RESUMO
The main goal of this study is to evaluate the efficacy of the paclitaxel (PTX) drug formulated with a liposomal nanosystem (L-PTX) in a peritoneal carcinomatosis derived from ovarian cancer. In vitro cell viability studies with the human ovarian cancer line A2780 showed a 50% decrease in the inhibitory concentration for L-PTX compared to free PTX. A2780 cells treated with the L-PTX formulation demonstrated a reduced capacity to form colonies in comparison to those treated with PTX. Cell death following L-PTX administration hinted at apoptosis, with most cells undergoing initial apoptosis. A2780 cells exhibited an inhibitory migration profile when analyzed by Wound Healing and real-time cell analysis (xCELLigence) methods after L-PTX administration. This inhibition was related to decreased expression of the zinc finger E-box-binding homeobox 1 (ZEB1) and transforming growth factor 2 (TGF-ß2) genes. In vivoL-PTX administration strongly inhibited tumor cell proliferation in ovarian peritoneal carcinomatosis derived from ovarian cancer, indicating higher antitumor activity than PTX. L-PTX formulation did not show toxicity in the mice model. This study demonstrated that liposomal paclitaxel formulations are less toxic to normal tissues than free paclitaxel and are more effective in inhibiting tumor cell proliferation/migration and inducing ZEB1/TGF-ß2 gene expression.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Neoplasias Peritoneais/tratamento farmacológicoRESUMO
Aim: To investigate the effect of liposomes containing the classical cytotoxic drugs paclitaxel and doxorubicin (Lipo-Pacli/Dox), against a metastatic breast cancer model. We also investigated if Lipo-Pacli/Dox was capable of reverting the tolerogenic environment of metastatic lesions. Materials & methods: Immunogenic cell death induction by the Pacli/Dox combination was assessed in vitro. Antitumor activity and in vivo safety of Lipo-Pacli/Dox were evaluated using a 4T1 breast cancer mouse model Results: Lipo-Pacli/Dox, with a size of 189 nm and zeta potential of -5.01 mV, promoted immune system activation and partially controlled the progression of pulmonary metastasis. Conclusion: Lipo-Pacli/Dox was useful to control both primary tumor and lung metastasis in breast cancer (4T1) mice model. Additionally, Lipo-Pacli/Dox acts as an immunological modulator for this metastatic breast cancer model.
Assuntos
Lipossomos , Neoplasias Pulmonares , Animais , Antibióticos Antineoplásicos , Linhagem Celular Tumoral , Doxorrubicina , Neoplasias Pulmonares/tratamento farmacológico , Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel , PrognósticoRESUMO
Liposomes are lipid vesicles widely used as nanocarriers in targeted drug delivery systems for therapeutic and/or diagnostic purposes. A strategy to prolong the blood circulation time of the liposomes includes the addition of a hydrophilic polymer polyethylene glycol (PEG) moiety onto the surface of the vesicle. Several studies claim that liposome PEGylation by a single chain length or a combination of PEG with different chain lengths may alter the liposomes' pharmacokinetic properties. Therefore, the purpose of this study was to evaluate the influence of PEG on the biodistribution of pH-sensitive liposomes in a tumor-bearing animal model. Three liposomal formulations (PEGylated or not) were prepared and validated to have a similar mean diameter, monodisperse distribution, and neutral zeta potential. The pharmacokinetic properties of each liposome were evaluated in healthy animals, while the biodistribution and scintigraphic images were evaluated in tumor-bearing mice. High tumor-to-muscle ratios were not statistically different between the PEGylated and non-PEGylated liposomes. While PEGylation is a well-established strategy for increasing the blood circulation of nanostructures, in our study, the use of polymer coating did not result in a better in vivo profile. Further studies must be carried out to confirm the feasibility of the non-PEGylated pH-sensitive liposomes for tumor treatment.
