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1.
PLoS One ; 15(3): e0227784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160196

RESUMO

Pleural empyema is an inflammatory condition characterized by accumulation of pus inside the pleural cavity, which is usually followed by bacterial pneumonia. During the disease process, the pro-inflammatory and pro-fibrotic cytokines in the purulent pleural effusion cause proliferation of fibroblasts and deposition of extracellular matrix, which lead to fibrin deposition and fibrothorax. Urokinase instillation therapy through a chest drainage tube is frequently used for fibrinolysis in patients with empyema. However, urokinase treatment requires multiple instillation (2-3 times per day, for 4-8 days) and easily flows out from the chest drainage tube due to its high water solubility. In this in vitro study, we developed a thermo-responsive hydrogel based on poloxamer 407 (P407) combined with hyaluronic acid (HA) for optimal loading and release of urokinase. Our results show that the addition of HA to poloxamer gels provides a significantly more compact microstructure, with smaller pore sizes (**p < 0.001). The differential scanning calorimetry (DSC) profile revealed no influence on the micellization intensity of poloxamer gel by HA. The 25% poloxamer-based gel was significantly superior to the 23% poloxamer-based gel, with slower gel erosion when comparing the 16th hour residual gel weight of both gels (*p < 0.05; **p < 0.001). The 25% poloxamer-HA gel also exhibited a superior urokinase release profile and longer release time. A Fourier-transform infrared spectroscopy (FT-IR) study of the P407/HA hydrogel showed no chemical interactions between P407 and HA in the hydrogel system. The thermoresponsive P407/HA hydrogel may have a promising potential in the loading and delivery of hydrophilic drugs. On top of that, in vitro toxicity test of this combination demonstrates a lower toxicity.


Assuntos
Portadores de Fármacos/química , Empiema Pleural/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Linhagem Celular , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Empiema Pleural/patologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibrina/metabolismo , Fibrinolíticos/farmacocinética , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/toxicidade , Hidrogéis/química , Hidrogéis/toxicidade , Poloxâmero/química , Poloxâmero/toxicidade , Temperatura , Fatores de Tempo , Testes de Toxicidade , Ativador de Plasminogênio Tipo Uroquinase/farmacocinética
2.
PLoS One ; 15(2): e0229121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32101539

RESUMO

Since dogs play a central role in the contamination of humans and livestock with Echinococcus granulosus, the development of an effective vaccine for dogs is essential to control the disease caused by this parasite. For this purpose, a formulation based on biodegradable polymeric nanoparticles (NPs) as delivery system of recombinant Echinococcus granulosus antigen (tropomyosin EgTrp) adjuved with monophosphoryl lipid A (MPLA) has been developed. The obtained nanoparticles had a size of approximately 200 nm in diameter into which the antigen was correctly preserved and encapsulated. The efficiency of this system to deliver the antigen was evaluated in vitro on canine monocyte-derived dendritic cells (cMoDCs) generated from peripheral blood monocytes. After 48 h of contact between the formulations and cMoDCs, we observed no toxic effect on the cells but a strong internalization of the NPs, probably through different pathways depending on the presence or not of MPLA. An evaluation of cMoDCs activation by flow cytometry showed a stronger expression of CD80, CD86, CD40 and MHCII by cells treated with any of the tested formulations or with LPS (positive control) in comparison to cells treated with PBS (negative control). A higher activation was observed for cells challenged with EgTrp-NPs-MPLA compared to EgTrp alone. Formulations with MPLA, even at low ratio of MPLA, give better results than formulations without MPLA, proving the importance of the adjuvant in the nanoparticles structure. Moreover, autologous T CD4+ cell proliferation observed in presence of cMoDCs challenged with EgTrp-NPs-MPLA was higher than those observed after challenged with EgTrp alone (p<0.05). These first results suggest that our formulation could be used as an antigen delivery system to targeting canine dendritic cells in the course of Echinococcus granulosus vaccine development.


