of life of cancer survivors. To overcome these problems, photodynamic therapy (PDT) has previously been investigated using PhotofrinTM as a photosensitizer (PS). However, Photofrin-PDT has shown limitations in treating prostate cancer due to its limited tumor-specificity and the depth of light penetration at 630 nm (the longest wavelength absorption of PhotofrinTM). The results presented herein show that this limitation can be solved by using a near infrared (NIR) compound as a photosensitizer (PS) for PDT and the same agent also acts as a sonosensitizer for SDT (using ultrasound to activate the compound). Compared to light, ultrasound has a stronger penetration ability in biological tissues. Exposing the PS (or sonosensitizer) to ultrasound (US) initiates an electron-transfer process with a biological substrate to form radicals and radical ions (type I reaction). In contrast, exposure of the PS to light (PDT) generates singlet oxygen (type II reaction). Therefore, the reactive oxygen species (ROS) produced by SDT and PDT follow two distinct pathways, i.e., type I (oxygen independent) and type II (oxygen dependent), respectively, and results in significantly enhanced destruction of tumor cells. The preliminary in vitro and in vivo results in a PC3 cell line and tumor model indicate that the tumor specificality of the therapeutic agent(s) can be increased by targeting galectin-1 and galectin-3, known for their overexpression in prostate cancer.
Assuntos
Fotoquimioterapia , Neoplasias da Próstata , Masculino , Humanos , Camundongos , Animais , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Fotoquimioterapia/métodos , Éter de Diematoporfirina , Qualidade de Vida , Neoplasias da Próstata/patologia , Oxigênio , Linhagem Celular TumoralRESUMO
To investigate and compare the pharmacokinetic profile and anti-cancer activity of fluorinated and iodinated photosensitizers (PSs), the 3-(1'-(o-fluorobenzyloxy)ethyl pyropheophorbide and the corresponding meta-(m-) and para (p-) fluorinated analogs (methyl esters and carboxylic acids) were synthesized. Replacing iodine with fluorine in PSs did not make any significant difference in fluorescence and singlet oxygen (a key cytotoxic agent) production. The nature of the delivery vehicle and tumor types showed a significant difference in uptake and long-term cure by photodynamic therapy (PDT), especially in the iodinated PS. An unexpected difference in the pharmacokinetic profiles of fluorinated vs. iodinated PSs was observed. At the same imaging parameters, the fluorinated PSs showed maximal tumor uptake at 2 h post injection of the PS, whereas the iodinated PS gave the highest uptake at 24 h post injection. Among all isomers, the m-fluoro PS showed the best in vivo anti-cancer activity in mice bearing U87 (brain) or bladder (UMUC3) tumors. A direct correlation between the tumor uptake and PDT efficacy was observed. The higher tumor uptake of m-fluoro PS at two hours post injection provides a solid rationale for developing the corresponding 18F-agent (half-life 110 min only) for positron imaging tomography (PET) of those cancers (e.g., bladder, prostate, kidney, pancreas, and brain) where 18F-FDG-PET shows limitations.
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Neoplasias , Fotoquimioterapia , Masculino , Animais , Camundongos , Fármacos Fotossensibilizantes/uso terapêutico , Clorofila A , Fotoquimioterapia/métodos , Neoplasias/tratamento farmacológico , Clorofila/farmacologia , Linhagem Celular TumoralRESUMO
To enhance uptake of photosensitizers by epithelial tumor cells by targeting these to EGFR, pyropheophorbide derivatives were synthesized that had erlotinib attached to different positions on the macrocycle. Although the addition of erlotinib reduced cellular uptake, several compounds showed prolonged cellular retention and maintained photodynamic efficacy. The aim of this study was to identify whether erlotinib moiety assists in tumor targeting through interaction with EGFR and whether this interaction inhibits EGFR kinase activity. The activity of the conjugates was analyzed in primary cultures of human head and neck tumor cells with high-level expression of EGFR, and in human carcinomas grown as xenografts in mice. Uptake of erlotinib conjugates did not correlate with cellular expression of EGFR and none of the compounds exerted EGFR-inhibitory activity. One derivative with erlotinib at position 3, PS-10, displayed enhanced tumor cell-specific retention in mitochondria/ER and improved PDT efficacy in a subset of tumor cases. Moreover, upon treatment of the conjugates with therapeutic light, EGFR-inhibitory activity was recovered that attenuated EGFR signal-dependent tumor cell proliferation. This finding suggests that tumor cell-specific deposition of erlotinib-pyropheophorbides, followed by light triggered release of EGFR-inhibitory activity, may improve photodynamic therapy by attenuating tumor growth that is dependent on EGFR-derived signals.
Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Animais , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Humanos , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Transdução de SinaisRESUMO
Phthalocyanines exhibit superior photoproperties that make them a surely attractive class of photosensitisers for photodynamic therapy of cancer. Several derivatives are at various phases of clinical trials, and efforts have been put continuously to improve their photodynamic efficacy. To this end, various strategies have been applied to develop advanced phthalocyanines with optimised photoproperties, dual therapeutic actions, tumour-targeting properties and/or specific activation at tumour sites. The advantageous properties and potential of phthalocyanines as advanced photosensitisers for photodynamic therapy of cancer are highlighted in this tutorial review.
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Indóis/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/uso terapêutico , Humanos , Indóis/química , Isoindóis , Luz , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismoRESUMO
A series of chlorin-bacteriochlorin dyads (derived from naturally occurring chlorophyll-a and bacteriochlorophyll-a), covalently connected either through the meso-aryl or ß-pyrrole position (position-3) via an ester linkage have been synthesized and characterized as a new class of far-red emitting fluorescence resonance energy transfer (FRET) imaging, and heavy atom-lacking singlet oxygen-producing agents. From systematic absorption, fluorescence, electrochemical, and computational studies, the role of chlorin as an energy donor and bacteriochlorin as an energy acceptor in these wide-band-capturing dyads was established. Efficiency of FRET evaluated from spectral overlap was found to be 95 and 98 % for the meso-linked and ß-pyrrole-linked dyads, respectively. Furthermore, evidence for the occurrence of FRET from singlet-excited chlorin to bacteriochlorin was secured from studies involving femtosecond transient absorption studies in toluene. The measured FRET rate constants, kFRET , were in the order of 1011 â s-1 , suggesting the occurrence of ultrafast energy transfer in these dyads. Nanosecond transient absorption studies confirmed relaxation of the energy transfer product, 1 BChl*, to its triplet state, 3 Bchl*. The 3 Bchl* thus generated was capable of producing singlet oxygen with quantum yields comparable to their monomeric entities. The occurrence of efficient FRET emitting in the far-red region and the ability to produce singlet oxygen make the present series of dyads useful for photonic, imaging and therapy applications.
Assuntos
Transferência Ressonante de Energia de Fluorescência , Porfirinas , Pirróis , Oxigênio SingleteRESUMO
BACKGROUND AND OBJECTIVES: In this study, we evaluated the impact of hyperthermia in photosensitizing efficacy of 3-[(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH or Photochlor) for the treatment of cancer by photodynamic therapy (PDT). STUDY DESIGN/MATERIALS AND METHODS: The outcome of both whole body hyperthermia (WBH) and local hyperthermia (LH) in combination with HPPH-PDT was determined in BALB/c and nude mice bearing Colon26 and U87 tumors, respectively. LH was performed by using an indigenously designed heating device, that was heated to the required temperature using a circulating water bath. The device which has flexible membrane on one side was placed on skin above the tumor. The temperature of the tumor was monitored using a thermocouple sensor placed on the surface of the tumor capable of measuring the temperature within 0.1°C. Uptake of the photosensitizer in tumors was determined by fluorescence using an IVIS or a Nuance Imaging System. The PDT was performed by exposing the tumors to 665 nm laser loght, (135 J/cm2 , 75 mW/cm2 ) at the maximal uptake time of HPPH. Tumor size was measured daily using vernier calipers. RESULTS: The improved PDT efficacy (long-term percentage tumor cure) in combination with hyperthermia is possible due to an increase in tumor-uptake of the photosensitizer (PS), confirmed by in vivo fluorescence imaging and also by increased tumor perfusion and decreased hypoxia as have been reported previously (Sen et al. [2011] Cancer Res. 71:3872-3880 In Vivo. 20:689-695). Interestingly, compared to whole body hyperthermia, the 14 C- HPPH biodistribution data under local hyperthermia showed similar tumor-uptake in BALB/c mice bearing Colon26 tumors, but significantly lower uptake in other organs and in the blood. CONCLUSION: Our study demonstrates that both, fever range whole body and local hyperthermia in combination with HPPH-PDT enhances the long-term tumor cure of BALB/c and nude mice implanted with Colon26 and U87 tumors respectively. Lasers Surg. Med. 50:506-512, 2018. © 2018 Wiley Periodicals, Inc.
