RESUMO
Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic joint inflammation and cartilage damage. Current therapeutic strategies often result in side effects, necessitating the development of targeted and safer treatment options. This study introduces a novel nanotherapeutic system, 2-APB@DGP-MM, which utilizes macrophage membrane (MM)-encapsulated nanoparticles (NPs) for the targeted delivery of 2-Aminoethyl diphenylborinate (2-APB) to inflamed joints more effectively. The NPs are designed with a matrix metalloproteinase (MMP)-cleavable peptide, allowing for MMP-responsive drug release within RA microenvironment. Comprehensive in vitro and in vivo assays confirmed the successful synthesis and loading of 2-APB into the DSPE-GPLGVRGC-PEG (DGP) NPs, as well as their ability to repolarize macrophages from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype. The NPs demonstrated high biocompatibility, low cytotoxicity, and enhanced cellular uptake. In a collagen-induced arthritis (CIA) mouse model, intra-articular injection of 2-APB@DGP-MM significantly reduced synovial inflammation and cartilage destruction. Histological analysis corroborated these findings, demonstrating marked improvements in joint structure and delayed disease progression. Above all, the 2-APB@DGP-MM nanotherapeutic system offers a promising and safe approach for RA treatment by modulating macrophage polarization and delivering effective agents to inflamed joints.
Assuntos
Artrite Reumatoide , Macrófagos , Nanopartículas , Animais , Camundongos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Artrite Reumatoide/tratamento farmacológico , Nanopartículas/química , Células RAW 264.7 , Masculino , Camundongos Endogâmicos DBA , Artrite Experimental/tratamento farmacológico , Compostos de Boro/química , Compostos de Boro/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Humanos , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacosRESUMO
Using the principle of "Magic Bullet", a cisplatin-derived platinum(IV) prodrug heterobimetallic Pt(IV)-Ru(II) complex, cis,cis,trans-[Pt(NH3)2Cl2{Ru(tpy-BODIPY)(tpy-COO)}(biotin)]Cl2 (Pt-Ru-B, 2), having two axial ligands, namely, biotin as water-soluble B-vitamin for enhanced cellular uptake and a BODIPY-ruthenium(II) (Ru-B, 1) photosensitizer having N,N,N-donor tpy (4'-phenyl-2,2':6',2â³-terpyridine) bonded to boron-dipyrromethene (BODIPY), is developed as a "Platin Bullet" for targeted photodynamic therapy (PDT). Pt-Ru-B exhibited intense absorption near 500 nm and emission near 513 nm (λex = 488 nm) in a 10% dimethyl sulfoxide-Dulbecco's phosphate-buffered saline medium (pH 7.2). The BODIPY complex on light activation generates singlet oxygen as the reactive oxygen species (ROS) giving a quantum yield (ΦΔ) of â¼0.64 from 1,3-diphenylisobenzofuran experiments. Pt-Ru-B exhibited preferential cellular uptake in cancer cells over noncancerous cells. The dichlorodihydrofluorescein diacetate assay confirmed the generation of cellular ROS. Confocal images revealed its mitochondrial internalization. Pt-Ru-B showed submicromolar photocytotoxicity in visible light (400-700 nm) in A549 and multidrug-resistant MDA-MB-231 cancer cells. It remained nontoxic in the dark and less toxic in nontumorigenic cells. Cellular apoptosis and alteration of the mitochondrial membrane potential were evidenced from the respective Annexin V-FITC/propidium iodide assay and JC-1 dye assay. A wound healing assay using A549 cells and Pt-Ru-B revealed inhibition of cancer cell migration, highlighting its potential as an antimetastatic agent.
