RESUMO
Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15's anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15's specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.
Assuntos
Camptotecina/farmacologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator 15 de Diferenciação de Crescimento/genética , Obesidade/prevenção & controle , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Camptotecina/farmacocinética , Linhagem Celular , Linhagem Celular Tumoral , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Células HEK293 , Células HL-60 , Humanos , Células MCF-7 , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/etiologia , Obesidade/genética , Células PC-3RESUMO
In the present study, we investigated the role of lipid composition of camptothecin (CPT)-loaded liposomes (CPT-Lips) to adjust their residence time, drug distribution, and therefore the toxicities and antitumor activity. The CPT was loaded into liposomes using a click drug loading method, which utilized liposomes preloaded with GSH and then exposed to CPT-maleimide. The method produced CPT-Lips with a high encapsulation efficiency (>95%) and sustained drug release. It is shown that the residence times of CPT-Lips in the body were highly dependent on lipid compositions with an order of non-PEGylated liposomes of unsaturated lipids < non-PEGylated liposomes of saturated lipids < PEGylated liposomes of saturated lipids. Interestingly, the fast clearance of CPT-Lips resulted in significantly decreased toxicities but did not cause a significant decrease in their in vivo antitumor activity. These results suggested that the lipid composition could effectively adjust the residence time of CPT-Lips in the body and further optimize their therapeutic index, which would guide the development of a liposomal formulation of CPT.
Assuntos
Camptotecina , Lipídeos , Lipossomos , Camptotecina/química , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Camptotecina/farmacologia , Lipossomos/química , Animais , Camundongos , Lipídeos/química , Humanos , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos/métodos , Polietilenoglicóis/química , Linhagem Celular Tumoral , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Feminino , Química Click/métodos , Camundongos Endogâmicos BALB CRESUMO
PURPOSE: Our previous screening studies identified Oroxylin A (OXA) as a strong inhibitor on the carboxyolesterase mediated hydrolysis of irinotecan to SN-38. The current study employed a whole-body physiologically based pharmacokinetic (PBPK) modeling approach to investigate the underlying mechanisms of the carboxylesterase-mediated pharmacokinetics interactions between irinotecan and OXA in rats. METHODS: Firstly, rats received irinotecan intravenous treatment at 35 µmol/kg without or with oral OXA pretreatment (2800 µmol/kg) daily for 5 days. On day 5, blood and tissues were collected for analyses of irinotecan/SN-38 concentrations and carboxylesterase expression. In addition, effects of OXA on the enzyme kinetics of irinotecan hydrolysis and unbound fractions of irinotecan and SN-38 in rat plasma, liver and intestine were also determined. Finally, a PBPK model that integrated the physiological parameters, enzyme kinetics, and physicochemical properties of irinotecan and OXA was developed. RESULTS: Our PBPK model could accurately predict the pharmacokinetic profiles of irinotecan/SN-38, with AUC0-6h and Cmax values within ±27% of observed values. When OXA was included as a carboxylesterase inhibitor, the model could also predict the irinotecan/SN-38 plasma concentrations within twofold of those observed. In addition, the PBPK model indicated inhibition of carboxylesterase-mediated hydrolysis of irinotecan in the intestinal mucosa as the major underlying mechanism for the pharmacokinetics interactions between irinotecan and OXA. CONCLUSION: A whole-body PBPK model was successfully developed to not only predict the impact of oral OXA pretreatment on the pharmacokinetics profiles of irinotecan but also reveal its inhibition on the intestinal carboxylesterase as the major underlying mechanism.