Assuntos
Antígenos de Protozoários/administração & dosagem , Células Dendríticas/imunologia , Cães/parasitologia , Equinococose/prevenção & controle , Echinococcus granulosus/imunologia , Vacinas Protozoárias/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Cães/sangue , Cães/imunologia , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Equinococose/imunologia , Equinococose/parasitologia , Equinococose/veterinária , Echinococcus granulosus/genética , Imunogenicidade da Vacina , Lipídeo A/análogos & derivados , Lipídeo A/química , Lipídeo A/toxicidade , Ativação Linfocitária/imunologia , Monócitos/fisiologia , Nanopartículas/química , Nanopartículas/toxicidade , Poliésteres/química , Poliésteres/toxicidade , Cultura Primária de Células , Vacinas Protozoárias/genética , Vacinas Protozoárias/imunologia , Testes de Toxicidade Aguda , Tropomiosina/administração & dosagem , Tropomiosina/genética , Tropomiosina/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
3.
Org Biomol Chem ; 18(10): 1978-1986, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32104826

RESUMO

Development of an intracellular delivery method for functional peptides via cell-penetrating peptides (CPPs) expands peptide use in basic research and therapeutic applications. Although direct conjugation of a functional peptide with a CPP is the simplest method for delivery, this method has not always been reliable. CPPs usually contain several positively charged amino acids that potentially interact non-specifically with negatively charged molecules in cells and subsequently interfere with conjugated functional peptide function. Here we demonstrate a new intracellular delivery method for peptides in which a functional peptide is released from a positively charged CPP via peptide nucleic acids (PNAs). We prepared an 8-mer PNA conjugated to octa-arginine in tandem (PNA1-CPP) and linked its complementary PNA to an autophagy inducing peptide (PNA2-AIP) by solid-phase peptide synthesis. PNA1-CPP and PNA2-AIP formed a 1 : 1 hybrid via PNA1/PNA2 interaction, thereby indirectly but stably connecting the AIP to the CPP. PNA2-AIP was successfully delivered into cells in a hybrid formation-dependent manner and at least some portion of the PNA1-CPP/PNA2-AIP hybrids dissociated into PNA2-AIP and PNA1-CPP inside the cells. Notably, PNA2-AIP delivered to cells induced more autophagy than AIP directly conjugated to CPP (CPP-AIP). Further, the PNA hybrid did not induce significant cell death. These findings indicate that the PNA1/PNA2 hybrid can function as a molecular glue enabling the delivery of functional peptides into cells.


Assuntos
Proteína Beclina-1/farmacologia , Peptídeos Penetradores de Células/metabolismo , Portadores de Fármacos/metabolismo , Fragmentos de Peptídeos/farmacologia , Ácidos Nucleicos Peptídicos/metabolismo , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Proteína Beclina-1/toxicidade , Peptídeos Penetradores de Células/toxicidade , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Células HeLa , Humanos , Zíper de Leucina , Oligopeptídeos/metabolismo , Oligopeptídeos/toxicidade , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Ácidos Nucleicos Peptídicos/toxicidade , Ligação Proteica
4.
Proc Natl Acad Sci U S A ; 117(9): 4518-4526, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071209

RESUMO

The inception and development of supramolecular chemistry have provided a vast library of supramolecular structures and materials for improved practice of medicine. In the context of therapeutic delivery, while supramolecular nanostructures offer a wide variety of morphologies as drug carriers for optimized targeting and controlled release, concerns are often raised as to how their morphological stability and structural integrity impact their in vivo performance. After intravenous (i.v.) administration, the intrinsic reversible and dynamic feature of supramolecular assemblies may lead them to dissociate upon plasma dilution to a concentration below their critical micellization concentration (CMC). As such, CMC represents an important characteristic for supramolecular biomaterials design, but its pharmaceutical role remains elusive. Here, we report the design of a series of self-assembling prodrugs (SAPDs) that spontaneously associate in aqueous solution into supramolecular polymers (SPs) with varying CMCs. Two hydrophobic camptothecin (CPT) molecules were conjugated onto oligoethylene-glycol (OEG)-decorated segments with various OEG repeat numbers (2, 4, 6, 8). Our studies show that the lower the CMC, the lower the maximum tolerated dose (MTD) in rodents. When administrated at the same dosage of 10 mg/kg (CPT equivalent), SAPD 1, the one with the lowest CMC, shows the best efficacy in tumor suppression. These observations can be explained by the circulation and dissociation of SAPD SPs and the difference in molecular and supramolecular distribution between excretion and organ uptake. We believe these findings offer important insight into the role of supramolecular stability in determining their therapeutic index and in vivo efficacy.


