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1.
Anticancer Res ; 40(10): 5371-5378, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988856

RESUMO

BACKGROUND/AIM: 18 kDa Translocator protein (TSPO) is a mitochondrial protein up-regulated in colorectal carcinoma (CRC). Our purpose was to develop a TSPO-targeted doxorubicin prodrug (Dox-TSPO) which can be loaded onto drug-eluting beads for transarterial chemoembolization. Furthermore, we evaluated its loading and release kinetics and effects on cell viability. MATERIALS AND METHODS: N-Fmoc-DOX-14-O-hemiglutarate was coupled with a TSPO ligand, 6-TSPOmbb732, using classical N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate coupling to produce Dox-TSPO. Loading and elution studies were performed using DC beads™. Cell viability studies were performed using CellTiter-Glo® Luminescent Cell Viability Assay. RESULTS: Dox-TSPO was successfully synthesized and readily loaded onto and eluted from DC beads™, albeit at a slower rate than free doxorubicin. CRC cell lines expressing TSPO were 2- to 4- fold more sensitive to Dox-TSPO compared to free doxorubicin at 72 h. CONCLUSION: Dox-TSPO is a promising candidate for targeted and directed cancer treatment of CRC liver metastases.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/farmacologia , Pró-Fármacos/farmacologia , Receptores de GABA/genética , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Humanos , Pró-Fármacos/química , Receptores de GABA/química
2.
PLoS Pathog ; 16(6): e1007806, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32497104

RESUMO

Coagulase-positive staphylococci, which frequently colonize the mucosal surfaces of animals, also cause a spectrum of opportunistic infections including skin and soft tissue infections, urinary tract infections, pneumonia, and bacteremia. However, recent advances in bacterial identification have revealed that these common veterinary pathogens are in fact zoonoses that cause serious infections in human patients. The global spread of multidrug-resistant zoonotic staphylococci, in particular the emergence of methicillin-resistant organisms, is now a serious threat to both animal and human welfare. Accordingly, new therapeutic targets that can be exploited to combat staphylococcal infections are urgently needed. Enzymes of the methylerythritol phosphate pathway (MEP) of isoprenoid biosynthesis represent potential targets for treating zoonotic staphylococci. Here we demonstrate that fosmidomycin (FSM) inhibits the first step of the isoprenoid biosynthetic pathway catalyzed by deoxyxylulose phosphate reductoisomerase (DXR) in staphylococci. In addition, we have both enzymatically and structurally determined the mechanism by which FSM elicits its effect. Using a forward genetic screen, the glycerol-3-phosphate transporter GlpT that facilitates FSM uptake was identified in two zoonotic staphylococci, Staphylococcus schleiferi and Staphylococcus pseudintermedius. A series of lipophilic ester prodrugs (termed MEPicides) structurally related to FSM were synthesized, and data indicate that the presence of the prodrug moiety not only substantially increased potency of the inhibitors against staphylococci but also bypassed the need for GlpT-mediated cellular transport. Collectively, our data indicate that the prodrug MEPicides selectively and robustly inhibit DXR in zoonotic staphylococci, and further, that DXR represents a promising, druggable target for future development.


Assuntos
Antibacterianos , Farmacorresistência Bacteriana Múltipla , Pró-Fármacos , Infecções Estafilocócicas , Staphylococcus , Zoonoses , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/metabolismo , Staphylococcus/genética , Staphylococcus/crescimento & desenvolvimento , Zoonoses/tratamento farmacológico , Zoonoses/genética , Zoonoses/metabolismo , Zoonoses/microbiologia
3.
Antiviral Res ; 180: 104857, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32562705

