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1.
J Nanobiotechnology ; 22(1): 358, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38907270

ABSTRACT

BACKGROUND: Hypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix (ECM) of tumor, as well as the potential resistance to chemotherapy, have severely impeded the resulting overall efficacy of HAP. RESULTS: A HAP potentiating strategy is proposed based on ultrasound responsive nanodroplets (PTP@PLGA), which is composed of protoporphyrin (PpIX), perfluoropropane (PFP) and a typical HAP, tirapazamine (TPZ). The intense vaporization of PFP upon ultrasound irradiation can magnify the sonomechanical effect, which loosens the ECM to promote the penetration of TPZ into the deep hypoxic region. Meanwhile, the PpIX enabled sonodynamic effect can further reduce the oxygen level, thus activating the TPZ in the relatively normoxic region as well. Surprisingly, abovementioned ultrasound effect also results in the downregulation of the stemness of cancer cells, which is highly associated with drug-refractoriness. CONCLUSIONS: This work manifests an ideal example of ultrasound-based nanotechnology for potentiating HAP and also reveals the potential acoustic effect of intervening cancer stem-like cells.


Subject(s)
Fluorocarbons , Nanoparticles , Prodrugs , Protoporphyrins , Tirapazamine , Humans , Tirapazamine/pharmacology , Tirapazamine/chemistry , Protoporphyrins/pharmacology , Protoporphyrins/chemistry , Fluorocarbons/chemistry , Fluorocarbons/pharmacology , Prodrugs/pharmacology , Prodrugs/chemistry , Cell Line, Tumor , Nanoparticles/chemistry , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Ultrasonic Waves , Animals , Extracellular Matrix/metabolism , Mice , Neoplasms/drug therapy
2.
Nanoscale ; 16(24): 11669-11678, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38855849

ABSTRACT

Implant infections are severe complications in clinical treatment, which often accompany the formation of bacterial biofilms with high antibiotic resistance. Sonodynamic therapy (SDT) is an antibiotic-free method that can generate reactive oxygen species (ROS) to kill bacteria under ultrasound (US) treatment. However, the extracellular polymeric substances (EPS) barrier of bacterial biofilms and the hypoxic microenvironment significantly limit the antibiofilm activity of SDT. In this study, lipid-shelled perfluoropentane (PFP) nanodroplets loaded with gallium protoporphyrin IX (GaPPIX) and oxygen (O2) (LPGO NDs) were developed for the treatment of implant infections. Under US stimulation, LPGO NDs undergo the cavitation effect and disrupt the biofilm structure like bombs due to liquid-gas phase transition. Meanwhile, the LPGO NDs release O2 and GaPPIX upon US stimulation. The released O2 can alleviate the hypoxic microenvironment in the biofilm and enhance the ROS formation by GaPPIX for enhanced bacterial killing. In vivo experimental results demonstrate that the LPGO NDs can efficiently treat implant infections of methicillin-resistant Staphylococcus aureus (MRSA) in a mouse model by disrupting the biofilm structure, alleviating hypoxia, and enhancing bacterial killing by SDT. Therefore, this work provides a new multifunctional sonosensitizer to overcome the limitations of SDT for treating implant infections.


Subject(s)
Biofilms , Fluorocarbons , Gallium , Methicillin-Resistant Staphylococcus aureus , Oxygen , Protoporphyrins , Staphylococcal Infections , Ultrasonic Therapy , Animals , Fluorocarbons/chemistry , Fluorocarbons/pharmacology , Mice , Gallium/chemistry , Gallium/pharmacology , Protoporphyrins/chemistry , Protoporphyrins/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Biofilms/drug effects , Oxygen/chemistry , Staphylococcal Infections/drug therapy , Reactive Oxygen Species/metabolism , Nanoparticles/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Mice, Inbred BALB C , Female , Pentanes
3.
Life Sci ; 351: 122808, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-38852796

ABSTRACT

As a precursor of protoporphyrin IX (PpIX), an endogenous pro-apoptotic and fluorescent molecule, 5-Aminolevulinic acid (5-ALA) has gained substantial attention for its potential in fluorescence-guided surgery as well as photodynamic therapy (PDT). Moreover, 5-ALA-PDT has been suggested as a promising chemo-radio sensitization therapy for various cancers. However, insufficient 5-ALA-induced PpIX fluorescence and the induction of multiple resistance mechanisms may hinder the 5-ALA-PDT clinical outcome. Reduced efficacy and resistance to 5-ALA-PDT can result from genomic alterations, tumor heterogeneity, hypoxia, activation of pathways related to cell surveillance, production of nitric oxide, and most importantly, deregulated 5-ALA transporter proteins and heme biosynthesis enzymes. Understanding the resistance regulatory mechanisms of 5-ALA-PDT may allow the development of effective personalized cancer therapy. Here, we described the mechanisms underlying resistance to 5-ALA-PTD across various tumor types and explored potential strategies to overcome this resistance. Furthermore, we discussed future approaches that may enhance the efficacy of treatments using 5-ALA-PDT.


