RESUMO
PURPOSE: The present study investigates and compares the dose-dependent pharmacokinetics and oral bioavailability of edelfosine in healthy, immunodeficient, and tumor-bearing immunosuppressed mouse animal models, as well as edelfosine uptake and apoptotic activity in the Z-138 mantle cell lymphoma (MCL) cell line. EXPERIMENTAL DESIGN: Biodistribution study of edelfosine was done in both BALB/c and severe combined immune deficiency (SCID) mice, and then the in vivo behavior of the drug after i.v. and oral administration was monitored. RESULTS: We found that edelfosine is incorporated and induces apoptosis in the Z-138 human mantle cell lymphoma cell line, whereas normal resting peripheral blood human lymphocytes were not affected. In vivo biodistribution studies revealed that accumulation of edelfosine in the tumor of a MCL-bearing mouse animal model was considerably higher (P < 0.01) than in the other organs analyzed. Besides, no statistical differences were observed between the pharmacokinetic parameters of BALB/c and SCID mice. Edelfosine presented slow elimination and high distribution to tissues. Bioavailability for a single oral dose of edelfosine was <10%, but a multiple-dose oral administration increased this value up to 64%. CONCLUSION: Our results show that edelfosine is widely scattered across different organs, but it is preferentially internalized by the tumor both in vitro and in vivo. Our data, together with the apoptotic action of the drug on cancer cells, support a rather selective action of edelfosine in cancer treatment, and that multiple oral administration is required to increase oral bioavailability.
Assuntos
Linfócitos/metabolismo , Linfoma de Célula do Manto/metabolismo , Camundongos SCID/metabolismo , Éteres Fosfolipídicos/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Linfoma de Célula do Manto/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Éteres Fosfolipídicos/uso terapêutico , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Nanomedicine and drug delivery technologies play a prominent role in modern medicine, facilitating better treatments than conventional drugs. Nanomedicine is being increasingly used to develop new methods of cancer diagnosis and treatment, since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Regenerative medicine provides another area where innovative drug delivery technology is being studied for improved tissue regeneration. Drug delivery systems can protect therapeutic proteins and peptides against degradation in biological environments and deliver them in a controlled manner. Similarly, the combination of drug delivery systems and stem cells can improve their survival, differentiation, and engraftment. The present review summarizes the most important steps carried-out by the group of Prof Blanco-Prieto in nanomedicine and drug delivery technologies. Throughout her scientific career, she has contributed to the area of nanomedicine to improve anticancer therapy. In particular, nanoparticles loaded with edelfosine, doxorubicin, or methotrexate have demonstrated great anticancer activity in preclinical settings of lymphoma, glioma, and pediatric osteosarcoma. In regenerative medicine, a major focus has been the development of drug delivery systems for brain and cardiac repair. In this context, several microparticle-based technologies loaded with biologics have demonstrated efficacy in clinically relevant animal models such as monkeys and pigs. The latest research by this group has shown that drug delivery systems combined with cell therapy can achieve a more complete and potent regenerative response. Cutting-edge areas such as noninvasive intravenous delivery of cardioprotective nanomedicines or extracellular vesicle-based therapies are also being explored. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
Assuntos
Sistemas de Liberação de Medicamentos , Nanomedicina , Nanoestruturas , Neoplasias/tratamento farmacológico , Medicina Regenerativa , Animais , HumanosRESUMO
Peripheral artery disease (PAD) is a major cause of acute and chronic illness, with extremely poor prognosis that remains underdiagnosed and undertreated. Trimethylamine-N-Oxide (TMAO), a gut derived metabolite, has been associated with atherosclerotic burden. We determined plasma levels of TMAO by mass spectrometry and evaluated their association with PAD severity and prognosis. 262 symptomatic PAD patients (mean age 70 years, 87% men) categorized in intermittent claudication (IC, n = 147) and critical limb ischemia (CLI, n = 115) were followed-up for a mean average of 4 years (min 1-max 102 months). TMAO levels were increased in CLI compared to IC (P < 0.001). Receiver operating characteristic (ROC) curves for severity (CLI) rendered a cutoff of 2.26 µmol/L for TMAO (62% sensitivity, 76% specificity). Patients with TMAO > 2.26 µmol/L exhibited higher risk of cardiovascular death (sub-hazard ratios ≥2, P < 0.05) that remained significant after adjustment for confounding factors. TMAO levels were associated to disease severity and CV-mortality in our cohort, suggesting an improvement of PAD prognosis with the measurement of TMAO. Overall, our results indicate that the intestinal bacterial function, together with the activity of key hepatic enzymes for TMA oxidation (FMO3) and renal function, should be considered when designing therapeutic strategies to control gut-derived metabolites in vascular patients.