RESUMO

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 worldwide pandemic. We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. We report here the evaluation of a library of nucleoside triphosphate analogues with a variety of structural and chemical features as inhibitors of the RdRps of SARS-CoV and SARS-CoV-2. These features include modifications on the sugar (2' or 3' modifications, carbocyclic, acyclic, or dideoxynucleotides) or on the base. The goal is to identify nucleotide analogues that not only terminate RNA synthesis catalyzed by these coronavirus RdRps, but also have the potential to resist the viruses' exonuclease activity. We examined these nucleotide analogues for their ability to be incorporated by the RdRps in the polymerase reaction and to prevent further incorporation. While all 11 molecules tested displayed incorporation, 6 exhibited immediate termination of the polymerase reaction (triphosphates of Carbovir, Ganciclovir, Stavudine and Entecavir; 3'-OMe-UTP and Biotin-16-dUTP), 2 showed delayed termination (Cidofovir diphosphate and 2'-OMe-UTP), and 3 did not terminate the polymerase reaction (2'-F-dUTP, 2'-NH2-dUTP and Desthiobiotin-16-UTP). The coronaviruses possess an exonuclease that apparently requires a 2'-OH at the 3'-terminus of the growing RNA strand for proofreading. In this study, all nucleoside triphosphate analogues evaluated form Watson-Crick-like base pairs. The nucleotide analogues demonstrating termination either lack a 2'-OH, have a blocked 2'-OH, or show delayed termination. Thus, these nucleotide analogues are of interest for further investigation to evaluate whether they can evade the viral exonuclease activity. Prodrugs of five of these nucleotide analogues (Cidofovir, Abacavir, Valganciclovir/Ganciclovir, Stavudine and Entecavir) are FDA-approved medications for treatment of other viral infections, and their safety profiles are well established. After demonstrating potency in inhibiting viral replication in cell culture, candidate molecules can be rapidly evaluated as potential therapies for COVID-19.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/virologia , Nucleotídeos/farmacologia , Pneumonia Viral/virologia , RNA Replicase/antagonistas & inibidores , Vírus da SARS/enzimologia , Síndrome Respiratória Aguda Grave/virologia , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus/enzimologia , Betacoronavirus/genética , Cidofovir/química , Cidofovir/farmacologia , Cidofovir/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Didesoxinucleosídeos/química , Didesoxinucleosídeos/farmacologia , Didesoxinucleosídeos/uso terapêutico , Ganciclovir/química , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Guanina/análogos & derivados , Guanina/química , Guanina/farmacologia , Guanina/uso terapêutico , Nucleotídeos/química , Nucleotídeos/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , RNA Viral/antagonistas & inibidores , RNA Viral/biossíntese , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Estavudina/química , Estavudina/farmacologia , Estavudina/uso terapêutico , Valganciclovir/química , Valganciclovir/farmacologia , Valganciclovir/uso terapêutico
4.
Nat Commun ; 11(1): 2323, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385252

RESUMO

An on-demand anesthetic that would only take effect when needed and where the intensity of anesthesia could be easily adjustable according to patients' needs would be highly desirable. Here, we design and synthesize a macromolecular prodrug (P407-CM-T) in which the local anesthetic tetracaine (T) is attached to the polymer poloxamer 407 (P407) via a photo-cleavable coumarin linkage (CM). P407-CM-T solution is an injectable liquid at room temperature and gels near body temperature. The macromolecular prodrug has no anesthetic effect itself unless irradiated with a low-power blue light emitting diode (LED), resulting in local anesthesia. By adjusting the intensity and duration of irradiation, the anesthetic effect can be modulated. Local anesthesia can be repeatedly triggered.


Assuntos
Anestésicos Locais/química , Anestesia Local/métodos , Animais , Sistemas de Liberação de Medicamentos , Humanos , Estrutura Molecular , Poloxâmero/química , Pró-Fármacos/química , Temperatura
5.
Int J Nanomedicine ; 15: 2921-2933, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425524

RESUMO

Background: Targeted prodrug has various applications as drug formulation for tumor therapy. Therefore, amphoteric small-molecule prodrug combined with nanoscale characteristics for the self-assembly of the nano-drug delivery system (DDS) is a highly interesting research topic. Methods and Results: In this study, we developed a prodrug self-assembled nanoplatform, 2-glucosamine-fluorescein-5(6)-isothiocyanate-glutamic acid-paclitaxel (2DA-FITC-PTX NPs) by integration of targeted small molecule and nano-DDS with regular structure and perfect targeting ability. 2-glucosamine (DA) and paclitaxel were conjugated as the targeted ligand and anti-tumor chemotherapy drug by amino acid group. 2-DA molecular structure can enhance the targeting ability of prodrug-based 2DA-FITC-PTX NPs and prolong retention time, thereby reducing the toxicity of normal cell/tissue. The fluorescent dye FITC or near-infrared fluorescent dye ICG in prodrug-based DDS was attractive for in vivo optical imaging to study the behavior of 2DA-FITC-PTX NPs. In vitro and in vivo results proved that 2DA-FITC-PTX NPs exhibited excellent targeting ability, anticancer activity, and weak side effects. Conclusion: This work demonstrates a new combination of nanomaterials for chemotherapy and may promote prodrug-based DDS clinical applications in the future.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Paclitaxel/administração & dosagem , Pró-Fármacos/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Fluoresceína-5-Isotiocianato/química , Glucosamina/química , Ácido Glutâmico/química , Humanos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Paclitaxel/química , Paclitaxel/farmacocinética , Pró-Fármacos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nat Chem Biol ; 16(5): 497-506, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32231343

