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1.
J Nanobiotechnology ; 17(1): 76, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217009

RESUMO

BACKGROUND: Molybdenum disulfide (MoS2) has been widely explored for biomedical applications due to its brilliant photothermal conversion ability. In this paper, we report a novel multifunctional MoS2-based drug delivery system (MoS2-SS-HA). By decorating MoS2 nanosheets with hyaluronic acid (HA), these functionalized MoS2 nanosheets have been developed as a tumor-targeting chemotherapeutic nanocarrier for near-infrared (NIR) photothermal-triggered drug delivery, facilitating the combination of chemotherapy and photothermal therapy into one system for cancer therapy. RESULTS: The nanocomposites (MoS2-SS-HA) generated a uniform diameter (ca. 125 nm), exhibited great biocompatibility as well as high stability in physiological solutions, and could be loaded with the insoluble anti-cancer drug erlotinib (Er). The release of Er was greatly accelerated under near infrared laser (NIR) irradiation, showing that the composites can be used as responsive systems, with Er release controllable through NIR irradiation. MTT assays and confocal imaging results showed that the MoS2-based nanoplatform could selectively target and kill CD44-positive lung cancer cells, especially drug resistant cells (A549 and H1975). In vivo tumor ablation studies prove a better synergistic therapeutic effect of the joint treatment, compared with either chemotherapy or photothermal therapy alone. CONCLUSION: The functionalized MoS2 nanoplatform developed in this work could be a potent system for targeted drug delivery and synergistic chemo-photothermal cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Dissulfetos/química , Portadores de Fármacos/química , Cloridrato de Erlotinib/farmacologia , Hipertermia Induzida , Molibdênio/química , Nanocompostos/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Cloridrato de Erlotinib/química , Feminino , Humanos , Ácido Hialurônico/química , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fototerapia
2.
AAPS PharmSciTech ; 20(3): 135, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30830506

RESUMO

Lung cancer patients develop acquired resistance to tyrosine kinase inhibitors including erlotinib (ERL) after few months of primary treatment. Evidently, new chemotherapy strategies to delay or overcome the resistance are urgently needed to improve the clinical outcome in non-small cell lung cancer (NSCLC) patients. In this paper, we have investigated the cytotoxic interaction of ERL and valproic acid (VA) in ERL-resistant NSCLC cells and developed a liquisolid formulation of ERL-VA for improving oral bioavailability of ERL. ERL is weakly basic, biopharmaceutical classification system (BCS) class II drug with extremely poor aqueous solubility while VA is a branched chain fatty acid. Ionic interaction between ERL and VA (1:2 M ratio) resulted in significant enhancement in saturation solubility of ERL at different pH range. Liquisolid formulation of ERL-VA (EVLF) developed using PEG 400 and mesoporous calcium silicate was characterized for solid state and in vitro dissolution in biorelevant dissolution medium (FaSSIF and FeSSIF). Cytotoxicity of ERL was enhanced by 2-5 folds on co-incubation with VA in HCC827/ERL cell line. Flow cytometry analysis using AnnexinV-FITC assay demonstrated that VA and ERL alone have poor apoptotic effect on HCC827/ERL cells while combination showed around 69% apoptotic cells. Western blot analysis confirmed the role of survivin in overcoming resistance. In vivo pharmacokinetic studies of EVLF in rats demonstrated a 199% relative bioavailability compared to ERL suspension. Thus, EVLF could be a promising alternative to current ERL formulations in the treatment of NSCLC.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular/efeitos dos fármacos , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Neoplasias Pulmonares/patologia , Ácido Valproico/química , Ácido Valproico/farmacologia , Administração Oral , Animais , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Compostos de Cálcio/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Cloridrato de Erlotinib/farmacocinética , Humanos , Neoplasias Pulmonares/metabolismo , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Silicatos/química , Solubilidade , Ácido Valproico/farmacocinética
3.
J Mol Model ; 25(3): 65, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30762124

