RESUMEN
Polyethylene (PE) is the most productive plastic product and includes three major polymers including high-density polyethylene (HDPE), linear low-density polyethylene (LLDPE) and low-density polyethylene (LDPE) variation in the PE depends on the branching of the polymer chain and its crystallinity. Tenebrio obscurus and Tenebrio molitor larvae biodegrade PE. We subsequently tested larval physiology, gut microbiome, oxidative stress, and PE degradation capability and degradation products under high-purity HDPE, LLDPE, and LDPE powders (<300 µm) diets for 21 days at 65 ± 5% humidity and 25 ± 0.5 °C. Our results demonstrated the specific PE consumption rates by T. molitor was 8.04-8.73 mg PE â 100 larvae-1â day-1 and by T. obscurus was 7.68-9.31 for LDPE, LLDPE and HDPE, respectively. The larvae digested nearly 40% of the ingested three PE and showed similar survival rates and weight changes but their fat content decreased by 30-50% over 21-day period. All the PE-fed groups exhibited adverse effects, such as increased benzoquinone concentrations, intestinal tissue damage and elevated oxidative stress indicators, compared with bran-fed control. In the current study, the digestive tract or gut microbiome exhibited a high level of adaptability to PE exposure, altering the width of the gut microbial ecological niche and community diversity, revealing notable correlations between Tenebrio species and the physical and chemical properties (PCPs) of PE-MPs, with the gut microbiome and molecular weight change due to biodegradation. An ecotoxicological simulation by T.E.S.T. confirmed that PE degradation products were little ecotoxic to Daphnia magna and Rattus norvegicus providing important novel insights for future investigations into the environmentally-friendly approach of insect-mediated biodegradation of persistent plastics.
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Biodegradación Ambiental , Larva , Microplásticos , Polietileno , Tenebrio , Animales , Tenebrio/metabolismo , Polietileno/metabolismo , Microplásticos/toxicidad , Microbioma Gastrointestinal/efectos de los fármacos , Estrés OxidativoRESUMEN
Tenebrio molitor and Tenebrio obscurus (Coleoptera: Tenebrionidae) larvae are two commercial insects that eat plant and crop residues as diets and also biodegrade synthetic plastics polyethylene (PE). We examined biodegradation of low-density PE (LDPE) foam (Mn = 28.9 kDa and Mw = 342.0 kDa) with and without respective co-diets, i.e., wheat brain (WB) or corn flour (CF), corn straw (CS), and rice straw (RS) at 4:1 (w/w), and their gut microbiome and genetic metabolic functional groups at 27.0 ± 0.5 °C after 28 days of incubation. The presence of co-diets enhanced LDPE consumption in both larvae and broad-depolymerized the ingested LDPE. The diet type shaped gut microbial diversity, potential pathways, and metabolic functions. The sequence of effectiveness of co-diets was WB or CF > CS > RS for larval development and LDPE degradation. Co-occurrence networks indicated that the larvae co-fed with LDPE displayed more complex correlations of gut microbiome than the larvae fed with single diets. The primary diet of WB or CF and crop residues CS and RS provided energy and nitrogen source to significantly enhance LDPE biodegradation with synergistic activities of the gut microbiota. For the larvae fed LDPE and LDPE plus co-diets, nitrogen fixation function was stimulated compared to normal diets and associated with LDPE biodegradation.