Assuntos
Portadores de Fármacos/química , Micelas , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Portadores de Fármacos/toxicidade , Feminino , Células HT29 , Humanos , Dose Máxima Tolerável , Camundongos , Camundongos Nus , Polietilenoglicóis/química , Polimerização , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Ratos , Ratos Sprague-Dawley
5.
Chem Commun (Camb) ; 56(11): 1661-1664, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31939463

RESUMO

We describe a novel class of stimuli-sensitive sulfonium-based synthetic lipids, which exhibit several favorable biophysical properties of phospholipids. The potent sulfonium-based lipid was successfully disassembled by glutathione to release the encapsulated drug molecules in a controlled manner. The cationic lipid also showed lower cytotoxicity against mammalian cells and displayed moderate antibacterial activities.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Compostos de Sulfônio/farmacologia , Antibacterianos/síntese química , Antibacterianos/toxicidade , Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Derivados de Benzeno/toxicidade , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Escherichia coli/efeitos dos fármacos , Humanos , Lipídeos/síntese química , Lipídeos/farmacologia , Lipídeos/toxicidade , Staphylococcus aureus/efeitos dos fármacos , Compostos de Sulfônio/síntese química , Compostos de Sulfônio/toxicidade
6.
J Nanobiotechnology ; 18(1): 14, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941495

RESUMO

BACKGROUND: In orthopedics, the treatment of implant-associated infections represents a high challenge. Especially, potent antibacterial effects at implant surfaces can only be achieved by the use of high doses of antibiotics, and still often fail. Drug-loaded magnetic nanoparticles are very promising for local selective therapy, enabling lower systemic antibiotic doses and reducing adverse side effects. The idea of the following study was the local accumulation of such nanoparticles by an externally applied magnetic field combined with a magnetizable implant. The examination of the biodistribution of the nanoparticles, their effective accumulation at the implant and possible adverse side effects were the focus. In a BALB/c mouse model (n = 50) ferritic steel 1.4521 and Ti90Al6V4 (control) implants were inserted subcutaneously at the hindlimbs. Afterwards, magnetic nanoporous silica nanoparticles (MNPSNPs), modified with rhodamine B isothiocyanate and polyethylene glycol-silane (PEG), were administered intravenously. Directly/1/7/21/42 day(s) after subsequent application of a magnetic field gradient produced by an electromagnet, the nanoparticle biodistribution was evaluated by smear samples, histology and multiphoton microscopy of organs. Additionally, a pathohistological examination was performed. Accumulation on and around implants was evaluated by droplet samples and histology. RESULTS: Clinical and histological examinations showed no MNPSNP-associated changes in mice at all investigated time points. Although PEGylated, MNPSNPs were mainly trapped in lung, liver, and spleen. Over time, they showed two distributional patterns: early significant drops in blood, lung, and kidney and slow decreases in liver and spleen. The accumulation of MNPSNPs on the magnetizable implant and in its area was very low with no significant differences towards the control. CONCLUSION: Despite massive nanoparticle capture by the mononuclear phagocyte system, no significant pathomorphological alterations were found in affected organs. This shows good biocompatibility of MNPSNPs after intravenous administration. The organ uptake led to insufficient availability of MNPSNPs in the implant region. For that reason, among others, the nanoparticles did not achieve targeted accumulation in the desired way, manifesting future research need. However, with different conditions and dimensions in humans and further modifications of the nanoparticles, this principle should enable reaching magnetizable implant surfaces at any time in any body region for a therapeutic reason.


Assuntos
Portadores de Fármacos/química , Compostos Férricos/química , Nanopartículas de Magnetita/química , Próteses e Implantes , Dióxido de Silício/química , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Feminino , Corantes Fluorescentes/química , Membro Posterior , Nanopartículas de Magnetita/toxicidade , Camundongos Endogâmicos BALB C , Ortopedia , Polietilenoglicóis/química , Porosidade , Rodaminas/química , Silanos/química , Distribuição Tecidual
7.
IET Nanobiotechnol ; 14(1): 105-111, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31935686

RESUMO

To sustained release of an anticancer drug, oxaliplatin (OX), a non-toxic and biocompatible nanocarrier based on bovine serum albumin (BSA) were synthesised by desolvation method and characterised using Fourier-transform infrared (FTIR) spectroscopy, field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM) and dynamic light scattering. The results showed that the BSA nanoparticles (BSANPs) with a mean magnitude of 187.9 ± 1.2 nm have spherical morphology with a smooth surface and a uniform distribution. Furthermore, OX was loaded onto the BSANPs and the loading was confirmed by FTIR, AFM and FESEM techniques. The percentage of encapsulation efficiency and drug loading were determined by absorption spectroscopy (UV-vis). The drug release studies showed that release of OX from BSANPs exhibited slower release rate. However, the release kinetics followed the first-order kinetic for both of them with the non-Fickian release behaviour. The electrochemical analysis showed stability of OX loaded onto the BSANPs (OX@BSANPs) and confirmed the diffusion mechanism. Furthermore, the results of MTT assay revealed increasing of normal cell viability and cancer cell death in the OX@BSANPs compared to only OX. It was shown that the BSANPs could be safely used as a biocompatible nanocarrier for the sustained release of OX.