Subject(s)
Aminolevulinic Acid , Drug Resistance, Neoplasm , Neoplasms , Photochemotherapy , Photosensitizing Agents , Aminolevulinic Acid/pharmacology , Humans , Photochemotherapy/methods , Neoplasms/drug therapy , Neoplasms/pathology , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Animals , Protoporphyrins/pharmacology , Protoporphyrins/metabolism
4.
Ultrason Sonochem ; 107: 106928, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38820932

ABSTRACT

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by infiltration of inflammatory cells, hyperplasia of synovium, and destruction of the joint cartilage. Owing to the low drug delivery efficiency and limited immunosuppression effect, complete cure for RA remains a formidable challenge. Here, we show that live macrophages (Mφs) carrying protoporphyrin-loaded Fe3O4 nanoparticles can migrate to the RA tissues and inhibit the inflammation by sonodynamic therapy. The inflammation of RA leads to the release of cytokines, which guides the migration of the Mφs into the RA tissues, realizing precise delivery of therapeutics. The following sonodynamic therapy induced by ultrasound and protoporphyrin destructs the proliferating synovial cells and also infiltrated inflammatory cells, demonstrating significant therapeutic effect for RA. Meanwhile, the cytokines and relapse of RA can be remarkably suppressed because of the efficient damage to the resident inflammatory cells.


Subject(s)
Arthritis, Rheumatoid , Macrophages , Protoporphyrins , Ultrasonic Therapy , Arthritis, Rheumatoid/therapy , Macrophages/drug effects , Macrophages/metabolism , Protoporphyrins/chemistry , Protoporphyrins/pharmacology , Animals , Ultrasonic Therapy/methods , Mice , RAW 264.7 Cells , Magnetite Nanoparticles/chemistry , Magnetite Nanoparticles/therapeutic use , Cytokines/metabolism , Humans
5.
Adv Mater ; 36(30): e2405002, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38738270

ABSTRACT

Owing to the increased tissue iron accumulation in patients with diabetes, microorganisms may activate high expression of iron-involved metabolic pathways, leading to the exacerbation of bacterial infections and disruption of systemic glucose metabolism. Therefore, an on-demand transdermal dosing approach that utilizes iron homeostasis regulation to combat antimicrobial resistance is a promising strategy to address the challenges associated with low administration bioavailability and high antibiotic resistance in treating infected diabetic wounds. Here, it is aimed to propose an effective therapy based on hemoglobin bionics to induce disturbances in bacterial iron homeostasis. The preferred "iron cargo" is synthesized by protoporphyrin IX chelated with dopamine and gallium (PDGa), and is delivered via a glucose/pH-responsive microneedle bandage (PDGa@GMB). The PDGa@GMB downregulates the expression levels of the iron uptake regulator (Fur) and the peroxide response regulator (perR) in Staphylococcus aureus, leading to iron nutrient starvation and oxidative stress, ultimately suppressing iron-dependent bacterial activities. Consequently, PDGa@GMB demonstrates insusceptibility to genetic resistance while maintaining sustainable antimicrobial effects (>90%) against resistant strains of both S. aureus and E. coli, and accelerates tissue recovery (<20 d). Overall, PDGa@GMB not only counteracts antibiotic resistance but also holds tremendous potential in mediating microbial-host crosstalk, synergistically attenuating pathogen virulence and pathogenicity.


Subject(s)
Anti-Bacterial Agents , Escherichia coli , Gallium , Homeostasis , Iron , Staphylococcus aureus , Iron/metabolism , Iron/chemistry , Gallium/chemistry , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Animals , Escherichia coli/drug effects , Hemoglobins/metabolism , Protoporphyrins/chemistry , Protoporphyrins/pharmacology , Protoporphyrins/therapeutic use , Humans , Dopamine/metabolism , Drug Resistance, Microbial/drug effects , Mice , Diabetes Mellitus/drug therapy , Diabetes Mellitus/metabolism
6.
Photodiagnosis Photodyn Ther ; 46: 104080, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38583747

ABSTRACT

SIGNIFICANCE: Photodynamic therapy (PDT) can be targeted toward different subcellular localizations, and it is proposed that different subcellular targets vary in their sensitivity to photobiological damage. Since singlet oxygen (1O2) has a very short lifetime with a limited diffusion length in cellular environments, measurement of cumulative 1O2 luminescence is the most direct approach to compare the PDT sensitivity of mitochondria and plasma membrane. APPROACH: PDT-generated near-infrared 1O2 luminescence at 1270 nm was measured together with cell viability for 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) and exogenous PpIX, at different incubation times. Confocal fluorescence microscopy indicated that ALA-induced PpIX (2 h) localized in the mitochondria, whereas exogenous PpIX (1 h) mainly localized to the plasma membrane. Cell viability was determined at several time points during PDT treatments using colony-forming assays, and the surviving fraction correlated well with cumulative 1O2 luminescence counts from PpIX in mitochondria and plasmas membrane, respectively. RESULTS: The mitochondria are more sensitive than the plasma membrane by a factor of 1.7. CONCLUSIONS: Direct 1O2 luminescence dosimetry's potential value for comparing the PDT sensitivity of different subcellular organelles was demonstrated. This could be useful for developing subcellular targeted novel photosensitizers to enhance PDT efficiency.


