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1.
J Photochem Photobiol B ; 223: 112301, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34492530

RESUMO

Prostate cancer (PCa) is the second most frequent cancer diagnosed in men worldwide. Among the common treatment options, photodynamic therapy (PDT) is being considered a promising local therapy to treat this cancer. Although PDT is an established treatment modality approved for several types of cancer, the low solubility, the reduced tumor selectivity, the absorption in the therapeutic window and the poor clearance from the body of the currently approved photosensitizers (PS) hampers its wide clinical application. In this regard, herein we synthesized three fluorinated porphyrinoid derivatives and entrapped them into polyvinylpyrrolidone (PVP) to prevent their aggregation and preserve their desirable photophysical properties under the physiological environment. In vitro studies revealed the negligible dark cytotoxicity of all PVP formulations (PS1@PVP, PS2@PVP and PS3@PVP) at the tested concentrations (5.0 to 20 µM), but also confirmed the significant photodynamic effect of PS2@PVP and PS3@PVP towards the PCa cell line PC-3, upon red light irradiation at an irradiance of 17.6 mW.cm-2. To provide insight into the underlying mechanisms of cell death under PDT treatment induced by PS2@PVP and PS3@PVP, their intracellular localization in PC-3 cells was firstly investigated by confocal microscopy. Since both PS2@PVP and PS3@PVP nanoparticles were mainly localized in mitochondria, the involvement of this organelle in PDT-induced apoptosis mediated by both formulations was further explored. Western blot analysis revealed that PDT treatment of PC-3 cells with either PS2@PVP or PS3@PVP resulted in the reduction of the expression level of the anti-apoptotic protein Bcl-2. As the photodamage to Bcl-2 after PDT with PS2@PVP and PS3@PVP was accompanied by the further activation of pro-caspase-3, we assumed that upon irradiation the photogenerated reactive oxygen species (ROS) were able to activate a caspase-dependent apoptotic response as a consequence of a post-mitochondrial event. Taken together, these findings demonstrate that among the tested fluorinated porphyrinoids, PS2@PVP and, particularly, PS3@PVP, are significantly more effective in overall PC-3 cell killing than PS1@PVP, thus highlighting their great potential as therapeutic agents for PCa.


Assuntos
Apoptose/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Composição de Medicamentos , Humanos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nanopartículas/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Porfirinas/uso terapêutico , Povidona/química , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
2.
J Photochem Photobiol B ; 222: 112258, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34399205

RESUMO

Photodynamic therapy (PDT) is an approved therapeutic approach and an alternative to conventional chemotherapy for the treatment of several types of cancer with the advantages of reducing the side effects and developing resistance mechanisms. Here, was evaluated the photosensitization capabilities of 5,10,15,20-tetrakis[4-(pyridinium-1-yl-methyl)phenyl]porphyrin (3), its N-confused isomer (4) and of the neutral precursors (1) and (2) and the results were compared with the ones obtained with the cationic 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP). Both regular porphyrin derivatives 1 and 3 showed higher efficiency to generate singlet oxygen than TMPyP. The PDT assays towards MCF-7 cells under red light irradiation (λ > 640 nm, 23.7 mW cm-2) demonstrated that the cationic porphyrin 3 is an efficient photosensitizer to kill MCF-7 breast cancer cells. The study of the cell death mechanisms induced by the photodynamic process showed that the studied porphyrin 3 and TMPyP caused cell death by autophagic flux and necrosis.


