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 BiológicaRESUMO
With the in-depth knowledge of the pathological and physiological characteristics of the intestinal barrier-portal vein/intestinal lymphatic vessels-systemic circulation axis, oral targeted drug delivery is frequently being renewed. With many advantages, such as high safety, convenient administration, and good patient compliance, many researchers have begun to explore targeted drug delivery from intravenous injections to oral administration. Over the past few decades, the fields of materials science and nanomedicine have produced various drug delivery platforms that hold great potential in overcoming the multiple barriers associated with oral drug delivery. However, the oral transport of particles into the systemic circulation is extremely difficult due to immune rejection and biochemical invasion in the intestine, which limits absorption and entry into the bloodstream. The feasibility of the oral delivery of targeted drugs to sites outside the gastrointestinal tract (GIT) is unknown. This article reviews the biological barriers to drug absorption, the in vivo fate and transport mechanisms of drug carriers, the theoretical basis for oral administration, and the impact of carrier structural evolution on oral administration to achieve this goal. Finally, this article reviews the characteristics of different nano-delivery systems that can enhance the bioavailability of oral therapeutics and highlights their applications in the efficient creation of oral anticancer nanomedicines.
Assuntos
Antineoplásicos , Nanomedicina , Neoplasias , Humanos , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Administração Oral , Animais , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Disponibilidade Biológica , Nanopartículas/química , Nanopartículas/administração & dosagemRESUMO
BACKGROUND: Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort. METHODS: The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro. RESULTS: Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC(0ât), AUC(0â∞), and Tmax rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib. CONCLUSIONS: Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib.
Assuntos
Interações Medicamentosas , Indóis , Microssomos Hepáticos , Nitrilas , Piridinas , Pirróis , Sunitinibe , Triazóis , Sunitinibe/farmacologia , Sunitinibe/farmacocinética , Animais , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Nitrilas/farmacocinética , Nitrilas/farmacologia , Humanos , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Pirróis/farmacocinética , Pirróis/farmacologia , Triazóis/farmacocinética , Triazóis/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismoRESUMO
Introduction: The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a large number of cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. STING agonists have demonstrated the ability to inflame the TME, reduce tumor burden, and confer anti-tumor activity in mouse models. 2'3' cyclic guanosine monophosphate adenosine monophosphate (2'3'-cGAMP) is a high-affinity endogenous ligand of STING. However, delivering cGAMP to antigen-presenting cells and tumor cells within the cytosol remains challenging due to membrane impermeability and poor stability. Methods: In this study, we encapsulated 2'3'-cGAMP in a lipid nanoparticle (cGAMP-LNP) designed for efficient cellular delivery. We assessed the properties of the nanoparticles using a series of in-vitro studies designed to evaluate their cellular uptake, cytosolic release, and minimal cytotoxicity. Furthermore, we examined the nanoparticle's anti-tumor effect in a syngeneic mouse model of pancreatic cancer. Results: The lipid platform significantly increased the cellular uptake of 2'3'-cGAMP. cGAMP-LNP exhibited promising antitumor activity in the syngeneic mouse model of pancreatic cancer. Discussion: The LNP platform shows promise for delivering exogenous 2'3'-cGAMP or its derivatives in cancer therapy.