Assuntos
Antineoplásicos , Nanopartículas/química , Oxaliplatina , Soroalbumina Bovina/química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Estabilidade de Medicamentos , Humanos , Oxaliplatina/química , Oxaliplatina/farmacocinética , Oxaliplatina/farmacologia , Tamanho da Partícula
8.
Environ Toxicol ; 35(2): 176-187, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31633292

RESUMO

Mesoporous silica is a drug carrier with strong targeting, large loading capacity, and easy modification of its surface while its toxicity draws increasing attention recently. In this study, we evaluated the impact of SBA-15 nanomaterials on hippocampal neurons. We found that SBA-15 induces oxidative damage to hippocampal neurons HT22, which further activates autophagy. Treatment with the mammalian target of rapamycin (mTOR) inhibitor AZD8055, the phosphorylation level of mTOR and P70S6K reduced and increased levels of p-AMPK meaning that the adenosine-activated protein kinase (AMPK)/mTOR/P70S6K pathway is involved in SBA-15 induced autophagy of HT22. These results suggested that mesoporous silica material SBA-15 might affect central nervous cells via oxidative stress activation of the AMPK/mTOR/P70S6K pathway, which provides a theoretical basis for safe administration of such materials in patients.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Dióxido de Silício/toxicidade , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Linhagem Celular , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Nanoestruturas/química , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Transdução de Sinais , Dióxido de Silício/química
9.
Mater Sci Eng C Mater Biol Appl ; 106: 110294, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753340

RESUMO

Controlled release strategies of DNA vaccine hold promise for the design of in vivo vaccination platforms, yet the formulation and sustained delivery still pose a substantial challenge. In this study, we developed a novel hybrid dual-particulate delivery system, nanoparticle-in-microsphere (NIM), to integrate the advantages of nano-sized polymer/DNA polyplex with the sustained-release microsphere for DNA vaccine delivery. The nano-sized cores, consisting of polyethylene glycol-graft-polyethylenimine (PEG-g-PEI)/DNA polyplexes, were formulated into PLGA microspheres using a solid-in-oil-in-water (S/O/W) emulsion. The PEG block was used as stabilizing excipient to make DNA soluble and stable in organic solvent to prevent the inactivation of DNA at aqueous-organic interface during encapsulation. The fashion of DNA in dry solid state greatly increased the encapsulation efficiency of DNA in NIMs. This new formulation exhibited a burst release less than 15% and then sustain release close to zero-order kinetics in physiological environment. In addition, the microspheres showed pH-sensitivity and degraded faster in lysosomal compartments, which contributed to the accelerated intracellular release kinetics of DNA. Finally, intramuscular injection of NIMs encoding HIV proteins elicited distinct humoral and cellular immune response in mice at low dose. These results thus may aid NIM-based vaccination towards more extensive clinical evaluations.


Assuntos
Microesferas , Nanopartículas/química , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Vacinas de DNA/imunologia , Animais , Células COS , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , HIV/genética , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Plasmídeos/química , Plasmídeos/metabolismo , Polietilenoimina/química , Células RAW 264.7 , Transfecção , Vacinas de DNA/química , Vacinas de DNA/metabolismo , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
10.
Carbohydr Polym ; 229: 115473, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826443

RESUMO

The development of solubilizers with high efficiency, high safety and simple technology is one of the important fields in modern pharmaceutical industry. Our previous study found that vinegar baked Radix Bupleurum polysaccharides (VBCP) was a potential candidate. This study aimed to clarify which polysaccharide in VBCP had solubility enhancement effect and its solubilizing mechanism. Here, we reported that a novel acidic branched polysaccharide from VBCP, VBCP-3-A, which was non-toxic and had high solubility to baicalin and rhein. It was much better than that of Tween 80. The solubilization mechanism might be that VBCP-3-A self-assembled to form micelle-like aggregates in water, which can encapsulate water-insoluble constituents through the interaction of both hydrogen bonding and hydrophobic forces. in vivo pharmacokinetic study showed that VBCP-3-A increased Cmax and AUC (0-t) of baicalin and rhein. Those results suggested that VBCP-3-A was a potential solubilizer with high efficiency and high safety.