Assuntos
Apoptose/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Apoptose/efeitos da radiação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Humanos , Luz , Células MCF-7 , Microscopia Confocal , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Porfirinas/uso terapêutico , Oxigênio Singlete/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445798

RESUMO

The bacterium Legionella pneumophila is still one of the probable causes of waterborne diseases, causing serious respiratory illnesses. In the aquatic systems, L. pneumophila exists inside free-living amoebae or can form biofilms. Currently developed disinfection methods are not sufficient for complete eradication of L. pneumophila biofilms in water systems of interest. Photodynamic inactivation (PDI) is a method that results in an antimicrobial effect by using a combination of light and a photosensitizer (PS). In this work, the effect of PDI in waters of natural origin and of different hardness, as a treatment against L. pneumophila biofilm, was investigated. Three cationic tripyridylporphyrins, which were previously described as efficient agents against L. pneumophila alone, were used as PSs. We studied how differences in water hardness affect the PSs' stability, the production of singlet oxygen, and the PDI activity on L. pneumophila adhesion and biofilm formation and in biofilm destruction. Amphiphilic porphyrin showed a stronger tendency for aggregation in hard and soft water, but its production of singlet oxygen was higher in comparison to tri- and tetracationic hydrophilic porphyrins that were stable in all water samples. All three studied porphyrins were shown to be effective as PDI agents against the adhesion of the L. pneumophila to polystyrene, against biofilm formation, and in the destruction of the formed biofilm, in their micromolar concentrations. However, a higher number of dissolved ions, i.e., water hardness, generally reduced somewhat the PDI activity of all the porphyrins at all tested biofilm growth stages.


Assuntos
Biofilmes/efeitos dos fármacos , Cátions/farmacologia , Dureza/efeitos dos fármacos , Legionella pneumophila/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Água/química , Amoeba/microbiologia , Oxigênio Singlete/farmacologia , Microbiologia da Água
4.
Cell Prolif ; 54(9): e13101, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34296479

RESUMO

OBJECTIVE: Osteosarcoma (OS) is characterized by high levels of the tumour-associated inflammatory microenvironment. Moreover, in approximately 60% of OS, telomere length is maintained by alternative lengthening of telomeres (ALT) pathway. Whether the ALT pathway can be exploited for OS therapeutic treatment and how the OS inflammatory microenvironment influences the anti-cancer drug effect remains unknown. Here, we examined the biological effects of TMPyP4 and cisplatin in the inflammatory microenvironment of OS cells. MATERIALS AND METHODS: Immunofluorescence in situ hybridization (IF-FISH) and C-circle experiments were used to detect the G-quadruplex and ALT activity. The redox potential of single guanine, G-quadruplex and G-quadruplex/TMPyP4 was evaluated by the lowest unoccupied molecular orbital energy (LUMO), zeta potential and cyclic voltammetry. Cell viability, flow cytometry and apoptosis, Western blot, comet assay, adhesion, transwell and scratch experiments were performed to compare the anti-tumour proliferation and migration effects of TMPyP4 and cisplatin in the inflammatory microenvironment. RESULTS: This study indicated that compared with cisplatin, TMPyP4 could induce the formation of human telomeres and FAK G-quadruplex in vitro and in vivo, and TMPyP4-treated OS cells showed fewer extrachromosomal C-circles and fewer ALT-associated promyelocytic leukaemia bodies. Consequently, the ALT activity and FAK-related cell migration were suppressed by TMPyP4. Mechanistically, the formation of G-quadruplex resulted in both lower redox potential than G within the genome and FAK transcription inhibition, and TMPyP4 could enhance this phenomenon, especially in the inflammatory microenvironment. CONCLUSIONS: Our results reveal that TMPyP4 is more suitable for OS treatment than cisplatin.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Quadruplex G/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Porfirinas/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Osteossarcoma/metabolismo , Telomerase/metabolismo , Telômero/efeitos dos fármacos
5.
Photochem Photobiol Sci ; 20(8): 985-996, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275118