Assuntos
Antineoplásicos , Biotina , Fotoquimioterapia , Fármacos Fotossensibilizantes , Pró-Fármacos , Rutênio , Humanos , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/síntese química , Rutênio/química , Rutênio/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Biotina/química , Biotina/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Compostos de Boro/síntese química , Porfobilinogênio/análogos & derivados , Porfobilinogênio/química , Porfobilinogênio/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Platina/química , Platina/farmacologia , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/químicaRESUMO
BACKGROUND: Chronic inflammatory skin diseases are of great social and medical importance and require effective drug therapy. Phosphodiesterase 4 (PDE4) inhibitors represent a possible therapeutic option by regulating inflammatory processes. PDEs cause the release of proinflammatory cytokines by interfering with signaling pathways. The PDE4 inhibitors apremilast (treatment of psoriasis and Behçet's disease), roflumilast (treatment of chronic obstructive pulmonary disease), and crisaborole (treatment of atopic dermatitis) are currently approved in Europe. PSORIASIS: Apremilast is used for second-line treatment of plaque psoriasis and psoriatic arthritis and has a favorable side effect profile. Topical PDE4 inhibitors are currently being researched and have not yet been approved by the European Medicines Agency (EMA). ATOPIC DERMATITIS: The topical PDE4 inhibitor crisaborole was approved by the EMA in 2020 as a topical treatment alternative to glucocorticoids and calcineurin inhibitors. Although the substance has shown good tolerability in studies and also alleviates the accompanying itching, it did not find its way onto the German market. BEHçET'S DISEASE: Apremilast is approved for the treatment of Behçet's disease in adults with refractory, severe oral ulcers. OUTLOOK: Case studies have also demonstrated the efficacy of systemic PDE4 inhibition in other skin diseases (including blistering autoimmune dermatoses, lichen planus, and acantholytic genodermatoses). The substances are also being researched and used to treat extracutaneous inflammatory diseases.
Assuntos
Inibidores da Fosfodiesterase 4 , Psoríase , Talidomida , Humanos , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/farmacologia , Talidomida/efeitos adversos , Psoríase/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Compostos de Boro/uso terapêutico , Compostos de Boro/farmacologia , Síndrome de Behçet/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Ciclopropanos , Compostos Bicíclicos Heterocíclicos com PontesRESUMO
Anticancer drugs inhibit DNA replication by intercalating between DNA base pairs, forming covalent bonds with nucleotide bases, or binding to the DNA groove. To develop safer drugs, novel molecular structures with alternative binding mechanisms are essential. Stable boron hydrides offer a promising alternative for cancer therapy, opening up additional options like boron neutron capture therapy based on 10B and thermal neutron beams or proton boron fusion therapy using 11B and proton beams. These therapies are more efficient when the boron compound is ideally located inside cancer cells, particularly in the nucleus. Current cancer treatments often utilize small, polycyclic, aromatic, planar molecules that intercalate between ds-DNA base pairs, requiring only a spacing of approximately 0.34 nm. In this paper, we demonstrate another type of intercalation. Notably, [3,3'-Fe(1,2-C2B9H11)2]-, ([o-FESAN]-), a compact 3D molecule measuring 1.1 nm × 0.6 nm, can as well intercalate by strong non-bonding interactions preferentially with guanine. Unlike known intercalators, which are positive or neutral, [o-FESAN]- is a negative species and when an [o-FESAN]- molecule approaches the negatively charged DNA phosphate chain an anion-anion interaction consistently anti-electrostatic via Ccluster-Hâ¯O-P bonds occurs. Then, when more molecules approach, an elongated outstandingly self-assembled structure of [o-FESAN]--[o-FESAN]- forms moving anions towards the interthread region to interact with base pairs and form aggregates of four [o-FESAN]- anions per base pair. These aggregates, in this environment, are generated by Ccluster-Hâ¯O-C, N-Hâ¯H-B and Ccluster-Hâ¯H-B interactions. The ferrabis(dicarbollide) boron-rich small molecules not only effectively penetrate the nucleus but also intercalate with ds-DNA, making them promising for cancer treatment. This amphiphilic anionic molecule, used as a carrier-free drug, can enhance radiotherapy in a multimodal perspective, providing healthcare professionals with improved tools for cancer treatment. This work demonstrates these findings with a plethora of techniques.