Assuntos
Proteínas de Membrana , Nanopartículas , Nucleotídeos Cíclicos , Neoplasias Pancreáticas , Microambiente Tumoral , Animais , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Nanopartículas/química , Nanopartículas/administração & dosagem , Nucleotídeos Cíclicos/farmacologia , Nucleotídeos Cíclicos/química , Nucleotídeos Cíclicos/farmacocinética , Nucleotídeos Cíclicos/administração & dosagem , Proteínas de Membrana/agonistas , Camundongos , Linhagem Celular Tumoral , Humanos , Microambiente Tumoral/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Lipossomos/química , Lipossomos/farmacologia , Lipossomos/farmacocinética , Lipossomos/administração & dosagemRESUMO
Venetoclax, a small molecule inhibitor of BCL-2, has demonstrated efficacy in treating acute leukemias and has been recommended as one of the first-line anti-leukemia therapies. Although venetoclax has been suggested to probably possess the ability to penetrate the central nervous system (CNS), current data to elucidate the characteristics of venetoclax in cerebrospinal fluid (CSF), bone marrow (BM), and plasma are still lacking. This study investigated the real-world characteristics of venetoclax concentrations in CSF, BM, and plasma in acute leukemia patients. Thirteen acute leukemia patients treated with venetoclax were included, with paired samples of CSF, BM, and plasma collected and venetoclax concentrations measured using LC-MS/MS. With the results, the median venetoclax concentrations were 2030 ng/mL in plasma, 16.7 ng/mL in CSF, and 1390 ng/mL in BM. The percentages of CSF/plasma and BM/plasma were 0.74% and 70.37%, respectively. While no direct correlation was observed between CSF and plasma venetoclax levels, there was a trend toward an improved CSF/plasma percentage over time following the last administration of venetoclax. In contrast, a strong correlation was found between BM and plasma levels. This study demonstrated that venetoclax could reach its effective concentration in most patients, suggesting its potential clinical utility in the management of CNS involvement in acute leukemia.
Assuntos
Medula Óssea , Compostos Bicíclicos Heterocíclicos com Pontes , Sulfonamidas , Humanos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/líquido cefalorraquidiano , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/líquido cefalorraquidiano , Sulfonamidas/sangue , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Medula Óssea/efeitos dos fármacos , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos/sangue , Espectrometria de Massas em Tandem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/líquido cefalorraquidiano , Leucemia Mieloide Aguda/sangue , Idoso de 80 Anos ou mais , Cromatografia Líquida , Leucemia/tratamento farmacológico , Leucemia/líquido cefalorraquidiano , Leucemia/sangue , Adulto JovemRESUMO
Seaweed endophytes are a rich source of microbial diversity and bioactive compounds. This review provides a comprehensive analysis of the microbial diversity associated with seaweeds and their interaction between them. These diverse bacteria and fungi have distinct metabolic pathways, which result in the synthesis of bioactive compounds with potential applications in a variety of health fields. We examine many types of seaweed-associated microorganisms, their bioactive metabolites, and their potential role in cancer treatment using a comprehensive literature review. By incorporating recent findings, we hope to highlight the importance of seaweed endophytes as a prospective source of novel anticancer drugs and promote additional studies in this area. We also investigate the pharmacokinetic and pharmacodynamic profiles of these bioactive compounds because understanding their absorption, distribution, metabolism, excretion (ADMET), and toxicity profiles is critical for developing bioactive compounds with anticancer potential into effective cancer drugs. This knowledge ensures the safety and efficacy of proposed medications prior to clinical trials. This study not only provides promise for novel and more effective treatments for cancer with fewer side effects, but it also emphasizes the necessity of sustainable harvesting procedures and ethical considerations for protecting the delicate marine ecology during bioprospecting activities.