RESUMO

Chronic lung infections are among the most diffused human infections, being often associated with multidrug-resistant bacteria. In this framework, the European project "Light4Lungs" aims at synthesizing and testing an inhalable light source to control lung infections by antimicrobial photoinactivation (aPDI), addressing endogenous photosensitizers only (porphyrins) in the representative case of S. aureus and P. aeruginosa. In the search for the best emission characteristics for the aerosolized light source, this work defines and calculates the photo-killing action spectrum for lung aPDI in the exemplary case of cystic fibrosis. This was obtained by applying a semi-theoretical modelling with Monte Carlo simulations, according to previously published methodology related to stomach infections and applied to the infected trachea, bronchi, bronchioles and alveoli. In each of these regions, the two low and high oxygen concentration cases were considered to account for the variability of in vivo conditions, together with the presence of endogenous porphyrins and other relevant absorbers/diffusers inside the illuminated biofilm/mucous layer. Furthermore, an a priori method to obtain the "best illumination wavelengths" was defined, starting from maximizing porphyrin and light absorption at any depth. The obtained action spectrum is peaked at 394 nm and mostly follows porphyrin extinction coefficient behavior. This is confirmed by the results from the best illumination wavelengths, which reinforces the robustness of our approach. These results can offer important indications for the synthesis of the aerosolized light source and definition of its most effective emission spectrum, suggesting a flexible platform to be considered in further applications.


Assuntos
Espectro de Ação , Antibacterianos/química , Antibacterianos/farmacologia , Pulmão/microbiologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Aerossóis , Biofilmes/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Porfirinas/química , Porfirinas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos da radiação , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/efeitos da radiação
6.
ACS Infect Dis ; 7(8): 2299-2309, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34314150

RESUMO

The emergence of drug-resistant pathogens causes the greatest challenge for drug development research. Recently, gallium(III)-based compounds have received great attention as novel antimicrobial agents against drug-resistant pathogens. Here, we synthesized a new ß-cyclodextrin Ga nanoparticle (CDGaTP) using Ga tetraphenylporphyrin (GaTP, a hemin analogue) and ß-cyclodextrin. The newly synthesized nanoparticle was nontoxic and efficient at a single dose, showing sustained drug release for 15 days in vitro. CDGaTP's activity with transferrin or lactoferrin was tested, and synergism in activity was observed against nontuberculosis mycobacteria (NTM), Mycobacterium avium (M. avium), and Mycobacteroides abscessus. Human serum albumin (HSA) decreased the efficacy of both GaTP and CDGaTP in a concentration-dependent manner. The NTMs incubated with GaTP or CDGaTP significantly produced reactive oxygen species (ROS), indicating potential inhibition of antioxidant enzymes, such as catalase. The single-dose CDGaTP displayed a prolonged intracellular inhibitory activity in an in vitro macrophage infection model against both NTMs. In addition, CDGaTP, not GaTP, was effective in a murine lung M. avium infection model when delivered via intranasal administration. These results suggest that CDGaTP provides new opportunities for the development of gallium-porphyrin based antibiotics.


Assuntos
Gálio , Mycobacterium abscessus , Porfirinas , beta-Ciclodextrinas , Animais , Antibacterianos/farmacologia , Gálio/farmacologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium avium , Porfirinas/farmacologia
7.
Biofouling ; 37(6): 656-665, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34304642

RESUMO

Antimicrobial photodynamic therapy (aPDT) has been considered as a potential alternative to antibiotics for the treatment of biofilm infections. There is evidence that an additional H2O2 enhances the antimicrobial efficacy of aPDT. However, the minimum H2O2 concentration to achieve this synergistic effect is unclear. A saliva-derived multi-species biofilm was treated with the photosensitizer chlorin e6 (Ce6, 50 µM), H2O2 (0.3, 3.3, 33.3 mM), or their combination for 5 min, followed by no irradiation or irradiation at 15 J (cm2)-1 (λ = 450 nm or 660 nm), with or without oxygen. Biofilm viability and metabolic activity were evaluated. The combination of 33.3 mM H2O2 and Ce6-aPDT strongly enhanced antimicrobial efficacy compared with either component alone, irrespective of oxygen availability and irradiation wavelength. In particular, the combination resulted in a 6.6-log colony forming unit (CFU) reduction anaerobically under blue irradiation. This combination is a promising treatment for biofilm infections, especially those thriving in an anaerobic microenvironment.