Subject(s)
Aminolevulinic Acid , Cell Membrane , Cell Survival , Mitochondria , Photochemotherapy , Photosensitizing Agents , Protoporphyrins , Singlet Oxygen , Protoporphyrins/pharmacology , Singlet Oxygen/metabolism , Photosensitizing Agents/pharmacology , Photochemotherapy/methods , Mitochondria/metabolism , Mitochondria/drug effects , Cell Survival/drug effects , Cell Membrane/metabolism , Cell Membrane/drug effects , Aminolevulinic Acid/pharmacology , Humans
7.
Cell Mol Biol (Noisy-le-grand) ; 70(4): 53-60, 2024 Apr 28.
Article in English | MEDLINE | ID: mdl-38678627

ABSTRACT

Cobalt protoporphyrin (CoPP) is a synthetic heme analog that has been observed to reduce food intake and promote sustained weight loss. While the precise mechanisms responsible for these effects remain elusive, earlier research has hinted at the potential involvement of nitric oxide synthase in the hypothalamus. This study aimed to delve into CoPP's impact on the activities of crucial antioxidant enzymes: superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) across seven distinct brain regions (hippocampus, hypothalamus, prefrontal cortex, motor cortex, striatum, midbrain, and cerebellum), as well as in the liver and kidneys. Female Wistar rats weighing 180 to 200 grams received a single subcutaneous dose of 25 µmol/kg CoPP. After six days, brain tissue was extracted to assess the activities of antioxidant enzymes and quantify malondialdehyde levels. Our findings confirm that CoPP administration triggers the characteristic effects of decreased food intake and reduced body weight. Moreover, it led to an increase in SOD activity in the hypothalamus, a pivotal brain region associated with food intake regulation. Notably, CoPP-treated rats exhibited elevated enzymatic activity of catalase, GR, and GST in the motor cortex without concurrent signs of heightened oxidative stress. These results underscore a strong connection between the antioxidant system and food intake regulation. They also emphasize the need for further investigation into the roles of antioxidant enzymes in modulating food intake and the ensuing weight loss, using CoPP as a valuable research tool.


Subject(s)
Antioxidants , Hypothalamus , Motor Cortex , Protoporphyrins , Animals , Female , Rats , Antioxidants/metabolism , Body Weight/drug effects , Catalase/metabolism , Eating/drug effects , Glutathione Peroxidase/drug effects , Glutathione Peroxidase/metabolism , Glutathione Reductase/drug effects , Glutathione Reductase/metabolism , Glutathione Transferase/drug effects , Glutathione Transferase/metabolism , Hypothalamus/metabolism , Hypothalamus/drug effects , Hypothalamus/enzymology , Malondialdehyde/metabolism , Motor Cortex/drug effects , Motor Cortex/metabolism , Motor Cortex/enzymology , Oxidative Stress/drug effects , Protoporphyrins/pharmacology , Rats, Wistar , Superoxide Dismutase/drug effects , Superoxide Dismutase/metabolism
8.
Arch Toxicol ; 98(6): 1781-1794, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38573338

ABSTRACT

Doxorubicin (DOX) is one of the most frequently used chemotherapeutic drugs belonging to the class of anthracyclines. However, the cardiotoxic effects of anthracyclines limit their clinical use. Recent studies have suggested that ferroptosis is the main underlying pathogenetic mechanism of DOX-induced cardiomyopathy (DIC). BTB-and-CNC homology 1 (Bach1) acts as a key role in the regulation of ferroptosis. However, the mechanistic role of Bach1 in DIC remains unclear. Therefore, this study aimed to investigate the underlying mechanistic role of Bach1 in DOX-induced cardiotoxicity using the DIC mice in vivo (DOX at cumulative dose of 20 mg/kg) and the DOX-treated H9c2 cardiomyocytes in vitro (1 µM). Our results show a marked upregulation in the expression of Bach1 in the cardiac tissues of the DOX-treated mice and the DOX-treated cardiomyocytes. However, Bach1-/- mice exhibited reduced lipid peroxidation and less severe cardiomyopathy after DOX treatment. Bach1 knockdown protected against DOX-induced ferroptosis in both in vivo and in vitro models. Ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis, significantly alleviated DOX-induced cardiac damage. However, the cardioprotective effects of Bach1 knockdown were reversed by pre-treatment with Zinc Protoporphyrin (ZnPP), a selective inhibitor of heme oxygenase-1(HO-1). Taken together, these findings demonstrated that Bach1 promoted oxidative stress and ferroptosis through suppressing the expression of HO-1. Therefore, Bach1 may present as a promising new therapeutic target for the prevention and early intervention of DOX-induced cardiotoxicity.


