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1.
AAPS PharmSciTech ; 25(7): 233, 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-39358486

RESUMO

Docetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C60 fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C60 fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63 nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use.


Assuntos
Antineoplásicos , Neoplasias da Mama , Ácidos Carboxílicos , Sobrevivência Celular , Docetaxel , Sistemas de Liberação de Medicamentos , Fulerenos , Fulerenos/química , Fulerenos/administração & dosagem , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/farmacologia , Docetaxel/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Feminino , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Ácidos Carboxílicos/química , Tamanho da Partícula , Portadores de Fármacos/química , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Nanoconjugados/química , Ratos , Células MCF-7 , Disponibilidade Biológica
2.
Int J Pharm ; 664: 124623, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39191333

RESUMO

Docetaxel (DTX) is a recommended treatment in patients with metastasic prostate cancer (PCa), despite its therapeutic efficacy is limited by strong systemic toxicity. However, in localized PCa, intratumoral (IT) administration of DTX could be an alternative to consider that may help to overcome the disadvantages of conventional intravenous (IV) therapy. In this context, we here present the first in vivo preclinical study of PCa therapy with nanomedicines of mesoporous silica nanoparticles (MSN) and DTX by IT injection over a xenograft mouse model bearing human prostate adenocarcinoma tumors. The efficacy and tolerability, the biodistribution and the histopathology after therapy have been investigated for the DTX nanomedicine and the free drug, and compared with the IV administration of DTX. The obtained results demonstrate that IT injection of DTX and DTX nanomedicines allows precise and selective therapy of non-metastatic PCa and minimize systemic diffusion of the drug, showing superior activity than IV route. This allows reducing the therapeutic dose by one order and widens substantially the therapeutic window for this drug. Furthermore, the use of DTX nanomedicines as IT injection promotes strong antitumor efficacy and drug accumulation at the tumor site, improving the results obtained with the free drug by the same route.


Assuntos
Antineoplásicos , Docetaxel , Nanopartículas , Neoplasias da Próstata , Dióxido de Silício , Ensaios Antitumorais Modelo de Xenoenxerto , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Animais , Dióxido de Silício/química , Dióxido de Silício/administração & dosagem , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Humanos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Nanopartículas/administração & dosagem , Nanopartículas/química , Distribuição Tecidual , Linhagem Celular Tumoral , Camundongos , Nanomedicina/métodos , Injeções Intralesionais , Camundongos Nus , Porosidade , Portadores de Fármacos/química , Portadores de Fármacos/administração & dosagem , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia
3.
J Control Release ; 374: 489-504, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39182692

RESUMO

Multimodal treatment of cancer is an unstoppable revolution in clinical application. However, designing a platform that integrates therapeutic modalities with different pharmacokinetic characteristics remains a great challenge. Herein, we designed a universal lipid nanoplatform equipping a ROS-cleavable docetaxel prodrug (DTX-L-DTX) and an NF-E2-related factor 2 (NRF2) inhibitor (clobetasol propionate, CP). This simply fabricated nanomedicine enables superior synergistic molecularly targeted/chemo/radio therapy for lung cancer cascade by a transcription factor-driven ROS self-sustainable motion. Chemotherapy is launched via ROS-triggered DTX release. Subsequently, CP inhibits the expression of NRF2 target genes, resulting in efficient targeted therapy, meanwhile inducing sustained ROS generation which in turn facilitates chemotherapy by overcoming ROS consumption during the DTX release process. Finally, the introduction of radiotherapy further amplifies ROS, offering continuous mutual feedback to amplify the ultimate treatment performance. This strategy is conceptually and operationally simple, providing solutions to challenges in clinical cancer treatment and beyond.


Assuntos
Antineoplásicos , Docetaxel , Neoplasias Pulmonares , Fator 2 Relacionado a NF-E2 , Pró-Fármacos , Espécies Reativas de Oxigênio , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Humanos , Animais , Pró-Fármacos/uso terapêutico , Pró-Fármacos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Docetaxel/farmacologia , Docetaxel/farmacocinética , Fator 2 Relacionado a NF-E2/metabolismo , Nanopartículas , Terapia Combinada , Camundongos Nus , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Células A549 , Liberação Controlada de Fármacos , Feminino
4.
J Control Release ; 374: 590-605, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39208936