Assuntos
Anti-Infecciosos , Fotoquimioterapia , Porfirinas , Anti-Infecciosos/farmacologia , Biofilmes , Peróxido de Hidrogênio/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia
9.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203767

RESUMO

The rapid growth of drug-resistant bacteria all over the world has given rise to a major research challenge, namely a search for alternative treatments to which bacteria will be unable to develop resistance. Photodynamic therapy is an approach of this kind. It involves the use of photosensitizers in combination with visible light at a certain wavelength to excite the former and generate reactive oxygen species. Various synthetic heterocyclic compounds are used as photosensitizers. Of these, derivatives of natural chlorophylls have a special place due to their properties. This review deals with the use of such compounds in antimicrobial PDT.


Assuntos
Antibacterianos/farmacologia , Clorofila/farmacologia , Fotoquimioterapia , Sequência de Aminoácidos , Antibacterianos/química , Cátions , Clorofila/química , Porfirinas/farmacologia
10.
Nanoscale ; 13(27): 11953-11962, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34212166

RESUMO

Chlorin e6 (Ce6) is a widely utilized photosensitizer in photodynamic therapy (PDT) against tumor growth, but its hydrophobic feature and the hypoxia in the tumor microenvironment greatly compromise its therapeutic efficacy. To address the issues, here we designed a new Ce6 derivative (TCe6) by coupling Ce6 with amphiphilic d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), endowing Ce6 with an excellent amphiphilic feature. In particular, the overall reactive oxygen species (ROS) generation by TCe6 was significantly enhanced because TPGS could interact with mitochondrial complex II to induce extra ROS production, amplifying the total ROS production under PDT. Inspired by the unique property of α-cyano-4-hydroxycinnamate (CHC) in regulating lactate metabolism to spare more intracellular oxygen for PDT, TCe6 was further co-assembled with CHC to construct TCe6/CHC nanoparticles (NPs) for addressing the insufficient oxygen issue in PDT. The as-prepared TCe6/CHC NPs not only increased the efficiency of cell internalization but also improved the solubility and stability of Ce6 and CHC. Thanks to the extra ROS production by the TPGS unit, the amphiphilic feature of TCe6 and the CHC-mediated hypoxia microenvironment, the TCe6/CHC NPs demonstrated excellent PDT against tumor growth. This work provided a versatile strategy to solve the current bottleneck in photosensitizer-based PDT, holding great promise for the design of advanced photodynamic nanoplatforms.


Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Lactatos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia
11.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202773

RESUMO

In recent years, antimicrobial photodynamic therapy (aPDT) has received increasing attention as a promising tool aimed at both treating microbial infections and sanitizing environments. Since biofilm formation on biological and inert surfaces makes difficult the eradication of bacterial communities, further studies are needed to investigate such tricky issue. In this work, a panel of 13 diaryl-porphyrins (neutral, mono- and di-cationic) was taken in consideration to photoinactivate Pseudomonas aeruginosa. Among cationic photosensitizers (PSs) able to efficiently bind cells, in this study two dicationic showed to be intrinsically toxic and were ruled out by further investigations. In particular, the dicationic porphyrin (P11) that was not toxic, showed a better photoinactivation rate than monocationic in suspended cells. Furthermore, it was very efficient in inhibiting the biofilms produced by the model microorganism Pseudomonas aeruginosa PAO1 and by clinical strains derived from urinary tract infection and cystic fibrosis patients. Since P. aeruginosa represents a target very difficult to inactivate, this study confirms the potential of dicationic diaryl-porphyrins as photo-activated antimicrobials in different applicative fields, from clinical to environmental ones.


Assuntos
Biofilmes/efeitos dos fármacos , Biofilmes/efeitos da radiação , Luz , Porfirinas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/efeitos da radiação , Antibacterianos/química , Antibacterianos/farmacologia , Cátions , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química
12.
Chem Commun (Camb) ; 57(59): 7296-7299, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34223569

RESUMO

A chlorine e6 (Ce6) and curcumin (Cur) based self-delivery nanomedicine (CeCu) is prepared for chemotherapy sensitized photodynamic therapy (PDT). The chemotherapeutic agent of Cur could inhibit the TrxR activity to destroy the cellular ROS-defence system for enhanced PDT, which provides synergistic effects for tumor precision therapy in consideration of the unfavorable tumor microenvironments.