Assuntos
Ânions , Antineoplásicos , DNA , Substâncias Intercalantes , Antineoplásicos/química , Antineoplásicos/farmacologia , DNA/química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Humanos , Ânions/química , Compostos de Boro/química , Compostos de Boro/farmacologia , Estrutura MolecularRESUMO
In this work, various novel pyridinyl- and pyridinium-modified Aza-BODIPY PSs were designed and constructed based on monoiodo Aza-BODIPY PSs (BDP-4 and BDP-15) in an attempt to construct "structure-inherent organelles-targeted" PSs to endow potential organelle-targeting ability. Pyridinyl PSs displayed potent photodynamic efficacy, and monorigidified PSs were very effective. The monorigidified PS 20 with meta-pyridinyl moiety displayed the most potent photoactivity and negligible dark toxicity with a favorable dark/phototoxicity ratio (>4800). To our surprise, monorigidified PS with meta-pyridinyl moiety (e.g., 20) was lipid droplet-targeted. 20 showed good cellular uptake and intracellular ROS generation compared with BDP-15. The preliminary cell death process exploration indicated that 20 resulted in lipid peroxidation and induced cell death through an iron-independent ferroptosis-like cell death pathway. In vivo antitumor efficacy experiments manifested that 20 significantly inhibited tumor growth and outperformed BDP-15 and Ce6 even under a single low-dose light irradiation (30 J/cm2).
Assuntos
Compostos de Boro , Fotoquimioterapia , Fármacos Fotossensibilizantes , Piridinas , Compostos de Piridínio , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Humanos , Animais , Compostos de Boro/farmacologia , Compostos de Boro/química , Compostos de Boro/síntese química , Camundongos , Compostos de Piridínio/farmacologia , Compostos de Piridínio/química , Compostos de Piridínio/síntese química , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Camundongos Endogâmicos BALB C , Camundongos Nus , Peroxidação de Lipídeos/efeitos dos fármacosRESUMO
The twist fusion of a benzothiophene group and the introduction of a 4-methyloxystyryl donor group to the BODIPY core resulted in large spin-orbit coupling values and smaller singlet-triplet energy gaps for the novel infrared absorbed photosensitizers named BSBDP. They show a high reactive oxygen species efficiency exceeding 69% and a fluorescence quantum yield of 23% and are successfully applied in imaging-guided photodynamic therapy in vitro and in vivo.
Assuntos
Compostos de Boro , Fotoquimioterapia , Fármacos Fotossensibilizantes , Tiofenos , Compostos de Boro/química , Compostos de Boro/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Tiofenos/química , Tiofenos/farmacologia , Humanos , Gotículas Lipídicas/química , Gotículas Lipídicas/metabolismo , Animais , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Estrutura MolecularRESUMO
Synergetic combination therapy is emerging as one of the most promising approaches for cancer treatment. Among the various therapeutic approaches, PDT has received particular attention due to its non-invasive nature. However, the therapeutic performance of PDT is severely affected by tumour hypoxia. Herein, we report a supramolecular strategy for the fabrication of a PDT-active 2D nanosheet loaded with a POD mimicking DNAzyme for the synergetic combination of PDT and CDT for targeted cancer therapy. Assembly of biotin-functionalized BODIPY (1) and cationic ß-cyclodextrin (ß-CD+) leads to the formation of a 1/ß-CD+ nanosheet with positively charged ß-CD+ on the surface of the sheet. The cationic face of the 1/ß-CD+ sheet was then loaded with a POD-mimicking Hem-loaded G-quadruplex aptamer (Hem/DNA1) via electrostatic interactions (1/ß-CD+/Hem/DNA1). Cellular internalization of the 1/ß-CD+/Hem/DNA1 nanosheet occurs via a receptor-mediated endocytic pathway, which then undergoes lysosomal escape. Subsequently, Hem/DNA1 on the surface of 1/ß-CD+/Hem/DNA1 reacts with endogenous H2O2via the Fenton pathway to produce ËOH and O2. Moreover, under cellular conditions, Hem inside the 1/ß-CD+/Hem/DNA1 nanosheet produces Fe2+, which then undergoes another Fenton reaction to produce ËOH and O2. The Fe3+ generated after the Fenton reaction is then reduced in situ to Fe2+ by glutathione for the next Fenton cycle. At the same time, photoirradiation of the 1/ß-CD+ nanosheet using a 635 nm laser produces 1O2via the PDT pathway by using endogenous O2. The most remarkable feature of the present nanoformulation is the cooperativity in its therapeutic action, wherein O2 produced during the CDT pathway was used by the 1/ß-CD+ sheet for improving its PDT efficacy in the hypoxic tumor microenvironment. This work represents a unique combination of CDT and PDT for targeted cancer therapy, wherein the CDT action of the nanoagent enhances the PDT efficacy and we strongly believe that this approach would encourage researchers to design similar combination therapy for advancements in the treatment of cancer.