Subject(s)
Basic-Leucine Zipper Transcription Factors , Cardiomyopathies , Doxorubicin , Ferroptosis , Heme Oxygenase-1 , Mice, Inbred C57BL , Mice, Knockout , Myocytes, Cardiac , Oxidative Stress , Animals , Ferroptosis/drug effects , Doxorubicin/toxicity , Oxidative Stress/drug effects , Cardiomyopathies/chemically induced , Cardiomyopathies/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Basic-Leucine Zipper Transcription Factors/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Male , Mice , Heme Oxygenase-1/metabolism , Heme Oxygenase-1/genetics , Cell Line , Rats , Cardiotoxicity , Antibiotics, Antineoplastic/toxicity , Lipid Peroxidation/drug effects , Protoporphyrins/pharmacology , Signal Transduction/drug effects , Cyclohexylamines , Membrane Proteins , Phenylenediamines
9.
Bioorg Med Chem ; 105: 117726, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38626642

ABSTRACT

5-Aminolevulinic acid (ALA) and its derivatives, serving as the endogenous precursor of the photosensitizer (PS) protoporphyrin IX (PpIX), successfully applied in tumor imaging and photodynamic therapy (PDT). ALA and its derivatives have been used to treat actinic keratosis (AK), basal cell carcinoma (BCC), and improve the detection of superficial bladder cancer. However, the high hydrophilicity of ALA and the conversion of PpIX to heme have limited the accumulation of PpIX, hindering the efficiency and potential application of ALA-PDT. This study aims to evaluate the PDT activity of three rationally designed series of ALA-HPO prodrugs, which were based on enhancing the lipophilicity of the prodrugs and reducing the labile iron pool (LIP) through HPO iron chelators to promote PpIX accumulation. Twenty-four ALA-HPO conjugates, incorporating amide, amino acid, and ester linkages, were synthesized. Most of the conjugates, exhibited no dark-toxicity to cells, according to bioactivity evaluation. Ester conjugates 19a-g showed promoted phototoxicity when tested on tumor cell lines, and this increased phototoxicity was strongly correlated with elevated PpIX levels. Among them, conjugate 19c emerged as the most promising (HeLa, IC50 = 24.25 ± 1.43 µM; MCF-7, IC50 = 43.30 ± 1.76 µM; A375, IC50 = 28.03 ± 1.00 µM), displaying superior photodynamic anticancer activity to ALA (IC50 > 100 µM). At a concentration of 80 µM, the fluorescence intensity of PpIX induced by compound 19c in HeLa, MCF-7, and A375 cells was 18.9, 5.3, and 2.8 times higher, respectively, than that induced by ALA. In conclusion, cellular phototoxicity showed a strong correlation with intracellular PpIX fluorescence levels, indicating the potential application of ALA-HPO conjugates in ALA-PDT.


Subject(s)
Aminolevulinic Acid , Antineoplastic Agents , Drug Screening Assays, Antitumor , Photochemotherapy , Photosensitizing Agents , Humans , Aminolevulinic Acid/pharmacology , Aminolevulinic Acid/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Pyridones/pharmacology , Pyridones/chemistry , Pyridones/chemical synthesis , Cell Line, Tumor , Protoporphyrins/chemistry , Protoporphyrins/pharmacology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Cell Survival/drug effects , Prodrugs/pharmacology , Prodrugs/chemistry , Prodrugs/chemical synthesis
10.
Chem Asian J ; 19(11): e202400257, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38632107

ABSTRACT

Apohemoprotein is focused on the field of theranostics, serving as a porphyrin carrier. Hemoglobin (Hb) consists of α2ß2 tetramer with iron(II)-protoporphyrin IX (heme) bound to each globin. However, heme-removed Hb (apoHb) causes dissociation at αß interfaces and aggregation under physiological conditions. We synthesized a stable apoHb derivative comprising intramolecular-crosslinked apoHb (apoXHb) and human serum albumin (HSA), apoXHb-HSA3. ApoXHb-HSA3 engendered no aggregates in the physiological solutions. Moreover, apoXHb-HSA3 was reconstituted with zinc(II)-protoporphyrin IX (ZnP), generating ZnXHb-HSA3, a potent photosensitizer for photodynamic therapy (PDT). The photophysical properties of ZnXHb-HSA3 were identical to those of zinc-substituted XHb (ZnXHb). Cellular uptake behavior was evaluated using various cancer cell lines. ZnXHb-HSA3 released ZnP around the cells, and the free ZnP penetrated cell membranes. In contrast, protein units were not observed within the cells. ZnXHb-HSA3 showed no cytotoxicity under dark conditions and demonstrated superior PDT activity in comparison to naked ZnXHb. ZnXHb-HSA3 acts as an innovative porphyrin carrier for enhanced PDT.