RESUMO

Soft spot analysis helps evaluate the site of the metabolic lability that impacts the bio-availability of the drug. However, given its laborious and time consuming experimentation, we propose a reliable and cheap in silico strategy. In this context, we hypothesized a mechanistic rationale for metabolism of erlotinib by the CYP3A4 enzyme. The comparison of the 3D conformations of the target CYP class of enzymes using MD simulations with GROMACS helped evaluate its impact on the metabolism. The molecular docking studies using Autodock-Vina ascertained the explicit role of the Fe ion present in the Heme moiety in this process. This mechanism was confirmed with respect to 13 other popular approved FDA kinase inhibitors using ab initio DFT calculations using Gaussian 09 (G09), molecular docking studies with Autodock-Vina, and MD simulations with GROMACS. We then developed a quantitative (Q-Met) metabolic profile of these soft spots in the molecules and demonstrated the lack of a linear relationship between the extent of metabolism and drug efficacy. We thus propose an economic in silico strategy for the early prediction of the lability in kinase inhibitors to help model their bio-availability and activity simultaneously, prior to clinical testing.


Assuntos
Citocromo P-450 CYP3A/química , Cloridrato de Erlotinib/farmacocinética , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Disponibilidade Biológica , Simulação por Computador , Citocromo P-450 CYP3A/metabolismo , Desenho de Drogas , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Termodinâmica
4.
BMC Pulm Med ; 19(1): 3, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30612556

RESUMO

BACKGROUND: EGFR mutations are routinely explored in lung adenocarcinoma by sequencing tumoral DNA. The aim of this study was to evaluate a fluorescent-labelled erlotinib based theranostic agent for the molecular imaging of mutated EGFR tumours in vitro and ex vivo using a mice xenograft model and fibred confocal fluorescence microscopy (FCFM). METHODS: The fluorescent tracer was synthesized in our laboratory by addition of fluorescein to an erlotinib molecule. Three human adenocarcinoma cell lines with mutated EGFR (HCC827, H1975 and H1650) and one with wild-type EGFR (A549) were xenografted on 35 Nude mice. MTT viability assay was performed after exposure to our tracer. In vitro imaging was performed at 1 µM tracer solution, and ex vivo imaging was performed on fresh tumours excised from mice and exposed to a 1 µM tracer solution in PBS for 1 h. Real-time molecular imaging was performed using FCFM and median fluorescence intensity (MFI) was recorded for each experiment. RESULTS: MTT viability assay confirmed that addition of fluorescein to erlotinib did not suppress the cytotoxic of erlotinib on tumoral cells. In vitro FCFM imaging showed that our tracer was able to distinguish cell lines with mutated EGFR from those lines with wild-type EGFR (p < 0.001). Ex vivo FCFM imaging of xenografts with mutated EGFR had a significantly higher MFI than wild-type (p < 0.001). At a cut-off value of 354 Arbitrary Units, MFI of our tracer had a sensitivity of 100% and a specificity of 96.3% for identifying mutated EGFR tumours. CONCLUSION: Real time molecular imaging using fluorescent erlotinib is able to identify ex vivo tumours with EGFR mutations.


Assuntos
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Imagem Molecular/métodos , Proteínas Mutantes/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/química , Feminino , Humanos , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Mutação , Transplante de Neoplasias
5.
J Biol Chem ; 293(50): 19211-19212, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30552114

RESUMO

The cytochromes P450 (CYPs) oxidatively transform a huge number of substrates in both prokaryotic and eukaryotic organisms, but the mechanisms by which they accommodate these diverse molecules remain unclear. A new study by Bart and Scott reports two co-crystal structures of CYP1A1 that reveal structural rearrangements and flexible interaction networks that explain how the active site cavity shapes itself around new ligands. These data open the door to an increased understanding of fundamental enzyme behavior and improved searches for anti-cancer compounds.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Inibidores Enzimáticos/metabolismo , Cloridrato de Erlotinib/metabolismo , Furocumarinas/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Citocromo P-450 CYP1A1/química , Inibidores Enzimáticos/química , Cloridrato de Erlotinib/química , Furocumarinas/química , Humanos , Ligantes , Ligação Proteica , Especificidade por Substrato
6.
J Photochem Photobiol B ; 183: 11-15, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29679689