Assuntos
Antineoplásicos , Bactérias , Endófitos , Fungos , Alga Marinha , Alga Marinha/química , Endófitos/metabolismo , Endófitos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Humanos , Fungos/efeitos dos fármacos , Fungos/metabolismo , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Neoplasias/tratamento farmacológico , Animais , BiodiversidadeRESUMO
Purpose: Renal cell carcinoma (RCC) is the most common and lethal type of urogenital cancer, with one-third of new cases presenting as metastatic RCC (mRCC), which, being the seventh most common cancer in men and the ninth in women, poses a significant challenge. For patients with poor prognosis, temsirolimus (TEM) has been approved for first-line therapy, possessing pharmacodynamic activities that block cancer cell growth and inhibit proliferation-associated proteins. However, TEM suffers from poor water solubility, low bioavailability, and systemic side effects. This study aims to develop a novel drug formulation for the treatment of RCC. Methods: In this study, amphiphilic block copolymer (poly(ethylene glycol) monomethyl ether-poly(beta-amino ester)) (mPEG-PBAE) was utilized as a drug delivery vehicle and TEM-loaded micelles were prepared by thin-film hydration method by loading TEM inside the nanoparticles. Then, the molecular weight of mPEG-PBAE was controlled to make it realize hydrophobic-hydrophilic transition in the corresponding pH range thereby constructing pH-responsive TEM-loaded micelles. Characterization of pH-responsive TEM-loaded nanomicelles particle size, potential and micromorphology while its determination of drug-loading properties, in vitro release properties. Finally, pharmacodynamics and hepatorenal toxicity were further evaluated. Results: TEM loading in mPEG-PBAE increased the solubility of TEM in water from 2.6 µg/mL to more than 5 mg/mL. The pH-responsive TEM-loaded nanomicelles were in the form of spheres or spheroidal shapes with an average particle size of 43.83 nm and a Zeta potential of 1.79 mV. The entrapment efficiency (EE) of pH-responsive TEM nanomicelles with 12.5% drug loading reached 95.27%. Under the environment of pH 6.7, the TEM was released rapidly within 12 h, and the release rate could reach 73.12% with significant pH-dependent characteristics. In vitro experiments showed that mPEG-PBAE preparation of TEM-loaded micelles had non-hemolytic properties and had significant inhibitory effects on cancer cells. In vivo experiments demonstrated that pH-responsive TEM-loaded micelles had excellent antitumor effects with significantly reduced liver and kidney toxicity. Conclusion: In conclusion, we successfully prepared pH-responsive TEM-loaded micelles. The results showed that pH-responsive TEM-loaded micelles can achieve passive tumor targeting of TEM, and take advantage of the acidic conditions in tumor tissues to achieve rapid drug release.
Assuntos
Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Micelas , Polietilenoglicóis , Sirolimo , Sirolimo/administração & dosagem , Sirolimo/química , Sirolimo/farmacocinética , Sirolimo/farmacologia , Sirolimo/análogos & derivados , Humanos , Polietilenoglicóis/química , Concentração de Íons de Hidrogênio , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Tamanho da Partícula , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Camundongos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Feminino , MasculinoRESUMO
Glioma is one of the most common central nervous system (CNS) cancers that can be found within the brain and the spinal cord. One of the pressing issues plaguing the development of therapeutics for glioma originates from the selective and semipermeable CNS membranes: the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). It is difficult to bypass these membranes and target the desired cancerous tissue because the purpose of the BBB and BSCB is to filter toxins and foreign material from invading CNS spaces. There are currently four varieties of Food and Drug Administration (FDA)-approved drug treatment for glioma; yet these therapies have limitations including, but not limited to, relatively low transmission through the BBB/BSCB, despite pharmacokinetic characteristics that allow them to cross the barriers. Steps must be taken to improve the development of novel and repurposed glioma treatments through the consideration of pharmacological profiles and innovative drug delivery techniques. This review addresses current FDA-approved glioma treatments' gaps, shortcomings, and challenges. We then outline how incorporating computational BBB/BSCB models and innovative drug delivery mechanisms will help motivate clinical advancements in glioma drug delivery. Ultimately, considering these attributes will improve the process of novel and repurposed drug development in glioma and the efficacy of glioma treatment.