Assuntos
Bupleurum/química , Portadores de Fármacos/química , Polissacarídeos/química , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Sequência de Carboidratos , Linhagem Celular , Portadores de Fármacos/toxicidade , Flavonoides/química , Flavonoides/farmacocinética , Humanos , Masculino , Micelas , Raízes de Plantas/química , Polissacarídeos/toxicidade , Ratos Sprague-Dawley , Solubilidade
11.
Artif Cells Nanomed Biotechnol ; 48(1): 77-83, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852325

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-producing cells. Due to the ability of apoptotic cells clearance to induce tolerance, we previously generated liposomes rich in phophatidylserine (PS) -a feature of apoptotic cells- loaded with insulin peptides to mimic apoptotic beta-cells. PS-liposomes arrested autoimmunity in experimental T1D through the induction of tolerance. The aim of this study was to investigate the potential of several peptides from different T1D autoantigens encapsulated in (PS)-liposomes for T1D prevention and to assess its safety. T1D autoantigens (Insulin, C-peptide, GAD65 and IA2) were encapsulated in PS-liposomes. Liposomes were administered to the 'gold-standard' model for the study of autoimmune T1D, the Non-Obese Diabetic mouse, that spontaneously develop the disease. Safety and toxicity of liposomes were also determined. Only PS-liposomes encapsulating insulin peptides decrease T1D incidence in the Non-Obese Diabetic mouse model. Disease prevention correlates with a decrease in the severity of the autoimmune islet destruction driven by leukocytes. PS-liposomes neither showed toxic effect nor secondary complications. Among the here referred autoantigens, insulin peptides are the best candidates to be encapsulated in liposomes, like an artificial apoptotic cell, for the arrest of autoimmunity in T1D in a safe manner.


Assuntos
Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Imunoterapia/métodos , Lipossomos/química , Nanotecnologia , Fosfatidilserinas/química , Animais , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Insulina/administração & dosagem , Insulina/farmacologia , Insulina/uso terapêutico , Camundongos , Segurança
12.
Mater Sci Eng C Mater Biol Appl ; 107: 110285, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761245

RESUMO

Polyester nanomaterials have been widely used in drug delivey application from a longer period of time. This study reports the synthesis of metal-free semi-aromatic polyester (SAP) nanomaterial for drug delivery and evaluate its in vivo acute and systemic toxicity for potential clinical application. The ring opening coplymerization of commercially available cyclohexene oxide (CHO) and phthalic anhydride (PA) monomers was carried out to synthesize fully alternating poly(CHO-co-PA) copolymer using metal-free activators. The obtained low Mn SAP was found to be biocompatible, hemocompataible and biodegradable nature. This copolymer was first-time used to fabricate curcumin (CUR) loaded nanoparticles (NPs). These NPs were physicochemically characterized by thermogravimetric analyzer (TGA), X-ray diffraction (XRD), and UV/visible spectrophotometer analysis. Further, these negatively charged core-shell spherical NPs exhibited slow sustained release behavior of CUR with anomalous transport and further displayed its higher intracellular uptake in SiHa cells at different time-periods compared to free CUR. In vitro anti-cancer therapeutic effects of free CUR and poly(CHO-alt-PA)-CUR NPs were evaluated on different cancer cells. We observed the increased cytotoxicity of CUR NPs with low IC50 values compared to free CUR. These results were further substantiated with ex vivo data where, a significant reduction was observed in CUR NPs treated tumor spheroid's size as compared to free CUR. Furthermore, the different doses of metal-free poly(CHO-alt-PA) nanomaterial were tested for its acute and systemic toxicity in BALB/c mice. We did not observe any significant toxicity of tested nanomaterial on vital organs, blood cells and the body weight of mice. Our study suggest that this metal-free SAP nanomaterial can be used for potential clinical application.