RESUMO

Bovine serum albumin (BSA) is the most abundant protein in the blood circulation and it is commonly used for drug delivery in blood. Therefore, we aim to study BSA interaction with erlotinib as an anticancer drug using surface plasmon resonance (SPR) and molecular modeling methods under physiological conditions (pH = 7.4). BSA immobilized on carboxymethyl dextran hydrogel Au chip (CMD) after activation with N-hydroxysuccinimide and N-ethyl-N-(3-diethylaminopropyl) carbodiimide and then the erlotinib binding to BSA at different concentrations was evaluated. Increasing of erlotinib concentration led to dose-response sensorgrams of BSA. The amount of equilibrium constant (KD) at 25 °C (4.25 × 10-9) showed the high affinity of erlotinib to BSA. Thermodynamic parameters were attained at four different temperatures. The positive value of enthalpy and entropy showed that hydrophobic forces play major role in the interaction of erlotinib with BSA. Besides, the positive value of Gibbs free energy demonstrated that the interaction of erlotinib with BSA was nonspontaneous and enthalpy driven and the complexion of drug were dependent on endothermic process. According to the molecular docking study, the most favorable binding sites of erlotinib on the BSA were subdomain IIIA and IB. Moreover, molecular docking study results showed that hydrogen binding has a role in intermolecular force that stabilize erlotinib-BSA complex.


Assuntos
Cloridrato de Erlotinib/metabolismo , Soroalbumina Bovina/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Bovinos , Cloridrato de Erlotinib/química , Ligações de Hidrogênio , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Soroalbumina Bovina/química , Ressonância de Plasmônio de Superfície , Termodinâmica
7.
Bioorg Med Chem Lett ; 28(6): 1143-1148, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29486966

RESUMO

Epidermal growth factor receptor (EGFR) has gained significant attention as a therapeutic target. Several EGFR targeting drugs (Gefitinib and Erlotinib) have been approved by US Food and Drug Administration (FDA) and have received high approval in clinical treatment. Nevertheless, the curative effect of these medicines varied in many solid tumors because of the different levels of expression and mutations of EGFR. Therefore, several PET radiotracers have been developed for the selective treatment of responsive patients who undergo PET/CT imaging for tyrosine kinase inhibitor (TKI) therapy. In this study, a novel fluorine-18 labeled 4-anilinoquinazoline based PET tracer, 1N-(3-(1-(2-18F-fluoroethyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (18F-FEA-Erlotinib), was synthesized and biological evaluation was performed in vitro and in vivo. 18F-FEA-Erlotinib was achieved within 50min with over 88% radiochemical yield (decay corrected RCY), an average specific activity over 50GBq/µmol, and over 99% radiochemical purity. In vitro stability study showed no decomposition of 18F-FEA-Erlotinib after incubated in PBS and FBS for 2h. Cellular uptake and efflux experiment results indicated the specific binding of 18F-FEA-Erlotinib to HCC827 cell line with EGFR exon 19 deletions. In vivo, Biodistribution studies revealed that 18F-FEA-Erlotinib exhibited rapid blood clearance both through hepatobiliary and renal excretion. The tumor uptake of 18F-FEA-Erlotinib in HepG2, HCC827, and A431 tumor xenografts, with different EGFR expression and mutations, was visualized in PET images. Our results demonstrate the feasibility of using 18F-FEA-Erlotinib as a PET tracer for screening EGFR TKIs sensitive patients.


Assuntos
Compostos de Anilina/farmacologia , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/farmacologia , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/síntese química , Cloridrato de Erlotinib/química , Radioisótopos de Flúor , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
8.
Drug Des Devel Ther ; 12: 1-8, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29296076

RESUMO

The aim of this study was to develop PEGylation liposomes formulations of erlotinib and evaluate their characteristics, stability, and release characteristics. The average particle sizes and entrapment efficiency of PEGylation erlotinib liposomes are 102.4±3.1 nm and 85.3%±1.8%, respectively. Transmission electron microscopy images showed that the liposomes dispersed well with a uniform shape and no changes during the storage. The in vitro drug-release kinetic model of erlotinib release from the PEGylation liposomes in phosphate-buffered saline fit well with the Higuchi equation. In vitro anticancer activity assay showed that the blank liposomes had lower cellular cytotoxicity and that the cellular cytotoxicity of erlotinib liposomes increased significantly under the same incubation condition, which should contribute to the increase in intracellular drug concentration by the transportation of liposomes. The two liposomes of erlotinib (with and without PEGylation) exhibited similar cellular cytotoxicity with no significantly different concentrations. Pharmacokinetic results indicated that erlotinib-loaded PEGylation liposomes can significantly change the pharmacokinetic behavior of drugs and improve the drug bioavailability by nearly 2 times compared to ordinary liposomes. No sign of damages such as the appearance of epithelial necrosis or sloughing of epithelial cells was detected in histological studies.