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Escarabajos , Microbioma Gastrointestinal , Tenebrio , Animales , Larva/metabolismo , Tenebrio/metabolismo , Polietileno , Poliestirenos , Carbono/metabolismo , Escarabajos/metabolismo , DietaRESUMEN
Liposomes decorated with tumour-targeting cell-penetrating peptides can enhance specific drug delivery at the tumour site. The TR peptide, c(RGDfK)-AGYLLGHINLHHLAHL(Aib)HHIL, is pH-sensitive and actively targets tumour cells that overexpress integrin receptor αvß3, such as B16F10 melanoma cells. Liposomes can be modified with the TR peptide by two different methods: utilization of the cysteine residue on TR to link DSPE-PEG2000-Mal contained in the liposome formula (LIPTR) or decoration of TR with a C18 stearyl chain (C18-TR) for direct insertion into the liposomal phospholipid bilayer through electrostatic and hydrophobic interactions (LIPC18-TR). We found that both TR and C18-TR effectively reversed the surface charge of the liposomes when the systems encountered the low pH of the tumour microenvironment, but LIPC18-TR exhibited a greater increase in the charge, which led to higher cellular uptake efficiency. Correspondingly, the IC50 values of PTX-LIPTR and PTX-LIPC18-TR in B16F10 cells in vitro were 2.1-fold and 2.5-fold lower than that of the unmodified PTX-loaded liposomes (PTX-LIP), respectively, in an acidic microenvironment (pH 6.3). In B16F10 tumour-bearing mice, intravenous administration of PTX-LIPTR and PTX-LIPC18-TR (8 mg/kg PTX every other day for a total of 4 injections) caused tumour reduction ratios of 39.4% and 56.1%, respectively, compared to 20.8% after PTX-LIP administration. Thus, we demonstrated that TR peptide modification could improve the antitumour efficiency of liposomal delivery systems, with C18-TR presenting significantly better results. After investigating different modification methods, our data show that selecting an adequate method is vital even when the same molecule is used for decoration.
Asunto(s)
Liposomas , Neoplasias , Ratones , Animales , Liposomas/química , Paclitaxel/química , Sistemas de Liberación de Medicamentos/métodos , Péptidos/química , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Breast cancer was the leading cause of newly diagnosed cases of tumors in 2020, ranking as the second highest cause of female death. Chemotherapy remains the conventional treatment of choice for breast tumors in most clinical cases. However, it is often accompanied by a poor prognosis and severe side effects, resulting from an insufficient accumulation of the drug at tumor sites and an unsystematic distribution of the drug across the body. Inspired by the fact that breast tumor cells overexpress integrin α2ß1 on the surface, we designed and constructed an integrin α2ß1 targeting DGEA-modified liposomal doxorubicin (DGEA-Lipo-DOX) platform for application in breast cancer therapy. The DGEA-Lipo-DOX was stable with a uniform particle size of 121.1 ± 3.8 nm and satisfactory drug encapsulation. Demonstrated in vitro and in vivo, the constructed platform exhibited improved antitumor ability. The DGEA-Lipo-DOX showed 4-fold enhanced blood circulation and 6-fold increased accumulation of DOX at the tumor sites compared to those of free DOX, resulting in a significantly enhanced antitumor efficacy in tumor-bearing mice. A preliminary safety evaluation suggested that the systemic toxicity of DOX was relieved by DGEA-Lipo delivery. Collectively, binding integrin α2ß1 by DGEA may represent an alternative therapeutic strategy for potentially safer breast cancer treatment.
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Antibióticos Antineoplásicos/farmacología , Neoplasias de la Mama/prevención & control , Doxorrubicina/análogos & derivados , Sistemas de Liberación de Medicamentos , Integrina alfa2beta1/antagonistas & inhibidores , Oligopéptidos/química , Animales , Antibióticos Antineoplásicos/química , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Doxorrubicina/química , Doxorrubicina/farmacología , Femenino , Humanos , Integrina alfa2beta1/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Ratas Sprague-Dawley , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The transformersome is a new kind of lipoid drug delivery carrier. It has a number of excellent properties, including deformability, pressure permeability, and amphiphilicity. It has been widely used in the field of percutaneous and oral administration of medication. However, due to factors concerning its formulation, the stability and effectiveness of intravenous injection and other systemic routes of administration of transfersomes should be carefully examined. As an alternative, the formulation can be enhanced or improved in order to better exploit the strengths and avoid the weaknesses. Because of its deformability, transfersome may have distinctive potential strengths in the penetration of physiological barriers, for example, the blood-brain barrier, and in the research and development of transdermal immunization vaccines. This review has summarized five aspects of transfersomes, including the main properties, the formulation and process influencing factors, evaluation methods, main administration routes, and problems. Herein, we have given some examples and analysis, summarized the research achievements and assessd prospects for future development.