RESUMO

Herein, we reported novel docetaxel-decorated solid lipid nanoparticle (DCT-SLN)-loaded dual thermoreversible system (DCT-DRTS) for intramuscular administration with reduced burst effect, sustained release and improved antitumor efficacy. The optimized DCT-DRTs was subjected to in-vitro and in-vivo analyses. Antitumor evaluation of the DCT-DRTS was executed and compared with DCT-hydrogel, and DCT-suspension trailed by the histopathological and immune-histochemical analyses. The DCT-SLN gave a mean particle size of 157 nm and entrapment efficiency of 93 %. It was a solid at room temperature, and changed to liquid at physiological temperature due to its melting point of about 32 °C. Unlikely, poloxamer mixture remained liquefied at 25-27 °C, however converted to gel at physiological temperature. This behavior demonstrated opposed reversible property of the DCT-SLN and poloxamer hydrogel in DCT-DRTS system, making it ideal for intramuscular administration and quick gelation inside the body. The DCT-DRTS sustained the drugs release and unlike DCT-hydrogel, the preliminary plasma concentration of DCT-DRTS was significantly reduced, overcoming the burst release. A meaningfully enhanced antitumor efficacy and improved survival rate was observed from DCT-DRTS in tumor cell xenograft athymic nude mice. Additionally, increased apoptotic and reduced proliferation markers were observed in DCT-DRTS treated tumor masses. It was concluded that DCT-DRTS may be a suitable choice for intramuscular administration of DCT with sustained release, improved bioavailability, reduced toxicity and enhanced antitumor effects.


Assuntos
Antineoplásicos , Preparações de Ação Retardada , Docetaxel , Hidrogéis , Nanopartículas , Animais , Hidrogéis/química , Hidrogéis/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Humanos , Injeções Intramusculares , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Nanopartículas/química , Nanopartículas/administração & dosagem , Preparações de Ação Retardada/química , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Temperatura , Camundongos Nus , Poloxâmero/química , Camundongos , Sistemas de Liberação de Medicamentos , Feminino , Lipídeos/química , Lipídeos/administração & dosagem , Masculino , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Taxoides/administração & dosagem , Taxoides/farmacocinética , Taxoides/química , Lipossomos
5.
Eur J Pharm Biopharm ; 203: 114435, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39103002

RESUMO

The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (∼95 %) and loading capacity (∼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (∼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors > 500 mm3 could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.


Assuntos
Antineoplásicos , Docetaxel , Glutationa , Lipossomos , Camundongos Endogâmicos BALB C , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/farmacologia , Docetaxel/química , Animais , Camundongos , Glutationa/química , Feminino , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Taxoides/administração & dosagem , Taxoides/farmacologia , Taxoides/farmacocinética , Taxoides/química , Polissorbatos/química , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico
6.
Int J Nanomedicine ; 19: 8603-8620, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39188859

RESUMO

Background: Chemotherapeutic drugs have some drawbacks in antineoplastic therapy, mainly containing seriously toxic side effects caused by injection and multi-drug resistance (MDR). Co-delivery with two or more drugs via nanomicelles is a promising strategy to solve these problems. Oral chemotherapy is increasingly preferred owing to its potential to enhance the life quality of patients. Methods and Results: The study intended to develop mixed micelles using D-α-Tocopherol poly(ethylene glycol) 1000 succinate (TPGS) and soluplus for the co-encapsulation of docetaxel (DTX) and curcumin (CUR), marked as (DTX+CUR)-loaded mixed micelles, treating drug-resistant breast cancer by oral administration. The (DTX+CUR)-loaded mixed micelles had a uniform particle size (~64 nm), high drug loading and encapsulation efficiency, in vitro sustained-release properties and good pH-dependent stability. In vitro cell study, the (DTX+CUR)-loaded mixed micelles displayed the highest cellular uptake, cytotoxicity, cell apoptosis-inducing rates and cell ROS-inducing levels on MCF-7/Adr cells. Notably, in vivo pharmacokinetic studies, (DTX+CUR)-loaded mixed micelles enhanced markedly the oral absorption of DTX compared to pure DTX, with a relative oral bioavailability of 574%. The (DTX+CUR)-loaded mixed micelles by oral administration had the same anticancer efficacy as taxotere by injection in resistant breast cancer bearing mice. Conclusion: (DTX+CUR)-loaded mixed micelles could provide a potential formulation for treating drug-resistant breast cancers by oral administration.