Assuntos
Metilaminas/metabolismo , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/mortalidade , Idoso , Feminino , Humanos , Masculino , Doença Arterial Periférica/diagnóstico , Prognóstico , Medição de RiscoRESUMO
Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochemical screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/metabolismo , Acetilação , Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/química , Estrutura Molecular , Diester Fosfórico Hidrolases/metabolismo , Relação Estrutura-AtividadeRESUMO
In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).
Assuntos
Doença de Alzheimer/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Acetilação/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Inibidores de Histona Desacetilases/química , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Camundongos , Inibidores da Fosfodiesterase 5/químicaRESUMO
The ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, edelfosine (ET-18-OCH(3)) is the prototype molecule of a promising class of antitumor drugs named alkyl-lysophospholipid analogues (ALPs) or antitumor ether lipids. This drug presents a very important drawback as can be the dose dependent haemolysis when administered intravenously. Lipid nanoparticles have been lately proposed for different drug encapsulation as an alternative to other controlled release delivery systems, such as liposomes or polymeric nanoparticles. The aim of this study was to develop a lipid nanoparticulate system that would decrease systemic toxicity as well as improve the therapeutic potential of the drug. Lipids employed were Compritol 888 ATO and stearic acid. The nanoparticles were characterized by photon correlation spectroscopy for size and size distribution, and atomic force microscopy (AFM) was used for the determination of morphological properties. By both differential scanning calorimetry (DSC) and X-ray diffractometry, crystalline behaviour of lipids and drug was assessed. The drug encapsulation efficiency and the drug release kinetics under in vitro conditions were measured by HPLC-MS. It was concluded that Compritol presents advantages as a matrix material for the manufacture of the nanoparticles and for the controlled release of edelfosine.
Assuntos
Lipídeos/administração & dosagem , Nanopartículas , Éteres Fosfolipídicos/química , Varredura Diferencial de Calorimetria , Química Farmacêutica , Microscopia de Força Atômica , Tamanho da Partícula , Difração de Raios XRESUMO
We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Desenho de Fármacos , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Doença de Alzheimer/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Neuroglia/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/síntese química , Inibidores da Fosfodiesterase 5/química , Relação Estrutura-AtividadeRESUMO
The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD.
Assuntos
Antiparkinsonianos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Receptores de Canabinoides/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Canabidiol/análogos & derivados , Canabidiol/farmacologia , Catalepsia/tratamento farmacológico , Catalepsia/metabolismo , Catalepsia/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Haloperidol , Ácido Homovanílico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Transtornos Parkinsonianos/patologia , RNA Mensageiro/metabolismoRESUMO
The use of molecular markers for inflammation in the gastrointestinal tract could empower optical imaging modalities for early diagnosis and eventually personalized timely treatments. A major hurdle to the widespread use of functional fluorescence imaging is the absence of suitable contrast agents, in particular to be administered via the oral route due to the usual proteolytic susceptibility of the biomarkers. By designing a retro-inverso peptide, starting from a previously described sequence specific for N-cadherin, we achieved resistance to gastrointestinal degradation and even slightly improved specificity towards the target, both in ex vivo and in vivo experimental colitis. Simulations at fundamental molecular level suggested that the introduced retro-inverso modifications did not affect the folding of the peptide, leaving its ability to interact with the binding pocket of the monomeric N-cadherin unaltered, even when fluorescently labeled. Possible further derivatization of this sequence could be envisaged to further extend the potential of the designed retro-inverso peptide as diagnostic or theranostic agent for the oral route.