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Sistemas de Liberación de Medicamentos , Liposomas , Administración Cutánea , Portadores de Fármacos , Investigación , PielRESUMEN
OBJECTIVE: To prepare encapsulated clopidogrel bisulfate (CLP) liposomes so as to deal with the poor water solubility of CLP, and to provide the experimental basis for the development of CLP formulations for intravascular injection. METHODS: CLP-loaded liposomes were prepared using thin film hydration/sonication method and pH gradient active drug loading technology. Then, the morphology, particle size, encapsulation efficiency, drug loading capacity, Zeta potentials and in vitro release behavior were characterized. Bilateral renal arteries of Sprague-Dawley (SD) rats were clamped with micro-artery clamps to establish the model of renal ischemia-reperfusion injury (IRI) in male SD rats. The study aimed to preliminarily investigate the therapeutic effect of CLP-loaded liposome pretreatment on renal IRI in rats. RESULTS: It was found that the optimal formulation and preparation technology of CLP liposomes were as follows: the CLP-to-phospholipid weight ratio of 1â¶10, phospholipid-to-cholesterol ratio of 6â¶1, octadecylamine-to-CLP ratio of 1.2â¶1, PEG 400-to-CLP ratio of 1â¶1, and incubation at 50 â for 40 min. Then, following ultrasonication of 100 W efficiency at 5-second intervals for 20 times, CLP loading was conducted using 5 mL of 0.1 mol/L citric acid buffer at pH 3.0. Liposome samples were prepared with the film dispersion method, and the pH value was adjusted to 7.5 through pH gradient active drug loading technology. The CLP-loaded liposomes obtained in this way had a rounded shape, good dispersity, an average particle size of (134.13±2.60) nm, polydispersity index (PDI) of 0.25±0.02, and a Zeta potential of (2.12±0.23) mV. The encapsulation efficiency was found to be (98.66±0.14)%, and the drug loading capacity was (7.47±0.01)%. The in vitro release results showed that 66.24% of CLP was released cumulatively within 72 h. Preliminary efficacy experiments showed that animals pretreated with CLP-loaded liposomes had lower serum levels of blood urea nitrogen and creatinine compared to the levels of IRI model rats without any pretreatment. CONCLUSION: CLP-loaded liposomes were successfully prepared, which might provide the experimental foundation for the future development of CLP formulations for injection.
Asunto(s)
Liposomas , Animales , Clopidogrel , Masculino , Tamaño de la Partícula , Ratas , Ratas Sprague-Dawley , SolubilidadRESUMEN
Though plastic nanoparticles have already raised much concern for their potential impact on health, our understanding of their biological effects is still utterly limited. Here we demonstrate for the first time that carboxyl-modified polystyrene nanoparticles (CPS) could effectively inhibit ferroptosis as a result of reduced cellular ROS which was triggered by transcription factor EB (TFEB) nucleus translocation. In this process, CPS first entered cells via macropinocytosis, then CPS-containing macropinosomes fused with lysosomes and expanded into abnormal lysosome-like large vacuoles in vacuolar-type H+-ATPase (V-ATPase) and aquaporins (AQPs) in a dependent way. These large vacuoles were detected both in vitro and in vivo, which was found to be a sign of lysosome stress. The lysosome stress induced deactivation of mammalian target of rapamycin (mTOR) which led to nucleus translocation of TFEB. Then, TFEB-dependent enhanced expression of lysosomal proteins and superoxide dismutase (SOD) which ultimately led to ROS reduction and inhibition of ferroptosis. Knockout of TFEB-enhanced ferroptosis was triggered by Erastin and abolished the effect of CPS on ROS and ferroptosis. In summary, our results reveal a novel mechanism whereby CPS reduced ROS and inhibited ferroptosis in a TFEB-dependent way. These findings have important implications for understanding the biological effects of polystyrene nanoparticles and searching for new anti-ROS and antiferroptosis particles or reagents.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Ferroptosis/efectos de los fármacos , Lisosomas/efectos de los fármacos , Nanopartículas , Poliestirenos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Humanos , Lisosomas/metabolismo , Ratones , Nanopartículas/química , Pinocitosis/efectos de los fármacos , Poliestirenos/química , Transporte de Proteínas/efectos de los fármacos , Células RAW 264.7RESUMEN
Celastrol (CLT)-loaded PEG-PLGA nanoparticles (NPs/CLT) coated with neutrophil membranes (NNPs/CLT) were explored for the management of acute pancreatitis (AP). PEG-PLGA nanoparticles sized around 150 nm were proven to selectively accumulate in the pancreas in rats with AP. NNPs were found to overcome the blood-pancreas barrier and specifically distributed to the pancreatic tissues. Moreover, NNPs showed more selective accumulation in the pancreas than nanoparticles without any membrane coating in AP rats. Compared to CLT solution and the NPs/CLT group, NNPs/CLT significantly downregulated the levels of serum amylase and pancreatic myeloperoxidase in AP rats. Also, using NNPs as the delivery vehicle significantly reduced the systemic toxicity of CLT in AP rats. Together, these results suggest that NNPs/CLT represent a highly promising delivery vehicle for the targeted therapy of AP.