Assuntos
Antineoplásicos , Portadores de Fármacos , Nanopartículas , Poliésteres/química , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Feminino , Hemólise/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/toxicidade , Ratos , Ratos Wistar
13.
Carbohydr Polym ; 229: 115508, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826471

RESUMO

Oral administration of nanoparticles is extremely limited due to the two processes of mucus permeation and epithelial absorption, which requires completely opposite surface properties of the nanocarriers. To tackle the contradiction, we developed a rational strategy to modify the surface of mesoporous carbon nanoparticles with chitosan concealed by a hydrophilic N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) layer. Probucol (PB) with the low poor permeability and solubility was loaded in optimal nanocarriers to realize the high loading efficacy and controlled release. The pHPMA polymer is a hydrophilic "mucus-inert" material, which could be dissociable from the surface of nanoparticles in the mucus, thus promoting their mucus permeation and causing exposure of chitosan in transepithelial transport. The swelling effect of chitosan under acidic conditions allowed regulation of PB release behavior. In conclusion, the mucus-permeable nanocarrier could effectively overcome multiple gastrointestinal absorption barriers and the oral bioavailability of PB-loaded HCMCN was 2.76-fold that of commercial preparation.


Assuntos
Carbono/química , Portadores de Fármacos/química , Nanopartículas/química , Polímeros/química , Probucol/química , Probucol/farmacocinética , Adesividade , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos/toxicidade , Interações Hidrofóbicas e Hidrofílicas , Masculino , Teste de Materiais , Camundongos , Membrana Mucosa/química , Porosidade , Probucol/administração & dosagem
14.
Carbohydr Polym ; 229: 115498, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826492

RESUMO

Controlled release and tumor-selective distribution are highly desirable for anticancer nanomedicines. Here, we design and synthesize an anisamide-conjugated N-octyl-N,O-maleoyl-O-phosphoryl chitosan (a-OMPC) which can form amphiphilic micelles featuring pH-responsive release and high affinity to sigma-1 receptor-overexpressed tumors for paclitaxel (PTX) delivery. Thereinto, maleoyl and phosphoryl groups cooperatively contribute to pH-responsive drug release due to a conversion from hydrophile to hydrophobe in the acidic microenvironment of endo/lysosomes. We demonstrated that PTX-loaded a-OMPC micelles (PTX-aM) enhanced the cellular internalization via the affinity between anisamide and sigma-1 receptor, rapidly released drug in endo/lysosomes and elevated the cytotoxicity against PC-3 cells. The in vivo studies further verified that PTX-aM could largely accumulate at the tumor site even after 24 h of administration, resulting in obvious inhibition effect and prolonged survival period in PC-3 tumor xenograft-bearing mice. Moreover, OMPC showed no obvious hemolytic and acute toxicity. Collectively, this chitosan derivate holds a promising potential in application of prostate cancer-targeted drug delivery system.


Assuntos
Quitosana/química , Interações Hidrofóbicas e Hidrofílicas , Terapia de Alvo Molecular , Paclitaxel/química , Paclitaxel/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores sigma/metabolismo , Animais , Quitosana/toxicidade , Preparações de Ação Retardada , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Regulação Neoplásica da Expressão Gênica , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Teste de Materiais , Camundongos , Micelas , Células PC-3 , Paclitaxel/uso terapêutico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Nanotoxicology ; 14(3): 341-354, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31852291

RESUMO

Gold nanoparticles (GNPs) are extremely useful for drug delivery, due in part to their highly tunable nature. However, this variability has prevented a clear understanding of the pharmacokinetics and toxicity of GNPs for drug delivery. Here, we present the clearance, organ distribution and acute toxicity testing of our drug delivery system which uses GNPs and two penta-peptides, to deliver a rationally designed peptide drug. We found that with or without our therapeutic, the GNP/peptide hybrid cleared rapidly from the blood in rats and accumulated mostly in the liver and spleen, although it was also detectable in several other organs. There were subtle but detectable differences between the behavior of our GNP hybrids with or without the therapeutic peptide. The GNP/peptide hybrid showed no evidence of toxicity at single doses up to 16 times the therapeutic dose, as measured by a battery of tests including, blood cell makeup, levels of markers of liver, kidney and spleen function, organ mass indexes, and histology. These results underline the importance of testing the pharmacokinetics and toxicity of all GNP preparations, as even minor changes to the surface coatings of GNPs can influence their behavior. On the other hand, the results herein can help guide the design and use of similar GNP/peptide drug delivery systems.