Assuntos
Hemina , Nanoestruturas , Fotoquimioterapia , beta-Ciclodextrinas , Humanos , beta-Ciclodextrinas/química , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Hemina/química , Quadruplex G , Animais , Camundongos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Linhagem Celular Tumoral , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismoRESUMO
With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.
Assuntos
Terapia por Captura de Nêutron de Boro , Vesículas Extracelulares , Terapia por Captura de Nêutron de Boro/métodos , Animais , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Camundongos , Humanos , Boranos/química , Boro/química , Compostos de Boro/química , Compostos de Boro/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Camundongos Nus , Camundongos Endogâmicos BALB CRESUMO
Photodynamic therapy (PDT) is a minimally invasive method for cancer treatment, one of the effects of which is the oxidation of membrane lipids. However, changes in biophysical properties of lipid membranes during PDT have been poorly explored. In this work, we investigated the effects of PDT on membrane microviscosity in cancer cells in the culture and tumor xenografts. Membrane microviscosity was visualized using fluorescence lifetime imaging microscopy (FLIM) with a viscosity-sensitive rotor BODIPY2. It was found that PDT using chlorine e6-based photosensitizer Photoditazine caused a quick, steady elevation of membrane microviscosity both in cellulo and in vivo. The proposed mechanisms responsible for the increase in microviscosity was lipid peroxidation by reactive oxygen species that resulted in a decrease of phosphatidylcholine and the fraction of unsaturated fatty acids in the membranes. Our results suggest that the increased microviscosity is an important factor that contributes to tumor cell damage during PDT.
Assuntos
Membrana Celular , Fotoquimioterapia , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Animais , Humanos , Viscosidade , Camundongos , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Microscopia de Fluorescência , Compostos de Boro/química , Compostos de Boro/farmacologia , Porfirinas/química , Porfirinas/farmacologiaRESUMO
Photodynamic therapy (PDT) is a clinically-approved cancer treatment that is based on production of cytotoxic reactive oxygen species to induce cell death. However, its efficiency depends on distribution of photosensitizer (PS) and depth of light penetration through the tissues. Tendency of pathological cancer tissues to exhibit lower pH than healthy tissues inspired us to explore dual-targeted pH-activatable photosensitizers based on tunable near-infrared (NIR) boron-dipyrromethene (BODIPY) dyes. Our BODIPY PSs were designed to carry three main attributes: (i) biotin or cRGD peptide as an effective cancer cell targeting unit, (ii) amino moiety that is protonated in acidic (pH <6.5) conditions for pH-activation of the PS based on photoinduced electron transfer (PET) and (iii) hydrophilic groups enhancing the water solubility of very hydrophobic BODIPY dyes. Illumination of such compounds with suitable light (>640nm) allowed for high phototoxicity against HeLa (αvß3 integrin and biotin receptor positive) and A549 (biotin receptor positive) cells compared to healthy MRC-5 (biotin negative) cells. Moreover, no dark toxicity was observed on selected cell lines (>10 µM) providing promising photosensitizers for tumour-targeted photodynamic therapy.