Assuntos
Neoplasias da Mama/fisiopatologia , Polietilenoglicóis/farmacocinética , Tecnécio/química , Animais , Tempo de Circulação Sanguínea , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Lipossomos , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Distribuição TecidualRESUMO
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells. In sequence, the purpose of this study was to evaluate the in vivo antitumor efficacy of this combined therapy as well as with these drugs individually, using a human NSCLC xenograft model. Some indicators of sub chronic toxicity that could be affected by treatments were also assessed. The results obtained in vivo with the combined treatment (1mg/kg+PTX 10mg/kg) showed the most effective reduction of the relative tumor volume and the highest inhibition of tumor growth and proliferation, when compared with those of the single treatments. Furthermore, scintigraphic images, obtained before and after the treatments, showed that the most effective protocol able to reduce the residual viable tumor mass was the combined treatment. All treatment regimens were well tolerated without significant changes in body weight and no histological and functional damage to liver and kidney tissues. These results corroborate our previous in vitro synergistic effects published. Taken together, these insights are novel and highlight the therapeutic potential of DACE and PTX combination scheme for NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Triterpenos/farmacologia , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/toxicidade , Compostos Radiofarmacêuticos/administração & dosagem , Fatores de Tempo , Testes de Toxicidade Subcrônica , Triterpenos/toxicidade , Carga Tumoral/efeitos dos fármacos , Imagem Corporal Total , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The use of nanoparticles for diagnostic approaches leads to higher accumulation in the targeting tissue promoting a better signal-to-noise ratio and consequently, early tumor detection through scintigraphic techniques. Such approaches have inherent advantages, including the possibility of association with a variety of gamma-emitting radionuclides available, among them, Tecnethium-99m (99mTc). 99mTc is readily conjugated with nanoparticles using chelating agents, such as diethylenetriaminepentaacetic acid (DTPA). Leveraging this approach, we synthesized polymeric micelles (PM) consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000) functionalized with DTPA for radiolabeling with 99mTc. Micelles made up of DSPE-mPEG2000 and DSPE-PEG2000-DTPA had a mean diameter of â¼10nm, as measured by DLS and SAXS techniques, and a zeta potential of -2.7±1.1mV. Radiolabeled micelles exhibited high radiochemical yields and stability. In vivo assays indicated long blood circulation time (456.3min). High uptake in liver, spleen and kidneys was observed in the biodistribution and imaging studies on healthy and tumor-bearing mice. In addition, a high tumor-to-muscle ratio was detected, which increased over time, showing accumulation of the PM in the tumor region. These findings indicate that this system is a promising platform for simultaneous delivery of therapeutic agents and diagnostic probes.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Nanopartículas/química , Neoplasias/tratamento farmacológico , Polímeros/química , Radioisótopos/química , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Polietilenoglicóis/química , Distribuição Tecidual/fisiologiaRESUMO
Nitroheterocyclic compounds have received considerable interest as hypoxia-selective cytotoxins (HSC) for cancer treatment. In the present study, we investigated antitumor activity of an iodide analogue of metronidazole, 1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I), using Swiss mice bearing solid Ehrlich tumor. MTZ-I showed potent anti-cancer activity at a dose of 40 mg/kg. MTZ-I loaded solid lipid nanoparticles (SLN) were developed as an alternative colloidal carrier system to enhance tumor drug uptake. SLN were characterized for particle size, polydispersity index, zeta potential and entrapment efficiency. In addition, the influence of presence of the cationic lipid stearylamine (STE) on stability of formulation was assessed. The results of DSC study showed that MTZ-I exhibited interaction with STE.