Assuntos
Nanomedicina , Fotoquimioterapia/métodos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/metabolismo , Curcumina/farmacologia , Humanos , Camundongos , Microscopia Confocal , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/química , Porfirinas/metabolismo , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Transplante Heterólogo , Microambiente Tumoral
13.
Talanta ; 233: 122536, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34215039

RESUMO

Preparation of porphyrin-based covalent organic frameworks (Por-COFs) with high photosensitizing activity for photodynamic inactivation of bacteria is of great challenge, but significant for economy and human health. Herein, we show a conjugation-regulating strategy to design and synthesize Por-COFs with high photosensitizing activity for the photodynamic inactivation of bacteria. Terephthalaldehyde (Da), 2,5-Dihydroxyterephthalaldehyde (Dha), and 2,5-Diethoxyterephthalaldehyde (Deta) with different conjugation degrees are selected to condense with 5,10,15,20-Tetrakis(4-aminophenyl)porphyrin (Tph) to synthesize COF-366, DhaTph, and JNU-2, respectively. The higher conjugation of Dha and Deta than Da leads to the higher conjugation of DhaTph and JNU-2, respectively. Moreover, the hydroxyl group in Dha and the ethoxy group in Deta further expand the conjugation of DhaTph and JNU-2 via the formation of intralayer extended π-cloud delocalization and p-π conjunction, respectively. The extension of conjugation for DhaTph and JNU-2 results in the increase of intersystem crossing process and significantly improves their photosensitizing activity. Furthermore, JNU-2 with the highest photosensitizing activity exhibits superior antibacterial effects toward Staphylococcus aureus (99.1%) and Escherichia coli (96.8%). This study offers a new conjugation-regulating strategy for designing high photosensitizing activity of Por-COFs for the inactivation of bacteria.


Assuntos
Estruturas Metalorgânicas , Porfirinas , Antibacterianos/farmacologia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Staphylococcus aureus
14.
Photodiagnosis Photodyn Ther ; 35: 102459, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34320427

RESUMO

In this manuscript, we report, the photophysical study of triplet excited states and antimicrobial photoinactivation of positively charged tetra-cisplatin porphyrin derivatives against Gram + and Gram ‒ bacterial strains. Isomeric cisplatin-porphyrins were used and applied in aPDT assays in the bacilli Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa (Gram negative) and a cocci Staphylococcus aureus (Gram positive) strains. The results show that compound substituted at meta position (3-cis-PtTPyP) is the more efficient photosensitizer against bacteria culture. In this way, tetra-cationic porphyrins containing cisplatin derivatives might be promising aPDT agents with potential applications in clinical infections.


Assuntos
Anti-Infecciosos , Fotoquimioterapia , Porfirinas , Cisplatino , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia
15.
J Photochem Photobiol B ; 221: 112239, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34116319

RESUMO

TONS504 (C51H58O5I2) is a chlorin derivative that exhibits a photodynamic antimicrobial effect (PAE) on various infectious keratitis pathogens. However, the molecular characteristics of TONS504 are not well understood. This study aimed to investigate the molecular characteristics of TONS504 by comparing its singlet oxygen (1O2) quantum yields and PAE with those of methylene blue (MB). To measure the 1O2 quantum yields, TONS504 and MB were dissolved in phosphate-buffered saline and phosphate-buffered saline containing 1% Triton X-100. The solutions were then activated by a Nd:YAG laser with an average output power of 8 mW. Near-infrared 1O2 luminescence was detected as an indicator of the 1O2 quantum yields. To evaluate the PAE, TONS504 and MB were activated by a light-emitting diode with a total light energy of 30 J/cm2. We compared the minimum molar concentration of each photosensitizer to show apparent PAEs on Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans. TONS504 exhibited higher 1O2 quantum yields than MB in PBS/Triton X-100 but not in PBS. S. aureus and C. albicans were reduced by TONS504 at lower concentrations than by MB, but this was not the case for P. aeruginosa. Our results provide insight on the molecular characteristics of TONS504 and suggest that TONS504 has excellent 1O2 quantum yields and PAE. Compared with MB, TONS504 in PBS has stronger efficacy toward some infectious keratitis pathogens but not others.


