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1.
Molecules ; 25(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012928

RESUMO

PEGylated nanomedicines are known to induce infusion reactions (IRs) that in some cases can be life-threatening. Herein, we report a case study in which a patient with rare mediastinal and intracardiac IgG4-related sclerosing disease received 8 treatments of intravenously administered PEGylated liposomal methylprednisolone-succinate (NSSL-MPS). Due to the ethical requirements to reduce IRs, the patient received a cocktail of premedication including low dose of steroids, acetaminophen and H2 blockers before each infusion. The treatment was well-tolerated in that IRs, complement activation, anti-PEG antibodies and accelerated blood clearance of the PEGylated drug were not detected. Prior to the clinical study, an in vitro panel of assays utilizing blood of healthy donors was used to determine the potential of a PEGylated drug to activate complement system, elicit pro-inflammatory cytokines, damage erythrocytes and affect various components of the blood coagulation system. The overall findings of the in vitro panel were negative and correlated with the results observed in the clinical phase.


Assuntos
Fatores Imunológicos/administração & dosagem , Lipossomos , Hemissuccinato de Metilprednisolona/administração & dosagem , Biomarcadores , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Suscetibilidade a Doenças , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Lipossomos/química , Masculino , Hemissuccinato de Metilprednisolona/farmacocinética , Polietilenoglicóis/química
2.
Nanomedicine ; 16: 34-44, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30529791

RESUMO

Glucocorticosteroids are the most efficacious anti-inflammatory agents and the gold standard treatment in Duchenne muscular dystrophy (DMD). However, their chronic use may lead to severe side effects. We evaluated the use of a novel injectable steroidal nano-drug in mdx mouse model of DMD by comparing the efficacy of nano-liposomes remotely loaded with the steroid prodrug, methylprednisolone hemisuccinate (MPS) with the same steroid as-is, in short (4-weeks) and long-term (58-weeks) treatments. Liposomal-MPS was selectively targeted to the mouse diaphragm, the most dystrophic muscle at early stage of the disease. The bioactivity of the steroidal nano-drug was evidenced by a significant decreased serum TGF-ß and reduced diaphragm macrophage infiltration after short-term treatment. In the long-term, the treatment with liposomal-MPS not only demonstrated improved muscle strength and mobility it also induced lower tibia and lumbar vertebrae osteoporosis indicating much lower bone related adverse effects.


Assuntos
Lipossomos/química , Distrofia Muscular de Duchenne/tratamento farmacológico , Esteroides/uso terapêutico , Animais , Creatina Quinase/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Inflamação/sangue , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos mdx , Força Muscular/efeitos dos fármacos , Distrofia Muscular de Duchenne/sangue , Esteroides/química , Fator de Crescimento Transformador beta/sangue
3.
ACS Nano ; 18(33): 22122-22138, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39119697

RESUMO

Binding of anti-PEG antibodies to poly(ethylene glycol) (PEG) on the surface of PEGylated liposomal doxorubicin (PLD) in vitro and in rats can activate complement and cause the rapid release of doxorubicin from the liposome interior. Here, we find that irinotecan liposomes (IL) and L-PLD, which have 16-fold lower levels of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-PEG2000 in their liposome membrane as compared to PLD, generate less complement activation but remain sensitive to destabilization and drug release by anti-PEG antibodies. Complement activation and liposome destabilization correlated with the theoretically estimated number of antibody molecules bound per liposome. Drug release from liposomes proceeded through the alternative complement pathway but was accelerated by the classical complement pathway. In contrast to PLD destabilization by anti-PEG immunoglobulin G (IgG), which proceeded by the insertion of membrane attack complexes in the lipid bilayer of otherwise intact PLD, anti-PEG IgG promoted the fusion of L-PLD, and IL to form unilamellar and oligo-vesicular liposomes. Anti-PEG immunoglobulin M (IgM) induced drug release from all liposomes (PLD, L-PLD, and IL) via the formation of unilamellar and oligo-vesicular liposomes. Anti-PEG IgG destabilized both PLD and L-PLD in rats, indicating that the reduction of PEG levels on liposomes is not an effective approach to prevent liposome destabilization by anti-PEG antibodies.