Assuntos
Antineoplásicos , Barreira Hematoencefálica , Neoplasias Encefálicas , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Glioma , Glioma/tratamento farmacológico , Humanos , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologiaRESUMO
BACKGROUND AND OBJECTIVE: Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥ 2 prior tyrosine kinase inhibitors. Here, we aimed to demonstrate similarity in efficacy/safety of asciminib 80 mg once daily (q.d.) versus 40 mg twice daily (b.i.d.) in patients with CML-CP without T315I mutation and support the use of the 200-mg b.i.d. dosage in patients harboring T315I, using model-informed drug development. METHODS: Data were collected from 199 patients in the phase I (NCT02081378; 10-200 mg b.i.d. or 10-400 mg q.d.) and 154 patients in the phase III (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure-response (efficacy/safety) analyses. RESULTS: PopPK showed comparable exposure (area under the curve, AUC0-24h) for 40 mg b.i.d. and 80 mg q.d. (12,638 vs 12,646 ng*h/mL); average maximum and minimum plasma concentrations for 80 mg q.d. were 1.61- and 0.72-fold those of 40 mg b.i.d., respectively. Exposure-response analyses predicted similar major molecular response rates for 40 mg b.i.d. and 80 mg q.d. (Week 24: 27.6% vs 24.8%; Week 48: 32.3% vs 30.6%). Results also established adequacy of 200 mg b.i.d. in patients with T315I mutation (Week 24: 20.7%; Week 48: 23.7%), along with a similar safety profile for all dose regimens. CONCLUSIONS: Similarity between 40 mg b.i.d. and 80 mg q.d. regimens was investigated, demonstrating similar and substantial efficacy with well-tolerated safety in patients without T315I mutation. The 200-mg b.i.d. dose was deemed safe and effective for patients with T315I mutation.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Mutação , Inibidores de Proteínas Quinases , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Cromossomo Filadélfia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Relação Dose-Resposta a Droga , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Adulto Jovem , Idoso de 80 Anos ou mais , Área Sob a Curva , Niacinamida/análogos & derivados , PirazóisRESUMO
Nanoparticle-mediated drug delivery offers a promising approach to targeted cancer therapy, leveraging the ability of nanoparticles to deliver therapeutic agents directly to cancerous tissues with minimal impact on surrounding healthy cells. The presence of these nanoparticles is governed by a concentration equation, which accounts for the diffusion, convection, and reaction of the nanoparticles with the blood components. It is well-known that whenever a disease or infection occurs in a human, in 80% of cases a rise in the concentration of hydrogen peroxide in the blood occurs. This is the reason why blood is assumed to contain hydrogen peroxide (in the present study), which is a biomarker of oxidative stress and inflammation. This study explores the integration of machine learning (ML) techniques into the optimization of drug delivery processes within the human cardiovascular system, focusing on the enhancement of these processes through the application of magnetic fields. By employing ML algorithms, we analyze and predict the behavior of nanoparticles as they navigate the complex fluid dynamics of the cardiovascular system, particularly under the influence of an external magnetic field. The predictive power of ML models enables the precise control of nanoparticle trajectories, optimizing their accumulation in cancerous tissues and improving the efficacy of the drug delivery system. The findings of this study demonstrate that ML-enhanced magnetic targeting can significantly enhance the precision and effectiveness of nanoparticle-mediated drug delivery, offering a new paradigm in cancer treatment strategies. This approach has the potential to revolutionize the field by providing personalized and highly efficient therapeutic solutions for cancer patients.
Assuntos
Sistemas de Liberação de Medicamentos , Aprendizado de Máquina , Campos Magnéticos , Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Nanopartículas/química , Sistemas de Liberação de Medicamentos/métodos , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/efeitos dos fármacos , Sistemas de Liberação de Fármacos por Nanopartículas , Peróxido de Hidrogênio/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinéticaRESUMO
The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.
Assuntos
Histona-Lisina N-Metiltransferase , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Animais , Relação Estrutura-Atividade , Quinazolinas/farmacologia , Quinazolinas/química , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Camundongos , Descoberta de Drogas , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , RatosRESUMO
Given the considerable potential of DOT1LR231Q inhibitors in lung cancer therapy and the problematic pharmacokinetics of nucleoside inhibitors, our group launched a development program of non-nucleoside DOT1LR231Q inhibitors to improve the pharmacokinetic properties. Herein, two series of non-nucleoside compounds bearing piperidine or 3-(aminomethyl)pyrrolidin-3-ol as "ribose mimics" were designed and evaluated through antiproliferation assay and western blot analysis. The optimal TB22 inhibited the proliferation of H460R231Q cells with an IC50 value of 2.85 µM, about 13-fold more potent than SGC0946. Notably, TB22 demonstrated significant in vivo efficacy (TGI = 60.57%) in H460R231Q cell-derived xenograft models and improved pharmacokinetic properties (t1/2 = 6.06 ± 2.94 h and CL = 55.18 ± 8.56 mL/kg/min). Moreover, a mechanism study validated that TB22 suppressed malignant phenotypes of lung cancer cells harboring R231Q mutation via the MAPK/ERK signaling pathway. This work provides a promising molecule for lung cancer therapy in favor of clinical patients.