RESUMO

We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4.


Assuntos
Inibidores Enzimáticos/farmacologia , Nitrilos/química , Nitrilos/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Ferroptose/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos SCID , Sondas Moleculares/química , Terapia de Alvo Molecular , Óxidos/química , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/química , Pró-Fármacos/química , Ratos Wistar , Selenocisteína/química , Selenocisteína/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
7.
Chemistry ; 26(45): 10297-10306, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32275091

RESUMO

PhotoCORMs are light-triggered compounds that release CO for medical applications. Here, we apply laser spectroscopy in the gas phase to TryptoCORM, a known photoCORM that has been shown to destroy Escherichia coli upon visible-light activation. Our experiments allow us to map TryptoCORM's photochemistry across a wide wavelength range by using novel laser-interfaced mass spectrometry (LIMS). LIMS provides the intrinsic absorption spectrum of the photoCORM along with the production spectra of all of its ionic photoproducts for the first time. Importantly, the photoproduct spectra directly reveal the optimum wavelengths for maximizing CO ejection, and the extent to which CO ejection is compromised at redder wavelengths. A series of comparative studies were performed on TryptoCORM-CH3 CN which exists in dynamic equilibrium with TryptoCORM in solution. Our measurements allow us to conclude that the presence of the labile CH3 CN facilitates CO release over a wider wavelength range. This work demonstrates the potential of LIMS as a new methodology for assessing active agent release (e.g. CO, NO, H2 S) from light-activated prodrugs.


Assuntos
Monóxido de Carbono/química , Escherichia coli/química , Pró-Fármacos/química , Cor , Luz , Espectrofotometria Infravermelho
8.
Int J Nanomedicine ; 15: 1771-1786, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214810

RESUMO

Purpose: In this study, pH-sensitive poly(2-ethyl-2-oxazoline)-poly(lactic acid)-poly(ß-amino ester) (PEOz-PLA-PBAE) triblock copolymers were synthesized and were conjugated with an antimalaria drug artesunate (ART), for inhibition of a colon cancer xenograft model. Methods: The as-prepared polymer prodrugs are tended to self-assemble into polymeric micelles in aqueous milieu, with PEOz segment as hydrophilic shell and PLA-PBAE segment as hydrophobic core. Results: The pH sensitivity of the as-prepared copolymers was confirmed by acid-base titration with pKb values around 6.5. The drug-conjugated polymer micelles showed high stability for at least 96 h in PBS and 37°C, respectively. The as-prepared copolymer prodrugs showed high drug loading content, with 9.57%±1.24% of drug loading for PEOz-PLA-PBAE-ART4. The conjugated ART could be released in a sustained and pH-dependent manner, with 92% of released drug at pH 6.0 and 57% of drug released at pH 7.4, respectively. In addition, in vitro experiments showed higher inhibitory effect of the prodrugs on rodent CT-26 cells than that of free ART. Animal studies also demonstrated the enhanced inhibitory efficacy of PEOz-PLA-PBAE-ART2 micelles on the growth of rodent xenograft tumor. Conclusion: The pH-responsive artesunate polymer prodrugs are promising candidates for colon cancer adjuvant therapy.