Assuntos
Doxorrubicina , Lipossomos , Polietilenoglicóis , Polietilenoglicóis/química , Lipossomos/química , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/análogos & derivados , Animais , Ratos , Anticorpos/química , Anticorpos/imunologia , Ativação do Complemento/efeitos dos fármacos , Fosfatidiletanolaminas/química , Liberação Controlada de Fármacos
4.
ACS Nano ; 17(14): 13147-13157, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37417667

RESUMO

Despite the worldwide success of mRNA-LNP Covid-19 vaccines, the nanoscale structures of these formulations are still poorly understood. To fill this gap, we used a combination of atomic force microscopy (AFM), dynamic light scattering (DLS), transmission electron microscopy (TEM), cryogenic transmission electron microscopy (cryo-TEM), and the determination of the intra-LNP pH gradient to analyze the nanoparticles (NPs) in BNT162b2 (Comirnaty), comparing it with the well-characterized PEGylated liposomal doxorubicin (Doxil). Comirnaty NPs had similar size and envelope lipid composition to Doxil; however, unlike Doxil liposomes, wherein the stable ammonium and pH gradient enables accumulation of 14C-methylamine in the intraliposomal aqueous phase, Comirnaty LNPs lack such pH gradient in spite of the fact that the pH 4, at which LNPs are prepared, is raised to pH 7.2 after loading of the mRNA. Mechanical manipulation of Comirnaty NPs with AFM revealed soft, compliant structures. The sawtooth-like force transitions seen during cantilever retraction imply that molecular strands, corresponding to mRNA, can be pulled out of NPs, and the process is accompanied by stepwise rupture of mRNA-lipid bonds. Unlike Doxil, cryo-TEM of Comirnaty NPs revealed a granular, solid core enclosed by mono- and bilipid layers. Negative staining TEM shows 2-5 nm electron-dense spots in the LNP's interior that are aligned into strings, semicircles, or labyrinth-like networks, which may imply cross-link-stabilized RNA fragments. The neutral intra-LNP core questions the dominance of ionic interactions holding together this scaffold, raising the possibility of hydrogen bonding between mRNA and the lipids. Such interaction, described previously for another mRNA/lipid complex, is consistent with the steric structure of the ionizable lipid in Comirnaty, ALC-0315, displaying free ═O and -OH groups. It is hypothesized that the latter groups can get into steric positions that enable hydrogen bonding with the nitrogenous bases in the mRNA. These structural features of mRNA-LNP may be important for the vaccine's activities in vivo.


Assuntos
COVID-19 , Nanopartículas , Humanos , Vacinas contra COVID-19 , Vacina BNT162 , Ligação de Hidrogênio , RNA Mensageiro/genética , Nanopartículas/química , Lipídeos/química , Lipossomos/química , RNA Interferente Pequeno/química
5.
J Control Release ; 354: 316-322, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36549393

RESUMO

The early and massive vaccination campaign in Israel with the mRNA-LNP Comirnaty® (Pfizer-BioNTech) vaccine against the SARS-CoV-2 virus made available large amounts of data regarding the efficacy and safety of this vaccine. Adverse reactions to mRNA-based SARS-CoV-2 vaccines are rare events, but due to large mediatic coverage they became feared and acted as a potential source of delay for the vaccination of the Israeli population. The experience with the reactogenicity of the polyethylene glycol (PEG) moiety of PEGylated liposomes, PEGylated proteins and other PEGylated drugs raised the fear that similar adverse effects can be associated with the PEG lipid which is an essential component of currently used mRNA-LNP vaccines against COVID-19. In this study we quantified the levels of anti-PEG IgG, IgM and IgE present in the blood of 79 volunteers immediately before and 3 weeks after receiving a first dose of Comirnaty® vaccine. Our in vitro results show that different humanized anti-PEG antibodies bind the PEGylated nano-liposomes in a concentration-dependent manner, but they bind with a lower affinity to the Comirnaty vaccine, despite it having a high mole% of neutral PEG2000-lipid on its surface. We found an increase in IgG concentration in the blood 3 weeks after the first vaccine administration, but no increase in IgM or IgE. In addition, no severe signs of adverse reactions to the Comirnaty vaccine were observed in the population studied despite the significant pre-existing high titers of IgG before the first dose of vaccine in 2 donors.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , Vacina BNT162 , SARS-CoV-2 , Vacinação , Lipossomos , Polietilenoglicóis , RNA Mensageiro , Lipídeos , Imunoglobulina E , Imunoglobulina G , Imunoglobulina M , Anticorpos Antivirais
6.
Nat Nanotechnol ; 17(4): 337-346, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35393599