Asunto(s)
Membrana Celular/química , Inflamación/tratamiento farmacológico , Nanopartículas/química , Neutrófilos/citología , Pancreatitis/tratamiento farmacológico , Vehículos Farmacéuticos/metabolismo , Triterpenos/química , Amilasas/sangre , Animales , Membrana Celular/metabolismo , Modelos Animales de Enfermedad , Interleucina-6/sangre , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/etiología , Masculino , Terapia Molecular Dirigida/métodos , Nanopartículas/metabolismo , Pancreatitis/complicaciones , Pancreatitis/diagnóstico por imagen , Tamaño de la Partícula , Triterpenos Pentacíclicos , Vehículos Farmacéuticos/química , Poliésteres/química , Poliésteres/metabolismo , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Ratas , Ratas Sprague-Dawley , Distribución Tisular , Resultado del Tratamiento , Triterpenos/metabolismo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Mesangial proliferative glomerulonephritis (MsPGN), one of the most common glomerulonephritis pathological types, often leads to end-stage renal disease over a prolonged period. But the current treatment of MsPGN is non-specific and causes serious side effects, thus novel therapeutics and targeting strategies are urgently demanded. By combining the advantages of PEG-PLGA nanoparticles and the size selection mechanism of renal glomerulus, we designed and developed a novel PEG-PLGA nanoparticle delivery system capable of delivering dexamethasone acetate (A-DEX) into glomerular mesangium. We determined that 90 nm was the optimum size to encapsulate A-DEX for glomerular mesangium targeting based on the size-selection mechanism of glomerulus. After intravenous administration in rats, 90 nm DiD-loaded NPs were found to accumulate to a greater extent in the kidney and kidney cortex compared with the free DiD solution. The 90 nm A-DEX NPs are also more stable at room temperature and showed a sustained release pattern. In rat glomerular mesangial cells (HBZY-1) in vitro, we found that the uptake of 90 nm A-DEX NPs was both temperature-dependent and energe-dependent, and they were mostly engulfed via clathrin-dependent endocytosis pathways. In summary, we have successfully developed a glomerular mesangium-targeted PEG-PLGA NPs, which is potential for the treatment of MsPGN.