Assuntos
Flavonoides , Fígado , Ratos , Animais , Irinotecano/farmacocinética , Fígado/metabolismo , Intestinos , Camptotecina/farmacocinéticaRESUMO
The inception and development of supramolecular chemistry have provided a vast library of supramolecular structures and materials for improved practice of medicine. In the context of therapeutic delivery, while supramolecular nanostructures offer a wide variety of morphologies as drug carriers for optimized targeting and controlled release, concerns are often raised as to how their morphological stability and structural integrity impact their in vivo performance. After intravenous (i.v.) administration, the intrinsic reversible and dynamic feature of supramolecular assemblies may lead them to dissociate upon plasma dilution to a concentration below their critical micellization concentration (CMC). As such, CMC represents an important characteristic for supramolecular biomaterials design, but its pharmaceutical role remains elusive. Here, we report the design of a series of self-assembling prodrugs (SAPDs) that spontaneously associate in aqueous solution into supramolecular polymers (SPs) with varying CMCs. Two hydrophobic camptothecin (CPT) molecules were conjugated onto oligoethylene-glycol (OEG)-decorated segments with various OEG repeat numbers (2, 4, 6, 8). Our studies show that the lower the CMC, the lower the maximum tolerated dose (MTD) in rodents. When administrated at the same dosage of 10 mg/kg (CPT equivalent), SAPD 1, the one with the lowest CMC, shows the best efficacy in tumor suppression. These observations can be explained by the circulation and dissociation of SAPD SPs and the difference in molecular and supramolecular distribution between excretion and organ uptake. We believe these findings offer important insight into the role of supramolecular stability in determining their therapeutic index and in vivo efficacy.
Assuntos
Portadores de Fármacos/química , Micelas , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Portadores de Fármacos/toxicidade , Feminino , Células HT29 , Humanos , Dose Máxima Tolerável , Camundongos , Camundongos Nus , Polietilenoglicóis/química , Polimerização , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
Numerous attempts to overcome the poor water solubility of cam ptothecin (CPT) by various nano drug delivery systems are described in various sources in the literature. However, the results of these approaches may be hampered by the incomplete separation of free CPT from the formulations, and this issue has not been investigated in detail. This study aimed to promote the solubility and continuous delivery of CPT by developing long-lasting liposomes using various weights (M.W. 2000 and 5000 Daltons) of the hydrophilic polymer polyethylene glycol (PEG). Conventional and PEGylated liposomes containing CPT were formulated via the lipid film hydration method (solvent evaporation) using a rotary flash evaporator after optimising various formulation parameters. The following physicochemical characteristics were investigated: surface morphology, particle size, encapsulation efficiency, in vitro release, and formulation stability. Different molecular weights of PEG were used to improve the encapsulation efficiency and particle size. The stealth liposomes prepared with PEG5000 were discrete in shape and with a higher encapsulation efficiency (83 ± 0.4%) and a prolonged rate of drug release (32.2% in 9 h) compared with conventional liposomes (64.8 ± 0.8% and 52.4%, respectively) and stealth liposomes containing PEG2000 (79.00 ± 0.4% and 45.3%, respectively). Furthermore, the stealth liposomes prepared with PEG5000 were highly stable at refrigeration temperature. Significant changes were observed using various pharmacokinetic parameters (mean residence time (MRT), half-life, elimination rate, volume of distribution, clearance, and area under the curve) of stealth liposomes containing PEG2000 and PEG5000 compared with conventional liposomes. The stealth liposomes prepared with PEG5000 showed promising results with a slow rate of release over a long period compared with conventional liposomes and liposomes prepared with PEG2000, with altered tissue distribution and pharmacokinetic parameters.
Assuntos
Camptotecina/farmacologia , Camptotecina/farmacocinética , Carcinoma de Ehrlich/tratamento farmacológico , Lipossomos/química , Polietilenoglicóis/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Liberação Controlada de Fármacos , Técnicas In Vitro , Masculino , Polietilenoglicóis/química , Solubilidade , Distribuição TecidualRESUMO
Glucose oxidase-mediated starvation therapy that effectively cuts off energy supply holds great promise in cancer treatment. However, high glutathione (GSH) contents and anoxic conditions severely reduce therapy efficiency and cannot fully kill cancer cells. Herein, to resolve the above problem, this study constructed a biomimetic nanosystem based on nanreproo-MnO2with porous craspedia globose-like structure and high specific surface area, and it was further modified with dopamine and folic acid to guarantee good biocompatibility and selectivity toward cancer cells. This nanosystem responsively degraded and reacted with GSH and acid to regenerate O2, which significantly increased intracellular O2levels, accelerated glucose consumption, and improved starvation therapy efficiency. Moreover, anticancer drug of camptothecin was further loaded, and notably enhanced cancer growth inhibition was obtained at very low drug concentrations. Most importantly, this novel therapy could unprecedentedly inhibit cancer cell migration to a very low ratio of 19%, and detailed cell apoptosis analyses revealed late stage apoptosis contributed most to the good therapeutic effect. This work reported a new train of thought to improve starvation therapy in biomedicine, and provided a new strategy to design targeted nanocarrier to delivery mixed drugs to overcome the restriction of starvation therapy and develop new therapy patterns.