Assuntos
Antineoplásicos , Proliferação de Células , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Camundongos , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Camundongos Nus , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Histona-Lisina N-MetiltransferaseRESUMO
Nanocarriers (NCs) play a crucial role in delivering theranostic agents to tumors, making them a pivotal focus of research. However, the persistently low delivery efficiency of engineered NCs has been a significant challenge in the advancement of nanomedicine, stirring considerable debate. Transvascular transport is a critical pathway for NC delivery from vessels to tumors, yet a comprehensive understanding of the interactions between NCs and vascular systems remains elusive. In recent years, considerable efforts have been invested in elucidating the transvascular transport mechanisms of NCs, leading to promising advancements in tumor delivery and theranostics. In this context, we highlight various delivery mechanisms, including the enhanced permeability and retention effect, cooperative immune-driven effect, active transcytosis, and cell/bacteria-mediated delivery. Furthermore, we explore corresponding strategies aimed at enhancing transvascular transport of NCs for efficient tumor delivery. These approaches offer intriguing solutions spanning physicochemical, biological, and pharmacological domains to improve delivery and therapeutic outcomes. Additionally, we propose a forward-looking delivery framework that relies on advanced tumor/vessel models, high-throughput NC libraries, nano-bio interaction datasets, and artificial intelligence, which aims to guide the design of next-generation carriers and implementation strategies for optimized delivery.
Assuntos
Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Nanopartículas/química , Portadores de Fármacos/química , Animais , Sistemas de Liberação de Medicamentos/métodos , Transcitose , Transporte Biológico , Nanomedicina Teranóstica/métodos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Nanomedicina/métodosRESUMO
Purpose: The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy. Patients and Methods: A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model. Results: The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups. Conclusion: We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Liberação Controlada de Fármacos , Ferroptose , Estruturas Metalorgânicas , Piridinas , Estruturas Metalorgânicas/química , Animais , Humanos , Piridinas/química , Piridinas/administração & dosagem , Piridinas/farmacocinética , Piridinas/farmacologia , Camundongos , Células Hep G2 , Concentração de Íons de Hidrogênio , Ferroptose/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Sistemas de Liberação de Medicamentos/métodos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Tamanho da Partícula , Nanopartículas/químicaRESUMO
This study aims to enhance the solubility of Olaparib, classified as biopharmaceutical classification system (BCS) class IV due to its low solubility and bioavailability using a solid self-nanoemulsifying drug delivery system (S-SNEDDS). For this purpose, SNEDDS formulations were created using Capmul MCM as the oil, Tween 80 as the surfactant, and PEG 400 as the co-surfactant. The SNEDDS formulation containing olaparib (OLS-352), selected as the optimal formulation, showed a mean droplet size of 87.0 ± 0.4 nm and drug content of 5.53 ± 0.09%. OLS-352 also demonstrated anticancer activity against commonly studied ovarian (SK-OV-3) and breast (MCF-7) cancer cell lines. Aerosil® 200 and polyvinylpyrrolidone (PVP) K30 were selected as solid carriers, and S-SNEDDS formulations were prepared using the spray drying method. The drug concentration in S-SNEDDS showed no significant changes (98.4 ± 0.30%, 25â) with temperature fluctuations during the 4-week period, demonstrating improved storage stability compared to liquid SNEDDS (L-SNEDDS). Dissolution tests under simulated gastric and intestinal conditions revealed enhanced drug release profiles compared to those of the raw drug. Additionally, the S-SNEDDS formulation showed a fourfold greater absorption in the Caco-2 assay than the raw drug, suggesting that S-SNEDDS could improve the oral bioavailability of poorly soluble drugs like olaparib, thus enhancing therapeutic outcomes. Furthermore, this study holds significance in crafting a potent and cost-effective pharmaceutical formulation tailored for the oral delivery of poorly soluble drugs.