Assuntos
Antineoplásicos , Neoplasias da Mama , Curcumina , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Micelas , Polietilenoglicóis , Curcumina/farmacocinética , Curcumina/química , Curcumina/administração & dosagem , Curcumina/farmacologia , Docetaxel/farmacocinética , Docetaxel/administração & dosagem , Docetaxel/química , Docetaxel/farmacologia , Humanos , Feminino , Animais , Neoplasias da Mama/tratamento farmacológico , Administração Oral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células MCF-7 , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Vitamina E/química , Vitamina E/administração & dosagem , Vitamina E/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Polivinil/química , Polivinil/farmacocinética , Polivinil/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Taxoides/farmacocinética , Taxoides/administração & dosagem , Taxoides/química , Taxoides/farmacologia , Liberação Controlada de Fármacos , Ratos Sprague-Dawley
7.
J Med Chem ; 67(16): 14370-14393, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39102508

RESUMO

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.


Assuntos
Antineoplásicos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Cães , Relação Estrutura-Atividade , Feminino , Descoberta de Drogas , Taxoides/farmacologia , Taxoides/farmacocinética , Taxoides/uso terapêutico , Taxoides/química , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Docetaxel/farmacocinética , Docetaxel/química
8.
ACS Appl Mater Interfaces ; 16(34): 44528-44537, 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39155662

RESUMO

The high level of accumulation of therapeutic agents in tumors is crucial for cancer treatment. Compared to the passive tumor-targeting effect, active tumor-targeting delivery systems, primarily mediated by peptides with high production costs and reduced circulation time, are highly desired. Platelet-driven technologies have opened new avenues for targeted drug delivery prevalently through a membrane coating strategy that involves intricate manufacturing procedures or the fucoidan-mediated hitchhiking method with limited platelet affinity. Here, a novel type of amphiphilic glycopolymer self-assembled micellar nanoparticle has been developed to adhere to naturally activated platelets in the blood. The simultaneous integration of fucose and sialic acid segments into glycopolymers enables closer mimicry of the structure of P-selectin glycoprotein ligand-1 (PSGL-1), thereby increasing the affinity for activated platelets. It results in the formation of glycopolymeric micelle-platelet hybrids, facilitating targeted drug delivery to tumors. The selective platelet-assisted cellular uptake of docetaxel (DTX)-loaded glycopolymeric micelles leads to lower IC50 values against 4T1 cells than that of free DTX. The directed tumor-targeting effect of activated platelets has significantly improved the tumor accumulation capacity of the glycopolymeric nanoparticles, with up to 21.0% found in tumors within the initial 0.2 h. Additionally, with acid-responsive drug release and inherent antimetastasis properties, the glycopolymeric nanoparticles ensured potent therapeutic efficacy, prolonged survival time, and reduced cardiotoxicity, presenting a new and unexplored strategy for platelet-directed drug delivery to tumors, showing promising prospects in treating localized tumors and preventing tumor metastasis.


Assuntos
Plaquetas , Docetaxel , Micelas , Nanopartículas , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Animais , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Nanopartículas/química , Camundongos , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologia , Camundongos Endogâmicos BALB C , Humanos , Feminino , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo
9.
Int J Nanomedicine ; 19: 8417-8436, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39176130

RESUMO

Purpose: Docetaxel (DTX) is a valuable anti-tumor chemotherapy drug with limited oral bioavailability. This study aims to develop an effective oral delivery system for DTX using natural nanoparticles (Nnps) derived from Coptidis Rhizoma extract. Methods: DTX-loaded self-assembled nanoparticles (Nnps-DTX) were created using an optimized heat-induction strategy. Nnps-DTX's shape, size, Zeta potential, and in vitro stability were all carefully examined. Additionally, the study investigated the encapsulation efficiency, loading capacity, crystal form, and intermolecular interactions of DTX in Nnps-DTX. Subsequently, the solubility, release, cellular uptake, metabolic stability, and preclinical pharmacokinetics of DTX in Nnps-DTX were systematically evaluated. Finally, the cytotoxicity of Nnps-DTX was assessed in three tumor cell lines. Results: Nnps-DTX was spherical in shape, 138.6 ± 8.2 nm in size, with a Zeta potential of -20.8 ± 0.6 mV, a DTX encapsulation efficiency of 77.6 ± 8.5%, and a DTX loading capacity of 6.8 ± 1.9%. Hydrogen bonds, hydrophobic interactions, and electrostatic interactions were involved in the formation of Nnps-DTX. DTX within Nnps-DTX was in an amorphous form, resulting in enhanced solubility (23.3 times) and release compared to free DTX. Following oral treatment, the mice in the Nnps-DTX group had DTX peak concentrations 8.8, 23.4, 44.6, and 5.7 times higher in their portal vein, systemic circulation, liver, and lungs than the mice in the DTX group. Experiments performed in Caco-2 cells demonstrated a significant increase in DTX uptake by Nnps-DTX compared to free DTX, which was significantly inhibited by indomethacin, an inhibitor of caveolae-mediated endocytosis. Furthermore, compared to DTX, DTX in Nnps-DTX demonstrated better metabolic stability in liver microsomes. Notably, Nnps-DTX significantly reduced the viability of MCF-7, HCT116, and HepG2 cells. Conclusion: The novel self-assembled nanoparticles considerably enhanced the cellular absorption, solubility, release, metabolic stability, and pharmacokinetics of oral DTX and demonstrated strong cytotoxicity against tumor cell lines.