Assuntos
Antineoplásicos , Glucose Oxidase , Neoplasias/terapia , Oxigênio/metabolismo , Hipóxia Tumoral/efeitos dos fármacos , Células A549 , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Biomimética , Camptotecina/farmacocinética , Camptotecina/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos , Glucose Oxidase/química , Glucose Oxidase/metabolismo , Glucose Oxidase/farmacologia , Células HeLa , Humanos , Indóis/química , Compostos de Manganês/química , Nanopartículas Metálicas/química , Nanomedicina , Óxidos/química , Polímeros/química , Propriedades de SuperfícieRESUMO
Simmitecan is a new ester anticancer prodrug which can exert the antiproliferation activity through its active metabolite, chimmitecan. In the current study, a simple and reliable liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of simmitecan and chimmitecan in human plasma. Both irinotecan and 7-ethyl-10-hydroxycamptothecin were used as the internal standards. Plasma samples were protein precipitated by acetonitrile (0.2% formic acid, v/v) and processed samples were chromatographed on a Hypersil GOLDTM C18 column (100 × 4.6 mm, i.d. 3.0 µm) with acetonitrile and 10 mM ammonium acetate (0.1% formic acid, v/v) as the mobile phase. The calibration curves showed good linearity (R ≥ 0.99) over the concentration range of 1-500 ng/mL and 0.25-125 ng/mL for simmitecan and chimmitecan, respectively. Intra- and inter-run precisions (CV%) were ≤10.2% for simmitecan and ≤12.1% for chimmitecan. The accuracies were 99.4-103.5% for simmitecan and 95.4-103.5% for chimmitecan. This method was further successfully applied to a pharmacokinetic study of simmitecan in Chinese advanced solid cancer patients after administration of simmitecan hydrochloride injection.
Assuntos
Antineoplásicos/sangue , Camptotecina/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Camptotecina/sangue , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Humanos , Limite de Detecção , Modelos Lineares , Neoplasias/tratamento farmacológico , Reprodutibilidade dos TestesRESUMO
The non-specific biodistribution of traditional chemotherapeutic drugs against tumors is the key factor that causes systemic toxicity and hinders their clinical application. In this study, a reduction-sensitive polymer conjugate micelle was manufactured to achieve tumor-specific targeting, reduce toxic side-effects and improve anti-tumor activity of a natural anti-cancer drug, hydroxycamptothecin (HCPT). Therefore, HCPT was conjugated with methoxy-poly(ethylene glycol)-poly(ß-benzyl-L-aspartate) (mPEG-PBLA) by a disulfide bond or succinate bond for the first time to obtain the mPEG-PBLA-SS-HCPT (PPSH) and mPEG-PBLA-CC-HCPT (PPCH) that would form micelles after high-speed agitation and dialysis. The PPSH micelles showed an average particle size of 126.3 nm, a low polydispersity index of 0.209, and a negative surface charge of -21.1 mV zeta potential. Transmission electron microscopy showed the PPSH micelles to have spherical morphology. PPSH had a low critical micelle concentration of 1.29 µg ml-1 with high dilution stability, storage stability and reproducibility. Moreover, the particle size of the PPSH micelles had no significant change after incubation with rat plasma for 72 h, probably resulting in high long circulation in the blood. The PPSH micelles showed significant reduction sensitivity to glutathione. Their sizes increased by 403.2 nm after 24 h post-incubation, and 87.6% drug release was achieved 48 h post-incubation with 40 mM glutathione solutions. The PPSH micelles showed stronger inhibition of HepG2 cells in vitro and growth of H-22 tumor in vivo than the PPCH and HCPT solutions after intravenous injection. The accumulation of PPSH micelles in the tumor tissue contributed to the high anti-tumor effect with little side-effect on the normal tissues. The reduction-sensitive PPSH micelles were a promising carrier of HCPT and other poorly soluble anti-cancer drugs.
Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos , Espaço Intracelular/química , Micelas , Peptídeos/química , Polietilenoglicóis/química , Animais , Camptotecina/sangue , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/farmacologia , Morte Celular/efeitos dos fármacos , Dissulfetos/química , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Oxirredução , Tamanho da Partícula , Peptídeos/síntese química , Polietilenoglicóis/síntese química , Ratos Sprague-Dawley , Succinatos/química , Distribuição TecidualRESUMO
10-Hydroxycamptothecin is a drug to cure various cancers. However, the 10-hydroxycamptothecin cannot be widely applied in clinics due to fast elimination and resistance of various cancers to the drug. Nevertheless, co-treatment with tetrandine is known to reverse the resistance of multi-drug resistant cancers, and may present an effective strategy to improve the efficacy of 10-hydroxycamptothecin. In order to improve the bioavailability and prolong the treatment time of the 10-hydroxycamptothecin in vivo, we prepared 10-hydroxycamptothecin-tetrandrine liposome complexes with 10-hydroxycamptothecin as the basic anticancer drug, tetrandrine and liposomes as carriers. In this article, an ultra-high performance liquid chromatography tandem mass spectrometry method for the analysis of 10-hydroxycamptothecin and tetrandrine in plasma has been developed, validated, and utilized to compare the pharmacokinetics of both drugs in the original dosage form and administered as liposome complexes. According to the pharmacokinetic parameters of mean residence time, half-life period and clearance rate, the 10-hydroxycamptothecin-tetrandrine liposome complexes prolongs the retention and circulation time of 10-hydroxycamptothecin in vivo, achieving a good sustained release effect. To the best of our current knowledge, the pharmacokinetic properties of 10-hydroxycamptothecin-tetrandrine liposome complexes in rats have not been reported yet. Our study can provide a helpful reference for further related study.
Assuntos
Antineoplásicos/farmacocinética , Benzilisoquinolinas/farmacocinética , Camptotecina/farmacocinética , Animais , Antineoplásicos/sangue , Antineoplásicos/química , Benzilisoquinolinas/sangue , Benzilisoquinolinas/química , Camptotecina/análogos & derivados , Camptotecina/sangue , Cromatografia Líquida de Alta Pressão , Lipossomos/sangue , Lipossomos/química , Lipossomos/farmacocinética , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em TandemRESUMO
Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising an anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7-8 with the topoisomerase I inhibitor DXd. In this study, we investigated the pharmacokinetics (PK), biodistribution, catabolism, and excretion profiles of T-DXd in HER2-positive tumour-bearing mice.Following intravenous (iv) administration of T-DXd, the PK profiles of T-DXd and total Ab (the sum of conjugated and unconjugated Ab) were almost similar, indicating that the linker is stable during circulation. Biodistribution studies using radiolabelled T-DXd demonstrated tumour-specific distribution and long-term retention. DXd was the main catabolite released from T-DXd in tumours, with exposure levels at least five times higher than those in normal tissues and seven times higher than those achieved by non-targeted control ADC. Following iv administration of DXd, it was rapidly cleared from the circulation (T1/2; 1.35 h) and excreted mainly through faeces as its intact form.The PK profiles reveal that T-DXd effectively delivers the expected payload, DXd, to tumours, while minimising payload exposure to the systemic circulation and normal tissues. The released DXd is rapidly cleared from systemic circulation, presumably via the bile with negligible metabolism, and excreted through the faeces.