Assuntos
Colite/diagnóstico por imagem , Peptídeos/administração & dosagem , Administração Oral , Animais , Caderinas/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Sulfato de Dextrana , Células Epiteliais/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Microscopia de FluorescênciaRESUMO
The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.
Assuntos
Antineoplásicos/farmacologia , Metilases de Modificação do DNA/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cristalografia por Raios X , Metilases de Modificação do DNA/química , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Interferons/imunologia , Interferons/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos , Simulação de Acoplamento Molecular , Análise de Sobrevida , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).
Assuntos
Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacologia , Acetilação/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Desenho de Fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacocinética , Histona Desacetilases/metabolismo , Humanos , Camundongos , Modelos Moleculares , Inibidores da Fosfodiesterase 5/síntese química , Inibidores da Fosfodiesterase 5/farmacocinéticaRESUMO
Nanomedicine has recently emerged as an exciting tool able to improve the early diagnosis and treatment of a variety of intractable or age-related brain disorders. The most relevant properties of nanomaterials are that they can be engineered to cross the blood brain barrier, to target specific cells and molecules and to act as vehicles for drugs. Potentially beneficial properties of nanotherapeutics derived from its unique characteristics include improved efficacy, safety, sensitivity and personalization compared to conventional medicines. In this review, recent advances in available nanostructures and nanomaterials for brain applications will be described. Then, the latest applications of nanotechnology for the diagnosis and treatment of neurological disorders, in particular brain tumors and neurodegenerative diseases, will be reviewed. Recent investigations of the neurotoxicity of the nanomaterial both in vitro and in vivo will be summarized. Finally, the ongoing challenges that have to be meet if new nanomedical products are to be put on the market will be discussed and some future directions will be outlined.
Assuntos
Neoplasias Encefálicas/diagnóstico , Nanoestruturas , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/metabolismo , Dopaminérgicos/administração & dosagem , Dopaminérgicos/química , Portadores de Fármacos/química , Humanos , Nanomedicina , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Nootrópicos/administração & dosagem , Nootrópicos/química , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológicoRESUMO
Breast cancer is a heterogeneous group of neoplasms predominantly originating in the terminal duct lobular units. It represents the leading cause of cancer death in women and the survival frequencies for patients at advanced stages of the disease remain low. New treatment options need to be researched to improve these rates. The anti-tumor ether lipid edelfosine (ET) is the prototype of a novel generation of promising anticancer drugs. However, it presents several drawbacks for its use in cancer therapy, including gastrointestinal and hemolytic toxicity and low oral bioavailability. To overcome these obstacles, ET was encapsulated in Precirol ATO 5 lipid nanoparticles (ET-LN), and its anti-tumor potential was in vitro tested in breast cancer. The formulated ET-LN were more effective in inhibiting cell proliferation and notably decreased cell viability, showing that the cytotoxic effect of ET was considerably enhanced when ET was encapsulated. In addition, ET and ET-LN were able to promote cell cycle arrest at G1 phase. Moreover, although both treatments provoked an apoptotic effect in a time-dependent manner, such anti-tumor effects were noticeably improved with ET-LN treatment. Therefore, our results indicate that encapsulating ET in LN played an essential role in improving the efficacy of the drug.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Nanopartículas/administração & dosagem , Éteres Fosfolipídicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diglicerídeos/química , Feminino , Humanos , Células MCF-7 , Nanopartículas/química , Éteres Fosfolipídicos/química , Polissorbatos/químicaRESUMO
Although current therapies have improved leukemia survival rates, adverse drug effects and relapse are frequent. Encapsulation of edelfosine (ET) in lipid nanoparticles (LNs) improves its oral bioavailability and decreases its toxicity. Here we evaluated the efficacy of ET-LN in myeloid leukemia cell lines. Drug-loaded LN were as effective as free ET in sensitive leukemia cell lines. Moreover, the encapsulated drug overcame the resistance of the K562 cell line to the drug. LN containing ET might be used as a promising drug delivery system in leukemia due to their capacity to overcome the in vivo pitfalls of the free drug and their efficacy in vitro in leukemia cell lines.