Assuntos
Antineoplásicos/administração & dosagem , Cloridrato de Erlotinib/administração & dosagem , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanomedicina/métodos , Nanopartículas , Inibidores de Proteínas Quinases/administração & dosagem , Tecnologia Farmacêutica/métodos , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacocinética , Humanos , Injeções Intravenosas , Lipossomos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Tamanho da Partícula , Polietilenoglicóis/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Artif Cells Nanomed Biotechnol ; 46(5): 1064-1075, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28758795

RESUMO

Systemic and uncontrolled administration of erlotinib hydrochloride (ETB) is associated with severe toxicity. A novel targeted and extended release nanosponge (NS) was synthesized from glutathione (GHS) by a one-step reaction between ß-cyclodextrin and pyromellitic dianhydride at room temperature for delivery of ETB in lung cancer. Characterization studies were performed using sophisticated instruments. In-vitro release study was performed in the presence of incremental concentrations of GHS which was analyzed using HPLC. Cell cytotoxicity study was evaluated on human lung cancer (A549) cell lines. In-vivo tumour inhibition and biodistribution of ETB-loaded GHS-NS (ETB-NS) were performed on BALB/c mice. NS obtained was spherical, size 212 ± 2.45 nm and high drug entrapment (92.34 ± 5.31%) (p < .001). In-vitro extended drug release (76.89 ± 0.1% release at 168 h), which was directly proportional to the concentration of GHS, demonstrated tumour targeting. There was enhanced in-vitro cytotoxicity and 97.5% inhibition in tumour growth on administering NS when compared to plain ETB (48% inhibition) indicating targeting of NS to the tumour site. Biodistribution study and in-vivo tumour growth inhibition study revealed drug release to the cancerous cell, thus preventing unnecessary drug exposure. ETB-NS exhibits extended drug release proportional to the external GSH concentration.


Assuntos
Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Glutationa/química , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Células A549 , Animais , Preparações de Ação Retardada , Cloridrato de Erlotinib/metabolismo , Cloridrato de Erlotinib/farmacocinética , Glutationa/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Tamanho da Partícula , Conformação Proteica , Distribuição Tecidual
10.
Eur J Pharm Sci ; 111: 257-269, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28989102

RESUMO

INTRODUCTION: Erlotinib is a well known FDA approved drug from category of tyrosine kinase inhibitors; used for the treatment of lung cancer. However its use is limited because of its poor water solubility. OBJECTIVE: The aim of present work was to improve solubility by developing a stable nanocrystal based drug delivery system of ERL with the aid of sodium lauryl sulfate as potential stabilizer and to carry out comparative evaluation of electrospraying and lyophilization as solidification techniques on its solid state properties. EXPERIMENTAL: Nanocrystal formulation was developed with antisolvent precipitation method having particle size, polydispersity index and zetapotential of 232.4±4.3nm, 0.162 and -9.82mV respectively. Further comparative evaluation of lyophilization and electrospraying was commenced as potential solidification techniques and solid powder matrix obtained from both the solidification techniques were compared in terms of size after re-dispersion (260±4.8 and 329±5.2nm respectively), particle morphology, surface area (0.984±0.11 and 0.341±0.05m2/g respectively), pore volume (0.0014 and 0.0009cc/g respectively), solid state of drug present and % drug release (~100% and ~78% respectively in 600min). In vitro cytotoxicity studies shared that obtained formulation was having reduced IC50 values in comparison to drug. Further intracellular reactive oxygen species production was found to be higher for formulation treated cells when compared to free drug. Overall developed formulation was found to be potential drug delivery system for lung cancer therapy.


Assuntos
Cloridrato de Erlotinib/química , Excipientes , Liofilização/métodos , Humanos , Microscopia de Força Atômica , Modelos Moleculares , Estrutura Molecular , Nanopartículas/química , Tamanho da Partícula , Solubilidade
11.
Int J Pharm ; 534(1-2): 1-13, 2017 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-28970115