Assuntos
Camptotecina/análogos & derivados , Imunoconjugados/farmacocinética , Trastuzumab/farmacocinética , Ado-Trastuzumab Emtansina , Animais , Camptotecina/farmacocinética , Linhagem Celular Tumoral , Camundongos , Inibidores da Topoisomerase IRESUMO
Context: Hydroxycamptothecin (HCPT) has antitumor activity in various cancers, but its poor bioavailability and efflux limit its clinical application. Verapamil has been demonstrated to improve the bioavailability of many drugs. However, the effect of verapamil on the pharmacokinetics of HCPT was not clear.Objective: The effect of verapamil on the pharmacokinetics of HCPT was investigated to clarify the drug-drug interaction between HCPT and verapamil.Materials and methods: The pharmacokinetic profiles of oral administration of HCPT (50 mg/kg) in two group of Sprague-Dawley rats (six rats each), with pre-treatment of verapamil (10 mg/kg/day) for 7 days were investigated, with the group without verapamil pre-treatment as control. Additionally, the metabolic stability and transport of HCPT in the presence or absence of verapamil were also investigated with the employment of the rat liver microsomes and Caco-2 cell transwell model.Results: Verapamil significantly increased the peak plasma concentration (from 91.97 ± 11.30 to 125.30 ± 13.50 ng/mL), and decrease the oral clearance (from 63.85 ± 10.79 to 32.95 ± 6.17 L/h/kg). The intrinsic clearance rate was also significantly decreased (from 39.49 ± 0.42 to 28.64 ± 0.30 µL/min/mg protein) by the preincubation of verapamil. The results of Caco-2 cell transwell experiments showed the efflux of HCPT was inhibited by verapamil, as the efflux ratio decreased from 1.82 to 1.21.Discussion and conclusions: The system exposure of HCPT was increased by verapamil. Verapamil may exert this effect through inhibiting the activity of CYP3A4 or P-gp, which are related to the metabolism and transport of HCPT.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Camptotecina/análogos & derivados , Verapamil/farmacologia , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Disponibilidade Biológica , Transporte Biológico , Células CACO-2 , Bloqueadores dos Canais de Cálcio/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Interações Medicamentosas , Humanos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Verapamil/administração & dosagemRESUMO
BACKGROUND: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive gastric or gastro-oesophageal junction cancer who received trastuzumab deruxtecan at the recommended doses for expansion. METHODS: This was an open-label, dose-escalation and dose-expansion phase 1 trial done at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years old in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive gastric or gastro-oesophageal junction cancer with previous trastuzumab treatment who received trastuzumab deruxtecan were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with gastric or gastro-oesophageal junction cancer has completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978. FINDINGS: Between Aug 28, 2015, and Aug 10, 2018, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. The most frequent grade 3 or worse treatment-emergent adverse events included anaemia (13 [30%]) and decreases in neutrophil (nine [20%]), platelet (eight [18%]), and white blood cell (seven [16%]) counts. Serious treatment-emergent adverse events occurred in 11 (25%) patients. There were four pneumonitis cases (three grade 2 and one grade 3). There were no drug-related deaths due to treatment-emergent adverse events. 19 (43·2%; 95% CI 28·3-59·0) of 44 patients had a confirmed objective response. INTERPRETATION: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in heavily pretreated patients with HER2-positive gastric or gastro-oesophageal junction cancer. These results support further investigation of trastuzumab deruxtecan for HER2-positive gastric or gastro-oesophageal junction cancer post-trastuzumab. FUNDING: Daiichi Sankyo Co, Ltd.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Receptor ErbB-2/análise , Terapia de Salvação , Neoplasias Gástricas/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Feminino , Seguimentos , Humanos , Imunoconjugados/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Distribuição Tecidual , TrastuzumabRESUMO
BACKGROUND: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and potent topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing, advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion. METHODS: We did an open-label, dose-escalation and dose-expansion phase 1 trial at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years of age in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with HER2-positive breast cancer has been completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978. FINDINGS: Between Aug 28, 2015, and Aug 10, 2018, 115 of 118 patients with HER2-positive breast cancer were treated with at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. Frequent grade 3 or worse treatment-emergent adverse events included anaemia (19 [17%] of 115) and decreased neutrophil (16 [14%]), white blood cell (ten [9%]), and platelet (nine [8%]) counts. At least one serious treatment-emergent adverse event occurred for 22 (19%) patients. Investigators reported 20 cases of interstitial lung disease, pneumonitis, or organising pneumonia, including one grade 3 event and two treatment-related deaths due to pneumonitis. One death unrelated to study treatment was due to progressive disease. 66 (59·5%; 95% CI 49·7-68·7) of 111 patients had a confirmed objective response. INTERPRETATION: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in trastuzumab emtansine-pretreated patients with HER2-positive breast cancer. These results suggest that further development in phase 2 and 3 clinical trials for HER2-positive breast cancer is warranted. FUNDING: Daiichi Sankyo Co, Ltd.
Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Receptor ErbB-2/análise , Terapia de Salvação , Idoso , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Neoplasias da Mama/patologia , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Feminino , Seguimentos , Humanos , Imunoconjugados/farmacocinética , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Distribuição Tecidual , TrastuzumabRESUMO
Nanostructured supramolecular polymers (SPs) are filamentous assemblies possessing a high degree of internal order and have important uses in regenerative medicine, drug delivery, and soft matter electronics. Despite recent advances in functional SPs, a challenging topic is the development of robust assembly protocols enabling the incorporation of various functional units without altering its supramolecular architecture. We report here the robust tubular assembly of camptothecin (CPT) analogues into functional SPs. Covalent linkage of two CPT moieties to various short hydrophilic segments (e.g., nonionic, cationic, anionic, and zwitterionic) leads to a class of CPT analogues that self-assemble in water into tubular SPs. Systemic administration of nonionic SPs effectively suppresses tumor growth. Furthermore, these tubular SPs act as universal dispersing agents in water for low-molecular-weight hydrophobes.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/síntese química , Camptotecina/análogos & derivados , Administração Intravenosa , Animais , Antineoplásicos Fitogênicos/química , Camptotecina/farmacocinética , Linhagem Celular Tumoral , Dicroísmo Circular , Ciclização , Desenho de Fármacos , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Dose Máxima Tolerável , Camundongos Nus , Microscopia Eletrônica de Transmissão , Nanoestruturas/química , Polímeros/química , Água/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background AR-67 is a novel camptothecin analogue at early stages of drug development. The phase 1 clinical trial in cancer patients with solid tumors was completed and a population pharmacokinetic model (POP PK) was developed to facilitate further development of this investigational agent. Methods Pharmacokinetic data collected in the phase 1 clinical trial were utilized for the development of a population POP PK by implementing the non-linear mixed effects approach. Patient characteristics at study entry were evaluated as covariates in the model. Subjects (N = 26) were treated at nine dosage levels (1.2-12.4 mg/m2/day) on a daily × 5 schedule. Hematological toxicity data were modeled against exposure metrics. Results A two-compartment POP PK model best described the disposition of AR-67 by fitting a total of 328 PK observations from 25 subjects. Following covariate model selection, age remained as a significant covariate on central volume. The final model provided a good fit for the concentration versus time data and PK parameters were estimated with good precision. Clearance, inter-compartmental clearance, central volume and peripheral volume were estimated to be 32.2 L/h, 28.6 L/h, 6.83 L and 25.0 L, respectively. Finally, exposure-pharmacodynamic analysis using Emax models showed that plasma drug concentration versus time profiles are better predictors of AR-67-related hematologic toxicity were better predictors of leukopenia and thrombocytopenia, as compared to total dose. Conclusions A POP PK model was developed to characterize AR-67 pharmacokinetics and identified age as a significant covariate. Exposure PK metrics Cmax and AUC were shown to predict hematological toxicity. Further efforts to identify clinically relevant determinants of AR-67 disposition and effects in a larger patient population are warranted.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Modelos Biológicos , Neoplasias/metabolismo , Compostos de Organossilício/farmacocinética , Adulto , Idoso , Antineoplásicos Fitogênicos/sangue , Camptotecina/sangue , Camptotecina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Compostos de Organossilício/sangueRESUMO