Assuntos
Antineoplásicos/administração & dosagem , Leucemia/tratamento farmacológico , Lipídeos/administração & dosagem , Nanopartículas/administração & dosagem , Éteres Fosfolipídicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Físico-Química , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Células HL-60 , Humanos , Células K562 , Leucemia/enzimologia , Leucemia/patologia , Lipídeos/química , Nanopartículas/química , Éteres Fosfolipídicos/químicaRESUMO
INTRODUCTION: Cancer is a leading cause of death worldwide and it is estimated that deaths from this disease will rise to over 11 million in 2030. Most cases of cancer can be cured with surgery, radiotherapy or chemotherapy if they are detected at an early stage. However, current cancer therapies are commonly associated with undesirable side effects, as most chemotherapy treatments are cytotoxic and present poor tumor targeting. AREAS COVERED: Lipid nanoparticles (LN) are one of the most promising options in this field. LN are made up of biodegradable generally recognized as safe (GRAS) lipids, their formulation includes different techniques, and most are easily scalable to industrial manufacture. LN overcome the limitations imposed by the need for intravenous administration, as they are mainly absorbed via the lymphatic system when they are administered orally, which improves drug bioavailability. Furthermore, depending on their composition, LN present the ability to cross the blood-brain barrier, thus opening up the possibility of targeting brain tumors. EXPERT OPINION: The drawbacks of chemotherapeutic agents make it necessary to invest in research to find safer and more effective therapies. Nanotechnology has opened the door to new therapeutic options through the design of formulations that include a wide range of materials and formulations at the nanometer range, which improve drug efficacy through direct or indirect tumor targeting, increased bioavailability and diminished toxicity.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Lipídeos , Nanopartículas , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Humanos , Lipídeos/química , Lipídeos/toxicidade , Nanopartículas/química , Nanopartículas/toxicidadeRESUMO
BACKGROUND: Lipid nanoparticles (LNs) made of synthetic lipids Compritol(®) 888 ATO and Precirol(®) ATO 5 were developed with an average size of 110.4 ± 2.1 and 103.1 ± 2.9 nm, and an encapsulation efficiency above 85% for both type of lipids. These LNs decrease the hemolytic toxicity of the drug by 90%. MATERIALS & METHODS: Pharmacokinetic and biodistribution profiles of the drug were studied after intravenous and oral administration of edelfosine-containing LNs. RESULTS: This provided an increase in relative oral bioavailability of 1500% after a single oral administration of drug-loaded LNs, maintaining edelfosine plasma levels over 7 days in contrast to a single oral administration of edelfosine solution, which presented a relative oral bioavailability of 10%. Moreover, edelfosine-loaded LNs showed a high accumulation of the drug in lymph nodes and resulted in slower tumor growth than the free drug in a murine lymphoma xenograft model, as well as potent extranodal dissemination inhibition.