RESUMO

The current study was aimed to prepare a molecular complex of erlotinib (ERL) with phospholipid (PC) for enhancement of solubility and thus bioavailability, therapeutic efficacy and reducing the toxicity of erlotinib. Phospholipid complex of drug was prepared by solvent evaporation method and characterized by differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FT-IR), proton and phosphorus nuclear magnetic resonance spectroscopy (1H NMR and 31P NMR), powder X-ray diffraction (P-XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), which all explained the interactions of two components, validating the complexation phenomenon. In silico study also supported the phase change and molecular interactions for the establishment of ERL-PC. Spherical shaped nanostructures with 183.37±28.61nm size, -19.52±6.94mV potential and 28.59±2.66% loading efficiency were formed following dispersion of ERL-PC in aqueous media. In vitro release study revealed the higher release of ERL-PC due to amorphization and solubilization of drug. Caco-2 cell uptake resulted in ∼2 fold higher uptake of ERL-PC than free drug. In vitro cell culture studies were performed using human pancreatic adenocarcinoma cell lines, which demonstrated the higher cytotoxicity and apoptosis in case of ERL-PC. In vivo pharmacokinetics also supported the in vitro observations and showed ∼1.7 fold higher bioavailability with ERL-PC than ERL. Finally, in vivo efficacy and toxicity studies explained the superiority of ERL-PC over the free drug. Based on the results, phospholipid complex appears to be a promising tool to enhance bioavailability, efficacy, cytotoxicity and safety of erlotinib.


Assuntos
Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Fosfolipídeos/química , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Varredura Diferencial de Calorimetria/métodos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Feminino , Humanos , Microscopia Eletrônica de Varredura/métodos , Nanoestruturas/química , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodos
12.
Bioorg Med Chem Lett ; 27(19): 4552-4557, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28893469

RESUMO

Molecular imaging using radiolabeled Tyrosine Kinase Inhibitors (TKI) is a promising strategy for detection and staging of EGFR-positive cancers. A novel analogue of one such TKI, Erlotinib has been developed for PET imaging by derivatizing the parent Erlotinib molecule for conjugation with the bifunctional chelator p-SCN-Bn-NOTA towards radiolabeling with 68Ga. NOTA-Erlotinib conjugate was synthesized and characterized by NMR and ESI-MS techniques. The conjugate was radiolabeled with 68Ga in 95±2% yield, as evidenced by HPLC characterization. The logP value of 68Ga-NOTA-Erlotinib was - (0.6±0.1). The 68Ga-NOTA-Erlotinib conjugate was characterized using its natGa-NOTA-Erlotinib surrogate. Cell viability studies showed that the NOTA-Erlotinib conjugate retained the biological efficacy of the parent Erlotinib molecule. Further, 68Ga-NOTA-Erlotinib exhibited an uptake of 9.8±0.4% in A431 cells which was inhibited by 55.1±0.2% on addition of cold Erlotinib (10µg) confirming the specificity of the radioconjugate for EGFR expressing cells. In the biodistribution studies carried out in tumor bearing SCID mice, 68Ga-NOTA-Erlotinib conjugate showed moderate tumor accumulation (1.5±0.1% ID/g at 30minp.i.; 0.7±0.2% ID/g at 1hp.i.). Hepatobiliary clearance of the radioconjugate was observed. The 68Ga-NOTA-Erlotinib conjugate was found to have high in vivo stability as determined by the metabolite analysis study using urine sample of the Swiss mice injected with the preparation. The overall properties of 68Ga-NOTA-Erlotinib are promising and merit further exploration. To the best of our knowledge, this is the first report on the design of a 68Ga labeled Erlotinib for PET imaging of EGFR and opens avenues for the successful development of 68Ga labeled TKI for imaging of EGFR over-expressing tumors.


Assuntos
Receptores ErbB/biossíntese , Cloridrato de Erlotinib/química , Neoplasias Pulmonares/diagnóstico , Imagem Molecular , Tomografia por Emissão de Pósitrons , Neoplasias Cutâneas/diagnóstico , Animais , Cloridrato de Erlotinib/síntese química , Cloridrato de Erlotinib/farmacocinética , Radioisótopos de Gálio , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Estrutura Molecular , Neoplasias Cutâneas/metabolismo , Distribuição Tecidual
13.
Med Oncol ; 34(10): 178, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28887613