Assuntos
Docetaxel , Nanopartículas , Animais , Docetaxel/farmacocinética , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/administração & dosagem , Humanos , Administração Oral , Nanopartículas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Camundongos , Linhagem Celular Tumoral , Coptis chinensis , Tamanho da Partícula , Masculino , Liberação Controlada de Fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Disponibilidade Biológica , Solubilidade , Ratos Sprague-Dawley , Camundongos Endogâmicos BALB C
10.
Cancer Chemother Pharmacol ; 94(3): 437-441, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38951305

RESUMO

PURPOSE: Docetaxel is a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity. METHODS: We performed a proof-of-concept study (EudraCT 2016-003785-77) to evaluate whether pharmacokinetics after a sub-pharmacological test dose of 1000 µg docetaxel (millidose) could be used to predict therapeutic dose exposure. Thirty prostate cancer patients eligible for treatment with docetaxel as part of routine clinical care were included. An intravenous docetaxel millidose was administered 1-7 days prior to therapeutic docetaxel. After both doses plasma docetaxel concentrations were measured by ultra- high performance liquid chromatography-tandem mass spectrometry. The docetaxel clearance was estimated with non-linear mixed effects modeling. RESULTS: Geometric mean docetaxel clearance was 57.9 L/h (GCV 78.6%) after admission of a millidose and 40.3 L/h (GCV 60.7%) after admission of a therapeutic dose. The millidose and therapeutic dose in a single patient were not significantly correlated (Spearman's rho R = 0.02, P = 0.92). CONCLUSION: Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.


Assuntos
Antineoplásicos , Docetaxel , Neoplasias da Próstata , Humanos , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Masculino , Neoplasias da Próstata/tratamento farmacológico , Idoso , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Pessoa de Meia-Idade , Relação Dose-Resposta a Droga , Espectrometria de Massas em Tandem , Estudo de Prova de Conceito , Cromatografia Líquida de Alta Pressão , Idoso de 80 Anos ou mais
11.
Drug Deliv Transl Res ; 14(12): 3585-3598, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39009933

RESUMO

Glioblastoma (GBM) is the deadliest adult brain cancer. The current standard-of-care chemotherapy using orally administered temozolomide (TMZ) presents poor improvement in patient survival, emphasizing the compelling need for new therapies. A possible chemotherapeutic alternative is docetaxel (DTX), which possesses higher tumoricidal potency against GBM cells. However, its limited blood-brain barrier (BBB) permeability poses a constraint on its application. Nonetheless, nanomedicine offers promising avenues for overcoming this challenge. Angiopep-2 (ANG2) is a peptide that targets the BBB-overexpressed low-density lipoprotein receptor (LDLR). In this work, we managed, for the first time, to employ a pioneering approach of covalently linking zein protein with polyethylene glycol (PEG) and ANG2 prior to its formulation into nanoparticles (ZNPs) with enhanced stability and LDLR-mediated brain targetability, respectively. Carbodiimide and click chemistry approaches were optimized, resulting in functional modification of zein with around 25% PEG, followed by functional modification of PEG with nearly 100% ANG2. DTX-loaded ZNPs presented 100 nm average size, indicating high suitability for BBB crossing through receptor-mediated transcytosis. ZNPs maintained the cytotoxic effect of the loaded DTX against GBM cells, while demonstrating a safe matrix against BBB cells. Importantly, these brain-targeted ZNPs showcased up to fourfold enhancement in blood-to-brain permeability in a BBB in vitro model, highlighting the potential of this novel approach of BBB targeting in significantly improving therapeutic outcomes for GBM patients. The versatility of the system and the possibility of significantly increasing drug concentration in the brain open the door to its future application in a wide range of other brain-related diseases.