Assuntos
Diglicerídeos , Ácidos Graxos , Linfoma/tratamento farmacológico , Nanopartículas , Animais , Diglicerídeos/administração & dosagem , Diglicerídeos/química , Diglicerídeos/farmacocinética , Ácidos Graxos/administração & dosagem , Ácidos Graxos/química , Ácidos Graxos/farmacocinética , Humanos , Infiltração Leucêmica/tratamento farmacológico , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Linfoma/patologia , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Éteres Fosfolipídicos/químicaRESUMO
Edelfosine is the prototype molecule of a family of anticancer drugs collectively known as synthetic alkyl-lysophospholipids. This drug holds promise as a selective antitumor agent, and a number of preclinical assays are in progress. In this study, we observe the accumulation of edelfosine in brain tissue after its oral administration in Compritol® and Precirol® lipid nanoparticles (LN). The high accumulation of edelfosine in brain was due to the inhibition of P-glycoprotein by Tween® 80, as verified using a P-glycoprotein drug interaction assay. Moreover, these LN were tested in vitro against the C6 glioma cell line, which was later employed to establish an in vivo xenograft mouse model of glioma. In vitro studies revealed that edelfosine-loaded LN induced an antiproliferative effect in C6 glioma cell line. In addition, in vivo oral administration of drug-loaded LN in NMRI nude mice bearing a C6 glioma xenograft tumor induced a highly significant reduction in tumor growth (p<0.01) 14days after the beginning of the treatment. Our results showed that Tween® 80 coated Compritol® and Precirol® LN can effectively inhibit the growth of C6 glioma cells in vitro and suggest that edelfosine-loaded LN represent an attractive option for the enhancement of antitumor activity on brain tumors in vivo.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Lipídeos/química , Nanopartículas/química , Éteres Fosfolipídicos/administração & dosagem , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioma/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Éteres Fosfolipídicos/farmacocinética , Éteres Fosfolipídicos/uso terapêutico , Polissorbatos/químicaRESUMO
PURPOSE: Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) remain B-cell malignancies with limited therapeutic options. The present study investigates the in vitro and in vivo effect of the phospholipid ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) in MCL and CLL. EXPERIMENTAL DESIGN: Several cell lines, patient-derived tumor cells, and xenografts in severe combined immunodeficient mice were used to examine the anti-MCL and anti-CLL activity of edelfosine. Furthermore, we analyzed the mechanism of action and drug biodistribution of edelfosine in MCL and CLL tumor-bearing severe combined immunodeficient mice. RESULTS: Here, we have found that the phospholipid ether edelfosine was the most potent alkyl-lysophospholipid analogue in killing MCL and CLL cells, including patient-derived primary cells, while sparing normal resting lymphocytes. Alkyl-lysophospholipid analogues ranked edelfosine > perifosine >> erucylphosphocholine > or = miltefosine in their capacity to elicit apoptosis in MCL and CLL cells. Edelfosine induced coclustering of Fas/CD95 death receptor and rafts in MCL and CLL cells. Edelfosine was taken up by malignant cells, whereas normal resting lymphocytes hardly incorporated the drug. Raft disruption by cholesterol depletion inhibited drug uptake, Fas/CD95 clustering, and edelfosine-induced apoptosis. Edelfosine oral administration showed a potent in vivo anticancer activity in MCL and CLL xenograft mouse models, and the drug accumulated dramatically and preferentially in the tumor. CONCLUSIONS: Our data indicate that edelfosine accumulates and kills MCL and CLL cells in a rather selective way, and set coclustering of Fas/CD95 and lipid rafts as a new framework in MCL and CLL therapy. Our data support a selective antitumor action of edelfosine.
Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Microdomínios da Membrana/efeitos dos fármacos , Éteres Fosfolipídicos/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Especificidade por Substrato/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
More than half of all people diagnosed with cancer receive chemotherapy. Unfortunately, most chemotherapy drugs cannot tell the difference between a cancer cell and a healthy cell. In this sense, some other drawbacks often encountered with antineoplastic compounds, such as poor stability and specificity and a high occurrence of drug-resistant tumor cells may be overcome to some degree by incorporating them into drug delivery systems. Solid Lipid Nanoparticles (SLN) have arisen considerable interest in recent years. These are particles of submicron size made from a lipid matrix that is solid at room and body temperature. Moreover, the biodegradable and biocompatible nature of SLN makes them less toxic than other nanoparticulate systems. SLN are capable of encapsulating hydrophobic and hydrophilic drugs, and they also provide protection against chemical, photochemical or oxidative degradation of drugs, as well as the possibility of a sustained release of the incorporated drugs. Along with these last issues, the feasibility of scaling up for large scale production and the low cost of lipids as compared to biodegradable polymers or phospholipids have favoured their use as potential drug delivery systems. This review focuses on the recent advances in SLN as carriers for chemotherapeutic agent delivery.