RESUMO
Despite the importance of PEGylation in achieving long nanoparticle circulation times, many nanoparticles are coated with PEGylating agents susceptible to enzymatic degradation. In this study, solid lipid nanoparticles (SLNs) prepared with ester-containing compounds were evaluated for their stability in the presence of carboxylesterase. SLN suspensions became turbid within 30 min of enzymatic exposure, indicating possible disassociation of a portion of the nanoparticles. The particle size of SLNs incubated with the enzyme was smaller than the size of controls, although their morphologies appeared similar in transmission electron microscopy images. Although SLNs offered some protection over micelles, PEG6000 monostearate was rapidly degraded within 15 min. Hydrolysis of polysorbate 60 was much slower, reaching only 36% in 2 h. These studies reveal the importance of confirming the stability of PEG surface coatings prior to undertaking in vivo experiments in small animal models, which can have considerably higher plasma esterase activity than humans.
Assuntos
Carboxilesterase/metabolismo , Nanopartículas/química , Polietilenoglicóis/química , Animais , Estabilidade de Medicamentos , Ácidos Graxos não Esterificados/química , Ácidos Graxos não Esterificados/metabolismo , Hidrólise , Propriedades de Superfície , SuínosRESUMO
As the physicochemical characteristics of solid lipid nanoparticles (SLNs) play a critical role in their success, it is important to understand how the materials and process used in their preparation affect these properties. In this study, two stearyl alcohol-based formulations were prepared using nanotemplate engineering technology and characterized. Both formulations were of a small particle size (<100 nm), ellipsoidal shape, and low polydispersity. (1)H NMR spectroscopy confirmed that the SLNs have the expected solid core structure and PEGylated surface. Analysis of the bulk materials indicated that a number of complex interactions are present among the SLN components, including a eutectic between stearyl alcohol and Brij 78. The decreased crystallinity resulting from these interactions may allow for enhanced drug loading. Physiological stability was identified and confirmed as a potential problem due to the low melting point of the eutectic. However, it is expected that with appropriate formulation modifications nanotemplate engineered SLNs will possess the properties necessary for a successful drug delivery system.
Assuntos
Fenômenos Químicos , Lipídeos/química , Nanopartículas/química , Nanotecnologia/métodos , Emulsões , Luz , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão , Espalhamento de Radiação , Difração de Raios XRESUMO
Dexamethasone (DEX) is mainly used as an anti-emetic agent in cancer therapy. We have recently demonstrated that DEX pretreatment increases the antitumor activity of the cancer chemotherapeutic agents carboplatin and gemcitabine, and decreases host toxicity in nude mouse xenograft models of human cancer. However, the underlying mechanisms are not fully understood. The present study was designed to determine the effects of DEX pretreatment on the anticancer activity of adriamycin (ADR) in a syngeneic model of breast cancer (4T1), emphasizing the effects of DEX on cytokine expression and modulation of ADR pharmacokinetics. We have demonstrated five major new findings about DEX pretreatment: a) it enhances the therapeutic effect of ADR, inducing almost complete inhibition of tumor growth; b) it increases tumor ADR accumulation; c) it modulates the expression of cytokines produced by the tumor, increasing TNFalpha and decreasing IL-1beta and VEGF expression; d) it enhances the effects of ADR on induction of apoptosis and inhibition of cell proliferation; and e) it suppresses nuclear NFkappaB activation and inhibits ADR-induced NFkappaB activation, possibly via IkappaB up-regulation. These findings suggest that DEX can be used as a chemosensitizer and chemoprotectant. These results provide a rationale for the expanded clinical use of DEX for cancer therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Citocinas/metabolismo , Dexametasona/uso terapêutico , Doxorrubicina/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Proliferação de Células/efeitos dos fármacos , Citocinas/genética , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Sinergismo Farmacológico , Feminino , Camundongos , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: The present study was undertaken to determine the effects of dexamethasone (DEX) pretreatment on antitumor activity and pharmacokinetics of the cancer chemotherapeutic agents carboplatin and gemcitabine. EXPERIMENTAL DESIGN: Antitumor activities of carboplatin and gemcitabine with or without DEX pretreatment were determined in six murine-human cancer xenograft models, including cancers of colon (LS174T), lung (A549 and H1299), and breast (MCF-7 and MDA-MB-468) and glioma (U87-MG). Effects of DEX on plasma and tissue pharmacokinetics of carboplatin and gemcitabine were also determined by using the LS174T, A549, and H1299 models. RESULTS: Although DEX alone showed minimal antitumor activity, DEX pretreatment significantly increased the efficacy of carboplatin, gemcitabine, or a combination of both drugs by 2-4-fold in all xenograft models tested. Without DEX treatment, the tumor exposure to carboplatin, measured by the area under the curve, was markedly lower than normal tissues. However, DEX pretreatment significantly increased tumor carboplatin levels, including 200% increase in area under the curve, 100% increase in maximum concentration, and 160% decrease in clearance. DEX pretreatment similarly increased gemcitabine uptake in tumors. CONCLUSIONS: To our knowledge, this is the first report that DEX significantly enhances the antitumor activity of carboplatin and gemcitabine and increases their accumulation in tumors. These results provide a basis for further evaluation of DEX as a chemosensitizer in patients.