Assuntos
Biotina , Compostos de Boro , Fotoquimioterapia , Fármacos Fotossensibilizantes , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Biotina/química , Compostos de Boro/química , Compostos de Boro/farmacologia , Concentração de Íons de Hidrogênio , Células HeLa , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Raios Infravermelhos , Células A549 , Sobrevivência Celular/efeitos dos fármacosRESUMO
The clearance of senescent cells may be detrimental to low cell density diseases, such as intervertebral disc degeneration (IVDD), and rejuvenating these cells presents a formidable obstacle. In this study, we investigate a mild-alkalization strategy employing magnesium boride-alginate (MB-ALG) hydrogels to rejuvenate senescent cells associated with age-related diseases. MB-ALG hydrogels proficiently ensnare senescent cells owing to their surface roughness. The hydrolysis of MB-ALG hydrogels liberates hydroxide ions (OH-), effecting a transition from an acidic microenvironment (pH â¼ 6.2) to a mildly alkaline state (pH â¼ 8.0), thereby fostering senescent cell proliferation via activation of the PI3K/Akt/mTOR pathway. Additionally, H2 aids in ROS clearance, which reduces cellular oxidative stress. And, Mg2+ rejuvenates senescent cells by inhibiting Ca2+ influx and fine-tuning the sirt1-p53 signaling pathways. Both in vitro and in vivo experiments conducted on rat intervertebral discs corroborate the sustained antisenescence and rejuvenation properties of MB-ALG hydrogels, with effects persisting for up to 12 weeks postoperation. These discoveries elucidate the role of mild-alkalization in dictating cellular destiny and provide key insights for addressing age-related diseases.
Assuntos
Alginatos , Senescência Celular , Hidrogéis , Alginatos/química , Alginatos/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Animais , Senescência Celular/efeitos dos fármacos , Ratos , Proliferação de Células/efeitos dos fármacos , Ratos Sprague-Dawley , Compostos de Boro/química , Compostos de Boro/farmacologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Magnésio/química , Magnésio/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
This study evaluated the therapeutic efficacy and underlying mechanisms of crisaborole combined with vitamin D in the treatment of allergic contact dermatitis. While crisaborole, a phosphodiesterase 4 inhibitor, and vitamin D analogs are commonly used in the treatment of atopic dermatitis, their combined therapeutic potential in allergic contact dermatitis (ACD) remains unexplored. Given their anti-inflammatory properties, we hypothesized that the combination of crisaborole and vitamin D could offer superior efficacy in mitigating the symptoms and underlying mechanisms of allergic contact dermatitis. In vitro, HaCaT cells stimulated with tumor necrosis factor-α and interferon-γ were treated with a combination of crisaborole and vitamin D, followed by cytokine expression analysis. In vivo, male C57BL/6 mice were divided into five groups and treated accordingly: blank control, dinitrochlorobenzene-induced model, crisaborole alone, vitamin D alone, and a combination of crisaborole and vitamin D. On day 14, dorsal skin and ear thickness were measured, followed by comprehensive pathological evaluations. In vivo and in vitro experiments showed that the expression levels of inflammatory factors were significantly lower in the DNCB + VD + Cri group than in the DNCB group. Histological analyses revealed that, compared with the DNCB group, the combined treatment group significantly reduced epidermal hyperkeratosis, improved epidermal transdermal water loss, decreased dermatitis scores, and diminished mast cell infiltration. Moreover, it lowered the expression levels of IL-6, IL-4, TNF-α, iNOS, IL-17, CC chemokine ligand 2 (CCL2), and CC chemokine receptor 2 (CCR2). CCL2 recognizes CCR2 and stimulates inflammatory cells, enhancing the inflammatory response. Increased CCL2 expression correlates with heightened inflammation and dendritic cell infiltration in ACD, while downregulation of CCL2 attenuates inflammation. Thus, the combined use of crisaborole and vitamin D demonstrates superior therapeutic efficacy over monotherapy in a mouse model of ACD. The combination of vitamin D and crisaborole significantly reduces inflammation and epidermal hyperkeratosis in a mouse model of allergic contact dermatitis, demonstrating superior therapeutic efficacy compared to either treatment alone. This suggests that the combined therapy could be a promising approach for the prevention and treatment of allergic contact dermatitis.
Assuntos
Compostos de Boro , Compostos Bicíclicos Heterocíclicos com Pontes , Dermatite Alérgica de Contato , Camundongos Endogâmicos C57BL , Vitamina D , Animais , Dermatite Alérgica de Contato/tratamento farmacológico , Dermatite Alérgica de Contato/patologia , Vitamina D/farmacologia , Vitamina D/administração & dosagem , Camundongos , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , Compostos de Boro/administração & dosagem , Masculino , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Quimioterapia Combinada , Citocinas/metabolismo , Modelos Animais de Doenças , Dinitroclorobenzeno , Pele/patologia , Pele/efeitos dos fármacos , Pele/metabolismoRESUMO
The development of new drug modalities has been facilitated recently by the introduction of boron as a component of organic compounds, and specifically within a benzoxaborale scaffold. This has enabled exploration of new chemical space and the development of effective compounds targeting a broad range of morbidities, including infections by protozoa, fungi, worms, and bacteria. Most notable is the recent demonstration of a single oral dose cure using acoziborole against African trypanosomiasis. Common and species-/structure-specific interactions between benzoxaboroles and parasite species have emerged and provide vital insights into the mechanisms of cidality, as well as potential challenges in terms of resistance and/or side effects. Here, we discuss the literature specific to benzoxaborole studies in parasitic protists and consider unanswered questions concerning this important new drug class.