Assuntos
Portadores de Fármacos/farmacocinética , Ouro/farmacocinética , Nanopartículas Metálicas/química , Oligopeptídeos/farmacocinética , Proteína Quinase C-delta/antagonistas & inibidores , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Sistemas de Liberação de Medicamentos , Células Epiteliais/efeitos dos fármacos , Feminino , Ouro/química , Ouro/toxicidade , Humanos , Masculino , Nanopartículas Metálicas/toxicidade , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Oligopeptídeos/toxicidade , Especificidade de Órgãos , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Testes de Toxicidade Aguda
16.
Anal Chim Acta ; 1095: 129-137, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31864613

RESUMO

Increasing nanomedicinal approaches have been developed to effectively inhibit tumor growth; however, critical questions such as whether a nanomedicinal approach can mitigate latent side effects are barely addressed. To this end, we established a zebrafish xenograft tumor model, combining pseudodynamic three-dimensional cardiac imaging and image analysis to enable simultaneous and quantitative determination of the change of tumor volume and cardiac function of zebrafish upon specific nanoformulation treatment. Doxorubicin (DOX), a well-known chemotherapeutic agent with cardiotoxicity, and a recently developed DOX-loaded nanocomposite were employed as two model drugs to demonstrate the effectiveness to utilize the proposed evaluation platform for rapid validation. The nanoformulation significantly mitigated DOX-associated cardiotoxicity, while retaining the efficacy of DOX in inhibiting tumor growth compared to administration of carrier-free DOX at the same dose. We anticipate that this platform possesses the potential as an efficient assessment system for nanoformulated cancer therapeutics with suspected toxicity and side effects to vital organs such as the heart.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Cardiotoxicidade/prevenção & controle , Doxorrubicina/uso terapêutico , Coração/efeitos dos fármacos , Nanocompostos/química , Animais , Técnicas de Imagem Cardíaca , Cardiotoxicidade/diagnóstico por imagem , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Ouro/química , Ouro/toxicidade , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Nanocompostos/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química , Dióxido de Silício/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
17.
Biomed Pharmacother ; 121: 109575, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31689599

RESUMO

The unloaded polymeric nanocapsules (NCs) present incredible characteristics as drug carriers. However, the toxicity caused by NCs with different coatings is still a challenge for contemporary toxicology. Allied to this, preclinical studies are performed in males, disregarding possible gender-dependent toxicity. Thus, the aim of present study was to evaluate the influence of different NCs coatings on toxicological and behavioral parameters in female rats. The physicochemical characterization of NCs with different surface coatings: NC1 (Polysorbate 80), NC2 (PEG), NC3 (Eudragit®RS 100) and NC4 (Chitosan) were performed. Female rats were treated with saline, NC1, NC2, NC3 or NC4 daily for 14 days, p.o. After 24 h of last treatment, animals were submitted to behavioral tests. Only after behavioral tests, female rats were euthanized, organs were removed and weighted. After, histopathological, biochemical and oxidative stress analysis were performed. All NCs-coatings did not cause alterations in behavioral tests. For markers of hepatic, renal damage and lipid profile, the different coatings showed a low toxicity. NCs did not alter weight of organs and histopathological analysis. Also, all NCs-coatings did not modify redox balance in organs studied, only NC2 induced a increase of FRAP levels in intestine. This study demonstrated that the different NCs-coatings did not cause behavioral changes and showed a low toxicity in female rats.


Assuntos
Comportamento Animal/efeitos dos fármacos , Portadores de Fármacos/química , Nanocápsulas , Polímeros/química , Animais , Portadores de Fármacos/toxicidade , Feminino , Polímeros/toxicidade , Ratos , Ratos Wistar
18.
Expert Opin Drug Deliv ; 16(11): 1227-1258, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31583914