Assuntos
Artesunato/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Polímeros/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Animais , Artesunato/química , Neoplasias do Colo/patologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Camundongos Endogâmicos BALB C , Micelas , Oxazóis/química , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Mater Sci Eng C Mater Biol Appl ; 108: 110461, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924029

RESUMO

A novel bio-responsive co-delivery system based on Poly(DEA)-b-Poly(ABMA-co-OEGMA) (PDPAO, prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization) copolymers was constructed for enhanced cellular internalization and effective combination therapy. Reduction-sensitive 6-mercaptopurine (6MP) based prodrug and pH-sensitive doxorubicin (DOX) based prodrug were grafted onto PDPAO by an azide-alkyne "Click Chemistry" reaction to acquire a pH/reduction-sensitive polymeric prodrug (PDPAO@imine-DOX/cis-6MP), which was able to self-aggregate to form polymeric micelles (M(DOX/6MP)) with an average particle size of 116 ± 2 nm in the water. The resultant micelles could maintain a stable sphere structure and show stability with a small particles' dispersion index in the blood. Importantly, it has been observed that the pH-sensitive surface charge-conversion accompanied pH-triggered DOX release in the biomimetic extracellular acidic environment of tumor tissue and a rapid dual-drug release triggered by pH and GSH in the intracellular environment. The in vitro evaluation of micelles on human cervical cancer (HeLa) and human promyelocytic leukemia (HL-60) cells showed an enhanced cellular uptake because of charge-conversion and exhibited a higher cell-killing performance. Moreover, the graft ratio of DOX and 6MP showed the ability to adjust the cytotoxicity; the micelles with a graft ratio of 2: 1 (M(DOX2/6MP)) displayed the higher cellular inhibition on either HeLa (combination index (CI) = 0.62) or HL-60 (CI = 0.35) cells. Overall, this novel dual-drug-conjugated delivery system might have important potential applications for combination therapy of cancer.


Assuntos
Química Click , Doxorrubicina , Portadores de Fármacos , Mercaptopurina , Neoplasias/tratamento farmacológico , Pró-Fármacos , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Células HL-60 , Células HeLa , Humanos , Mercaptopurina/química , Mercaptopurina/farmacologia , Neoplasias/metabolismo , Neoplasias/patologia , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia
10.
PLoS One ; 15(1): e0227104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31914458

RESUMO

Despite the availability of highly effective direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infections, sustained viral response (SVR) rates remain suboptimal for difficult-to-treat patient populations such as those with HCV genotype 3, cirrhosis or prior treatment experience, warranting development of more potent HCV replication antivirals. AT-527 is the hemi-sulfate salt of AT-511, a novel phosphoramidate prodrug of 2'-fluoro-2'-C-methylguanosine-5'-monophosphate that has potent in vitro activity against HCV. The EC50 of AT-511, determined using HCV laboratory strains and clinical isolates with genotypes 1-5, ranged from 5-28 nM. The active 5'-triphosphate metabolite, AT-9010, specifically inhibited the HCV RNA-dependent RNA polymerase. AT-511 did not inhibit the replication of other selected RNA or DNA viruses in vitro. AT-511 was approximately 10-fold more active than sofosbuvir (SOF) against a panel of laboratory strains and clinical isolates of HCV genotypes 1-5 and remained fully active against S282T resistance-associated variants, with up to 58-fold more potency than SOF. In vitro, AT-511 did not inhibit human DNA polymerases or elicit cytotoxicity or mitochondrial toxicity at concentrations up to 100 µM. Unlike the other potent guanosine analogs PSI-938 and PSI-661, no mutagenic O6-alkylguanine bases were formed when incubated with cytochrome P450 (CYP) 3A4, and AT-511 had IC50 values ≥25 µM against a panel of CYP enzymes. In hepatocytes from multiple species, the active triphosphate was the predominant metabolite produced from the prodrug, with a half-life of 10 h in human hepatocytes. When given orally to rats and monkeys, AT-527 preferentially delivered high levels of AT-9010 in the liver in vivo. These favorable preclinical attributes support the ongoing clinical development of AT-527 and suggest that, when used in combination with an HCV DAA from a different class, AT-527 may increase SVR rates, especially for difficult-to-treat patient populations, and could potentially shorten treatment duration for all patients.