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Dexametasona/análogos & derivados , Portadores de Fármacos/química , Mesangio Glomerular/metabolismo , Nanopartículas/química , Poliésteres/química , Polietilenglicoles/química , Animales , Dexametasona/metabolismo , Diseño de Fármacos , Liberación de Fármacos , Tamaño de la Partícula , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Gemcitabine (Gem) is a standard first-line treatment for pancreatic cancer (PC). However, its chemotherapeutic efficacy is hampered by various limitations such as short half-life, metabolic inactivation, and lack of tumor localizing. We previously synthesized a lipophilic Gem derivative (Gem formyl hexadecyl ester, GemC16) that exhibited improved antitumor activity in vitro. In this study, a target ligand N,N-dimethyl-1,3-propanediamine was conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[hydroxyl succinimidyl (polyethylene glycol-2000)] (DSPE-PEG-NHS) to form DSPE-PEG-2N. Then, pancreas-targeting liposomes (2N-LPs) were prepared using the film dispersion-ultrasonic method. GemC16-loaded 2N-LPs displayed near-spherical shapes with an average size distribution of 157.2 nm (polydispersity index (PDI) = 0.201). The encapsulation efficiency of GemC16 was up to 97.3% with a loading capacity of 8.9%. In human PC cell line (BxPC-3) and rat pancreatic acinar cell line (AR42J), cellular uptake of 2N-LPs was significantly enhanced compared with that of unmodified PEG-LPs. 2N-LPs exhibited more potent in vitro cytotoxicity against BxPC-3 and AR42J cell lines than PEG-LPs. After systemic administration in mice, 2N-LPs remarkably increased drug distribution in the pancreas. In an orthotopic tumor mouse model of PC, GemC16-bearing liposomes were more effective in preventing tumor growth than free GemC16. Among these treatments, 2N-LPs showed the best curative effect. Together, 2N-LPs represent a promising nanocarrier to achieve pancreas-targeting drug delivery, and this work would provide new ideas for the chemotherapy of PC.
Asunto(s)
Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Portadores de Fármacos/química , Liposomas/química , Páncreas/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Diaminas/síntesis química , Diaminas/química , Diaminas/toxicidad , Portadores de Fármacos/síntesis química , Portadores de Fármacos/toxicidad , Sistemas de Liberación de Medicamentos/métodos , Liposomas/síntesis química , Liposomas/toxicidad , Ratones Endogámicos C57BL , Páncreas/patología , Neoplasias Pancreáticas/patología , Fosfatidiletanolaminas/síntesis química , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/toxicidad , Polietilenglicoles/síntesis química , Polietilenglicoles/química , Polietilenglicoles/toxicidad , GemcitabinaRESUMEN
Cholesterol facilitated the formation of T cell receptor on cytotoxic CD8+ T lymphocytes (CTLs). However, the activation of CD8+ T cells always resulted in the upregulation of acetyl-CoA acetyltransferase-1 (ACAT-1) and enhanced the esterification of cholesterol. To relieve the suppression on CD8+ T cells, an ACAT-1 inhibitor avasimibe was combined with chemo-immunotherapy. Paclitaxel and immunoadjuvant αGC were co-encapsulated in liposomes modified with pH sensitive TH peptide (PTX/αGC-TH-Lip). After intravenous injections, the combination of avasimibe significantly elevated the free cholesterol level and relieved the inhibition of CD8+ T cells caused by PTX/αGC-TH-Lip, leading to enhanced CTL responses and anti-tumor effects of PTX/αGC-TH-Lip in B16F10 melanoma xenograft and lung metastasis models. The adoptive immunotherapy further confirmed the enhanced anti-tumor immune responses of the combined strategy. The combination of avasimibe and PTX/αGC-TH-Lip was proven as a feasible approach to enhance the antitumor effects of chemo-immunotherapy by relieving the inhibition of CD8+ T cells.