Subject(s)
Hemoglobins , Photochemotherapy , Photosensitizing Agents , Serum Albumin, Human , Zinc , Humans , Zinc/chemistry , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemical synthesis , Hemoglobins/chemistry , Hemoglobins/metabolism , Serum Albumin, Human/chemistry , Cell Survival/drug effects , Porphyrins/chemistry , Porphyrins/pharmacology , Cell Line, Tumor , Drug Carriers/chemistry , Drug Carriers/chemical synthesis , Protoporphyrins/chemistry , Protoporphyrins/pharmacology
11.
Br J Pharmacol ; 181(16): 2886-2904, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38679457

ABSTRACT

BACKGROUND AND PURPOSE: Chronic inflammation plays a pivotal role in the development of Type 2 diabetes mellitus (T2DM). Previous studies have shown that haem oxygenase-1 (HO-1) plays a proinflammatory role during metabolic stress, suggesting that HO-1 inhibition could be an effective strategy to treat T2DM. However, the application of HO-1 inhibitors is restricted due to solubility-limited bioavailability. In this study, we encapsulated the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), within nanoparticles and investigated their role in regulating glucose homeostasis and chronic inflammation during obesity. EXPERIMENTAL APPROACH: We delivered DMSO-dissolved ZnPP (DMSO-ZnPP) and ZnPP-laden nanoparticles (Nano-ZnPP) to diet-induced obese male mice for 6 weeks. Glucose and insulin tolerance tests were carried out, liver and adipose tissue gene expression profiles analysed, and systemic inflammation analysed using flow cytometry. KEY RESULTS: Nanoparticles significantly increased the delivery efficiency of ZnPP in both cells and mice. In mice with diet-induced obesity, inhibition of HO-1 by Nano-ZnPP significantly decreased adiposity, increased insulin sensitivity, and improved glucose tolerance. Moreover, Nano-ZnPP treatment attenuated both local and systemic inflammatory levels during obesity. Mechanistically, Nano-ZnPP significantly attenuated glucagon, TNF, and fatty acid synthesis signalling pathways in the liver. In white adipose tissue, the oxidative phosphorylation signalling pathway was enhanced and the inflammation signalling pathway diminished by Nano-ZnPP. Our results show that Nano-ZnPP has better effects on the improvement of glucose homeostasis and attenuation of chronic inflammation, than those of DMSO-dissolved ZnPP. CONCLUSIONS AND IMPLICATIONS: These findings indicate that ZnPP-laden nanoparticles are potential therapeutic agents for treating T2DM.


Subject(s)
Homeostasis , Inflammation , Mice, Inbred C57BL , Nanoparticles , Obesity , Protoporphyrins , Animals , Obesity/drug therapy , Obesity/metabolism , Male , Mice , Nanoparticles/chemistry , Inflammation/drug therapy , Inflammation/metabolism , Protoporphyrins/pharmacology , Protoporphyrins/administration & dosage , Homeostasis/drug effects , Heme Oxygenase-1/metabolism , Glucose/metabolism , Diet, High-Fat/adverse effects
12.
J Nanobiotechnology ; 22(1): 161, 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38589895

ABSTRACT

Antibiotic resistance has garnered significant attention due to the scarcity of new antibiotics in development. Protoporphyrin IX (PpIX)-mediated photodynamic therapy shows promise as a novel antibacterial strategy, serving as an alternative to antibiotics. However, the poor solubility of PpIX and its tendency to aggregate greatly hinder its photodynamic efficacy. In this study, we demonstrate that alkylated EDTA derivatives (aEDTA), particularly C14-EDTA, can enhance the solubility of PpIX by facilitating its dispersion in aqueous solutions. The combination of C14-EDTA and PpIX exhibits potent antibacterial activity against Staphylococcus aureus (S. aureus) when exposed to LED light irradiation. Furthermore, this combination effectively eradicates S. aureus biofilms, which are known to be strongly resistant to antibiotics, and demonstrates high therapeutic efficacy in an animal model of infected ulcers. Mechanistic studies reveal that C14-EDTA can disrupt PpIX crystallization, increase bacterial membrane permeability and sequester divalent cations, thereby improving the accumulation of PpIX in bacteria. This, in turn, enhances reactive oxygen species (ROS) production and the antibacterial photodynamic activity. Overall, this effective strategy holds great promise in combating antibiotic-resistant strains.