Assuntos
Antivirais/farmacologia , Guanosina/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Pró-Fármacos/farmacologia , Animais , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacocinética , Linhagem Celular , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Feminino , Guanosina/análogos & derivados , Guanosina/metabolismo , Guanosina/farmacocinética , Haplorrinos , Hepacivirus/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacocinética , Ratos
11.
Arch Pharm Res ; 43(1): 118-133, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31916145

RESUMO

Albumin is a biocompatible, non-immunogenic and versatile drug carrier system. It has been widely used to extend the half-life, enhance stability, provide protection from degradation and allow specific targeting of therapeutic agents to various disease states. Understanding the role of albumin as a drug delivery and distribution system has increased remarkably in the recent years from the development of albumin-binding prodrugs to albumin as a drug carrier system. The extraordinary surface property of albumin makes it possible to bind various endogenous and exogenous molecules. This review succinctly deals with several albumin-drug conjugates and nanoparticles along with their preparation techniques and focuses on surface-modified albumin and targeting of albumin formulation to specific organs and tissues. It also summarizes research efforts on albumin nanoparticles used for delivering drugs to tumor cells and describes their role in permeation through tumor vasculature and in receptor mediated endocytosis, which is also described in this review. The versatility of albumin and ease of preparation makes it a suitable drug carrier system, swhich is the major objective of this review.


Assuntos
Albuminas/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Nanotecnologia , Neoplasias/tratamento farmacológico , Pró-Fármacos/química , Animais , Portadores de Fármacos/química , Endocitose/efeitos dos fármacos , Humanos , Neoplasias/patologia , Pró-Fármacos/farmacologia
13.
J Colloid Interface Sci ; 565: 483-493, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31982715

RESUMO

The complex biology of glioma compromises therapeutic efficacy and results in poor prognosis. Photodynamic therapy (PDT) has emerged as a promising modality for localized tumor ablation with limited damage to healthy brain tissues. However, low photosensitizer concentration and hypoxic microenvironment in glioma tissue hamper the practical applications of PDT. To address the challenges, biocompatible periodic mesoporous organosilica coated Prussian blue nanoparticles (PB@PMOs) are constructed to load a biosafe prodrug 5-aminolevulinic acid (5-ALA), which is pronouncedly converted to protoporphyrin IX (PpIX) in malignant cells. PB@PMO-5-ALA induces a higher accumulation of PpIX in glioma cells compared to free 5-ALA. Meanwhile, the PB@PMOs, with a mean edge length of 81 nm and good biocompatibility, effectively decompose hydrogen peroxide to oxygen in a temperature-responsive manner. Oxygen supply further contributes to the promotion of 5-ALA-PDT. Thus, the photodynamic effect of PB@PMO-5-ALA is significantly improved, imposing augmented cytotoxicity to glioma U87MG cells. Furthermore, ex vivo fluorescence imaging elucidates the tumor PpIX increases by 75% in PB@PMO-5-ALA treated mice than that in 5-ALA treated ones post 12 h injection. Magnetic resonance imaging (MRI) and iron staining strongly demonstrate the accumulation of PB@PMO-5-ALA in glioma tissues with negative contrast enhancement and blue staining deposits, respectively. The nanoparticle accumulation and high PpIX level collaboratively enhance PDT efficacy through PB@PMO-5-ALA, which efficiently suppresses tumor growth, providing a promising option with safety for local glioma ablation.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Ácidos Levulínicos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Neoplasias Encefálicas/diagnóstico por imagem , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Ferrocianetos/química , Ferrocianetos/farmacologia , Glioma/diagnóstico por imagem , Humanos , Ácidos Levulínicos/química , Nanopartículas/química , Imagem Óptica , Compostos de Organossilício/química , Compostos de Organossilício/farmacologia , Oxigênio/química , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Porosidade , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Propriedades de Superfície , Microambiente Tumoral/efeitos dos fármacos
14.
Dalton Trans ; 49(5): 1613-1619, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31942585