Assuntos
Antineoplásicos , Barreira Hematoencefálica , Neoplasias Encefálicas , Docetaxel , Glioblastoma , Polietilenoglicóis , Zeína , Zeína/química , Docetaxel/administração & dosagem , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/farmacologia , Glioblastoma/tratamento farmacológico , Polietilenoglicóis/química , Polietilenoglicóis/administração & dosagem , Humanos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Barreira Hematoencefálica/metabolismo , Nanopartículas/química , Nanopartículas/administração & dosagem , Nanomedicina , Animais , Peptídeos/química , Peptídeos/administração & dosagem , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos
12.
Eur J Pharm Biopharm ; 201: 114386, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38950717

RESUMO

The goal of the study was to fabricate folic acid functionalized docetaxel (DOC)/erlotinib (ERL)-loaded solid lipid nanoparticles (SLNs) to synergistically increase the anticancer activity against triple-negative breast cancer. DOC/ERL-SLNs were prepared by the high shear homogenization - ultrasound dispersion method (0.1 % w/v for DOC, and 0.3 %w/v for ERL) and optimized using Plackett Burman Design (PBD) followed by Box Behnken Design (BBD). The optimized SLNs demonstrated particle size < 200 nm, PDI < 0.35, and negative zeta potential with entrapment and loading efficiency of ∼80 and ∼4 %, respectively. The SLNs and folic acid functionalized SLNs (FA-SLNs) showed sustained release for both drugs, followed by Higuchi and Korsemeyer-Peppas drug release models, respectively. Further, the in vitro pH-stat lipolysis model demonstrated an approximately 3-fold increase in the bioaccessibility of drugs from SLNs compared to suspension. The TEM images revealed the spherical morphology of the SLNs. DOC/ERL loaded SLNs showed dose- and time-dependent cytotoxicity and exhibited a synergism at a molar ratio of 1:3 in TNBC with a combination index of 0.35 and 0.37, respectively. FA-DOC/ERL-SLNs showed enhanced anticancer activity as evidenced by MMP and ROS assay and further inhibited the colony-forming ability and the migration capacity of TNBC cells. Conclusively, the study has shown that SLNs are encouraging systems to improve the pharmaceutical attributes of poorly bioavailable drugs.


Assuntos
Docetaxel , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Cloridrato de Erlotinib , Lipídeos , Nanopartículas , Tamanho da Partícula , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Docetaxel/administração & dosagem , Docetaxel/farmacologia , Docetaxel/farmacocinética , Humanos , Nanopartículas/química , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/farmacocinética , Linhagem Celular Tumoral , Feminino , Lipídeos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Sobrevivência Celular/efeitos dos fármacos , Ácido Fólico/química , Lipossomos
13.
Int J Nanomedicine ; 19: 5071-5094, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846644

RESUMO

Background: The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges. Methods: DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated. Results: The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX. Conclusion: The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations.


Assuntos
Disponibilidade Biológica , Docetaxel , Estabilidade de Medicamentos , Nanopartículas , Tamanho da Partícula , Soroalbumina Bovina , Docetaxel/farmacocinética , Docetaxel/química , Docetaxel/administração & dosagem , Animais , Soroalbumina Bovina/química , Soroalbumina Bovina/farmacocinética , Soroalbumina Bovina/administração & dosagem , Nanopartículas/química , Taxoides/farmacocinética , Taxoides/química , Taxoides/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Liberação Controlada de Fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Ratos Sprague-Dawley , Masculino , Composição de Medicamentos/métodos , Ratos
14.
Cancer Chemother Pharmacol ; 94(3): 475-481, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38814342