Subject(s)
Photochemotherapy , Staphylococcus aureus , Animals , Protoporphyrins/pharmacology , Edetic Acid/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry
13.
Carbohydr Polym ; 336: 122114, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38670775

ABSTRACT

5-aminolevulinic acid (5-ALA) has been fully demonstrated as a biodegradable, without resistance, and pollution-free pesticide. However, the lack of targeting and the poor adhesion result in a low utilization rate, limiting its practical application. Herein, a dew-responsive polymer pro-pesticide Pec-hyd-ALA was successfully synthesized by grafting 5-ALA onto the pectin (PEC) backbone via acid-sensitive acylhydrazone bonds. When the pro-pesticide is exposed to acid dew on plant surfaces at night, 5-ALA is released and subsequently converted to photosensitize (Protoporphyrin IX, PpIX)in plant cells, leading to its accumulation and promoting photodynamic inactivation (PDI). An inverted fluorescence microscope has verified the accumulation of tetrapyrrole in plant cells. In addition, the highly bio-adhesive PEC backbone effectively improved the wetting and retention of 5-ALA on leaves. The pot experiment also demonstrated the system's control effect on barnyard grass. This work provides a promising approach to improving the herbicidal efficacy of 5-ALA.


Subject(s)
Aminolevulinic Acid , Herbicides , Pectins , Photosensitizing Agents , Pectins/chemistry , Herbicides/chemistry , Herbicides/pharmacology , Aminolevulinic Acid/chemistry , Aminolevulinic Acid/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Protoporphyrins/chemistry , Protoporphyrins/pharmacology , Plant Leaves/chemistry , Wettability
14.
J Photochem Photobiol B ; 254: 112892, 2024 May.
Article in English | MEDLINE | ID: mdl-38513542

ABSTRACT

BACKGROUND: The dramatic increase of drug-resistant bacteria necessitates urgent development of platforms to simultaneously detect and inactivate bacteria causing wound infections, but are confronted with various challenges. Delta amino levulinic acid (ALA) induced protoporphyrin IX (PpIX) can be a promising modality for simultaneous bioburden diagnostics and therapeutics. Herein, we report utility of ALA induced protoporphyrin (PpIX) based simultaneous bioburden detection, photoinactivation and therapeutic outcome assessment in methicillin resistant Staphylococcus aureus (MRSA) infected wounds of mice. METHODS: MRSA infected wounds treated with 10% ALA were imaged with help of a blue LED (∼405 nm) based, USB powered, hand held device integrated with a modular graphic user interface (GUI). Effect of ALA application time, bacteria load, post bacteria application time points on wound fluorescence studied. PpIX fluorescence observed after excitation with blue LEDs was used to detect bioburden, start red light mediated antimicrobial photodynamic therapy (aPDT), determine aPDT effectiveness and assess selectivity of the approach. RESULTS: ALA-PpIX fluorescence of wound bed discriminates infected from uninfected wounds and detects clinically relevant load. While wound fluorescence pattern changes as a function of ALA incubation and post infection time, intra-wound inhomogeneity in fluorescence correlates with the Gram staining data on presence of biofilms foci. Lack of red fluorescence from wound granulation tissue treated with ALA suggests selectivity of the approach. Further, significant reduction (∼50%) in red fluorescence, quantified using the GUI, relates well with bacteria load reduction observed post topical aPDT. CONCLUSION: The potential of ALA induced PpIX for simultaneous detection of bioburden, photodynamic inactivation and "florescence-guided aPDT assessment" is demonstrated in MRSA infected wounds of mice.


Subject(s)
Methicillin-Resistant Staphylococcus aureus , Photochemotherapy , Mice , Animals , Aminolevulinic Acid/pharmacology , Aminolevulinic Acid/therapeutic use , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Photochemotherapy/methods , Fluorescence , Protoporphyrins/pharmacology
15.
Small ; 20(28): e2309882, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38342670

ABSTRACT

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.


Subject(s)
Cyclooxygenase 2 , Peptides , Photochemotherapy , Photochemotherapy/methods , Cyclooxygenase 2/metabolism , Peptides/chemistry , Peptides/pharmacology , Animals , Humans , Cell Line, Tumor , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Reactive Oxygen Species/metabolism , Female , Meloxicam/pharmacology , Meloxicam/therapeutic use , Mice , Protoporphyrins/chemistry , Protoporphyrins/pharmacology , Dinoprostone/metabolism
16.
Biochem Pharmacol ; 217: 115851, 2023 11.
Article in English | MEDLINE | ID: mdl-37858868