Assuntos
Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Emulsões , Ftalazinas , Piperazinas , Solubilidade , Piperazinas/química , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Humanos , Ftalazinas/química , Ftalazinas/administração & dosagem , Ftalazinas/farmacocinética , Ftalazinas/farmacologia , Emulsões/química , Sistemas de Liberação de Medicamentos/métodos , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Química Farmacêutica/métodos , Tamanho da Partícula , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacologia , Tensoativos/química , Portadores de Fármacos/química , Polietilenoglicóis/química , Células MCF-7 , Liberação Controlada de Fármacos , Nanopartículas/química , Composição de Medicamentos/métodosRESUMO
Background: The combination of nanoplatform-based chemotherapy and photodynamic therapy (PDT) is a promising way to treat cancer. Celastrol (Cela) exhibits highly effective anti-hepatoma activity with low water solubility, poor bioavailability, non-tumor targeting, and toxic side effects. The combination of Cela-based chemotherapy and PDT via hepatoma-targeting and reactive oxygen species (ROS)-responsive polymeric micelles (PMs) could solve the application problem of Cela and further enhance antitumor efficacy. Methods: In this study, Cela and photosensitizer chlorin e6 (Ce6) co-loaded glycyrrhetinic acid-modified carboxymethyl chitosan-thioketal-rhein (GCTR) PMs (Cela/Ce6/GCTR PMs) were prepared and characterized. The safety, ROS-sensitive drug release, and intracellular ROS production were evaluated. Furthermore, the in vitro anti-hepatoma effect and cellular uptaken in HepG2 and BEL-7402 cells, and in vivo pharmacokinetic, tissue distribution, and antitumor efficacy of Cela/Ce6/GCTR PMs in H22 tumor-bearing mice were then investigated. Results: Cela/Ce6/GCTR PMs were successfully prepared with nanometer-scale particle size, favorable drug loading capacity, and encapsulation efficiency. Cela/Ce6/GCTR PMs exhibited a strong safety profile and better hemocompatibility, exhibiting less damage to normal tissues. Compared with Cela-loaded GCTR PMs, the ROS-responsiveness of Cela/Ce6/GCTR PMs was increased, and the release of Cela was accelerated after combination with PDT. Cela/Ce6/GCTR PMs can efficiently target liver tumor cells by uptake and have a high cell-killing effect in response to ROS. The combination of GCTR PM-based chemotherapy and PDT resulted in increased bioavailability of Cela and Ce6, improved liver tumor targeting, and better anti-hepatoma effects in vivo. Conclusion: Hepatoma-targeting and ROS-responsive GCTR PMs co-loaded with Cela and Ce6 combined with PDT exhibited improved primary hepatic carcinoma therapeutic effects with lower toxicity to normal tissues, overcoming the limitations of monotherapy and providing new strategies for tumor treatment.
Assuntos
Carcinoma Hepatocelular , Quitosana , Clorofilídeos , Neoplasias Hepáticas , Micelas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Espécies Reativas de Oxigênio , Animais , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/administração & dosagem , Células Hep G2 , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia , Porfirinas/administração & dosagem , Quitosana/química , Quitosana/análogos & derivados , Linhagem Celular Tumoral , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/farmacocinética , Triterpenos/química , Triterpenos/farmacologia , Triterpenos/farmacocinética , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/farmacocinética , Ácido Glicirretínico/análogos & derivados , Polímeros/química , Distribuição Tecidual , Liberação Controlada de Fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Masculino , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinéticaRESUMO
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 (â¼95 %) and loading capacity (â¼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (â¼50 % 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 farmacológicoRESUMO
Efficient tumour treatment is hampered by the poor selectivity of anticancer drugs, resulting in scarce tumour accumulation and undesired off-target effects. Nano-sized drug-delivery systems in the form of nanoparticles (NPs) have been proposed to improve drug distribution to solid tumours, by virtue of their ability of passive and active tumour targeting. Despite these advantages, literature studies indicated that less than 1% of the administered NPs can successfully reach the tumour mass, highlighting the necessity for more efficient drug transporters in cancer treatment. Living cells, such as blood cells, circulating immune cells, platelets, and stem cells, are often found as an infiltrating component in most solid tumours, because of their ability to naturally circumvent immune recognition, bypass biological barriers, and reach inaccessible tissues through innate tropism and active motility. Therefore, the tumour-homing ability of these cells can be harnessed to design living cell carriers able to improve the transport of drugs and NPs to tumours. Albeit promising, this approach is still in its beginnings and suffers from difficult scalability, high cost, and poor reproducibility. In this review, we present an overview of the most common cell transporters of drugs and NPs, and we discuss how different cell types interact with biological barriers to deliver cargoes of various natures to tumours. Finally, we analyse the different techniques used to load drugs or NPs in living cells and discuss their advantages and disadvantages.