RESUMO

We herein designed two new PtIV prodrugs of oxoplatin (cis,cis,cis-[PtCl2(NH3)2(OH)2]), [PtIVCl2(NH3)2(O2C-FA)2] (Pt-2) and [PtIVCl2(NH3)2(O2C-RH)2] (Pt-3), by conjugating with ferulic acid (FA-COOH) and rhein (RH-COOH) which have well-known biological activities. Three other Pt(iv) complexes of [PtIVCl2(NH3)2(O2C-BA)2] (Pt-1), [PtIVCl2(NH3)2(O2C-CA)2] (Pt-4) and [PtIVCl2(NH3)2(O2C-TCA)2] (Pt-5) (where BA-COOH = benzoic acid, CA-COOH = crotonic acid and TCA-COOH = trans-cinnamic acid) were also prepared for the comparative study. Like most PtIV prodrug complexes, the cytotoxicity of Pt-3 containing the biologically active rhein (RH-COOH) ligand against lung carcinoma (A549 and A549/DDP) cells was higher than those of Pt-1, Pt-2, Pt-4, cisplatin and Pt-5. Moreover, the cytotoxicity of Pt-3 in HL-7702 normal cells was lower than those of PtIV derivatives bearing BA-COOH, FA-COOH, TCA-COOH and CA-COOH ligands. The highly efficacious Pt-2 and Pt-3 were found to accumulate strongly in the A549/DDP cells, with the prodrug Pt-3 showing highest levels of penetration into the mitochondria. The prodrug Pt-3 effectively entered the A549/DDP cells and caused mitochondrial damage, significantly greater than Pt-2. In addition, the prodrug Pt-3 exhibited higher antitumor efficacy (inhibition rates (IR) = 67.45%) than Pt-2 (28.12%) and cisplatin (33.05%) in the A549/DDP xenograft mouse model. Thus, the prodrug Pt-3 containing the rhein (RH-COOH) ligand is a promising candidate drug targeting the mitochondria.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Cisplatino/análogos & derivados , Ácidos Cumáricos/farmacologia , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/farmacologia , Células A549 , Animais , Antraquinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Ácidos Cumáricos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
15.
Molecules ; 25(2)2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31963730

RESUMO

In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug's expected activity was lost after PPG protection. In BRCA1- and BRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP.


Assuntos
Técnicas de Química Sintética , Desenho de Fármacos , Ftalazinas/química , Ftalazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Estabilidade de Medicamentos , Humanos , Processos Fotoquímicos , Ftalazinas/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Pró-Fármacos/síntese química , Relação Estrutura-Atividade , Raios Ultravioleta
16.
Eur J Med Chem ; 186: 111878, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757524

RESUMO

We have previously disclosed compound 3 (CZh-226), a potent and selective PAK4 inhibitor, but its development was delayed due to poor oral pharmacokinetics. In an attempt to improve this issue, we synthesised a series of prodrugs by masking its terminal nitrogen of the piperazine moiety. Most synthesised prodrugs of 3 have low or no inhibition of PAK4 activity. The stability of synthetic prodrugs was evaluated in PBS, SGF, SIF, rat plasma and liver S9 fraction. Of these, prodrug 19 was not only stable under both acidic and neutral conditions but also could be quickly converted to parent drug 3 in rat plasma and liver S9 fraction. Such effective conversion into parent drug 3 was observed in rats, providing higher exposure of 3 compared to its direct administration. When given via oral route at daily doses of 25 and 50 mg/kg, the prodrug 19 was effective and well tolerated in mouse model of HCT-116 and B16F10.


Assuntos
Antineoplásicos/farmacologia , Piperazinas/farmacologia , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Fígado/química , Fígado/metabolismo , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piperazinas/síntese química , Piperazinas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Quinases Ativadas por p21/metabolismo
17.
Biomater Sci ; 8(1): 473-484, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31755481

RESUMO

Compared to normal tissues, unique conditions in the tumor microenvironment, such as a lower pH, can induce accurate release of a drug into specific lesions. This strategy provides an efficient approach to overcome the issues of unexpected drug leakage and poor circulation stability, thereby reducing the side effects and enhancing the effect of cancer treatment. In this study, we designed a class of acid activatable supramolecular nano-prodrugs (DOM@DOX) with a bottlebrush architecture based on the dextran (DEX) polysaccharide, which connects with a hydrophilic polyethylene glycol chain by atom transfer radical polymerization and further conjugates with an anticancer drug doxorubicin (DOX) at the backbone of the copolymer via an acidity-responsive hydrazine bond. Furthermore, the DOM@DOX prodrug has a high drug loading up to 48 wt% for DOX, and the prodrug can maintain a stable nano-sized spherical shape in aqueous solution by a self-assembly strategy. In an acidic environment inside tumor cells, the hydrazine bond of the prodrug breaks, leading to the release of DOX from parental micelles. Owing to the small size of the carrier, the prodrug exhibits good intratumoral permeability, good circulation stability and significant tumor suppression efficiency in tumor-bearing mouse models, which is beneficial for the development of new generation nanomedicine for enhanced chemotherapy.