RESUMO

After over a billion of vaccinations with messenger RNA-lipid nanoparticle (mRNA-LNP) based SARS-CoV-2 vaccines, anaphylaxis and other manifestations of hypersensitivity can be considered as very rare adverse events. Although current recommendations include avoiding a second dose in those with first-dose anaphylaxis, the underlying mechanisms are unknown; therefore, the risk of a future reaction cannot be predicted. Given how important new mRNA constructs will be to address the emergence of new viral variants and viruses, there is an urgent need for clinical approaches that would allow a safe repeated immunization of high-risk individuals and for reliable predictive tools of adverse reactions to mRNA vaccines. In many aspects, anaphylaxis symptoms experienced by the affected vaccine recipients resemble those of infusion reactions to nanomedicines. Here we share lessons learned over a decade of nanomedicine research and discuss the current knowledge about several factors that individually or collectively contribute to infusion reactions to nanomedicines. We aim to use this knowledge to inform the SARS-CoV-2 lipid-nanoparticle-based mRNA vaccine field.


Assuntos
Anafilaxia , COVID-19 , Anafilaxia/etiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Humanos , Lipossomos , Nanomedicina , Nanopartículas , RNA Mensageiro/genética , SARS-CoV-2/genética , Vacinas Sintéticas , Vacinas de mRNA
7.
Micromachines (Basel) ; 12(6)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071476

RESUMO

The understanding that systemic context and tissue crosstalk are essential keys for bridging the gap between in vitro models and in vivo conditions led to a growing effort in the last decade to develop advanced multi-organ-on-a-chip devices. However, many of the proposed devices have failed to implement the means to allow for conditions tailored to each organ individually, a crucial aspect in cell functionality. Here, we present two 3D-print-based fabrication methods for a generic multi-organ-on-a-chip device: One with a PDMS microfluidic core unit and one based on 3D-printed units. The device was designed for culturing different tissues in separate compartments by integrating individual pairs of inlets and outlets, thus enabling tissue-specific perfusion rates that facilitate the generation of individual tissue-adapted perfusion profiles. The device allowed tissue crosstalk using microchannel configuration and permeable membranes used as barriers between individual cell culture compartments. Computational fluid dynamics (CFD) simulation confirmed the capability to generate significant differences in shear stress between the two individual culture compartments, each with a selective shear force. In addition, we provide preliminary findings that indicate the feasibility for biological compatibility for cell culture and long-term incubation in 3D-printed wells. Finally, we offer a cost-effective, accessible protocol enabling the design and fabrication of advanced multi-organ-on-a-chip devices.

8.
Theranostics ; 10(9): 3867-3879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226525

RESUMO

The encapsulation of Glucocorticoids (GCs) into long-circulating liposomes (LCLs) is a proven strategy to reduce the side effects of glucocorticoids and improve the treatment of inflammatory diseases, such as rheumatoid arthritis (RA). With the aim of supporting the development of GC-loaded LCLs, and potentially predict patient response to therapy clinically, we evaluated a direct PET imaging radiolabelling approach for preformed GC-LCLs in an animal model of human inflammatory arthritis. Methods: A preformed PEGylated liposomal methylprednisolone hemisuccinate (NSSL-MPS) nanomedicine was radiolabelled using [89Zr]Zr(oxinate)4 (89Zr-oxine), characterised and tracked in vivo using PET imaging in a K/BxN serum-transfer arthritis (STA) mouse model of inflammatory arthritis and non-inflamed controls. Histology and joint size measurements were used to confirm inflammation. The biodistribution of 89Zr-NSSL-MPS was compared to that of free 89Zr in the same model. A therapeutic study using NSSL-MPS using the same time points as the PET/CT imaging was carried out. Results: The radiolabelling efficiency of NSSL-MPS with [89Zr]Zr(oxinate)4 was 69 ± 8 %. PET/CT imaging of 89Zr-NSSL-MPS showed high uptake (3.6 ± 1.5 % ID; 17.4 ± 9.3 % ID/mL) at inflamed joints, with low activity present in non-inflamed joints (0.5 ± 0.1 % ID; 2.7 ± 1.1 % ID/mL). Importantly, a clear correlation between joint swelling and high 89Zr-NSSL-MPS uptake was observed, which was not observed with free 89Zr. STA mice receiving a therapeutic dose of NSSL-MPS showed a reduction in inflammation at the time points used for the PET/CT imaging compared with the control group. Conclusions: PET imaging was used for the first time to track a liposomal glucocorticoid, showing high uptake at visible and occult inflamed sites and a good correlation with the degree of inflammation. A subsequent therapeutic response matching imaging time points in the same model demonstrated the potential of this radiolabeling method as a theranostic tool for the prediction of therapeutic response - with NSSL-MPS and similar nanomedicines - in the treatment of inflammatory diseases.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Glucocorticoides/uso terapêutico , Lipossomos/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Animais , Artrite Reumatoide/diagnóstico por imagem , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Inflamação/tratamento farmacológico , Camundongos , Nanomedicina/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Medicina de Precisão/métodos , Distribuição Tecidual
9.
Int J Nanomedicine ; 13: 6345-6357, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349254