Assuntos
Azul de Metileno/química , Fármacos Fotossensibilizantes/química , Porfirinas/química , Oxigênio Singlete/química , Candida albicans/efeitos dos fármacos , Luz , Azul de Metileno/farmacologia , Testes de Sensibilidade Microbiana , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Oxigênio Singlete/metabolismo , Staphylococcus aureus/efeitos dos fármacos
16.
Inorg Chem ; 60(13): 9416-9426, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34115484

RESUMO

In this study, we addressed an important drawback of our previously reported tetraplatinated (metallo)porphyrin-based photosensitizers (PSs) for photodynamic therapy (PDT), namely, the poor solubility in aqueous media. We aimed to create tetraplatinated porphyrin-based PSs that are soluble in aqueous media modified with polysorbate (Tween) and do not need to be pre-dissolved in organic solvents. A structural optimization of the previously reported PSs resulted in the synthesis of an extremely potent novel porphyrin-based PS. The novel PS displays effective phototoxicity upon light irradiation against multicellular tumor spheroids and has a phototoxic index (PI) of 6030 in HeLa cells. This PI value is, to the best of our knowledge, the highest value reported for any porphyrin so far.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Fosfatos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Polissorbatos/química , Porfirinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Hipóxia Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Porfirinas/química , Solubilidade
17.
Nanoscale ; 13(22): 9989-10001, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34076013

RESUMO

Photodynamic therapy (PDT) is frequently used in cancer treatment in clinical settings. However, its applications in stroma-rich solid tumors, e.g., triple negative breast cancer, are limited by abnormal mechanical microenvironments. Solid stress accumulated in stroma-rich solid tumors compresses tumor blood vessels, hampers the delivery of photosensitizers (PSs) in tumor tissues, and poses a major challenge for potent PDT. Here, we report a novel combination strategy to augment PDT based cancer therapy by combining hydroxyethyl starch-chlorin e6 conjugate self-assembled nanoparticles (HES-Ce6 NPs) with the transforming growth factor-ß (TGFß) inhibitor LY2157299 (LY). HES-Ce6 conjugates, as synthesized by one step esterification reaction, could self-assemble into uniform HES-Ce6 NPs, which exhibited enhanced photostability and generated more reactive oxygen species (ROS) under 660 nm laser irradiation than free Ce6. Prior to PDT, intragastric administration of LY decreased collagen deposition, alleviated solid stress, and decompressed tumor blood vessels. As a result, the reconstructed tumor mechanical microenvironment promoted accumulation and penetration of HES-Ce6 NPs into tumor tissues, contributing to augmented antitumor efficacy of HES-Ce6 NP mediated PDT. Modulating tumor mechanical microenvironments using TGFß blockade to enhance the delivery of PSs in tumors with excessive extracellular matrix represents an efficient strategy for treating stroma-rich solid tumors.


Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Pirazóis/farmacologia , Quinolinas/farmacologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Microambiente Tumoral
18.
Int J Biol Macromol ; 184: 20-28, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34118287