Assuntos
Antineoplásicos , Sistemas de Liberação de Medicamentos , Nanomedicina , Nanopartículas , Neoplasias , Humanos , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Nanopartículas/química , Sistemas de Liberação de Medicamentos/métodos , Animais , Transporte Biológico/fisiologia , Portadores de Fármacos/químicaRESUMO
PURPOSE OF REVIEW: Amino acids are critical to health, serving both as constituents of proteins and in signaling and metabolism. Amino acids are consumed as nutrients, supplements, and nutraceuticals. Much remains to be learned about amino acid function. Physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling is an emerging tool for studying their complex biology. This review highlights recent PBPK-PD models developed to study amino acid physiology and metabolism and discusses their potential for addressing unresolved questions in the field. RECENT FINDINGS: PBPK-PD models provided several insights. They revealed the interplay between the mechanisms by which leucine governs skeletal muscle protein metabolism in healthy adults. The models also identified optimal dosing regimens of amino acid supplementation to treat sickle-cell disease and recurrent hypoglycemia, and to minimize drug side effects in seizure disorders. Additionally, they characterized the effects of novel anticancer drugs that seek to deprive cancer cells of amino acids. Future models may inform treatment strategies for sarcopenia, characterize distinctions between animal- and plant-based nutrition, and inform nutrient-drug interactions in Parkinson's disease. SUMMARY: PBPK-PD models are powerful tools for studying amino acid physiology and metabolism, with applications to nutrition, pharmacology, and their interplay.
Assuntos
Aminoácidos , Suplementos Nutricionais , Modelos Biológicos , Músculo Esquelético , Humanos , Aminoácidos/farmacocinética , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Anemia Falciforme/tratamento farmacológico , Leucina/farmacocinética , Leucina/farmacologia , Antineoplásicos/farmacocinética , Sarcopenia/tratamento farmacológico , Sarcopenia/metabolismo , Hipoglicemia , Doença de Parkinson/tratamento farmacológico , Proteínas Musculares/metabolismoRESUMO
INTRODUCTION: In the last decade, various Machine Learning techniques have been proposed aiming to individualise the dose of anticancer drugs mostly based on a presumed drug effect or measured effect biomarkers. The aim of this scoping review was to comprehensively summarise the research status on the use of Machine Learning for precision dosing in anticancer drug therapy. METHODS: This scoping review was conducted in accordance with the interim guidance by Cochrane and the Joanna Briggs Institute. We systematically searched the databases Medline (via PubMed), Embase and the Cochrane Library for research articles and reviews including results published after 2016. Results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. RESULTS: A total of 17 relevant studies was identified. In 12 of the included studies, Reinforcement Learning methods were used, including Classical, Deep, Double Deep and Conservative Q-Learning and Fuzzy Reinforcement Learning. Furthermore, classical Machine Learning methods were compared in terms of their performance and an artificial intelligence platform based on parabolic equations was used to guide dosing prospectively and retrospectively, albeit only in a limited number of patients. Due to the significantly different algorithm structures, a meaningful comparison between the various Machine Learning approaches was not possible. CONCLUSION: Overall, this review emphasises the clinical relevance of Machine Learning methods for anticancer drug dose optimisation, as many algorithms have shown promising results enabling model-free predictions with the potential to maximise efficacy and minimise toxicity when compared to standard protocols.