RESUMO

BACKGROUND: It has been proposed that many hypersensitivity reactions to nanopharmaceuticals represent complement (C)-activation-related pseudoallergy (CARPA), and that pigs provide a sensitive animal model to study the phenomenon. However, a recent study suggested that pulmonary hypertension, the pivotal symptom of porcine CARPA, is not mediated by C in cases of polystyrene nanoparticle (PS-NP)-induced reactions. GOALS: To characterize PS-NPs and reexamine the contribution of CARPA to their pulmonary reactivity in pigs. STUDY DESIGN: C activation by 200, 500, and 750 nm (diameter) PS-NPs and their opsonization were measured in human and pig sera, respectively, and correlated with hemodynamic effects of the same NPs in pigs in vivo. METHODS: Physicochemical characterization of PS-NPs included size, ζ-potential, cryo-transmission electron microscopy, and hydrophobicity analyses. C activation in human serum was measured by ELISA and opsonization of PS-NPs in pig serum by Western blot and flow cytometry. Pulmonary vasoactivity of PS-NPs was quantified in the porcine CARPA model. RESULTS: PS-NPs are monodisperse, highly hydrophobic spheres with strong negative surface charge. In human serum, they caused size-dependent, significant rises in C3a, Bb, and sC5b-9, but not C4d. Exposure to pig serum led within minutes to deposition of C5b-9 and opsonic iC3b on the NPs, and opsonic iC3b fragments (C3dg, C3d) also appeared in serum. PS-NPs caused major hemodynamic changes in pigs, primarily pulmonary hypertension, on the same time scale (minutes) as iC3b fragmentation and opsonization proceeded. There was significant correlation between C activation by different PS-NPs in human serum and pulmonary hypertension in pigs. CONCLUSION: PS-NPs have extreme surface properties with no relevance to clinically used nanomedicines. They can activate C via the alternative pathway, entailing instantaneous opsonization of NPs in pig serum. Therefore, rather than being solely C-independent reactivity, the mechanism of PS-NP-induced hypersensitivity in pigs may involve C activation. These data are consistent with the "double-hit" concept of nanoparticle-induced hypersensitivity reactions involving both CARPA and C-independent pseudoallergy.


Assuntos
Ativação do Complemento/imunologia , Complemento C3b/metabolismo , Hipersensibilidade a Drogas/imunologia , Fatores Imunológicos/metabolismo , Nanopartículas/administração & dosagem , Poliestirenos/química , Circulação Pulmonar/imunologia , Animais , Ativação do Complemento/efeitos dos fármacos , Hipersensibilidade a Drogas/tratamento farmacológico , Humanos , Lipossomos/química , Masculino , Nanopartículas/química , Circulação Pulmonar/efeitos dos fármacos , Propriedades de Superfície , Suínos
10.
J Drug Target ; 24(9): 805-820, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27750439

RESUMO

BACKGROUND: Steroids are the most efficacious anti-inflammatory agents. However, their toxicities and side-effects compromise their clinical application. Various strategies and major efforts were dedicated for formulating viable liposomal glucocorticosteroids (GCs), so far none of these were approved. OBJECTIVES: To evaluate these approaches for formulating GC-delivery systems, especially liposomes, and with focus on the Barenholz Lab experience. METHODS: We developed PEGylated nano-liposomes (NSSL) remotely loaded with water-soluble amphipathic weak acid GC-prodrugs. Their remote loading results in high, efficient and stable loading to the level that enables human clinical use. We characterized them for their physical chemistry and stability. We demonstrated their therapeutic efficacy in relevant animal models and studied their pharmacokinetics (PK), biodistribution (BD) and pharmacodynamics advantages over the free pro-drugs. RESULTS: Our steroidal nano-drugs demonstrate much superior PK, BD, tolerability and therapeutic efficacies compared to the free pro-drugs and to most drugs currently used to treat these diseases. These nano-drugs act as robust immune-suppressors, affecting cytokines secretion and diminishing hemorrhage and edema. CONCLUSIONS: The combination of improved physical-chemistry, PK, BD, tolerability and therapeutic efficacy of these steroidal nano-drugs over the pro-drugs "as-is" support their further clinical development as potential therapeutic agents for treating inflammatory diseases.