RESUMO

Introduction: Cell penetrating peptides (CPPs) known as protein translocation domains (PTD), membrane translocating sequences (MTS), or Trojan peptides (TP) are able to cross biological membranes without clear toxicity using different mechanisms, and facilitate the intracellular delivery of a variety of bioactive cargos. CPPs could overcome some limitations of drug delivery and combat resistant strains against a broad range of diseases. Despite delivery of different therapeutic molecules by CPPs, they lack cell specificity and have a short duration of action. These limitations led to design of combined cargo delivery systems and subsequently improvement of their clinical applications. Areas covered: This review covers all our studies and other researchers in different aspects of CPPs such as classification, uptake mechanisms, and biomedical applications. Expert opinion: Due to low cytotoxicity of CPPs as compared to other carriers and final degradation to amino acids, they are suitable for preclinical and clinical studies. Generally, the efficiency of CPPs was suitable to penetrate the cell membrane and deliver different cargos to specific intracellular sites. However, no CPP-based therapeutic approach has approved by FDA, yet; because there are some disadvantages for CPPs including short half-life in blood, and nonspecific CPP-mediated delivery to normal tissue. Thus, some methods were used to develop the functions of CPPs in vitro and in vivo including the augmentation of cell specificity by activatable CPPs, specific transport into cell organelles by insertion of corresponding localization sequences, incorporation of CPPs into multifunctional dendrimeric or liposomal nanocarriers to improve selectivity and efficiency especially in tumor cells.


Assuntos
Peptídeos Penetradores de Células/administração & dosagem , Portadores de Fármacos/administração & dosagem , Animais , Transporte Biológico , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/toxicidade , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Humanos , Relação Estrutura-Atividade
19.
Nanoscale ; 11(43): 20956-20967, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31660562

RESUMO

The γ-cyclodextrin-based metal-organic framework (γ-CD-MOF) composite was designed and prepared toward targeted anticancer drug delivery and cancer therapy. Large amounts of graphene quantum dots (GQDs) were embedded in the γ-CD-MOF matrix (denoted as GQDs@γ-CD-MOF) to endow the γ-CD-MOF with strong fluorescence, which was then modified by pH responsive poly(ethyleneglycol)dimethacrylate (PEGMA) through surface initiated atom transfer radical polymerization (SI-ATRP) to fabricate the PEGMA@GQDs@γ-CD-MOF composite. Then, the cancer cell-targeted probe was obtained by immobilizing the AS1411 aptamer over it (denoted as AS1411@PEGMA@GQDs@γ-CD-MOF) and it exhibits pH-responsive release function and excellent targeting ability. Large amounts of antitumour drug, doxorubicin hydrochloride (DOX), could be encapsulated within this composite due to the chemical-rich functionality, and the resultant pH-responsive DOX delivery system (denoted as DOX/AS1411@PEGMA@GQDs@γ-CD-MOF) displayed a higher DOX loading of 89.1% with sustained release than the pristine γ-CD-MOF and GQDs@γ-CD-MOF. The targeting specificity investigation revealed that this DOX delivery system was effectively internalized via receptor mediated endocytosis with high selectivity. The in vivo antitumour study with tumour-bearing mice illustrated that the tumour growth can be effectively suppressed and partially ablated with negligible side effects after treatments. Therefore, the proposed AS1411@PEGMA@GQD@γ-CD-MOF composite is promising for effective DOX delivery and tumour growth inhibition both in vitro and in vivo, showing great potential for anticancer therapy.


Assuntos
Antineoplásicos/química , Estruturas Metalorgânicas/química , Metacrilatos/química , Polietilenoglicóis/química , Pontos Quânticos/química , gama-Ciclodextrinas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Grafite/química , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oligodesoxirribonucleotídeos/química
20.
Dalton Trans ; 48(43): 16233-16241, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31598614

RESUMO

Biotinylated pharmaceuticals are of great interest due to the strong interactions between biotinyl-functionality and streptavidin/avidin, which opens up avenues for efficient targeting and localisation. Three new carbon monoxide-releasing molecules (CO-RMs) have been synthesised and characterised using chemical and biological analysis. An alkyne-containing CO-RM 2 was found to be toxic to RAW 264.7 murine macrophages; and thus therapeutically viable CO-RM 1 was employed as the alkyne precursor for [3 + 2] cycloaddition chemistry enabling a new acid-containing CO-RM 4 and biotin-bioconugate-CO-RM (BiotinCORM 5) to be prepared. CO-RM 4 showed significantly improved solubility and BiotinCORM 5 acts as a photo-CO-RM. We have found that an avidin-CORM adduct of 5 is a CO-releasing protein, releasing CO on irradiation with light (400 nm). The avidin-biotinCORM adduct of 5 was found to have a binding energy of 10 kcal mol-1.


Assuntos
Avidina/química , Biotina/química , Monóxido de Carbono/química , Portadores de Fármacos/química , Estreptavidina/química , Alquinos/química , Animais , Reação de Cicloadição , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Camundongos , Estrutura Molecular , Processos Fotoquímicos , Células RAW 264.7
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