Drug self-delivery systems consisting of small-molecule active drugs with nanoscale features for intracellular delivery without the need for additional polymeric carriers have drawn much attention recently. In this work, we proposed a highly efficient strategy to fabricate protonized and reduction-responsive self-assembled drug nanoparticles from an amphiphilic small-molecule camptothecin-ss-1,2,3-triazole-gemcitabine conjugate (abbreviated as CPT-ss-triazole-GEM) for combination chemotherapy, which was prepared via a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction. To obtain this drug-triazole-drug conjugate, we first prepared a CPT derivate containing a propargyl group linked with a disulfide group and a GEM derivate attached to an azide group. Subsequently, the two kinds of modified drugs were connected together through a CuAAC reaction between the alkynyl and azide groups to yield the CPT-ss-triazole-GEM prodrug. The characterizations of chemical structures of these intermediates and the final product were performed by 1H NMR, Fourier transform infrared, and liquid chromatography/mass spectrometry measurements. This amphiphilic small-molecule drug-triazole-drug conjugate displayed a high drug loading content, that is, 36.0% of CPT and 27.2% of GEM. This kind of amphiphilic small-molecule prodrugs could form spherical nanoparticles in an aqueous solution in the absence of any other polymeric carriers, in which the hydrophobic CPT formed the core of the nanoparticles, whereas the hydrophilic GEM and protonated 1,2,3-triazole group yielded the shell. In the tumor microenvironment, the prodrug nanoparticles could release both pristine drugs simultaneously. Under the conditions of pH 7.4, and pH 7.4 and 2 µM glutathione (GSH), the prodrug nanoparticles could maintain stability and only 7% of CPT was leaked. However, in a high-GSH environment (pH 7.4 and 10 mM GSH) with the same incubation time, the disulfide linkage would be dissociated and lead to about 34% of CPT release. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test demonstrated that these prodrug nanoparticles showed a higher cytotoxicity toward HepG2 cells than free CPT and free GEM on both 48 and 72 h of incubation. Both in vitro cellular uptake and flow cytometry results implied that these prodrug nanoparticles could be internalized by HepG2 cells with efficient drug release inside cells. The pharmacokinetics and tissue distribution of the prodrug showed a moderate half-life in vivo, and the prodrug peak concentration in most of the collected tissues appeared at 0.25 h after administration. In addition, the CPT-ss-triazole-GEM prodrug could not cross the blood-brain barrier. Even more important is the fact that there is no accumulation in tissues and a rapid elimination of this small-molecule prodrug could be achieved. In brief, this protonized and reduction-sensitive prodrug simultaneously binds both antitumor drugs and has good self-delivery behavior through the donor-acceptor interaction of the H-bonding ligand, that is, the 1,2,3-triazole group. It provides a new method for combined drug therapy.
Assuntos
Camptotecina/química , Química Click/métodos , Desoxicitidina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Pró-Fármacos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/química , Desoxicitidina/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Meia-Vida , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Masculino , Pró-Fármacos/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Triazóis/química , Triazóis/farmacocinética , GencitabinaRESUMO
The physicochemical properties of nanomedicine can be altered with a tumor microenvironment, which influence the precise delivery of drug molecules to the lesion. Thus, the therapeutic efficiency is restrained. Here, a covalent self-assembled nanomicelle (CSNM) based starburst polyprodrug was constructed with the unimolecular micelle-templated self-assembly method and was expected to overcome biological barriers. It aimed to enhance the tumor penetration and chemotherapy efficiency of drugs. In CSNM, a hydrophilic copolymer was glued around a camptothecin (CPT) linked starburst polymeric prodrug [ß-CD-P (CPT- co-NH2)] for protecting the positive charge of the prodrug with a reduction-triggered reversibility in conjugation and activity. Then, the complex was tracelessly delivered into a negatively charged cell membrane, leading to enhanced cellular uptake. Finally, the disulfide bond in the CPT prodrug can be broken under the reductive microenvironment within tumor cells and liberated the CPT molecules. Both in vitro and in vivo results demonstrated the benefits of our CSNM system, including high drug loading, controllable drug release, excellent uptake by tumor cells and remarkable antitumor efficiency. In essence, our findings suggested CSNM as an innovative strategy for drug delivery in chemotherapy, producing a competitive versatility in the development of biomedicine.