Assuntos
Inflamação/tratamento farmacológico , Lipossomos/química , Nanotecnologia , Pró-Fármacos/farmacologia , Esteroides/administração & dosagem , Esteroides/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Humanos
11.
PLoS One ; 10(7): e0130442, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26147975

RESUMO

The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of ß-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Lipossomos/química , Nanopartículas/química , Doenças Neurodegenerativas/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios/farmacocinética , Apolipoproteínas E/metabolismo , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/farmacologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Inflamação/metabolismo , Hemissuccinato de Metilprednisolona/química , Hemissuccinato de Metilprednisolona/farmacocinética , Hemissuccinato de Metilprednisolona/farmacologia , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Doenças Neurodegenerativas/metabolismo , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Distribuição Tecidual
12.
PLoS One ; 8(8): e72722, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23991146

RESUMO

Cerebral malaria is the most severe complication of Plasmodium falciparum infection, and a leading cause of death in children under the age of five in malaria-endemic areas. We report high therapeutic efficacy of a novel formulation of liposome-encapsulated water-soluble glucocorticoid prodrugs, and in particular ß-methasone hemisuccinate (BMS), for treatment of experimental cerebral malaria (ECM), using the murine P. berghei ANKA model. BMS is a novel derivative of the potent steroid ß-methasone, and was specially synthesized to enable remote loading into nano-sterically stabilized liposomes (nSSL), to form nSSL-BMS. The novel nano-drug, composed of nSSL remote loaded with BMS, dramatically improves drug efficacy and abolishes the high toxicity seen upon administration of free BMS. nSSL-BMS reduces ECM rates in a dose-dependent manner and creates a survival time-window, enabling administration of an antiplasmodial drug, such as artemisone. Administration of artemisone after treatment with the nSSL-BMS results in complete cure. Treatment with BMS leads to lower levels of cerebral inflammation, demonstrated by changes in cytokines, chemokines, and cell markers, as well as diminished hemorrhage and edema, correlating with reduced clinical score. Administration of the liposomal formulation results in accumulation of BMS in the brains of sick mice but not of healthy mice. This steroidal nano-drug effectively eliminates the adverse effects of the cerebral syndrome even when the treatment is started at late stages of disease, in which disruption of the blood-brain barrier has occurred and mice show clear signs of neurological impairment. Overall, sequential treatment with nSSL-BMS and artemisone may be an efficacious and well-tolerated therapy for prevention of CM, elimination of parasites, and prevention of long-term cognitive damage.


Assuntos
Betametasona/uso terapêutico , Modelos Animais de Doenças , Lipossomos , Malária Cerebral/tratamento farmacológico , Nanopartículas , Doença Aguda , Animais , Sequência de Bases , Betametasona/administração & dosagem , Primers do DNA , Malária Cerebral/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Plasmodium berghei/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real
13.
J Control Release ; 160(2): 299-305, 2012 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-22226777