Assuntos
Clorofila/análogos & derivados , Neoplasias do Colo/terapia , Hipertermia Induzida/métodos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Animais , Clorofila/farmacologia , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Advances in in vivo stability and preferential tumor uptake of cancer nanomedicine are warranted for effective chemotherapy. Here, we describe a novel nanoformulation using an unconventional polymeric tubule-forming phospholipid, DC8,9PC. We report that DC8,9PC transitions to stable vesicles (LNPs) in the presence of PEGylated lipid (DSPE-PEG2000); the resulting DC8,9PC:DSPE-PEG2000 LNPs efficiently included a hydrophobic PDT drug, HPPH. Remarkably, these LNPs incorporated unusually high DSPE-PEG2000 concentrations; LNP10-HPPH and LNP20-HPPH (10 & 20 mol% PEGylated lipid, respectively) exhibited >90% serum stability at 37⯰C. Increased PEGylation in the LNPs correlated with enhanced tumor accumulation in intravenously injected HT29 tumor mouse xenographs. Colon-26 bearing BALB/c mice, intravenously injected with LNP20-HPPH showed superior PDT efficacy and animal survival (no tumor recurrence up to 100 days) as compared to a formulation currently used in clinical trials. Taken together, we present a simple stealth binary lipid nanosystem with enhanced efficiency of tumor accumulation and superior therapeutic efficacy.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Fosfolipídeos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem , Polímeros/química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Portadores de Fármacos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Photodynamic therapy (PDT) of cancer is dependent on three primary components: photosensitizer (PS), light and oxygen. Because these components are interdependent and vary during the dynamic process of PDT, assessing PDT efficacy may not be trivial. Therefore, it has become necessary to develop pre-treatment planning, on-line monitoring and dosimetry strategies during PDT, which become more critical for two or more chromophore systems, for example, PS-CD (Photosensitizer-Cyanine dye) conjugates developed in our laboratory for fluorescence-imaging and PDT of cancer. In this study, we observed a significant impact of variable light dosimetry; (i) high light fluence and fluence rate (light dose: 135 J/cm², fluence rate: 75 mW/cm²) and (ii) low light fluence and fluence rate (128 J/cm² and 14 mW/cm² and 128 J/cm² and 7 mW/cm²) in photobleaching of the individual chromophores of PS-CD conjugates and their long-term tumor response. The fluorescence at the near-infrared (NIR) region of the PS-NIR fluorophore conjugate was assessed intermittently via fluorescence imaging. The loss of fluorescence, photobleaching, caused by singlet oxygen from the PS was mapped continuously during PDT. The tumor responses (BALB/c mice bearing Colon26 tumors) were assessed after PDT by measuring tumor sizes daily. Our results showed distinctive photobleaching kinetics rates between the PS and CD. Interestingly, compared to higher light fluence, the tumors exposed at low light fluence showed reduced photobleaching and enhanced long-term PDT efficacy. The presence of NIR fluorophore in PS-CD conjugates provides an opportunity of fluorescence imaging and monitoring the photobleaching rate of the CD moiety for large and deeply seated tumors and assessing PDT tumor response in real-time.