Assuntos
Camptotecina , Micelas , Nanoestruturas , Neoplasias Experimentais , Pró-Fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Células HeLa , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Irinotecan (CPT-11) is a drug used against a wide range of tumor types. The individualized dosing of CPT-11 is essential to ensure optimal pharmacotherapy in cancer patients, given the wide interindividual pharmacokinetic variability of this drug and its active metabolite SN-38. Moreover, the reabsorption from SN-38-G to SN-38, by enterohepatic recirculation, is critical due to its influence in the treatment tolerance. The aim of this research was to build a joint population pharmacokinetic model for CPT-11 and its metabolites (SN-38, and its glucuronide, SN-38-G) that enabled an individualized posology adjustment. METHODS: We used data of 53 treatment cycles of FOLFIRINOX scheme corresponding to 20 patients with metastatic colorectal cancer. In order to build the population pharmacokinetic model, we implemented parametric and non-parametric methods using the Pmetrics library package for R. We also built multivariate regression models to predict the area under the curve and the maximum concentration using basal covariates. RESULTS: The final model was a multicompartmental model which represented the transformations from CPT-11 to its active metabolite SN-38 and from SN-38 to inactive SN-38-G. Besides, the model also represented the extensive elimination of SN-38-G and the reconversion of the remaining SN-38-G to SN-38 by enterohepatic recirculation. We carried out internal validation with 1000 simulations. The regression models predicted the PK parameters with R squared adjusted up to 0.9499. CONCLUSION: CPT-11, SN-38, and SN-38-G can be correctly described by the multicompartmental model presented in this work. As far as we know, it is the first time that a joint model for CPT-11, SN-38, and SN-38-G that includes the process of reconversion from SN-38-G to SN-38 is characterized.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Irinotecano/farmacocinética , Modelos Biológicos , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Glucuronatos/farmacocinética , Humanos , Irinotecano/administração & dosagem , Irinotecano/sangue , Leucovorina/administração & dosagem , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacocinéticaRESUMO
Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) conjugated to a topoisomerase I inhibitor (DXd) at a drug-to-antibody ratio (DAR) of 7-8. Here, we examined the pharmacokinetic (PK) profiles of DS-8201a and DXd in cynomolgus monkeys, a cross-reactive species. Following intravenous (iv) administration of DS-8201a, the linker was stable in plasma, and systemic DXd exposure was low. DXd was rapidly cleared following iv dosing. Biodistribution studies revealed that intact DS-8201a was present mostly in the blood without tissue-specific retention. The major pathway of excretion for DXd was the faecal route following iv administration of radiolabelled DS-8201a. The only detectable metabolite in the urine and faeces was unmetabolized DXd. DXd is a substrate of organic anion transporting polypeptides, P-gp, and breast cancer resistance protein. In conclusion, the stable linker in circulation and the high clearance of DXd upon release resulted in the low systemic exposure to DXd. Furthermore, the minimal tissue-specific retention and rapid excretion of DXd into faeces as its unmetabolized form with potentially limited impact on drug - drug interaction as a victim were also critical elements of the PK profile of DS-8201a.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Camptotecina/análogos & derivados , Imunoconjugados/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Ductos Biliares/cirurgia , Células CACO-2 , Camptotecina/farmacocinética , Radioisótopos de Carbono/farmacocinética , Humanos , Inativação Metabólica , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Macaca fascicularis , Masculino , Proteínas de Neoplasias/metabolismo , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Distribuição Tecidual , Inibidores da Topoisomerase I/farmacocinética , TrastuzumabRESUMO
Nanoparticle-based therapeutics are being used to treat patients with solid tumors. Whereas nanoparticles have been shown to preferentially accumulate in solid tumors of animal models, there is little evidence to prove that intact nanoparticles localize to solid tumors of humans when systemically administered. Here, tumor and adjacent, nonneoplastic tissue biopsies are obtained through endoscopic capture from patients with gastric, gastroesophageal, or esophageal cancer who are administered the nanoparticle CRLX101. Both the pre- and postdosing tissue samples adjacent to tumors show no definitive evidence of either the nanoparticle or its drug payload (camptothecin, CPT) contained within the nanoparticle. Similar results are obtained from the predosing tumor samples. However, in nine of nine patients that were evaluated, CPT is detected in the tumor tissue collected 24-48 h after CRLX101 administration. For five of these patients, evidence of the intact deposition of CRLX101 nanoparticles in the tumor tissue is obtained. Indications of CPT pharmacodynamics from tumor biomarkers such as carbonic anhydrase IX and topoisomerase I by immunohistochemistry show clear evidence of biological activity from the delivered CPT in the posttreatment tumors.