RESUMO

We have previously shown that intravenous (i.v.) treatment with sterically stabilized nano-liposomes (NSSL) actively remote-loaded with the glucocorticoid (GC) methylprednisolone hemisuccinate (NSSL-MPS) or betamethasone hemisuccinate (NSSL-BMS) significantly decreased severity of adjuvant arthritis in Lewis rats (a model of human rheumatoid arthritis) throughout all disease stages. Here, we compared i.v. or subcutaneous (s.c.) weekly treatment with each of the two NSSL-GC to weekly or daily treatment with the free drugs or with the TNF-α antagonists Infliximab and Etanercept. Therapeutic efficacy and effects on the profile of pro-inflammatory (IL-6, TNF-α, and INF-γ) and anti-inflammatory (IL-10 and TGF-ß) cytokines in rat sera and splenocyte tissue culture supernatants were compared to those of the liposomal and free drugs. Both s.c. and i.v. NSSL-GC suppressed arthritis significantly, compared to higher doses of the free drugs or to TNF-α antagonists. NSSL-GC also suppressed the secretion of pro-inflammatory cytokines, but did not change the levels of TGF- ß. The highly efficacious anti-inflammatory therapeutic feature of these nano-drugs makes them candidates for treatment of human rheumatoid arthritis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Citocinas/sangue , Portadores de Fármacos/química , Glucocorticoides/uso terapêutico , Nanopartículas/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/sangue , Artrite Experimental/imunologia , Betametasona/administração & dosagem , Betametasona/uso terapêutico , Células Cultivadas , Esquema de Medicação , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/sangue , Injeções Intravenosas , Injeções Subcutâneas , Lipossomos , Hemissuccinato de Metilprednisolona/administração & dosagem , Hemissuccinato de Metilprednisolona/uso terapêutico , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Endogâmicos Lew , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Resultado do Tratamento
14.
PLoS One ; 6(10): e25721, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21998684

RESUMO

We report here the design, development and performance of a novel formulation of liposome- encapsulated glucocorticoids (GCs). A highly efficient (>90%) and stable GC encapsulation was obtained based on a transmembrane calcium acetate gradient driving the active accumulation of an amphipathic weak acid GC pro-drug into the intraliposome aqueous compartment, where it forms a GC-calcium precipitate. We demonstrate fabrication principles that derive from the physicochemical properties of the GC and the liposomal lipids, which play a crucial role in GC release rate and kinetics. These principles allow fabrication of formulations that exhibit either a fast, second-order (t(1/2) ~1 h), or a slow, zero-order release rate (t(1/2) ~ 50 h) kinetics. A high therapeutic efficacy was found in murine models of experimental autoimmune encephalomyelitis (EAE) and hematological malignancies.


Assuntos
Química Farmacêutica/métodos , Glucocorticoides/administração & dosagem , Glucocorticoides/química , Nanoestruturas/química , Animais , Cápsulas , Fenômenos Químicos , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapêutico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Leucemia/tratamento farmacológico , Lipossomos , Linfoma de Células T/tratamento farmacológico , Hemissuccinato de Metilprednisolona/administração & dosagem , Hemissuccinato de Metilprednisolona/química , Hemissuccinato de Metilprednisolona/farmacocinética , Hemissuccinato de Metilprednisolona/uso terapêutico , Camundongos , Esclerose Múltipla/tratamento farmacológico , Proteína Proteolipídica de Mielina/efeitos adversos , Solubilidade , Água/química
15.
Expert Opin Drug Deliv ; 7(10): 1175-89, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20858166

RESUMO

IMPORTANCE OF THE FIELD: Foreign body (FB) injuries occur under many circumstances: at work, when practising a hobby, in car accidents, or in violence-afflicted zones. Owing to the nature of these injuries, they are not restricted to a certain part of the body and may affect several organs simultaneously. In general, an FB will be surgically removed when it is a cause of pain or infection or when jeopardizing a critical biological function. However, in many cases removing the FB is not possible owing to risk of harming adjacent delicate tissue. Furthermore, often when surgically removing the FB, microscopic fragments or debris remain at the site of invasion, becoming a cause of pain and recurring infection and inflammation. FB-related complications can also originate from micro- or nanoparticles released by degradation of medical implants. The use of advanced drug delivery technologies to target the tissue surrounding the FB, or the FB itself, may be of therapeutic benefit. Liposomes, vesicles with an aqueous core entrapped in one or more lipid bilayers, are widely used as drug delivery systems. Previous studies show that nanoliposomes can effectively target infected and inflamed tissue. The working hypothesis of this paper is that nanoliposomes, of specific lipid composition, may be used to target FB under conditions of inflammation. AREAS COVERED IN THIS REVIEW: A comprehensive literature review regarding the use of liposomes for targeting and treating infection and inflammation, as well as a prospective on conjugates that can improve FB targeting in vivo. WHAT THE READER WILL GAIN: The article aims to assess whether nanoliposomes loaded with a therapeutic compound may be advantageous for treating FB-related pathologies. TAKE HOME MESSAGE: Nanoliposomes are promising candidates for targeting FB-induced infection and inflammation. Certain properties, related to the micro-anatomy and physiology of inflammation as well as to the liposome physicochemical properties, make possible 'passive' targeting of the FB region. Conjugating specific ligands to the surface of the liposomes can improve their efficacy by adding an element of 'active' targeting. Despite the great clinical need, the use of nano-based technologies to target and treat FB-induced infection, inflammation and pain has not been exploited yet. The use of drug-loaded nanoliposomes for this application seems to be most promising and should be evaluated with high priority.