Assuntos
Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Lipídeos/química , Metronidazol/análogos & derivados , Metronidazol/administração & dosagem , Nanocápsulas/administração & dosagem , Nanocápsulas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Difusão , Camundongos , Nanocápsulas/ultraestrutura , Tamanho da Partícula , Resultado do TratamentoRESUMO
This work aims to develop solid lipid nanoparticles (SLNs) loaded with retinoic acid (RA) to evaluate the influence of two lipophilic amines, stearylamine (SA) and benethamine (BA), and one hydrophilic, triethylamine (TA), on drug-encapsulation efficiency (EE) and cytotoxicity in cancer cell lines. The SLNs were characterized for EE, size, and zeta potential. The mean particle size decreased from 155 ± 1 nm (SLNs without amine) to 104 ± 4, 95 ± 1, and 96 ± 1 nm for SLNs prepared with SA, BA, and TA, respectively. SA-RA-loaded SLNs resulted in positively charged particles, whereas those with TA and BA were negatively charged. The EEs were significantly improved with the addition of the amines, and they increased from 36% ± 6% (without amine) to 97% ± 2%, 90% ± 2%, and 100% ± 1% for SA, TA, and BA, respectively. However, stability studies showed higher EE for BA-RA-loaded SLNs than TA-RA-loaded SLNs after 30 days. The formulations containing SA loaded or unloaded (blank SLNs) with RA were cytotoxic in normal and cancer cell lines. In contrast, the blank SLNs containing TA or BA did not show cytotoxicity in human breast adenocarcinoma cells (MCF-7), while RA-loaded SLNs with the respective amines were significantly more cytotoxic than free RA. Furthermore, the cytotoxicity of BA-RA-loaded SLNs was significantly higher than TA-RA-loaded SLNs. These findings are in agreement with the data obtained in the evaluation of subdiploid DNA content and cell-cycle analysis, which showed better anticancer activity for BA-RA-loaded SLNs than TA-RA-loaded SLNs and free RA. Taken together, these findings suggest that the BA-RA-loaded SLN formulation is a promising alternative for the intravenous administration of RA in the treatment of cancer.
Assuntos
Lipídeos/química , Nanocápsulas/química , Nanocápsulas/ultraestrutura , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Tretinoína/administração & dosagem , Tretinoína/química , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Cristalização/métodos , Difusão , Sinergismo Farmacológico , Humanos , Íons , Resultado do TratamentoRESUMO
Cisplatin (CDDP) is one of the most active cytotoxic agents commonly used in the treatment of peritoneal carcinomatosis. The disadvantages of its clinical use are systemic side-effects, such as nephrotoxicity and myelotoxicity. Long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP) were developed by our research group aiming to promote the release of CDDP near the tumor as well as decreasing toxicity. The aim of this study was to evaluate the antitumor efficacy and toxicity of SpHL-CDDP after intraperitoneal administration in initial or disseminated tumor-bearing mice, at a dose of 12 mg/kg. The survival was monitored and blood samples were collected for biochemical and hematological analysis. Kidneys, liver and spleen were removed for histopathological examination. Tumor cells were evaluated for cellular viability and cell cycle. The survival of animals treated with SpHL-CDDP was higher than those treated with free CDDP. The cell death caused by treatment with SpHL-CDDP occurred through induction of apoptosis, with a cell cycle arrest at the G0/G1 phase. The treatment of mice presenting initial cancer with both formulations provoked a suppression of granulocytes. Mice treated with free CDDP also showed a decrease in platelet count, which suggests a high myelotoxicity. In an advanced cancer model, SpHL-CDDP treatment allowed an improvement of the immune response. Mice affected by cancer at an early stage and treated with free CDDP or SpHL-CDDP showed a lower urea/creatinine index compared with the saline control group. These findings indicate that both treatments were able to reduce the renal damage caused by peritoneal carcinomatosis. Microscopic analysis of kidneys from mice treated with SpHL-CDDP showed a discrete morphological alteration, while tubular necrosis was observed for free CDDP-treated mice. Concerning hepatotoxicity, no alteration in clinical chemistry parameters was observed. These findings reveal that SpHL-CDDP can improve the antitumor efficacy and decrease renal and bone marrow toxicity.