ABSTRACT

5-Aminolevulinic acid (ALA) has been approved by the U. S. FDA for fluorescence-guided resection of high-grade glioma and photodynamic therapy (PDT) of superficial skin precancerous and cancerous lesions. As a prodrug, ALA administered orally or topically is metabolized in the heme biosynthesis pathway to produce protoporphyrin IX (PpIX), the active drug with red fluorescence and photosensitizing property. Preferential accumulation of PpIX in tumors after ALA administration enables the use of ALA for PpIX-mediated tumor fluorescence diagnosis and PDT, functioning as a photo-theranostic agent. Extensive research is currently underway to further enhance ALA-mediated PpIX tumor disposition for better tumor visualization and treatment. Particularly, the discovery of PpIX as a specific substrate of ATP binding cassette subfamily G member 2 (ABCG2) opens the door to therapeutic enhancement with ABCG2 inhibitors. Studies with human tumor cell lines and human tumor samples have demonstrated ABCG2 as an important biological determinant of reduced ALA-PpIX tumor accumulation, inhibition of which greatly enhances ALA-PpIX fluorescence and PDT response. These studies strongly support targeting ABCG2 as an effective therapeutic enhancement approach. In this review, we would like to summarize current research of ABCG2 as a drug efflux transporter in multidrug resistance, highlight previous works on targeting ABCG2 for therapeutic enhancement of ALA, and provide future perspectives on how to translate this ABCG2-targeted therapeutic enhancement strategy from bench to bedside.


Subject(s)
Aminolevulinic Acid , Photochemotherapy , Humans , Aminolevulinic Acid/pharmacology , Aminolevulinic Acid/therapeutic use , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Protoporphyrins/pharmacology , Cell Line, Tumor , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Neoplasm Proteins/metabolism
17.
Mol Pharm ; 20(8): 4058-4070, 2023 08 07.
Article in English | MEDLINE | ID: mdl-37471668

ABSTRACT

There is a major need for the development of new therapeutics to combat antibiotic-resistant Staphylococcus aureus. Recently, gallium (Ga)-based complexes have shown promising antimicrobial effects against various bacteria, including multidrug-resistant organisms, by targeting multiple heme/iron-dependent metabolic pathways. Among these, Ga protoporphyrin (GaPP) inhibits bacterial growth by targeting heme pathways, including aerobic respiration. Ga(NO3)3, an iron mimetic, disrupts elemental iron pathways. Here, we demonstrate the enhanced antimicrobial activity of the combination of GaPP and Ga(NO3)3 against methicillin-resistant S. aureus (MRSA) under iron-limited conditions, including small colony variants (SCV). This therapy demonstrated significant antimicrobial activity without inducing slow-growing SCV. We also observed that the combination of GaPP and Ga(NO3)3 inhibited the MRSA catalase but not above that seen with Ga(NO3)3 alone. Neither GaPP nor Ga(NO3)3 alone or their combination inhibited the dominant superoxide dismutase expressed (SodA) under the iron-limited conditions examined. Intranasal administration of the combination of the two compounds improved drug biodistribution in the lungs compared to intraperitoneal administration. In a murine MRSA lung infection model, we observed a significant increase in survival and decrease in MRSA lung CFUs in mice that received combination therapy with intranasal GaPP and Ga(NO3)3 compared to untreated control or mice receiving GaPP or Ga(NO3)3 alone. No drug-related toxicity was observed as assessed histologically in the spleen, lung, nasal cavity, and kidney for both single and repeated doses of 10 mg Ga /Kg of mice over 13 days. Our results strongly suggest that GaPP and Ga(NO3)3 in combination have excellent synergism and potential to be developed as a novel therapy for infections with S. aureus.


Subject(s)
Gallium , Methicillin-Resistant Staphylococcus aureus , Animals , Mice , Protoporphyrins/pharmacology , Protoporphyrins/metabolism , Staphylococcus aureus , Tissue Distribution , Anti-Bacterial Agents/pharmacology , Gallium/pharmacology , Heme/metabolism , Iron/metabolism , Microbial Sensitivity Tests
18.
Tuberculosis (Edinb) ; 142: 102390, 2023 09.
Article in English | MEDLINE | ID: mdl-37506532

ABSTRACT

Non-Tuberculous Mycobacterial Pulmonary Disease (NTM-PD) caused by Mycobacterium abscessus is a frequent complication in patients with cystic fibrosis (CF) that worsens lung function over time. Currently, there is no cure for NTM-PD, hence new therapies are urgently required. Disrupting bacterial iron uptake pathways using gallium-protoporphyrin (IX) (GaPP), a heme analog, has been proposed as a novel antibacterial approach to tackle multi-drug resistant M. abscessus. However, the antibacterial activity of GaPP has been tested only in iron-deficient media, which cannot accurately mirror the potential activity in vivo. Herein, we investigated the potential synergistic activity between GaPP and the iron-chelating agent deferiprone (Def) in regular media against M. abscessus-infected macrophages. The safety of the treatment was assessed in vitro using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in Nuli-1 and THP-1 cell lines. Def-GaPP had synergistic activity against M. abscessus-infected macrophages where 10 mM-12.5 mg/L of Def-GaPP reduced the viability by up to 0.9 log10. Furthermore, Def-GaPP showed no cytotoxicity to Nuli-1 and THP-1 cell lines at the effective antibacterial concentrations (10 mM-12.5 mg/L) of Def- GaPP. These data encourage future investigation of Def-GaPP as a novel antimicrobial against NTM-PD.