RESUMO

This study aimed to investigate the use of glycol chitosan (GC) for the synthesis of MnO2 nanoparticles (NPs) and to evaluate whether the prepared GC-MnO2 NPs enhance the light-triggered photodynamic effects of chlorin e6 (Ce6) via the generation of oxygen and alleviation of hypoxia in lipopolysaccharide (LPS)-activated macrophages (RAW 264.7), which produce excessive amounts of reactive oxygen species (ROS). GC-MnO2 NPs were synthesized by a simple reaction between GC and KMnO4 in water. The prepared GC-MnO2 NPs were spherical in shape, with a mean diameter of approximately 60 nm. The particles effectively generated oxygen via H2O2-induced degradation under hypoxic conditions, which led to an increase in the singlet oxygen levels upon laser irradiation. Furthermore, GC-MnO2 NPs significantly enhanced the light-triggered photodynamic effects of Ce6 on activated macrophages under hypoxic conditions, as shown by the increased levels of cell death and cell membrane damage in activated macrophages. Therefore, these results suggest that GC can be used as an alternative natural polymer for the synthesis of MnO2 NPs and that oxygen-generating GC-MnO2 NPs enhance the light-triggered photodynamic effects of Ce6 on activated macrophages by alleviating hypoxia.


Assuntos
Quitosana/química , Peróxido de Hidrogênio/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Compostos de Manganês/química , Óxidos/química , Oxigênio/química , Porfirinas/farmacologia , Animais , Morte Celular , Hipóxia Celular , Lipopolissacarídeos/efeitos adversos , Terapia com Luz de Baixa Intensidade , Camundongos , Nanopartículas , Tamanho da Partícula , Fotoquimioterapia , Porfirinas/química , Células RAW 264.7 , Água/química
19.
Chem Asian J ; 16(15): 2022-2026, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34096181

RESUMO

A vancomycin (Van) modification strategy on a porphyrinic metal-organic framework (MOF) PCN-224 is presented. The obtained Van-PCN-224 gives the combined advantages of porphyrinic MOF and Van with high photosensitive activity and excellent targeted antibacterial activity against Staphylococcus aureus. The features make Van-PCN-224 promising for antimicrobial therapy.


Assuntos
Antibacterianos/farmacologia , Estruturas Metalorgânicas/farmacologia , Porfirinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Tamanho da Partícula , Porfirinas/química , Propriedades de Superfície , Vancomicina/química
20.
Bioconjug Chem ; 32(6): 1067-1077, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34033716

RESUMO

Passing through the blood-brain barrier (BBB) to treat neurological conditions is one of the main hurdles in modern medicine. Many drugs with promising in vitro profiles become ineffective in vivo due to BBB restrictive permeability. In particular, this includes drugs such as antiviral porphyrins, with the ability to fight brain-resident viruses causing diseases such as HIV-associated neurocognitive disorders (HAND). In the last two decades, BBB shuttles, particularly peptide-based ones, have shown promise in carrying various payloads across the BBB. Thus, peptide-drug conjugates (PDCs) formed by covalent attachment of a BBB peptide shuttle and an antiviral drug may become key therapeutic tools in treating neurological disorders of viral origin. In this study, we have used various approaches (guanidinium, phosphonium, and carbodiimide-based couplings) for on-resin synthesis of new peptide-porphyrin conjugates (PPCs) with BBB-crossing and potential antiviral activity. After careful fine-tuning of the synthetic chemistry, DIC/oxyma has emerged as a preferred method, by which 14 different PPCs have been made and satisfactorily characterized. The PPCs are prepared by coupling a porphyrin carboxyl group to an amino group (either N-terminal or a Lys side chain) of the peptide shuttle and show effective in vitro BBB translocation ability, low cytotoxicity toward mouse brain endothelial cells, and low hemolytic activity. Three of the PPCs, MP-P5, P4-MP, and P4-L-MP, effectively inhibiting HIV infectivity in vitro, stand out as most promising. Their efficacy against other brain-targeting viruses (Dengue, Zika, and SARS-CoV-2) is currently under evaluation, with preliminary results confirming that PPCs are a promising strategy to treat viral brain infections.


Assuntos
Fármacos Anti-HIV/farmacocinética , Barreira Hematoencefálica/metabolismo , Peptídeos/farmacocinética , Porfirinas/farmacocinética , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Transporte Biológico , Linhagem Celular , Descoberta de Drogas , Células HEK293 , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Camundongos , Peptídeos/química , Peptídeos/farmacologia , Porfirinas/química , Porfirinas/farmacologia
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