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma de Ehrlich/tratamento farmacológico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Lipossomos/efeitos adversos , Animais , Apoptose , Modelos Animais de Doenças , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/efeitos adversos , Feminino , Histocitoquímica , Concentração de Íons de Hidrogênio , Injeções Intraperitoneais , Rim/patologia , Lipossomos/administração & dosagem , Fígado/patologia , Camundongos , Baço/patologia , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
Topical treatment of cutaneous leishmaniasis represents an exciting alternative for reducing toxicity associated with parenteral administration of conventional amphotericin B. This work aims to develop and to characterize amphotericin B-loaded new carriers and to investigate their potential for topical delivery by conducting permeation studies with pig ear skin in comparison with marketed formulations. Among other formulations, nanoemulsions were developed and characterized for size, encapsulation efficiency, and zeta potential. To mimic use conditions in topical therapy of cutaneous leishmaniasis, in vitro skin permeation experiments were conducted using a damaged skin model. High encapsulation efficiency (95%) and low particle size (239 nm) were obtained for amphotericin B-loaded nanoemulsion by employing an ion pairing between the drug and stearylamine. Amphotericin B permeation after 24 h across the dermal membrane was low, regardless of the type of formulation tested. In contrast, amphotericin B penetration into dermal membranes (microg/cm2) from solution (control), aqueous Amphocil, hydroalcoholic Amphocil, Fungizone, mixture Fungizone-Lipofundin, and NE was 17.5 +/- 4, 15.2 +/- 3, 9.6 +/- 3, 3.5 +/- 1, 1.7 +/- 0.3, and 1.1 +/- 0.1, respectively. Amphocil provided the best results, highlighted by its high improvement of dermal penetration of amphotericin B.
Assuntos
Anfotericina B/administração & dosagem , Anfotericina B/farmacocinética , Antiprotozoários/administração & dosagem , Antiprotozoários/farmacocinética , Leishmaniose Cutânea/tratamento farmacológico , Nanopartículas/administração & dosagem , Administração Cutânea , Aminas/química , Anfotericina B/química , Análise de Variância , Animais , Antiprotozoários/química , Química Farmacêutica , Estabilidade de Medicamentos , Emulsões/química , Emulsões/farmacocinética , Leishmaniose Cutânea/metabolismo , Nanopartículas/química , Pele/química , Pele/metabolismo , Absorção Cutânea , SuínosRESUMO
In the present study, PEG-coated pH-sensitive and PEG-folate-coated pH-sensitive liposomes containing the ¹59Gd-DTPA-BMA were prepared and radiolabeled through neutron activation technique, aiming to study the in vivo antitumoral activity and toxicity on mice bearing a previously-developed solid Ehrlich tumor. The treatment efficacy was verified through tumoral volume increase and histomorphometry studies. The toxicity of formulations was investigated through animal weight variations, as well as hematological and biochemical tests. The results showed that after 31 days of treatment, animals treated with radioactive formulations had a lower increase in tumor volume and a significantly higher percentage of necrosis compared with controls revealed by histomorphometry studies. Furthermore, mice treated with radioactive formulations exhibited lower weight gain without significant hematological or biochemical changes, except for toxicity to hepatocytes which requires more detailed studies. From the results obtained to date, we believe that the radioactive formulations can be considered potential therapeutic agents for cancer.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma de Ehrlich/radioterapia , Sistemas de Liberação de Medicamentos , Ácido Fólico/análogos & derivados , Gadolínio DTPA/administração & dosagem , Polietilenoglicóis/química , Compostos Radiofarmacêuticos/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma de Ehrlich/patologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Sistemas de Liberação de Medicamentos/efeitos adversos , Feminino , Ácido Fólico/química , Gadolínio , Gadolínio DTPA/efeitos adversos , Gadolínio DTPA/uso terapêutico , Concentração de Íons de Hidrogênio , Dose Letal Mediana , Lipossomos , Fígado/patologia , Fígado/fisiopatologia , Fígado/efeitos da radiação , Camundongos , Necrose , Radioisótopos , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/uso terapêutico , Propriedades de Superfície , Carga Tumoral/efeitos da radiação , Aumento de Peso/efeitos da radiaçãoRESUMO