Assuntos
Infecções/tratamento farmacológico , Inflamação/tratamento farmacológico , Lipossomos/administração & dosagem , Terapia de Alvo Molecular , Próteses e Implantes/efeitos adversos , Animais , Sistemas de Liberação de Medicamentos , Corpos Estranhos/complicações , Corpos Estranhos/diagnóstico por imagem , Corpos Estranhos/tratamento farmacológico , Humanos , Infecções/complicações , Inflamação/complicações , Lipídeos/química , Nanopartículas/uso terapêutico , Preparações Farmacêuticas , Radiografia
16.
J Control Release ; 137(1): 63-8, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19303426

RESUMO

The ability of low frequency ultrasound (LFUS) to trigger the release of drugs from nano sterically stabilized liposomes (nSSL) in vitro, without affecting the drugs' chemical integrity or biological potency, has been previously shown. Herein, the ability of LFUS to (a) trigger the release of cisplatin from nSSL in vivo, and (b) affect the therapeutic efficacy by locally releasing the drug, was studied. For this, nSSL loaded with the anti-cancer chemotherapeutic agent cisplatin were injected intraperitoneally (i.p.) to mice bearing well-developed J6456 murine lymphoma tumors in their peritoneal cavity. Then, LFUS was applied externally to the abdominal wall for 120 s, and drug release was quantified. Nearly 70% of the liposomal cisplatin was released in tumors exposed to LFUS, compared to <3% in those not exposed to LFUS. The effect of LFUS-induced localized drug release on the therapeutic efficacy was tested on BALB/c mice with C26 colon adenocarcinoma tumors in a footpad. Mice were injected intravenously with nSSL cisplatin, and 24 h later, the tumor was exposed to LFUS. The group treated by liposomal cisplatin combined with LFUS, compared to all other groups (i.e., free cisplatin with or without LFUS, or liposomal cisplatin without LFUS, or LFUS alone, or no treatment) had the best therapeutic score; tumors stopped proliferating and then regressed over time. This work presents a modality for the release of drugs from liposomes in vivo using LFUS. Implications of these findings for clinical applications of LFUS-induced liposomal drug release are discussed.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Lipossomos/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Ultrassom , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Antineoplásicos/sangue , Cápsulas , Cisplatino/sangue , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Feminino , Injeções Intraperitoneais , Injeções Intravenosas , Linfoma/tratamento farmacológico , Linfoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanotecnologia/métodos , Neoplasias Experimentais/patologia , Tamanho da Partícula , Distribuição Aleatória , Fatores de Tempo
17.
J Drug Target ; 16(7): 591-5, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18686129

RESUMO

The ability of nano (approximately 100 nm) sterically stabilized liposomes (nSSLs) to target tissue invaded by a foreign body was demonstrated. Radioactively labeled nSSL remote loaded with the anti-inflammatory drug methylprednisolone hemisuccinate (MPS), to form nSSL-MPS, were injected i.v. to mice that, 2 or 3 weeks earlier, had either a thorn or a needle implanted in a hind leg. Twenty-four hours post-nSSL-MPS injection, animals were sacrificed, and the level of liposomes in the vicinity of the foreign body, in comparison to the tissue in the contralateral (normal) leg, was measured. The level of liposomes in the tissue surrounding the foreign body was twice as high as the level of liposomes found in the normal leg. Furthermore, the level of liposomes in the normal leg was similar to the level of liposomes measured in the legs of control animals that did not have an implanted foreign body and were treated with nSSL-MPS. The implications of these findings and the clinical applications of liposomal targeting are discussed.


Assuntos
Sistemas de Liberação de Medicamentos , Reação a Corpo Estranho/tratamento farmacológico , Lipossomos , Hemissuccinato de Metilprednisolona/administração & dosagem , Nanopartículas , Polietilenoglicóis/administração & dosagem , Animais , Feminino , Hemissuccinato de Metilprednisolona/uso terapêutico , Camundongos , Tamanho da Partícula , Polietilenoglicóis/química
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