Assuntos
Compostos de Boro , Animais , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Humanos , Boro/farmacologiaRESUMO
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Excessive stimulation of the inositol (1,4,5)-trisphosphate (IP3) signaling pathway has been linked to AF through abnormal calcium handling. However, little is known about the mechanisms involved in this process. We expressed the fluorescence resonance energy transfer (FRET)-based cytosolic cyclic adenosine monophosphate (cAMP) sensor EPAC-SH187 in neonatal rat atrial myocytes (NRAMs) and neonatal rat ventricular myocytes (NRVMs). In NRAMs, the addition of the α1-agonist, phenylephrine (PE, 3 µM), resulted in a FRET change of 21.20 ± 7.43%, and the addition of membrane-permeant IP3 derivative 2,3,6-tri-O-butyryl-myo-IP3(1,4,5)-hexakis(acetoxymethyl)ester (IP3-AM, 20 µM) resulted in a peak of 20.31 ± 6.74%. These FRET changes imply an increase in cAMP. Prior application of IP3 receptor (IP3R) inhibitors 2-aminoethyl diphenylborinate (2-APB, 2.5 µM) or Xestospongin-C (0.3 µM) significantly inhibited the change in FRET in NRAMs in response to PE. Xestospongin-C (0.3 µM) significantly inhibited the change in FRET in NRAMs in response to IP3-AM. The FRET change in response to PE in NRVMs was not inhibited by 2-APB or Xestospongin-C. Finally, the localization of cAMP signals was tested by expressing the FRET-based cAMP sensor, AKAP79-CUTie, which targets the intracellular surface of the plasmalemma. We found in NRAMs that PE led to FRET change corresponding to an increase in cAMP that was inhibited by 2-APB and Xestospongin-C. These data support further investigation of the proarrhythmic nature and components of IP3-induced cAMP signaling to identify potential pharmacological targets.NEW & NOTEWORTHY This study shows that indirect activation of the IP3 pathway in atrial myocytes using phenylephrine and direct activation using IP3-AM leads to an increase in cAMP and is in part localized to the cell membrane. These changes can be pharmacologically inhibited using IP3R inhibitors. However, the cAMP rise in ventricular myocytes is independent of IP3R calcium release. Our data support further investigation into the proarrhythmic nature of IP3-induced cAMP signaling.
Assuntos
AMP Cíclico , Citosol , Transferência Ressonante de Energia de Fluorescência , Átrios do Coração , Receptores de Inositol 1,4,5-Trifosfato , Miócitos Cardíacos , Animais , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , AMP Cíclico/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/citologia , Citosol/metabolismo , Ratos , Ratos Sprague-Dawley , Células Cultivadas , Animais Recém-Nascidos , Compostos de Boro/farmacologia , Fenilefrina/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Inositol 1,4,5-Trifosfato/metabolismo , Sistemas do Segundo Mensageiro/efeitos dos fármacosRESUMO
Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen (1O2) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (â OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H2O2), the therapeutic effect of which is highly dependent on the concentration of H2O2. Herein, we propose a BODIPY-ferrocene conjugate with a balanced 1O2 and â OH generation capacity, which can serve as a high-efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as-prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY-ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT.