Assuntos
Dextranos/química , Micelas , Pró-Fármacos/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Imagem Óptica , Polietilenoglicóis/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico
18.
Biomater Sci ; 8(1): 266-277, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31690897

RESUMO

Allotransplantation offers the potential to restore the anatomy and function of injured tissues and organs, but typically requires life-long, systemic administration of immunosuppressive drugs to prevent rejection, which can result in serious complications. Targeting the immunosuppressive drug to the graft favors local tissue concentration versus systemic drug exposure and end-organ toxicity. This could reduce the overall dose and dosing frequency of immunosuppressive drugs, and improve the safety and efficacy of treatment. Here, we developed dibenzocyclooctyne (DBCO)-modified prodrugs of the immunosuppressive drugs tacrolimus, rapamycin and mycophenolic acid, and demonstrated their targeted conjugation both in vitro and in vivo to azido-modified hydrogels via Click chemistry. Such azido-modified hydrogels placed in transplanted tissues enable sustained local release of drugs, and could be repeatedly refilled with systemically administered acid-labile prodrugs after drug exhaustion. Thus, clickable prodrugs with degradable linkers provide new possibilities for graft targeted immunosuppression in the context of allotransplantation.


Assuntos
Química Click , Imunossupressores/química , Pró-Fármacos/química , Alginatos/química , Animais , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Meia-Vida , Hidrocarbonetos Cíclicos/química , Hidrogéis/química , Concentração de Íons de Hidrogênio , Imunossupressores/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ácido Micofenólico/química , Pró-Fármacos/metabolismo , Sirolimo/química , Tacrolimo/química
19.
Chemistry ; 26(1): 148-154, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31503360

RESUMO

We present a new approach for the identification of inhibitors of phosphorylation-dependent protein-protein interaction domains, in which phenolic fragments are adapted by in silico O-phosphorylation before docking-based screening. From a database of 10 369 180 compounds, we identified 85 021 natural product-derived phenolic fragments, which were virtually O-phosphorylated and screened for in silico binding to the STAT3 SH2 domain. Nine screening hits were then synthesized, eight of which showed a degree of in vitro inhibition of STAT3. After analysis of its selectivity profile, the most potent inhibitor was then developed to Stafia-1, the first small molecule shown to preferentially inhibit the STAT family member STAT5a over the close homologue STAT5b. A phosphonate prodrug based on Stafia-1 inhibited STAT5a with selectivity over STAT5b in human leukemia cells, providing the first demonstration of selective in vitro and intracellular inhibition of STAT5a by a small-molecule inhibitor.


Assuntos
Organofosfonatos/química , Fator de Transcrição STAT5/antagonistas & inibidores , Proteínas Supressoras de Tumor/antagonistas & inibidores , Sítios de Ligação , Produtos Biológicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Organofosfonatos/metabolismo , Organofosfonatos/farmacologia , Fosforilação , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Fator de Transcrição STAT5/metabolismo , Relação Estrutura-Atividade , Proteínas Supressoras de Tumor/metabolismo , Domínios de Homologia de src
20.
Colloids Surf B Biointerfaces ; 185: 110537, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629094

RESUMO

Self-assembling prodrug containing pH- and redox-responsive functional groups was prepared by covalent conjugation of Doxorubicin (Dox) and lipoic acid (LA) to a polyaldehyde Dextran (PAD). The resultant amphiphilic DoxPADLA forms, in a single step, hemocompatible vesicular systems able to respond to intracellular signals without using external crosslinking agents. Camptothecin (CPT) was encapsulated exploiting the hydrophobic interactions with the vesicle membrane, and release experiments, carried out in media mimicking the physiological and endolysosomial compartments, in the absence or presence of Glutathione, proved the ability of the system to modulate drug release in relation to the variation of pH and redox potential. Cytotoxicity assays and confocal experiments demonstrated the efficacy of the vesicle formulation in enhancing the synergistic anticancer effect of the delivered Dox and CPT and a rapid and significant internalization of the carrier in cancer cells.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Dextranos/química , Sistemas de Liberação de Medicamentos , Pró-Fármacos/química , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Sobrevivência Celular , Dextranos/síntese química , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Endocitose , Esterificação , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Oxirredução , Pró-Fármacos/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
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