Assuntos
Clorofila/análogos & derivados , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/tratamento farmacológico , Glicoconjugados/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Radiometria/métodos , Animais , Carbocianinas/química , Carbocianinas/farmacocinética , Clorofila/síntese química , Clorofila/farmacologia , Neoplasias do Colo/patologia , Relação Dose-Resposta à Radiação , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Glicoconjugados/síntese química , Indóis/química , Indóis/farmacocinética , Raios Infravermelhos , Camundongos , Camundongos Endogâmicos BALB C , Imagem Óptica/métodos , Fotodegradação , Fotoquimioterapia/instrumentação , Fármacos Fotossensibilizantes/síntese química , Propionatos/química , Propionatos/farmacocinética , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo , Espectrometria de Fluorescência/métodos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Herein we report the syntheses and comparative photophysical, electrochemical, in vitro, and in vivo biological efficacy of 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-cyanine dye (HPPH-CD) and the corresponding indium (In), gallium (Ga), and palladium (Pd) conjugates. The insertion of a heavy metal in the HPPH moiety makes a significant difference in FRET (Förster resonance energy transfer) and electrochemical properties, which correlates with singlet oxygen production [a key cytotoxic agent for photodynamic therapy (PDT)] and long-term in vivo PDT efficacy. Among the metalated analogs, the In(III) HPPH-CD showed the best cancer imaging and PDT efficacy. Interestingly, in contrast to free base HPPH-CD, which requires a significantly higher therapeutic dose (2.5 µmol/kg) than imaging dose (0.3 µmol/kg), the corresponding In(III) HPPH-CD showed excellent imaging and therapeutic potential at a remarkably low dose (0.3 µmol/kg) in BALB/c mice bearing Colon26 tumors. A comparative study of metalated and corresponding nonmetalated conjugates further confirmed that STAT-3 dimerization can be used as a biomarker for determining the level of photoreaction and tumor response.
Assuntos
Metais/química , Neoplasias Experimentais/patologia , Fotoquimioterapia , Porfirinas/química , Animais , Transferência Ressonante de Energia de Fluorescência , Camundongos , Espectrofotometria UltravioletaRESUMO
We have previously shown that the (124)I-analog of methyl 3-(1'-m-iodobenzyloxy) ethyl-3-devinyl-pyropheophorbide-a derived as racemic mixture from chlorophyll-a can be used for PET (positron emission tomography)-imaging in animal tumor models. On the other hand, as a non-radioactive analog, it showed excellent fluorescence and photodynamic therapy (PDT) efficacy. Thus, a single agent in a mixture of radioactive ((124)I-) and non-radioactive ((127)I) material can be used for both dual-imaging and PDT of cancer. Before advancing to Phase I human clinical trials, we evaluated the activity of the individual isomers as well as the impact of a chiral center at position-3(1) in directing in vitro/in vivo cellular uptake, intracellular localization, epithelial tumor cell-specific retention, fluorescence/PET imaging, and photosensitizing ability. The results indicate that both isomers (racemates), either as methyl ester or carboxylic acid, were equally effective. However, the methyl ester analogs, due to subcellular deposition into vesicular structures, were preferentially retained. All derivatives containing carboxylic acid at the position-17(2) were noted to be substrate for the ABCG2 (a member of the ATP binding cassette transporters) protein explaining their low retention in lung tumor cells expressing this transporter. The compounds in which the chirality at position-3 has been substituted by a non-chiral functionality showed reduced cellular uptake, retention and lower PDT efficacy in mice bearing murine Colon26 tumors.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Clorofila/análogos & derivados , Neoplasias do Colo/radioterapia , Neoplasias Pulmonares/radioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Transporte Biológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/ultraestrutura , Linhagem Celular Tumoral , Clorofila/síntese química , Clorofila/química , Clorofila/farmacologia , Clorofila A , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias do Colo/ultraestrutura , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Radioisótopos do Iodo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Imagem Molecular/métodos , Transplante de Neoplasias , Especificidade de Órgãos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/síntese química , Spirulina/química , Estereoisomerismo , Carga Tumoral/efeitos dos fármacosRESUMO