Subject(s)
Anti-Bacterial Agents , Deferiprone , Gallium , Iron Chelating Agents , Mycobacterium Infections, Nontuberculous , Mycobacterium abscessus , Protoporphyrins , Deferiprone/pharmacology , Gallium/pharmacology , Protoporphyrins/pharmacology , Humans , Mycobacterium abscessus/drug effects , Mycobacterium Infections, Nontuberculous/microbiology , Anti-Bacterial Agents/pharmacology , Iron Chelating Agents/pharmacology , THP-1 Cells , Drug Synergism
19.
Pharmacol Ther ; 248: 108487, 2023 08.
Article in English | MEDLINE | ID: mdl-37392940

ABSTRACT

Protoporphyrin IX (PPIX) is an intermediate in the heme biosynthesis pathway. Abnormal accumulation of PPIX due to certain pathological conditions such as erythropoietic protoporphyria and X-linked protoporphyria causes painful phototoxic reactions of the skin, which can significantly impact daily life. Endothelial cells in the skin have been proposed as the primary target for PPIX-induced phototoxicity through light-triggered generation of reactive oxygen species. Current approaches for the management of PPIX-induced phototoxicity include opaque clothing, sunscreens, phototherapy, blood therapy, antioxidants, bone marrow transplantation, and drugs that increase skin pigmentation. In this review, we discuss the present understanding of PPIX-induced phototoxicity including PPIX production and disposition, conditions that lead to PPIX accumulation, symptoms and individual differences, mechanisms, and therapeutics.


Subject(s)
Endothelial Cells , Protoporphyria, Erythropoietic , Humans , Endothelial Cells/metabolism , Protoporphyrins/pharmacology , Protoporphyrins/metabolism , Protoporphyria, Erythropoietic/metabolism , Protoporphyria, Erythropoietic/pathology , Protoporphyria, Erythropoietic/therapy , 5-Aminolevulinate Synthetase
20.
Photodiagnosis Photodyn Ther ; 43: 103632, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37236519

ABSTRACT

INTRODUCTION: Protoporphyrin-IX (PpIX), a photosensitizer used in photodynamic therapy, has limitations due to its hydrophobicity, rapid photobleaching, and low absorption peak in the red region. These limitations make the use of PpIX less effective for photodynamic therapy treatments. In this study, we harnessed the power of microfluidic technology to manipulate the properties of PpIX and quickly synthesize albumin-based hybrid nanoshells with high reproducibility. METHODS AND MATERIAL: To begin with, we designed a microfluidic chip with SolidWorksⓇ software; then the chip was fabricated in Poly(methyl methacrylate) (PMMA) material using micromilling and thermal bonding. We synthesized PpIX-loaded CTAB micelles and subsequently transformed the PpIX structure into photo-protoporphyrin (PPP,) by opto-microfluidic chip (Integrating a microfluidic chip with a light source). Simultaneously with CTAB-PPP synthesis complex, we trapped it in binding sites of bovine serum albumin (BSA). Afterward, we used the same method (without irradiating) to generate a hybrid nanostructure consisting of hollow gold nanoshells (HGN) and BSACTAB-PPP. Then, after physical characterization of nanostructures, the photodynamic effects of the agents (HGNs, CTAB-PpIX, BSA-CTABPpIX, HGN-BSA-CTAB-PpIX, CTAB-PPP, BSA-CTAB-PPP, and HGNs-BSA-CTAB-PPP) were evaluated on MDA-MB-231 and 4T1 cells and the cytotoxic properties of the therapeutic agents after treatment for 24, 48, and 72 hours were investigated using MTT assay. Finally, we analyzed the findings using GraphPad Prism 9.0 software. RESULTS: Results revealed that the opto-microfluidic assisted synthesis of HGN-BSA-CTAB-PPP is highly efficient and reproducible, with a size of 120 nm, a zeta potential of -16 mV, and a PDI index of 0.357. Furthermore, the cell survival analysis demonstrated that the HGNBSA-CTAB-PPP hybrid nanostructure can significantly reduce the survival of MDA-MB-231 and 4T1 cancer cells at low radiation doses (< 10 J/cm2) when exposed to an incoherent light source due to its strong absorption peak at a wavelength of 670 nm. CONCLUSION: This research indicates that developing albumin-based multidrug hybrid nanostructures using microfluidic technology could be a promising approach to design more efficient photodynamic therapy studies.


Subject(s)
Nanoshells , Photochemotherapy , Triple Negative Breast Neoplasms , Humans , Photochemotherapy/methods , Photosensitizing Agents/therapeutic use , Protoporphyrins/pharmacology , Gold/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Cetrimonium , Microfluidics , Reproducibility of Results , Serum Albumin, Bovine , Cell Line, Tumor
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