Cisplatin (CDDP) is one of the most active cytotoxic agents and has been widely used in the treatment of peritoneal carcinomatosis by the intraperitoneal (i.p.) route. However, CDDP, a low-molecular-weight compound, is rapidly absorbed by the capillaries in the i.p. serosa and transferred to the bloodstream, inducing the appearance of systemic side-effects, such as nephrotoxicity. Furthermore, the i.p. CDDP chemotherapy is limited to patients whose residual tumor nodules are less than 0.5 cm in diameter after surgical debulking. The failure of i.p. therapy is attributed to the poor penetration of CDDP into larger tumors. One strategy to improve drug delivery in the peritoneal region and reduce toxicity is the use of drug delivery systems. The objective of the present work was to evaluate the biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP), as compared with free CDDP, after their i.p. administration in Ehrlich ascitic tumor-bearing mice. After administering a 6 mg/kg single i.p. bolus injection of either free CDDP or SpHL-CDDP, ascitic fluid (AF), blood and organs (kidneys, liver, spleen and lungs) were collected and analyzed for CDDP content. The area under the CDDP concentration-time curve (AUC) obtained for AF and blood after SpHL-CDDP administration was 3.3-fold larger and 1.3-fold lower, respectively, when compared with free CDDP treatment, thus indicating its high retention within the peritoneal cavity. The determination of the ratio between AUC in each tissue and that in blood (Kp) showed a lower accumulation of CDDP in kidneys after SpHL-CDDP treatment. The SpHL-CDDP treatment demonstrated a significant uptake by the liver and spleen. SpHL-CDDP treatment led to a higher survival rate of mice with initial or disseminated peritoneal carcinomatosis than CDDP treatment. These results indicate that SpHL-CDDP may be useful for i.p. chemotherapy due to their greater concentration in the peritoneal cavity.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Carcinoma de Ehrlich/tratamento farmacológico , Cisplatino/farmacologia , Cisplatino/farmacocinética , Lipossomos/farmacocinética , Neoplasias Peritoneais/tratamento farmacológico , Estruturas Animais/química , Animais , Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Modelos Animais de Doenças , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Lipossomos/administração & dosagem , Camundongos , Análise de Sobrevida , Resultado do TratamentoRESUMO
PEG-coated pH-sensitive and PEG-folate-coated pH-sensitive liposomes containing the Gd-DTPA-BMA complex were prepared and radiolabeled by neutron activation. The radiolabeled liposomes presented significant in vitro cytotoxic activity against Ehrlich tumor cells when compared with controls. The biodistribution profile of these liposomes and free (159)Gd-DTPA-BMA were studied in mice bearing a previously-developed solid Ehrlich tumor. The results demonstrated an important uptake of the formulations by the tumor tissue, with a tissue/blood partition coefficient (Kp) 3.88 and 14.16 times higher than that of the free complex for pH-sensitive PEG-coated and PEG-folate-coated liposomes containing the (159)Gd-DTPA-BMA complex, respectively. Both formulations accumulated in the liver and spleen, thereby revealing some difficulty in escaping the action of the MPS cells. The formulation without folate presented a lower renal uptake, which is desirable in patients with chronic renal failure due to the potential risk of nephrogenic systemic fibrosis (NFS). The scintigraphic study revealed that the target/non-target ratio is always greater than three for pH-sensitive PEG-coated liposome formulations and above nine for pH-sensitive PEG-folate-coated liposome formulations. The results obtained in this study demonstrated that the formulations employed can be considered to be a potential alternative for the treatment of cancer, including patients with chronic renal failure.