We report herein a simple and efficient approach to the synthesis of a variety of meso-substituted purpurinimides. The reaction of meso-substituted purpurinimide with N-bromosuccinimide regioselectively introduced a bromo functionality at the 20-position, which on further reaction with a variety of boronic acids under Suzuki reaction conditions yielded the corresponding meso-substituted analogues. Interestingly, the free base and the metalated analogues showed remarkable differences in photosensitizing efficacy (PDT) and tumor-imaging ability. For example, the free-base conjugate showed significant in vitro PDT efficacy, but limited tumor avidity in mice bearing tumors, whereas the corresponding Ni(II) derivative did not produce any cell kill, but showed excellent tumor-imaging ability at a dose of 0.3â µmol kg(-1) at 24, 48, and 72â h post-injection. The limited PDT efficacy of the Ni(II) analogue could be due to its inability to produce singlet oxygen, a key cytotoxic agent required for cell kill in PDT. Based on electrochemical and spectroelectrochemical data in DMSO, the first one-electron oxidation (0.52â V vs. SCE) and the first one-electron reduction (-0.57-0.67â V vs. SCE) of both the free base and the corresponding Ni(II) conjugates are centered on the cyanine dye, whereas the second one-electron reduction (-0.81â V vs. SCE) of the two conjugates is assigned to the purpurinimide part of the molecule. Reduction of the cyanine dye unit is facile and occurs prior to reduction of the purpurinimide group, which suggests that the cyanine dye unit as an oxidant could be the driving force for quenching of the excited triplet state of the molecules. An interaction between the cyanine dye and the purpurinimide group is clearly observed in the free-base conjugate, which compares with a negligible interaction between the two functional groups in the Ni(II) conjugate. As a result, the larger HOMO-LUMO gap of the free-base conjugate and the corresponding smaller quenching constant is a reason to decrease the intramolecular quenching process and increase the production of singlet oxygen to some degree.
Assuntos
Carbocianinas/síntese química , Níquel/química , Fármacos Fotossensibilizantes/síntese química , Porfirinas/síntese química , Animais , Bromosuccinimida/química , Carbocianinas/química , Fluorescência , Camundongos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Imagem Óptica , Oxirredução , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Porfirinas/química , Oxigênio Singlete/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
CONTEXT: Ultrasound-guided internal jugular vein (IJV) cannulation is known for increasing success rate and decreasing rate of complications. The ultrasound image can be used as a real time image during cannulation or to prelocate the IJV before attempting cannulation. AIMS: This study compares both the ultrasound-guided technique with the classical anatomical landmark technique (central approach) for right IJV cannulation in terms of success rate, complications, and time for cannulation. SETTINGS AND DESIGN: A prospective, randomized, observational study was conducted at a tertiary care hospital. MATERIAL AND METHODS: One hundred twenty patients requiring IJV cannulation were included in this study and were randomly allocated in three groups. Number of attempts, success rate, venous access time, catheterization time, and complications were observed in each group. STATISTICAL ANALYSIS USED: Statistical analysis was performed using STATA-9 software. Demographic data were compared using one-way analysis of variance (ANOVA). Nonparametric data were compared using the Kruskall-Wallis test, and multiple comparisons were done applying The Mann-Whitney test for individual pairs of groups. Nominal data were compared by applying the Chi-square test and Fisher exact test. RESULTS: Successful cannulation (≤3 attempt) was achieved in 90.83% of patients without any statistical significant difference between the groups. Venous access time and catheterization time was found to be significantly less in both the ultrasound groups than the anatomical land mark group. Number of attempts and success in first attempt was similar between the groups. CONCLUSIONS: Both the ultrasound techniques are found to be better than the anatomical landmark technique. Further, ultrasound-guided prelocation was found to be as effective as ultrasound guided real-time imaging technique for right IJV cannulation.
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Guest Editors Pui-Chi Lo, Dennis Ng, Ravindra Pandey, and Petr Zimcik introduce the Special Collection on Photodynamic Therapy and give an overview of the developments and challenges in this exciting field.