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for non-small cell lung cancer patients with an EGFR gene mutation. However, skin disorders are known as adverse events. In the present study, we investigated whether EGFR-TK occupancy is useful as an index for assessing clinical efficacy and adverse events for the proper use and development of EGFR-TKIs. Average binding occupancies (Φ ss) of EGFR-TKIs, gefitinib and erlotinib, for the EGFR-TK of cancer or skin cells were calculated. The relationships of Φ ss with response rate (RR) or frequency of rash were analyzed using the ternary complex model. Then, the relationships between the dose of EGFR-TKIs and RR or frequency of rash were examined. Gefitinib showed a greater difference for Φ ss value for both wild-type and mutant EGFR as compared to erlotinib at usual dose. The RR increased in a nonlinear manner rapidly rising when Φ ss exceeded 95%. It was thought that a very high Φ ss value might be needed to obtain the therapeutic effect of EGFR-TKIs. Meanwhile, the frequency of rash increased in a linear manner along with elevation of Φ ss. It was shown that the K d ratio (K d for mutant/K d for wild type) was less than 0.001, when the high RR and low frequency of rash were obtained simultaneously. The results showed that the therapeutic effects and skin disorder can be assessed by using Φ ss. Furthermore, it is likely that a proper choice of drug and dose can be made by using Φ ss in EGFR-TKI therapy.


Assuntos
Receptores ErbB/antagonistas & inibidores , Modelos Biológicos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Receptores ErbB/química , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/efeitos adversos , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/uso terapêutico , Gefitinibe , Humanos , Cinética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Quinazolinas/efeitos adversos , Quinazolinas/química , Quinazolinas/uso terapêutico
14.
ChemMedChem ; 12(18): 1504-1511, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28776965

RESUMO

Small-molecular-target-based photodynamic therapy-a promising targeted anticancer strategy-was developed by conjugating zinc(II) phthalocyanine with a small-molecular-target-based anticancer drug. To prevent self-aggregation and avoid problems of phthalocyanine isomerization, two silicon phthalocyanines di-substituted axially with erlotinib have been synthesized and fully characterized. These conjugates are present in monomeric form in various solvents as well as culture media. Cell-based experiments showed that these conjugates localize in lysosomes and mitochondria, while maintaining high photodynamic activities (IC50 values as low as 8 nm under a light dose of 1.5 J cm-2 ). With erlotinib as the targeting moiety, two conjugates were found to exhibit high specificity for EGFR-overexpressing cancer cells. Various poly(ethylene glycol) (PEG) linker lengths were shown to have an effect on the photophysical/photochemical properties and on in vitro phototoxicity.


Assuntos
Antineoplásicos/química , Cloridrato de Erlotinib/química , Indóis/química , Compostos de Organossilício/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Receptores ErbB/metabolismo , Células Hep G2 , Humanos , Luz , Neoplasias Hepáticas/tratamento farmacológico , Microscopia Confocal , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Zinco/química
15.
Adv Healthc Mater ; 6(21)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28766870

RESUMO

3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient-derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified in 50% of GBM patients. Here, hyaluronic acid (HA) decorated methacrylamide-functionalized gelatin (GelMA) hydrogels are used to examine the synergies between microenvironmental factors and a model EGFR tyrosine kinase inhibitor (TKI) using patient-derived xenograft cells. The in vitro behavior of 3 patient-derived xenografts that reflect a clinically relevant range of EGFR variants is characterized: GBM10 (EGFR, wild type), GBM12 (EGFR+), and GBM6 (EGFRvIII). GelMA hydrogels support xenograft culture; cells remain viable, active, respond to matrix-immobilized HA, and upregulate genes associated with matrix remodeling and tumor growth. Interestingly, matrix-immobilized HA alters the response of GBM cells to a model tyrosine kinase inhibitor, erlotinib. While constitutively activated EGFRvIII cells are sensitive to TKI in gelatin hydrogels, hyaluronic acid mediated adhesive signaling interacts with EGFRvIII signaling to increase cell metabolic activity, increase soluble hyaluronic acid synthesis, and modify response to erlotinib exposure.


Assuntos
Materiais Biocompatíveis/química , Receptores ErbB/metabolismo , Ácido Hialurônico/química , Inibidores de Proteínas Quinases/química , Acrilamidas/química , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/toxicidade , Matriz Extracelular/metabolismo , Gelatina/química , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Hidrogéis/química , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/toxicidade , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos
16.
PLoS One ; 12(6): e0179333, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28628631