RESUMO

PURPOSE: To determine the bioavailability, safety, and tolerability of a single dose of oral docetaxel plus encequidar (oDox + E) and compare its pharmacokinetic exposure with current standard of care IV docetaxel. INTRODUCTION: Docetaxel is a taxane widely used as an anti-neoplastic agent. Due to low oral bioavailability secondary to gut P-glycoprotein (P-gp) efflux, its current use is limited to intravenous administration. Oral docetaxel may provide a less resource intensive, more convenient, and tolerable alternative. Encequidar is a first in class, minimally absorbed, oral gut-specific P-gp inhibitor. We tested whether oDox + E can achieve comparable pharmacokinetic exposure to IV docetaxel. METHODS: A multicentre, phase I open-label, pharmacokinetic trial was undertaken to determine the bioavailability, safety, and tolerability of a single dose of oDox + E (at 75 mg/m2 + 15 mg, 150 mg/m2 + 15 mg, and 300 mg/m2 + 15 mg) in metastatic prostate cancer (mPC) patients compared to standard of care IV docetaxel as prescribed by their oncologists. The 15 mg of Encequidar at each dose level was given one hour prior to oral docetaxel. RESULTS: 11 patients were enrolled; 9 patients completed the study. Oral docetaxel exposure increased with dose, achieving the highest at 300 mg/m2 oDox + E (with AUC0 - infinity of 1343.3 ± 443.0 ng.h/mL compared to the IV docetaxel AUC0 - infinity of 2000 ± 325 ng.h/mL) and became non-linear at 300 mg/m2. The mean absolute bioavailability of oDox + E across all 3 dose levels was 16.14% (range: 8.19-25.09%). No patient deaths, dose limiting toxicity, treatment-related serious adverse event or grade 4 toxicity were observed. Maximal tolerated dose was not reached. CONCLUSION: oDox + E has a safe and tolerable adverse event profile in patients with metastatic prostate cancer. The increase in oral bioavailability of oDox + E suggests a multi-dose oDox + E regimen could theoretically achieve exposures comparable with standard of care IV docetaxel. Further development to examine the optimal multiple dose regimen of oDox + E is warranted. TRIAL REGISTRATION NUMBER: U1111-1173-5473.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Disponibilidade Biológica , Docetaxel , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Relação Dose-Resposta a Droga , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia
15.
ACS Appl Mater Interfaces ; 16(17): 21722-21735, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38629735

RESUMO

While temozolomide (TMZ) has been a cornerstone in the treatment of newly diagnosed glioblastoma (GBM), a significant challenge has been the emergence of resistance to TMZ, which compromises its clinical benefits. Additionally, the nonspecificity of TMZ can lead to detrimental side effects. Although TMZ is capable of penetrating the blood-brain barrier (BBB), our research addresses the need for targeted therapy to circumvent resistance mechanisms and reduce off-target effects. This study introduces the use of PEGylated mesoporous silica nanoparticles (MSN) with octyl group modifications (C8-MSN) as a nanocarrier system for the delivery of docetaxel (DTX), providing a novel approach for treating TMZ-resistant GBM. Our findings reveal that C8-MSN is biocompatible in vitro, and DTX@C8-MSN shows no hemolytic activity at therapeutic concentrations, maintaining efficacy against GBM cells. Crucially, in vivo imaging demonstrates preferential accumulation of C8-MSN within the tumor region, suggesting enhanced permeability across the blood-brain tumor barrier (BBTB). When administered to orthotopic glioma mouse models, DTX@C8-MSN notably prolongs survival by over 50%, significantly reduces tumor volume, and decreases side effects compared to free DTX, indicating a targeted and effective approach to treatment. The apoptotic pathways activated by DTX@C8-MSN, evidenced by the increased levels of cleaved caspase-3 and PARP, point to a potent therapeutic mechanism. Collectively, the results advocate DTX@C8-MSN as a promising candidate for targeted therapy in TMZ-resistant GBM, optimizing drug delivery and bioavailability to overcome current therapeutic limitations.


Assuntos
Barreira Hematoencefálica , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Nanopartículas , Dióxido de Silício , Temozolomida , Temozolomida/química , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Temozolomida/farmacocinética , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Dióxido de Silício/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Animais , Nanopartículas/química , Humanos , Camundongos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Porosidade , Portadores de Fármacos/química , Camundongos Nus , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos
16.
Int J Pharm ; 656: 124091, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38588758

RESUMO

The development of nanoparticles could help to improve the efficacy/toxicity balance of drugs. This project aimed to develop liposomes and immunoliposomes using microfluidic mixing technology.Various formulation tests were carried out to obtain liposomes that met the established specifications. The liposomes were then characterized in terms of size, polydispersity index (PDI), docetaxel encapsulation rate and lamellarity. Antiproliferative activity was tested in human breast cancer models ranging from near-negative (MDA-MB-231), positive (MDA-MB-453) to HER2 positive. Pharmacokinetic studies were performed in C57BL/6 mice.Numerous batches of liposomes were synthesised using identical molar ratios and by varying the microfluidic parameters TFR, FRR and buffer. All synthesized liposomes have a size < 200 nm, but only Lipo-1, Lipo-6, Lipo-7, Lipo-8 have a PDI < 0.2, which meets our initial requirements. The size of the liposomes was correlated with the total FRR, for a 1:1 FRR the size is 122.2 ± 12.3 nm, whereas for a 1:3 FRR the size obtained is 163.4 ± 34.0 nm (p = 0.019. Three batches of liposomes were obtained with high docetaxel encapsulation rates > 80 %. Furthermore, in vitro studies on breast cancer cell lines demonstrated the efficacy of liposomes obtained by microfluidic mixing technique. These liposomes also showed improved pharmacokinetics compared to free docetaxel, with a longer half-life and higher AUC (3-fold and 3.5-fold increase for the immunoliposome, respectively).This suggests that switching to the microfluidic process will produce batches of liposomes with the same characteristics in terms of in vitro properties and efficacy, as well as the ability to release the encapsulated drug over time in vivo. This time-efficiency of the microfluidic technique is critical, especially in the early stages of development.