Assuntos
Carboplatina/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Dexametasona/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Neoplasias da Mama/tratamento farmacológico , Carboplatina/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Desoxicitidina/farmacocinética , Sinergismo Farmacológico , Glioma/tratamento farmacológico , Meia-Vida , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Transplante Heterólogo , GencitabinaRESUMO
PURPOSE: Hematoprotective strategies may offer new approaches to prevent chemotherapy-induced hematotoxicity. The present study was undertaken to investigate the chemoprotective effects of dexamethasone and its optimal dose and the underlying mechanisms. METHODS: Lethal toxicity and hematotoxicity of carboplatin were compared in CD-1 mice with or without dexamethasone pretreatment. Plasma and tissue pharmacokinetics of carboplatin were determined in CD-1 mice. Carboplatin was quantified by HPLC. Gemcitabine was analyzed by radioactivity counting. RESULTS: Pretreatment with dexamethasone prevented lethal toxicity of carboplatin in a dose- and schedule-dependent manner. The best protective effects of dexamethasone pretreatment as measured by survival were observed at the dose level of 0.1 mg/mouse per day for 5 days (80% vs 10% in controls). In contrast, posttreatment with dexamethasone had no protective effects. Pretreatment with dexamethasone significantly prevented the decrease in granulocyte counts. To elucidate the mechanisms by which dexamethasone pretreatment reduces hematotoxicity, we examined the effects of dexamethasone pretreatment on the pharmacokinetics of carboplatin and gemcitabine in CD-1 mice. No significant differences in plasma pharmacokinetics of carboplatin or gemcitabine were observed between control and mice pretreated with dexamethasone. However, dexamethasone pretreatment significantly decreased carboplatin and gemcitabine uptake in spleen and bone marrow with significant decreases in AUC, T(1/2), and C(max), and an increase in CL. CONCLUSIONS: To our knowledge, this is the first time that dexamethasone has been shown to significantly decrease host tissue uptake of chemotherapeutic agents, suggesting a mechanism responsible for the chemoprotective effects of dexamethasone. This study provides a basis for future study to evaluate dexamethasone as a chemoprotectant in cancer patients.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Medula Óssea/efeitos dos fármacos , Carboplatina/farmacocinética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Animais , Área Sob a Curva , Medula Óssea/patologia , Carboplatina/antagonistas & inibidores , Desoxicitidina/administração & dosagem , Desoxicitidina/antagonistas & inibidores , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Glucocorticoides/administração & dosagem , Injeções Intravenosas , Injeções Subcutâneas , Longevidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , GencitabinaRESUMO
Nanocarrier systems are frequently characterized by their size distribution, while drug encapsulation in nanocarriers is generally characterized in terms of an entire population, assuming that drug distribution is uniform. Careful characterization of nanocarriers and assessment of their behavior in biological environments are essential for adequate prediction of the fate of the nanoparticles in vivo. Solid lipid nanoparticles containing [(3)H]-dexamethasone palmitate (an ester prodrug) and [(14)C]-stearyl alcohol (a component of the nanoparticle matrix) were prepared using the nanotemplate engineering method for bioresponsive tumor delivery to overcome interstitial fluid pressure gradients, a physiological barrier to tumor uptake of chemotherapeutic agents. While particle size analysis indicated a uniform size distribution of 93.2 ± 0.5 nm, gel filtration chromatography (GFC) revealed two nanoparticle populations. Drug encapsulation efficiency was 97%, but it distributed differently in the two populations, with average drug/lipid ratios of 0.04 and 0.25, respectively. The difference in surface properties resulted in distinguishing protein adsorption features of the two populations. GFC and HPLC profiles of the mixture of nanoparticles and human serum albumin (HSA) showed that no HSA was adsorbed to the first population of nanoparticles, but minor amounts were adsorbed to the second population. After 24 h incubation in 50% human plasma, ≥80% of the [(3)H]-dexamethasone palmitate was associated with nanoparticles. Thus, characterization of solid lipid nanoparticles produced by this method may be challenging from a regulatory perspective, but the strong association of the drug with the nanoparticles in plasma indicates that this nanocarrier system has the potential for in vivo application.