Assuntos
Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/metabolismo , Gadolínio DTPA/administração & dosagem , Gadolínio DTPA/farmacocinética , Lipossomos/química , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/diagnóstico por imagem , Química Farmacêutica/métodos , Portadores de Fármacos/química , Ácido Fólico/química , Gadolínio/administração & dosagem , Gadolínio/química , Humanos , Concentração de Íons de Hidrogênio , Marcação por Isótopo/métodos , Lipossomos/administração & dosagem , Camundongos , Dermopatia Fibrosante Nefrogênica/tratamento farmacológico , Dermopatia Fibrosante Nefrogênica/metabolismo , Polietilenoglicóis/química , Radioisótopos/administração & dosagem , Radioisótopos/química , Cintilografia/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Distribuição TecidualRESUMO
The present work describes the preparation, labeling, physicochemical characterization, and in vitro cytotoxic evaluation of long circulating pH-sensitive liposomes containing (159)Gd-DTPA-BMA. These liposomes were successfully obtained and submitted to neutron irradiation for gadolinium labeling. Their size, distribution, and homogeneity were determined by photon correlation spectroscopy, while their zeta potential was determined by laser Doppler anemometry. The morphology and structural organization were evaluated by atomic force microscopy. The stability and release profiles of Gd-DTPA-BMA in the liposomes were determined in vitro in Dubelco's Modified Eagle's Medium and rat serum at 70%. The results showed that liposomes remained physically stable after 8 h of irradiation and presented a low release profile of its content in two different biological mediums. The formulation of liposomes containing (159)Gd and its respective controls were evaluated by in vitro cytotoxicity against tumor cells RT2. The results showed increased cytotoxic activity of approximately 1170 fold in relation to free Gd-DTPA-BMA.
Assuntos
Gadolínio DTPA/química , Compostos Radiofarmacêuticos/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Físico-Química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Estabilidade de Medicamentos , Gadolínio DTPA/administração & dosagem , Gadolínio DTPA/sangue , Gadolínio DTPA/farmacologia , Técnicas In Vitro , Lipossomos , Camundongos , Microscopia de Força Atômica , Estrutura Molecular , Tamanho da Partícula , Fótons , Radioisótopos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacologia , Ratos , Solubilidade , Propriedades de SuperfícieRESUMO
Long-circulating and pH-sensitive liposomes, containing cisplatin (SpHL-CDDP), have been developed as an alternative aimed at avoiding severe side effects as well as the appearance of resistance, which can limit the use of free cisplatin. However, physical (i.e., aggregation/fusion) and chemical instabilities limit the use of these drug carriers as pharmaceutical products. The preparation of freeze-dried pharmaceuticals has proven to be a successful strategy implemented to improve the stability of these formulations. In addition, the development of an economically feasible, reproducible process of liposome production, on a large scale, has also become necessary. A pilot production process, using three stages (i.e., reverse-phase evaporation, homogenization under high pressure, and ultrafiltration), was used to prepare SpHL-CDDP. The optimization of factors related to the homonogenization under high pressure (i.e., pressure and number of cycles), ultrafiltration (i.e., number of cycles), and storage stability at 4°C were assessed by means of particle size, zeta potential, and encapsulation percentage. A 500-bar pressure and 9 cycles were adopted as measures for the production of SpHL-CDDP, which presented a mean diameter of 99.0 ± 3.9 nm and an encapsulation percentage of 12.9 ± 2.3. The use of trehalose as a cryoprotectant was investigated, regarding its effective ability to control the vesicle diameter and retain encapsulated CDDP after the freeze-drying/rehydration step. After 135 days of storage, freeze-dried or liquid SpHL-CDDP showed no significant change in mean diameter. However, the freeze-dried SpHL-CDDP proved to be more efficient, in terms of CDDP retention, than did the liposomal liquid dispersion.
Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Concentração de Íons de Hidrogênio , Lipossomos , Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Tamanho da Partícula , Projetos Piloto , Pele/metabolismoRESUMO
A d-glucose-MAG(3) derivative was successfully synthesized and radiolabeled in high labeling yield. Biodistribution studies and scintigraphic images in Ehrlich tumor-bearing mice were performed. This compound showed high accumulation in tumor tissue with high tumor-to-muscle ratio. Thus, d-glucose-MAG(3) could be considered as agent for tumor diagnosis.
Assuntos
Carcinoma de Ehrlich/metabolismo , Glucose/farmacocinética , Compostos de Organotecnécio/química , Animais , Carcinoma de Ehrlich/patologia , Glucose/síntese química , Glucose/química , Camundongos , Distribuição TecidualRESUMO
AIMS: The objective of this work was to evaluate the acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP), after their intraperitoneal administration in male and female mice. MAIN METHODS: After single administration of free CDDP (5,10,and 20 mg/kg) or SpHL-CDDP (7,12,30,45 and 80 mg/kg), the body weight was recorded and the LD(50) was calculated. Blood samples were collected for biochemical and hematological analysis. Kidneys, liver, spleen and bone marrow were removed to histopathological examination. KEY FINDINGS: Mice treated with high doses of free CDDP showed a greater loss of body weight and more delayed recovery time than those treated with SpHL-CDDP. The LD(50) values for SpHL-CDDP treatment for male and female mice groups were 2.7 and 3.2 fold higher, respectively, than that obtained for free CDDP. The red and white blood cells counts and quantification of hemoglobin and hematocrit presented no change upon administration of SpHL-CDDP treatment. Free CDDP treatment, however, did lead to an appearance of mild anemia and a reduction in total white blood cell counts. As regards nephrotoxicity, it was observed that free CDDP treatment caused pronounced alterations in the blood urea and creatinine levels of mice. In contrast, these parameters were slightly altered only after SpHL-CDDP treatment at a dose of 30 mg/kg. Microscopic analysis of kidneys from mice treated with SpHL-CDDP showed no morphological alteration. Concerning hepatotoxicity, no histopathological alteration was observed after both treatments. SIGNIFICANCE: These findings reveal that SpHL-CDDP can eliminate CDDP-induced toxicity and is thus a promising candidate for intraperitoneal chemotherapy.
Assuntos
Antineoplásicos , Cisplatino , Lipossomos/toxicidade , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Medula Óssea/patologia , Cisplatino/administração & dosagem , Cisplatino/toxicidade , Feminino , Testes Hematológicos , Concentração de Íons de Hidrogênio , Injeções Intraperitoneais , Rim/citologia , Rim/patologia , Lipossomos/química , Masculino , Camundongos , Neoplasias Peritoneais/tratamento farmacológico , Taxa de SobrevidaRESUMO
This paper discusses the development of a series of sulfur-containing compounds that show an interesting in vivo activity against infection by Schistosoma mansoni. These substances include the aminoalkanethiols, aminoalkanethiosulfuric acids and aminoalkyl disulfides, among others. Although the aminoethanethiols and their disulfide derivatives have presented a relatively high toxicity for the host animal, the aminoalkanethiosulfuric acids have a low toxicity and a high specificity for the adult female S. mansoni worms. In vitro studies with schistosomula, lung-phase schistosomula and adult worms have demonstrated effects on the tegument and the metabolism on these different stages of S. mansoni worms. The encapsulation of these drugs in a nanoemulsion has resulted in an increase in the in vitro activity.