Assuntos
Antineoplásicos , Compostos de Boro , Compostos Ferrosos , Metalocenos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Oxigênio Singlete , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Metalocenos/química , Compostos de Boro/química , Compostos de Boro/farmacologia , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Oxigênio Singlete/metabolismo , Oxigênio Singlete/química , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Excessive reactive oxygen species (ROS) in cellular environments leads to oxidative stress, which underlies numerous diseases, including inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, and cancer. Oxidative stress can be particularly damaging to biological membranes such as those found in mitochondria, which are abundant with polyunsaturated fatty acids (PUFAs). Oxidation of these biological membranes results in concomitant disruption of membrane structure and function, which ultimately leads to cellular dysfunction. Graphene quantum dots (GQDs) have garnered significant interest as a therapeutic agent for numerous diseases that are linked to oxidative stress. Specifically, GQDs have demonstrated an ability to protect mitochondrial structure and function under oxidative stress conditions. However, the fundamental mechanisms by which GQDs interact with membranes in oxidative environments are poorly understood. Here, we used C11-BODIPY, a fluorescent lipid oxidation probe, to develop quantitative fluorescence assays that determine both the extent and rate of oxidation that occurs to PUFAs in biological membranes. Based on kinetics principles, we have developed a generalizable model that can be used to assess the potency of antioxidants that scavenge ROS in the presence of biological membranes. By augmenting our fluorescence assays with 1H NMR spectroscopy, the results demonstrate that GQDs scavenge nascent hydroxyl and peroxyl ROS that interact with membranes and that GQDs are potent inhibitors of ROS-induced lipid oxidation in PUFA-containing biological membranes. The antioxidant potency of GQDs is comparable to or even greater than established antioxidant molecules, such as ascorbic acid and Trolox. This work provides mechanistic insights into the mitoprotective properties of GQDs under oxidative stress conditions, as well as a quantitative framework for assessing antioxidant interactions in biological membrane systems.
Assuntos
Grafite , Peroxidação de Lipídeos , Pontos Quânticos , Pontos Quânticos/química , Grafite/química , Grafite/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Antioxidantes/farmacologia , Antioxidantes/química , Teste de Materiais , Compostos de Boro/química , Compostos de Boro/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Humanos , Corantes Fluorescentes/química , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Ácidos Graxos Insaturados/metabolismo , Estrutura MolecularRESUMO
Triple negative breast cancer (TNBC) is a notoriously difficult disease to treat, and many of the existing TNBC chemotherapeutics lack tumor selectivity and the capability for simultaneously visualizing and monitoring their own activity in the biological context. However, TNBC cells have been known to generate high levels of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2). To this end, three novel small molecule theranostics 1a, 1c, and 2 consisting of both H2O2-responsive nitrogen mustard prodrug and profluorophore character have been designed, synthesized, and evaluated as targeted cancer therapeutics and bioimaging agents. The three theranostics comprise of boronate esters that deactivate nitrogen mustard functional groups and fluorophores but allow their selective activation through H2O2-specific oxidative deboronation for the release of the active drug and fluorophore. The three theranostics demonstrated H2O2-inducible DNA-alkylating capability and fluorescence turn-on properties in addition to selective anticancer activity. They are particularly effective in killing TNBC MDA-MB-468 cells with high H2O2 level while safe to normal epithelial MCF-10A cell. The conjugated boron-masked fluorophores in 1c and 2 are highly responsive towards H2O2, which enabled tracking of the theranostics in living cellular mitochondria and nucleus organelles. The three theranostics 1a, 1c, and 2 are capable of both selective release of the active drug to take effect in H2O2-rich cancer sites and simultaneously monitoring its activity. This single molecule system is of utmost importance to understand the function, efficacy, and mechanism of the H2O2-activated prodrugs and theranostics within the living recipient.