Assuntos
Neoplasias , Fotoquimioterapia , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Photobac is a near infrared photosensitizer (PS) derived from naturally occurring bacteriochlorophyll- a, with a potential for treating a variety of cancer types (U87, F98 and C6 tumor cells in vitro). The main objective of the studies presented herein was to evaluate the efficacy, toxicity and pharmacokinetic profile of Photobac in animals (mice, rats and dogs) and submit these results to the United States Food and Drug Administration (US FDA) for its approval to initiate Phase I human clinical trials of glioblastoma, a deadly cancer disease with no long term cure. The photodynamic therapy (PDT) efficacy of Photobac was evaluated in mice subcutaneously implanted with U87 tumors, and in rats bearing C6 tumors implanted in brain. In both tumor types, the Photobac-PDT was quite effective. The long-term cure in rats was monitored by magnetic resonance imaging (MRI) and histopathology analysis. A detailed pharmacology, pharmacokinetics and toxicokinetic study of Photobac was investigated in both non-GLP and GLP facilities at variable doses following the US FDA parameters. Safety Pharmacology studies suggest that there is no phototoxicity, cerebral or retinal toxicity with Photobac. No metabolites of Photobac were observed following incubation in rat, dog, mini-pig and human hepatocytes. Based on current biological data, Photobac-IND received the approval for Phase-I human clinical trials to treat Glioblastoma (brain cancer), which is currently underway at our institute. Photobac has also received an orphan drug status from the US FDA, because of its potential for treating Glioblastoma as no effective treatment is currently available for this deadly disease.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Fotoquimioterapia , Ratos , Cães , Animais , Camundongos , Humanos , Suínos , Bacterioclorofilas/uso terapêutico , Glioblastoma/patologia , Fotoquimioterapia/métodos , Bacterioclorofila A/uso terapêutico , Porco Miniatura , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Modelos AnimaisRESUMO
A series of new bacteriochlorins was synthesized using 13(2)-oxo-bacteriopyropheophorbide a (derived from bacteriochlorophyll a) as a starting material, which on reacting with o-phenylenediamine and 1,10-diaminonaphthalene afforded highly conjugated annulated bacteriochlorins with fused quinoxaline, benzimidazole, and perimidine rings, respectively. The absorption spectra of these novel bacteriochlorins demonstrated remarkably red-shifted intense Q(y) absorption bands observed in the range of 816-850 nm with high molar extinction coefficients (89,900-136,800). Treatment of 13(2)-oxo-bacteriopyropheophorbide a methyl ester with diazomethane resulted in the formation of bacterioverdins containing a fused six-membered methoxy-substituted cyclohexenone (verdin) as an isomeric mixture. The pure isomers which exhibit long-wavelength absorptions in the near-IR region (865-890 nm) are highly stable at room temperature with high reactivity with O(2) at the triplet photoexcited state and favorable redox potential and could be potential candidates for use as photosensitizers in photodynamic therapy (PDT).
Assuntos
Bacterioclorofila A/química , Bacterioclorofila A/síntese química , Porfirinas/química , Porfirinas/síntese química , Absorção , Eletroquímica , Estrutura Molecular , Fotoquímica , Fotoquimioterapia , Fármacos Fotossensibilizantes , Teoria Quântica , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
We report a novel post-loading approach for constructing a multifunctional biodegradable polyacrylamide (PAA) nanoplatform for tumor-imaging (fluorescence) and photodynamic therapy (PDT). This approach provides an opportunity to post-load the imaging and therapeutic agents at desired concentrations. Among the PAA nanoparticles, a formulation containing the photosensitizer, HPPH [3-(1'-hexyloxyethyl)pyropheophorbide-a], and the cyanine dye in a ratio of 2:1 minimized the undesirable quenching of the HPPH electronic excitation energy because of energy migration within the nanoparticles and/or Förster (fluorescence) resonance energy transfer (FRET) between HPPH and cyanine dye. An excellent tumor-imaging (NIR fluorescence) and phototherapeutic efficacy of the nanoconstruct formulation is demonstrated. Under similar treatment parameters the HPPH in 1% Tween 80/5% aqueous dextrose formulation was less effective than the nanoconstruct containing HPPH and cyanine dye in a ratio of 2 to 1. This is the first example showing the use of the post-loading approach in developing a nanoconstructs for tumor-imaging and therapy.