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Linfocitos T CD8-positivos/inmunología , Colesterol/metabolismo , Inmunoterapia Adoptiva , Neoplasias Pulmonares/terapia , Melanoma Experimental/terapia , Paclitaxel/farmacología , Linfocitos T Citotóxicos/inmunología , Acetamidas , Acetatos/farmacología , Acetil-CoA C-Acetiltransferasa/antagonistas & inhibidores , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/patología , Proliferación Celular , Péptidos de Penetración Celular/administración & dosificación , Péptidos de Penetración Celular/química , Células Cultivadas , Colesterol/química , Inductores del Citocromo P-450 CYP3A/farmacología , Esterificación , Femenino , Humanos , Liposomas/administración & dosificación , Liposomas/química , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Sulfonamidas , Ácidos Sulfónicos/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/patologíaRESUMEN
Cancer associated fibroblasts (CAFs) which shape the tumor microenvironment (TME) and the presence of blood brain barrier (BBB) remain great challenges in targeting breast cancer and its brain metastasis. Herein, we reported a strategy using PTX-loaded liposome co-modified with acid-cleavable folic acid (FA) and BBB transmigrating cell penetrating peptide dNP2 peptide (cFd-Lip/PTX) for enhanced delivery to orthotopic breast cancer and its brain metastasis. Compared with single ligand or non-cleavable Fd modified liposomes, cFd-Lip exhibited synergistic TME targeting and BBB transmigration. Moreover, upon arrival at the TME, the acid-cleavable cFd-Lip/PTX showed sensitive cleavage of FA, which reduced the hindrance effect and maximized the function of both FA and dNP2 peptide. Consequently, efficient targeting of folate receptor (FR)-positive tumor cells and FR-negative CAFs was achieved, leading to enhanced anti-tumor activity. This strategy provides a feasible approach to the cascade targeting of TME and BBB transmigration in orthotopic and metastatic cancer treatment.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Paclitaxel/administración & dosificación , Microambiente Tumoral/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Péptidos de Penetración Celular/química , Femenino , Ácido Fólico/química , Humanos , Concentración de Iones de Hidrógeno , Ligandos , Liposomas/administración & dosificación , Liposomas/química , Ratones , Ratones Endogámicos BALB C , Paclitaxel/química , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PEGylation can stabilize drug delivery systems for cancer therapy by creating repulsive interactions with biological components in vivo. While these interactions reduce nonspecific adsorption of drug-loaded particles onto nontarget surfaces, they also inhibit internalization of particles into target cells. To circumvent this so-called "PEG-dilemma", we have developed nanoparticles with a PEG coating that is shed after arrival in target tissue. Positively charged polycation nanoparticles were assembled with microRNA-34a via electrostatic interactions and then coated again via electrostatic interactions with an anionic PEG derivative that separates from the nanoparticle in the acidic tumor microenvironment. The resulting ternary nanoparticles with a sheddable shell have nearly neutral surface charge, which markedly reduces nonspecific adsorption. Shedding the PEG coat enhanced nanoparticle uptake into CD44-positive melanoma cells and promoted microRNA-34a release, which down-regulated CD44 expression and thereby inhibited tumor growth. We conclude that nanocarriers with a sheddable shell show promise for cancer therapy.
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Receptores de Hialuranos/metabolismo , Melanoma/metabolismo , Melanoma/terapia , MicroARNs/fisiología , Nanopartículas/química , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Citometría de Flujo , Humanos , Inmunohistoquímica , Melanoma/genética , Ratones , MicroARNs/genética , Polietilenglicoles/química , Polímeros/químicaRESUMEN
Here, a biocompatible amphiphilic copolymer of low molecular weight heparin (LMWH) and doxorubicin (DOX) connected by an acid-sensitive hydrazone bond for enhanced tumor treatment efficacy and safety has been designed and tested. The conjugate combines DOX delivery with LMWH antimetastatic capabilities. After the nanoparticles reach the tumor site, the acidic tumor microenvironment triggers the breakage of the hydrazone bond releasing DOX from the nanoparticles, which results in an increase in the cellular uptake and enhanced in vivo antitumor efficacy. A 3.4-fold and 1.5-fold increase in tumor growth inhibition were observed compared to the saline-treated control group and free DOX treated group, respectively. The LMWH-based nanoparticles effectively inhibited interactions between tumor cells and platelets mediated by P-selectin reducing metastasis of cells in both in vitro and in vivo models. The improved safety and therapeutic effect of LMWW-DOX nanoparticles offers new potential for tumor therapy.