Assuntos
Antineoplásicos , Neoplasias da Mama , Docetaxel , Lipossomos , Camundongos Endogâmicos C57BL , Polietilenoglicóis , Docetaxel/farmacocinética , Docetaxel/administração & dosagem , Docetaxel/química , Animais , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Polietilenoglicóis/química , Linhagem Celular Tumoral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Microfluídica/métodos , Camundongos , Tamanho da Partícula , Proliferação de Células/efeitos dos fármacos
17.
Biomater Adv ; 160: 213833, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38564997

RESUMO

Conventional chemotherapy and poor targeted delivery in brain cancer resulting to poor treatment and develop resistance to anticancer drugs. Meanwhile, it is quite challenging to diagnose/detection of brain tumor at early stage of cancer which resulting in severity of the disease. Despite extensive research, effective treatment with real-time imaging still remains completely unavailable, yet. In this study, two brain cancer cell specific moieties i.e., AS1411 aptamer and RGD are decorated on the surface of chitosan-PLGA nanoparticles to improve targeted co-delivery of docetaxel (DTX) and upconversion nanoparticles (UCNP) for effective brain tumor therapy and real-time imaging. The nanoparticles were developed by a slightly modified emulsion/solvent evaporation method. This investigation also translates the successful synthesis of TPGS-chitosan, TPGS-RGD and TPGS-AS1411 aptamer conjugates for making PLGA nanoparticle as a potential tool of the targeted co-delivery of DTX and UCNP to the brain cancer cells. The developed nanoparticles have shown an average particle size <200 nm, spherical in shape, high encapsulation of DTX and UCNP in the core of nanoparticles, and sustained release of DTX up to 72 h in phosphate buffer saline (pH 7.4). AS1411 aptamer and RGD functionalized theranostic chitosan-PLGA nanoparticles containing DTX and UCNP (DUCPN-RGD-AS1411) have achieved greater cellular uptake, 89-fold improved cytotoxicity, enhanced cancer cell arrest even at lower drug conc., improved bioavailability with higher mean residence time of DTX in systemic circulation and brain tissues. Moreover, DUCPN-RGD-AS1411 have greatly facilitated cellular internalization and higher accumulation of UCNP in brain tissues. Additionally, DUCPN-RGD-AS1411 demonstrated a significant suppression in tumor growth in brain-tumor bearing xenograft BALB/c nude mice with no impressive sign of toxicities. DUCPN-RGD-AS1411 has great potential to be utilized as an effective and safe theranostic tool for brain cancer and other life-threatening cancer therapies.


Assuntos
Aptâmeros de Nucleotídeos , Neoplasias Encefálicas , Quitosana , Docetaxel , Oligodesoxirribonucleotídeos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Humanos , Camundongos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Aptâmeros de Nucleotídeos/administração & dosagem , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Quitosana/química , Docetaxel/farmacocinética , Docetaxel/administração & dosagem , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Nanopartículas/química , Oligopeptídeos/química , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Nanomedicina Teranóstica/métodos
18.
J Control Release ; 369: 325-334, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38565395

RESUMO

Challenges for glioma treatment with nanomedicines include physio-anatomical barriers (the blood-brain barrier and blood-brain tumor barrier), low drug loading capacity, and limited circulation time. Here, a red blood cell membrane-coated docetaxel drug nanocrystal (pV-RBCm-NC(DTX)), modified with pHA-VAP (pV) for all-stage targeting of glioma, was designed. The NC(DTX) core exhibited a high drug loading capacity but low in vivo stability, and the RBCm coating significantly enhanced the stability and prolonged in vivo circulation. Moreover, the Y-shaped targeting ligand pV was modified by a mild avidin-biotin interaction, which endowed RBCm-NC(DTX) with superior barrier-crossing ability and therapeutic efficacy. The integration of nanocrystal technology, cell membrane coating, and the avidin-biotin insertion method into this active targeting biomimetic formulation represents a promising drug delivery strategy for glioma.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Docetaxel , Membrana Eritrocítica , Glioma , Nanopartículas , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/química , Glioma/tratamento farmacológico , Animais , Nanopartículas/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/química , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Masculino , Sistemas de Liberação de Medicamentos , Avidina/administração & dosagem , Avidina/química , Humanos , Biotina/química , Biotina/administração & dosagem , Ratos Sprague-Dawley , Barreira Hematoencefálica/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus
19.
Cancer Chemother Pharmacol ; 94(1): 79-87, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38456955