Assuntos
Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Pró-Fármacos/química , Isótopos de Carbono/química , Cromatografia em Gel , Dexametasona/química , Portadores de Fármacos/isolamento & purificação , Portadores de Fármacos/metabolismo , Estabilidade de Medicamentos , Ésteres , Álcoois Graxos/química , Humanos , Lipídeos/sangue , Lipídeos/isolamento & purificação , Albumina Sérica/metabolismo , Trítio/químicaRESUMO
PURPOSE: 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and its high potency in preclinical models. Here, we report the initial phase I experience with i.v. AR-67 in adults with refractory solid tumors. EXPERIMENTAL DESIGN AND METHODS: AR-67 was infused over 1 hour daily five times, every 21 days, using an accelerated titration trial design. Plasma was collected on the 1st and 4th day of cycle 1 to determine pharmacokinetic parameters. RESULTS: Twenty-six patients were treated at nine dosage levels (1.2-12.4 mg/m(2)/d). Dose-limiting toxicities were observed in five patients and consisted of grade 4 febrile neutropenia, grade 3 fatigue, and grade 4 thrombocytopenia. Common toxicities included leukopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%). No diarrhea was observed. The maximum tolerated dosage was 7.5 mg/m(2)/d. The lactone form was the predominant species in plasma (>87% of area under the plasma concentration-time curve) at all dosages. No drug accumulation was observed on day 4. Clearance was constant with increasing dosage and hematologic toxicities correlated with exposure (P < 0.001). A prolonged partial response was observed in one subject with non-small cell lung cancer. Stable disease was noted in patients with small cell lung cancer, non-small cell lung cancer, and duodenal cancer. CONCLUSIONS: AR-67 is a novel, blood-stable camptothecin with a predictable toxicity profile and linear pharmacokinetics. The recommended phase II dosage is 7.5 mg/m(2)/d five times every 21 days.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/patologia , Compostos de Organossilício/administração & dosagem , Compostos de Organossilício/efeitos adversos , Compostos de Organossilício/farmacocinética , Compostos de Organossilício/uso terapêutico , RecidivaRESUMO
PURPOSE: To determine tolerability, pharmacokinetics, and pharmacodynamics of PD-0325901, a highly potent, selective, oral mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor in advanced cancer patients. EXPERIMENTAL DESIGN: Sixty-six patients received PD-0325901 at doses from 1 mg once daily to 30 mg twice daily (BID). Cycles were 28 days; three administration schedules were evaluated. Pharmacokinetic parameters were assessed and tumor biopsies were done to evaluate pharmacodynamics. RESULTS: Common adverse events were rash, diarrhea, fatigue, nausea, and visual disturbances including retinal vein occlusion (RVO; n = 3). Neurotoxicity was frequent in patients receiving >or=15 mg BID. The maximum tolerated dose, 15 mg BID continuously, was associated with late-onset RVO outside the dose-limiting toxicity window. An alternative dose and schedule, 10 mg BID 5 days on/2 days off, was therefore expanded; one RVO event occurred. Three of 48 evaluable patients with melanoma achieved confirmed partial responses; 10 had stable disease >or=4 months. PD-0325901 exposure was generally dose proportional. Doses >or=2 mg BID consistently caused >or=60% suppression of phosphorylated ERK in melanoma. Fifteen patients showed significant decreases (>or=50%) in Ki-67. CONCLUSIONS: PD-0325901 showed preliminary clinical activity. The maximum tolerated dose, based on first cycle dose-limiting toxicities, was 15 mg BID continuously. However, 10 and 15 mg BID continuous dosing and 10 mg BID 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrollment to this trial was stopped. Intermittent dose scheduling between 2 and 10 mg BID should be explored to identify a recommended dose with long-term PD-0325901 use.