Assuntos
Resinas Acrílicas/síntese química , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Corantes Fluorescentes , Nanocápsulas/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Linhagem Celular Tumoral , Meios de Contraste/uso terapêutico , Difusão , Corantes Fluorescentes/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanocápsulas/química , Imagem Óptica/métodos , Fotoquimioterapia/métodos , Resultado do TratamentoRESUMO
In recent years several review articles and books have been published on the use of porphyrin-based compounds in photodynamic therapy (PDT). This critical review is focused on (i) the basic concept of PDT, (ii) advantages of long-wavelength absorbing photosensitizers (PS), (iii) a brief discussion on recent advances in developing PDT agents, and (iv) the various synthetic strategies designed at the Roswell Park Cancer Institute, Buffalo, for developing highly effective long-wavelength PDT agents and their utility in constructing the conjugates with tumor-imaging and therapeutic potential (Theranostics). The clinical status of certain selected PDT agents is also summarized (205 references).
Assuntos
Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Porfirinas/química , Animais , Clorofila/análogos & derivados , Clorofila/química , Clorofila/uso terapêutico , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêuticoRESUMO
Pheophorbide-based photosensitizers have demonstrated tumor cell-specific retention. The lead compound 3-[1'-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH) in a clinical trial for photodynamic therapy of head and neck cancer lesions indicated a complete response in 80% of patients. The question arises whether the partial response in 20% of patients is due to inefficient retention of photosensitizers by tumor cells and, if so, can the photosensitizer preference of individual cancer cases be identified prior to photodynamic therapy. This study determined the specificity of head and neck cancer cells and tumor tissues for the uptake and retention of diffusible pheophorbides differing in peripheral groups on the macrocycle that contribute to cellular binding. The relationship between photosensitizer level and light-mediated photoreaction was characterized to identify markers for predicting the effectiveness of photodynamic therapy in situ. The experimental models were stromal and epithelial cells isolated from head and neck tumor samples and integrated into monotypic tissue cultures, reconstituted three-dimensional co-cultures, and xenografts. Tumor cell-specific photosensitizer retention patterns were identified, and a procedure was developed to allow the diagnostic evaluation of HPPH binding by tumor cells in individual cancer cases. The findings of this study may assist in designing conditions for photosensitizer application and photodynamic therapy of head and neck cancer lesions optimized for each patient's case.
Assuntos
Neoplasias de Cabeça e Pescoço , Fotoquimioterapia , Clorofila/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
We have previously shown that a radioactive (123I)-analog of methyl 3-(1'-(iodobexyloxy) ethyl-3-devinylpyropheophorbide-a (PET-ONCO), derived from chlorophyll-a can be used for positron emission tomography (PET) imaging of a variety of tumors, including those where 18F-FDG shows limitations. In this study, the photodynamic therapy (PDT) efficacy of the corresponding non-radioactive photosensitizer (PS) was investigated in a variety of tumor types (NSCLC, SCC, adenocarcinoma) derived from lung cancer patients in mice tumor models. The in vitro and in vivo efficacy was also investigated in combination with doxorubicin, and a significantly enhanced long-term tumor response was observed. The toxicity and toxicokinetic profile of the iodinated PS was also evaluated in male and female Sprague-Dawley rats and Beagle dog at variable doses (single intravenous injections) to assess reversibility or latency of any effects over a 28-day dose free period. The no-observed-adverse-effect (NOAEL) of the PS was considered to be 6.5 mg/kg for male and female rats, and for dogs, 3.45 mg/kg, the highest dose levels evaluated, respectively. The corresponding plasma Cmax and AYClast for male and female rats were 214,000 and 229,000 ng/mL and 3,680,000 and 3,810,000 h * ng/mL, respectively. For male and female dogs, the corresponding plasma Cmax and AYClast were 76,000 and 92,400 ng/mL and 976,000 and 1,200,000 h * ng/mL, respectively.