RESUMO

EGFR inhibitors, even with therapeutics superiorities in anticancer, can cause idiosyncratic pulmonary and hepatic toxicities that are associated with the reactive electrophile bioactivated by Cytochrome P450s (P450s). Until now, neither has the electrophilic intermediate been caught experimentally, nor has the subtle mechanism been declared. Herein, the underlying mechanism of bioactivation mediated by P450s was explored by DFT calculations for a case of EGFR inhibitor, Erlotinib. Based on the calculation and analysis, we suggest that with other metabolites, reactive electrophiles of Erlotinib: epoxide and quinine-imine, can be generated by several steps along the oxidative reaction pathway. The generation of epoxide needs two steps: (1) the addition of Erlotinib to Compound I (Cpd I) and (2) the rearrangement of protons. Whereas, quinine-imine needs a further oxidation step (3) via which quinone is generated and ultimately turns into quinine-imine. Although both reactive electrophiles can be produced for either face-on or side-on pose of Erlotinib, the analysis of energy barriers indicates that the side-on path is preferred in solvent environment. In the rate-determining step, e.g. the addition of Erlotinib to the porphyrin, the reaction barrier for side-on conformation is decreased in aqueous and protein environment compared with gas phase, whereas, the barrier for face-on pose is increased in solvent environment. The simulated mechanism is in good agreement with the speculation in previous experiment. The understanding of the subtle mechanism of bioactivation of Erlotinib will provide theoretical support for toxicological mechanism of EGFR inhibitors.


Assuntos
Antineoplásicos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Cloridrato de Erlotinib/metabolismo , Antineoplásicos/química , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP3A/metabolismo , Compostos de Epóxi/química , Compostos de Epóxi/metabolismo , Cloridrato de Erlotinib/química , Modelos Moleculares , Oxirredução , Teoria Quântica , Quinonas/química , Quinonas/metabolismo , Termodinâmica
17.
Drug Dev Ind Pharm ; 43(9): 1557-1565, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28554216

RESUMO

OBJECTIVES: Nanoparticulation using fat and supercritical fluid (NUFSTM) is a drug delivery platform technology enabling efficient and effective formulation of poorly soluble drugs. We performed experiments to examine whether NUFS™ could improve poor bioavailability and reduce fed-fasted bioavailability variances of erlotinib (Ert). METHODS: NUFS-Ert was prepared using NUFS™ technology; its physical properties were characterized, and drug release was measured. Furthermore, in vitro and in vivo efficacy tests and pharmacokinetic analysis were performed. RESULTS: NUFS-Ert nanoparticles had an average size of 250 nm and were stable for 2 months at 40 °C, 4 °C, and room temperature. The dissolution rate of NUFS-Ert increased in bio-relevant dissolution media. NUFS-Ert was more potent in inhibiting EGF signaling and in suppressing the proliferation of A549, a human non-small cell lung cancer cell line. Furthermore, A549 xenografts in BALB/c nude mice treated with NUFS-Ert regressed more efficiently than those in the mice treated with vehicle or Tarceva®. In addition, experimental lung metastasis was more efficiently inhibited by NUFS-Ert than by Tarceva®. The relative bioavailability of NUFS-Ert compared with that of Tarceva® was 550% and the ratio of the area under the concentration-time curve (AUC) of fed state to the AUC of fasted state was 1.8 for NUFS-Ert and 5.8 for Tarceva®. CONCLUSIONS: NUFS-Ert could improve poor bioavailability and reduce fed-fasted bioavailability variances of Ert. NUFS-Ert was more efficacious than Tarceva®.


Assuntos
Antineoplásicos/farmacocinética , Disponibilidade Biológica , Cloridrato de Erlotinib/farmacocinética , Excipientes/química , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Animais , Antineoplásicos/química , Química Farmacêutica , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Humanos , Camundongos Nus , Solubilidade
18.
Drug Res (Stuttg) ; 67(6): 343-348, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28288490

RESUMO

Poor water solubility and low oral bioavailability limit the clinical application of Erlotinib as an anticancer. For this purpose, we encapsulated erlotinib in the solid lipid nanoparticles (SLN) and designed a spray-dried dry powder inhalable (DPI) formulation. Erlotinib-loaded SLNs were prepared using self-nanoemulsifying and characterized for physicochemical properties. Pulmonary deposition of spray-dried DPI formulation was performed using Next Generation Impactor. The particle size and zeta potential of Erlotinib-loaded SLNs were 300 to 800 nm and -18 to -32 mV, respectively. High drug entrapment efficiency in the narrow range of 80-85% was achieved. Cytotoxicity results indicated that cell growth inhibition of free drug and drug loaded nanoparticles is dose- and time-dependent. Inhalable dry powders prepared from drug-loaded SLNs were found to have a fine particle fraction in the range of 6.92±0.99 -11.24±2.4%, mean mass aerodynamic diameter in the range of 4.52±0.1 to 6.67±0.5 µm. The findings revealed that the proposed inhalable dry powder formulation loaded with erlotinib SLN has potential in lung cancer therapy through pulmonary route.