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Doxorrubicina/farmacología , Portadores de Fármacos/química , Heparina de Bajo-Peso-Molecular/farmacología , Nanopartículas/química , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Polímeros/farmacología , Animales , Línea Celular Tumoral , Doxorrubicina/química , Sistemas de Liberación de Medicamentos/métodos , Heparina de Bajo-Peso-Molecular/química , Hidrazonas/química , Masculino , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neoplasias/metabolismo , Selectina-P/metabolismo , Polímeros/químicaRESUMEN
Several targeted drug delivery systems have recently been developed to increase the bioavailability of a drug at its site of action, allowing simultaneous reduction of the total necessary drug dose as well as side effects. Here, we designed a cationic gene vector containing matrix metalloproteinase-2 (MMP2)-cleavable substrate peptides that specifically target tumor sites where MMP2 levels are high. The targeted delivery system is fabricated by linking enzyme-cleavable polyethylene glycol (PEG) derivatives to cationic ß-cyclodextrin-polyethylenimine conjugates, which reduce the toxicity of polyethylenimine and condense the therapeutic cargo. In the present study, tumor suppressor microRNA miR-34a, which suppresses onset and progression of many types of cancers, was investigated for its therapeutic potential for treating breast cancer. The PEG coating markedly reduces nonspecific interaction between cationic particles and serum proteins, permitting accumulation at the target site; subsequent peptide cleavage by MMP2 facilitates miR-34a delivery into tumor cells. The nanopreparation shows excellent stability, and its internalization, tumor targeting, and antitumor efficacy in vitro and in vivo are better than those of a nanopreparation containing MMP2-uncleavable peptide.
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Neoplasias de la Mama/tratamiento farmacológico , Cationes/química , Vectores Genéticos/química , MicroARNs/química , Péptido Hidrolasas/metabolismo , Péptidos/química , Polietilenglicoles/química , Animales , Cationes/administración & dosificación , Línea Celular , Línea Celular Tumoral , Perros , Sistemas de Liberación de Medicamentos/métodos , Femenino , Vectores Genéticos/administración & dosificación , Humanos , Células de Riñón Canino Madin Darby , Metaloproteinasa 2 de la Matriz/metabolismo , MicroARNs/administración & dosificación , Nanopartículas/administración & dosificación , Nanopartículas/química , Péptidos/administración & dosificación , Polietileneimina/administración & dosificación , Polietileneimina/química , beta-Ciclodextrinas/administración & dosificación , beta-Ciclodextrinas/químicaRESUMEN
Scopoletin is an active coumarin possessing a variety of pharmacological activities, including anti-hyperuricemic effect, but with poor solubility. To improve its oral bioavailability, we attempted to encapsulate scopoletin into Soluplus micelles (Soluplus-based scopoletin micelles, Sco-Ms) and evaluated the hypouricemic action of Sco-Ms. Sco-Ms were prepared using a thin-film hydration method. Sco-Ms displayed near spherical shapes with an average size of 59.4±2.4 nm (PDI=0.08±0.02). The encapsulation efficiency of scopoletin was 87.3%±1.5% with a loading capacity of 5.5%±0.1%. Sco-Ms were further characterized using transmission electron microscopy, powder X-ray diffraction, Fourier transform infrared techniques and scanning electron microscopy. After oral administration in rats, Sco-Ms exhibited significantly improved absorption in each intestinal segment compared to free scopoletin, with the duodenum and jejunum being the main absorption regions. In rats administered Sco-Ms (at an equivalent dose of free scopoletin of 100 mg/kg, po), the AUC0-∞ and Cmax of Sco-Ms were 4.38- and 8.43-fold, respectively, as large as those obtained following administration of free scopoletin. After oral administration in rats, Sco-Ms did not alter the tissue distributions of scopoletin, but significantly increased the scopoletin levels in the liver. In potassium oxonate-induced hyperuricemic mice, oral administration of Sco-Ms (at an equivalent dose of free scopoletin of 300 mg/kg) reduced the serum uric acid concentration to the normal level. The results suggest that Soluplus-based micelle system greatly improves the bioavailability of poorly water-soluble drugs, such as scopoletin, and represents a promising strategy for their oral delivery.