RESUMO

PURPOSE: An oral docetaxel formulation boosted by the Cytochrome P450 (CYP) 3 A inhibitor ritonavir, ModraDoc006/r, is currently under clinical investigation. Based on clinical data, the incidence of grade 1-2 diarrhea is increased with this oral docetaxel formulation compared to the conventional intravenous administration. Loperamide, a frequently used diarrhea inhibitor, could be added to the regimen as symptomatic treatment. However, loperamide is also a substrate of the CYP3A enzyme, which could result in competition between ritonavir and loperamide for this protein. Therefore, we were interested in the impact of coadministered loperamide on the pharmacokinetics of ritonavir-boosted oral docetaxel. METHODS: We administered loperamide simultaneously or with an 8-hour delay to humanized CYP3A4 mice (with expression in liver and intestine) receiving oral ritonavir and docetaxel. Concentrations of docetaxel, ritonavir, loperamide and two of its active metabolites were measured. RESULTS: The plasma exposure (AUC and Cmax) of docetaxel was not altered during loperamide treatment, nor were the ritonavir plasma pharmacokinetics. However, the hepatic and intestinal dispositions of ritonavir were somewhat changed in the simultaneous, but not 8-hour loperamide treatment groups, possibly due to loperamide-induced delayed drug absorption. The pharmacokinetics of loperamide itself did not seem to be influenced by ritonavir. CONCLUSION: These results suggest that delayed loperamide administration can be added to ritonavir-boosted oral docetaxel treatment, without affecting the overall systemic exposure of docetaxel.


Assuntos
Citocromo P-450 CYP3A , Docetaxel , Interações Medicamentosas , Loperamida , Ritonavir , Taxoides , Ritonavir/administração & dosagem , Ritonavir/farmacocinética , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Loperamida/administração & dosagem , Loperamida/farmacocinética , Animais , Camundongos , Citocromo P-450 CYP3A/metabolismo , Administração Oral , Taxoides/farmacocinética , Taxoides/administração & dosagem , Humanos , Distribuição Tecidual , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Área Sob a Curva , Antidiarreicos/administração & dosagem , Antidiarreicos/farmacocinética , Camundongos Transgênicos
20.
J Pharmacokinet Pharmacodyn ; 51(4): 367-384, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38554227

RESUMO

The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in significant differences in treatment efficacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models. The GastroPlus™ was used to develop the PBPK models, which were refined and validated with observed data. The established PBPK models accurately described the pharmacokinetics (PKs) of three drugs in cancer patients, and the predicted-to-observed ratios of all the PK parameters met the acceptance criterion. The PBPK model predicted no significant changes in plasma concentrations of these drugs during co-administration, which was consistent with the observed clinical phenomenon. Besides, the verified PBPK models were then used to predict the effect of other Cytochrome P450 3A4 (CYP3A4) inhibitors/inducers on these drug exposures. In the DDI simulation, strong CYP3A4 modulators changed the exposure of three drugs by 0.71-1.61 fold. Therefore, patients receiving these drugs in combination with strong CYP3A4 inhibitors should be monitored regularly to prevent adverse reactions. Furthermore, co-administration of docetaxel, cyclophosphamide, or epirubicin with strong CYP3A4 inducers should be avoided. In conclusion, the PBPK models can be used to further investigate the DDI potential of each drug and to develop dosage recommendations for concurrent usage by additional perpetrators or victims.


Assuntos
Ciclofosfamida , Citocromo P-450 CYP3A , Docetaxel , Interações Medicamentosas , Epirubicina , Modelos Biológicos , Humanos , Epirubicina/farmacocinética , Epirubicina/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/administração & dosagem , Ciclofosfamida/farmacocinética , Ciclofosfamida/administração & dosagem , Feminino , Citocromo P-450 CYP3A/metabolismo , Pessoa de Meia-Idade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Adulto , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Taxoides/farmacocinética , Taxoides/administração & dosagem , Simulação por Computador , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Indutores do Citocromo P-450 CYP3A/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacocinética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
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