Assuntos
Antineoplásicos/administração & dosagem , Cloridrato de Erlotinib/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas , Células A549 , Administração por Inalação , Aerossóis , Antineoplásicos/química , Antineoplásicos/farmacologia , Química Farmacêutica/métodos , Relação Dose-Resposta a Droga , Inaladores de Pó Seco , Emulsões , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Humanos , Lipídeos/química , Neoplasias Pulmonares/patologia , Tamanho da Partícula , Solubilidade , Fatores de Tempo , Distribuição Tecidual
19.
Drug Dev Ind Pharm ; 43(8): 1244-1253, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28323493

RESUMO

Non-small cell lung cancer (NSCLC) patients with sensitizing mutations in the exons 18-21 of the epithelial growth factor receptor (EGFR) gene show increased kinase activity of EGFR. Hence, tyrosine kinase inhibitors (TKIs) such as erlotinib (ETB) have commonly been used as the second line therapeutic option for the treatment of metastatic NSCLC. While the ETB is available as an oral dosage form, the local delivery of this TKI to the diseased cells of the lung may ameliorate its therapeutic impacts. In the current study, we report on the development of ETB-loaded solid lipid nanoparticle (SLN) based formulation of dry powder inhaler (ETB-SLN DPI). ETB-SLNs were formulated using designated amount of compritol/poloxamer 407. The engineered ETB-SLNs showed sub-100 nm spherical shape with an encapsulation efficiency of 78.21%. MTT assay and DAPI staining revealed that the ETB-SLNs enhanced the cytotoxicity of cargo drug molecules in the human alveolar adenocarcinoma epithelial A549 cells as a model for NSCLC. To attain the ETB-SLN DPI, the ETB-SLNs were efficiently spray dried into microparticles (1-5 µm) along with mannitol. The ETB-SLN DPI powder displayed suitable flowability and aerodynamic traits. The Carr's Index, Hausner ratio and Next Generation Impactor (NGI) analyses confirmed deep inhalation pattern of the formulation. Based on these findings, we propose the ETB-SLN DPI as a promising treatment modality for the NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Inaladores de Pó Seco/métodos , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacologia , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Administração por Inalação , Linhagem Celular Tumoral , Química Farmacêutica , Inaladores de Pó Seco/instrumentação , Cloridrato de Erlotinib/química , Humanos
20.
Chem Biol Drug Des ; 90(4): 629-636, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28303669

RESUMO

Present work elucidates identification of next generation inhibitors for clinically relevant mutations of epidermal growth factor receptor (EGFR) using structure-based bioactive pharmacophore modeling followed by virtual screening (VS) techniques. Three-dimensional (3D) pharmacophore models of EGFR and its different mutants were generated. This includes seven 3D pharmacophoric points with three different chemical features (descriptors), that is, one hydrogen bond donor, three hydrogen bond acceptors and three aromatic rings. Pharmacophore models were validated using decoy dataset, Receiver operating characteristic plot, and external dataset compounds. The robust, bioactive 3D e-pharmacophore models were then used for VS of four different small compound databases: FDA approved, investigational, anticancer, and bioactive compounds collections of Selleck Chemicals. CUDC101 a multitargeted kinase inhibitor showed highest binding free energy and 3D pharmacophore fit value than the well known EGFR inhibitors, Gefitinib and Erlotinib. Further, we obtained ML167 as the second best hit on VS from bioactive database showing high binding energy and pharmacophore fit value with respect to EGFR receptor and its mutants. Optimistically, presented drug discovery based on the computational study serves as a foundation in identifying and designing of more potent EGFR next-generation kinase inhibitors and warrants further experimental studies to fight against lung cancer.


Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Projeto Auxiliado por Computador , Bases de Dados de Produtos Farmacêuticos , Desenho de Drogas , Receptores ErbB/genética , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Gefitinibe , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Simulação de Acoplamento Molecular , Mutação , Relação Quantitativa Estrutura-Atividade , Quinazolinas/química , Quinazolinas/farmacologia
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