Assuntos
Antineoplásicos , Corantes Fluorescentes , Peróxido de Hidrogênio , Nanomedicina Teranóstica , Humanos , Alquilação , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluorescência , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Peróxido de Hidrogênio/farmacologia , Estrutura Molecular , Imagem Óptica , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologiaRESUMO
The spin-orbit charge transfer intersystem crossing (SOCT-ISC) photophysical process has shown great potential for constructing heavy-atom-free photosensitizers (PSs) for photodynamic therapy (PDT) of tumors. However, for almost all such PSs reported to date, the SOCT-ISC is driven by the acceptor-excited photoinduced electron transfer (a-PeT). In this work, for the first time the donor-excited photoinduced electron transfer (d-PeT)-driven SOCT-ISC mechanism is utilized to construct the heavy-atom-free PSs for PDT of tumors by directly installing the electron-deficient N-alkylquinolinium unit (as an electron acceptor) into the meso-position of the near-infrared (NIR) distyryl Bodipy chromophore (as an electron donor). In the less polar environment, the PSs exist as the monomer and promote the production of singlet oxygen (1O2) (Type-II) relying on the d-PeT-driven population of the triplet excited state via SOCT-ISC, whereas in the aqueous environment, they exist as nanoaggregates and induce the generation of superoxides (O2-â¢) and hydroxyl radicals (HOâ¢) (Type-I) via the d-PeT-driven formation of the delocalized charge-separated state. The PSs could rapidly be internalized into cancer cells and induce the simultaneous production of intracellular 1O2, O2-â¢, and HO⢠upon NIR light irradiation, endowing the PSs with superb photocytotoxicity with IC50 values up to submicromolar levels whether under normoxia or under hypoxia. Based on the PSs platform, a tumor-targetable PS is developed, and its abilities in killing cancer cells and in ablating tumors without damage to normal cells/tissues under NIR light irradiation are verified in vitro and in vivo. The study expands the design scope of PSs by introducing the d-PeT conception, thus being highly valuable for achieving novel PSs in the realm of tumor PDT.
Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/efeitos da radiação , Humanos , Camundongos , Animais , Transporte de Elétrons/efeitos dos fármacos , Oxigênio Singlete/metabolismo , Oxigênio Singlete/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Compostos de Boro/efeitos da radiação , Linhagem Celular Tumoral , Raios Infravermelhos , Sobrevivência Celular/efeitos dos fármacos , Hipóxia Tumoral/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
The potential of using image-guided photodynamic therapy (ig-PDT) for cancer, especially with highly biocompatible fluorescent agents free of heavy atoms, is well recognized. This is due to key advantages related to minimizing adverse side effects associated with standard cancer chemotherapy. However, this theragnostic approach is strongly limited by the lack of synthetically-accessible and easily-modulable chemical scaffolds, enabling the rapid design and construction of advanced agents for clinical ig-PDT. In fact, there are still very few ig-PDT agents clinically approved. Herein we report a readily accessible, easy-tunable and highly fluorescent all-organic small photosensitizer, as a model design for accelerating the development and translation of advanced ig-PDT agents for cancer. This scaffold is based on BODIPY, which assures high fluorescence, accessibility, and ease of performance adaptation by workable chemistry. The optimal PDT performance of this BODIPY dye, tested in highly resistant pancreatic cancer cells, despite its high fluorescent behavior, maintained even after fixation and cancer cell death, is based on its selective accumulation in mitochondria. This induces apoptosis upon illumination, as evidenced by proteomic studies and flow cytometry. All these characteristics make the reported BODIPY-based fluorescent photosensitizer a valuable model for the rapid development of ig-PDT agents for clinical use.
Assuntos
Compostos de Boro , Corantes Fluorescentes , Fotoquimioterapia , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/síntese química , Humanos , Compostos de Boro/química , Compostos de Boro/farmacologia , Compostos de Boro/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Estrutura Molecular , Linhagem Celular Tumoral , Imagem Óptica , Sobrevivência Celular/efeitos dos fármacosRESUMO
Boron neutron capture therapy (BNCT) is a unique radiotherapy of selectively eradicating tumor cells using boron compounds (e.g., 4-borono-L-phenylalanine [BPA]) that are heterogeneously taken up at the cellular level. Such heterogenicity potentially reduces the curative efficiency. However, the effects of temporospatial heterogenicity on cell killing remain unclear. With the technical combination of radiation track detector and biophysical simulations, this study revealed the cell cycle-dependent heterogenicity of BPA uptake and subsequent biological effects of BNCT on HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators, as well as the modification effects of polyvinyl alcohol (PVA). The results showed that the BPA concentration in the S/G2/M phase was higher than that in the G1/S phase and that PVA enhances the biological effects both by improving the uptake and by canceling the heterogenicity. These findings might contribute to a maximization of therapeutic efficacy when BNCT is combined with PVA and/or cell cycle-specific anticancer agents.