Assuntos
Benzamidas/farmacologia , Benzamidas/farmacocinética , Difenilamina/análogos & derivados , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Difenilamina/farmacocinética , Difenilamina/farmacologia , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Taxa de Sobrevida , Distribuição Tecidual , Resultado do TratamentoRESUMO
The pre-administration of dexamethasone (DEX) has previously been shown to enhance the anti-tumor efficacy of chemotherapeutic agents. The delivery of anti-inflammatory agents specifically to tumors via nanoparticle carriers is expected to promote the effectiveness of chemotherapeutic agents while avoiding systemic toxicities. The process for preparing solid lipid nanoparticles containing anti-inflammatory agents using the nanotemplate engineering method was optimized. Due to the solubilization of DEX in the bulk aqueous phase, its more lipophilic palmitate ester was synthesized and incorporated in nanoparticles that included a pegylating agent, PEG6000 mono-stearate, as part of the formulation. The stealth properties of these nanoparticles were demonstrated to be enhanced compared to latex particles by measuring the adsorption of radioiodinated IgG (185 microg vs. 6.7 microg IgG/mg NP). In addition, the uptake of (14)C-labeled nanoparticles by murine macrophages was shown to decrease from 36.6% to 14.7% of the nanoparticles/mg cell protein as the amount of pegylating agent in the formulation increased from 0 to 4 mg/mL. The high loading values and low burst effect observed for these DEX palmitate-containing nanoparticles in addition to their stealth properties are expected to allow for the delivery of sufficient amounts of DEX to tumors to enhance the uptake of chemotherapeutic agents.
Assuntos
Adjuvantes Farmacêuticos/química , Anti-Inflamatórios/química , Antineoplásicos/química , Nanopartículas/química , Adjuvantes Farmacêuticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/administração & dosagem , Tamanho da PartículaRESUMO
BACKGROUND: Gonadotropin releasing hormone (GnRH)-DT vaccine elicits antibody that may inhibit prostate cancers indirectly by blocking GnRH induced gonadotropin release, and consequent androgen synthesis, and directly by immune effector and antiproliferative mechanisms. A pilot study was performed to determine how to best combine GnRH-DT vaccine with potentially immunosuppressive chemotherapy. METHODS: Patients with metastatic, hormone-refractory prostate cancer were randomized into either a concurrent cohort, in which they received docetaxel on day 1 of weeks 1, 4, 7, and 10 and GnRH-DT vaccine on day 2 of weeks 1, 3, and 7 or a sequential cohort, in which they received GnRH-DT vaccine on weeks 1, 3, and 7 before beginning docetaxel on week 10. GnRH-DT vaccine was administered intramuscularly. Docetaxel was infused intravenously after pre-medication with high-dose dexamethasone, and infusions repeated every 3 weeks in the absence of toxicity or progressive cancer. RESULTS: GnRH-DT vaccine and docetaxel were well tolerated without evidence of significant local or systemic toxicities. Anti-GnRH antibody was elicited in six of six treated concurrently and five of six treated sequentially. The kinetics of antibody induction and the titers of antibody achieved in both treatment cohorts were similar. Anti-GnRH antibody persisted for up to 28 weeks in a patient maintained on docetaxel. CONCLUSION: The administration of docetaxel with high-dose dexamethasone does not inhibit the ability of patients with advanced prostate cancer to be immunized with GnRH-DT vaccine.