Assuntos
Antiprotozoários/toxicidade , Antiprotozoários/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Compostos de Enxofre/toxicidade , Compostos de Enxofre/uso terapêutico , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Feminino , Humanos , Camundongos , Compostos de Enxofre/química , Compostos de Enxofre/farmacologiaRESUMO
This paper describes the influence of cationic lipid composition on physico-chemical properties of complexes formed between oligonucleotides (ON) and cationic emulsions. Formulations containing medium chain triglycerides, egg lecithin, increasing amounts of either oleylamine (OA) or 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and water were prepared by a spontaneous emulsification procedure. ON adsorption on emulsions was evidenced by the inversion of the zeta-potential, the increase in droplet size, and the morphology of the oil droplet examined through transmission electron microscopy. Adsorption isotherms showed a higher amount of ON adsorbed on emulsions containing DOTAP when compared to emulsions containing OA. In a final step, the role of the main parameters, which may in fact influence the ON release rate from emulsions, was investigated. ON were progressively released from emulsions with an increase in dilution ratio and remained quite similar for both OA and DOTAP emulsions over time. Conversely, the effect of the cationic lipid composition was observed upon increasing the charge ratio of complexes. ON release at a same charge ratio was lower from emulsions containing DOTAP (bearing dioleyl chains) than from those containing OA (bearing monoleyl chain).
Assuntos
Emulsões , Técnicas de Transferência de Genes , Lipídeos/química , Oligonucleotídeos/química , Adsorção , Aminas/química , Cátions , Ácidos Graxos Monoinsaturados/química , Lecitinas/química , Estrutura Molecular , Tamanho da Partícula , Compostos de Amônio Quaternário/química , Solubilidade , Eletricidade Estática , Fatores de Tempo , Triglicerídeos/química , Água/químicaRESUMO
The aim of this article included the development and evaluation of the capacity of nanoemulsions to improve the activity of the novel schistosomicidal drug-2-(butylamino)-1-phenyl-1-ethanethiosulfuric acid (BphEA). BphEA is a compound with a poor solubility in water, which makes its application as a drug difficult. Nanoemulsion formulations presenting anionic (NANOSTOA, NANOST and NANOLP) and cationic (NANOSTE) interfacial charges were prepared to encapsulate BphEA. These formulations were characterized by the encapsulation rate, diameter, and zeta potential. NANOSTOA, NANOST, and NANOLP presented an entrapment efficiency and zeta potential of 18.7+/-1.8% and -33.6+/-1.2 mV; 20.5+/-3.0% and -31.5+/-5.7 mV; as well as 33.8+/-7.2% and -62.6+/-1.3 mV, respectively. NANOSTE presented an entrapment efficiency of 51.8+/-5.0% and a zeta potential of 25.7+/-3.9 mV. The mean droplet size (between 200 and 252 nm) and polydispersity index (between 0.158 and 0.294) were similar for all formulations. The stability study showed no alteration in these formulations' zeta potential and size. The in vitro schistosomicidal activity of BphEA was higher with the use of NANOSTE than with free BphEA. In addition, release studies revealed a good stability of NANOSTE containing BphEA in a biological medium. These results indicate that cationic nanoemulsions can represent an interesting delivery system for the pharmaceutical formulation of BphEA.
Assuntos
Portadores de Fármacos , Emulsões , Lipídeos/química , Nanopartículas , Esquistossomicidas/química , Ésteres do Ácido Sulfúrico/química , Animais , Química Farmacêutica , Composição de Medicamentos , Estabilidade de Medicamentos , Cinética , Membranas/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Tamanho da Partícula , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/síntese química , Esquistossomicidas/farmacologia , Solubilidade , Ésteres do Ácido Sulfúrico/síntese química , Ésteres do Ácido Sulfúrico/farmacologia , Água/químicaRESUMO
The nutritional quality of protein hydrolysates has been related in several reports to their di- and tripeptide contents. In the present work different hydrolytic conditions were tested using papain in order to prepare casein hydrolysates with a suitable peptide profile for being used in special diets. The hydrolysates were fractionated by size-exclusion HPLC and the rapid Correct Fraction Area method was used for quantifying the peptides. Among the five hydrolytic conditions studied, three of them gave rise to preparations having nutritionally similar peptide profiles. However, the use of the temperature of 37 degrees C and enzyme:substrate ratio (E:S) of 2% may probably be the most economical condition for industrial production.