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Hiperuricemia/tratamiento farmacológico , Polietilenglicoles/química , Polivinilos/química , Escopoletina/administración & dosificación , Escopoletina/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Masculino , Ratones Endogámicos ICR , Micelas , Ratas Sprague-Dawley , Escopoletina/farmacocinéticaRESUMEN
Alpha (α)-asarone (1-propenyl-2,4,5-methoxybenzol) (ARE) has been extensively used to treat chronic obstructive pulmonary diseases (COPD), bronchial asthma, pneumonia, and epilepsy. Due to its poor solubility and bioavailability, ARE was clinically administered via intravenous injection. However, severe allergies were often reported due to the presence of solublizers in the injection formulation. In our study, we sought to explore the biopharmaceutical classification of ARE, elucidate the mechanisms behind ARE absorption, and to develop a viable formulation to improve the oral bioavailability of ARE. ARE was not a P-glycoprotein substrate, which was absorbed in the passive mode without site specificity in the gastrointestinal tract. Solid dispersions prepared using hydrophilic matrix materials such as Pluronic F68, and polyethylene glycol (PEG) of varying molecular weights (PEG4K, PEG10K, and PEG20K) were proven to significantly improve the dissolution of ARE in vitro and the oral bioavailability of ARE in rats, which represent a promising strategy for the oral administration of ARE and other BCS II compounds.
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Anisoles/química , Portadores de Fármacos/química , Poloxámero/química , Polietilenglicoles/química , Administración Oral , Derivados de Alilbenceno , Animales , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Interacciones Hidrofóbicas e Hidrofílicas , Poloxámero/farmacología , Polietilenglicoles/farmacología , Ratas , SolubilidadRESUMEN
The clinical use of dabigatran etexilate (DABE) is limited by its poor absorption and relatively low bioavailability. Our study aimed to explore the potential of a mixed micelle system composed of Soluplus® and D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) to improve the oral absorption and bioavailability of DBAE. DBAE was first encapsulated into Soluplus/TPGS mixed micelles by a simple thin film hydration method. The DBAE loaded micelles displayed an average size distribution of around 83.13 nm. The cellular uptake of DBAE loaded micelles in Caco-2 cell monolayer was significantly enhanced by 2-2.6 fold over time as compared with DBAE suspension. Both lipid raft/caveolae and macropinocytosis-mediated the cell uptake of DBAE loaded micelles through P-glycoprotein (P-gp)-independent pathway. Compared with the DBAE suspension, the intestinal absorption of DBAE from DBAE mixed micelles in rats was significantly improved by 8 and 5-fold in ileum at 2 h and 4 h, respectively. Moreover, DBAE mixed micelles were absorbed into systemic circulation via both portal vein and lymphatic pathway. The oral bioavailability of DBAE mixed micelles in rats was 3.37 fold higher than that of DBAE suspension. DBAE mixed micelles exhibited a comparable anti-thrombolytic activity with a thrombosis inhibition rate of 63.18% compared with DBAE suspension in vivo. Thus, our study provides a promising drug delivery system to enhance the oral bioavailability and therapeutic efficacy of DBAE.
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Dabigatrán/farmacología , Dabigatrán/farmacocinética , Polietilenglicoles/química , Polivinilos/química , Vitamina E/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Administración Oral , Disponibilidad Biológica , Células CACO-2 , Dabigatrán/química , Sistemas de Liberación de Medicamentos/métodos , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacología , Humanos , Absorción Intestinal/efectos de los fármacos , Micelas , Trombosis/tratamiento farmacológicoRESUMEN
This study examined the ability of amphiphilic poly(ethylene glycol) (PEG) derivatives to assemble into micelles for drug delivery. Linear PEG chains were modified on one end with hydrophobic vitamin E succinate (VES), and PEG and VES were mixed in different molar ratios to make amphiphiles, which were characterized in terms of critical micelle concentration (CMC), drug loading capacity (DLC), serum stability, tumor spheroid penetration and tumor targeting in vitro and in vivo. The amphiphile PEG5K-VES6 (PAMV6), which has a wheat-like structure, showed a CMC of 3.03 × 10(-6) M, good serum stability, and tumor accumulation. The model drug, pirarubicin (THP), could be efficiently loaded into PAMV6 micelles at a DLC of 24.81%. PAMV6/THP micelles were more effective than THP solution at inducing cell apoptosis and G2/M arrest in 4T1 cells. THP-loaded PAMV6 micelles also inhibited tumor growth much more than free THP in a syngeneic mouse model of breast cancer. PAMV6-based micellar systems show promise as nanocarriers for improved anticancer chemotherapy.
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Neoplasias de la Mama/metabolismo , Portadores de Fármacos/química , Diseño de Fármacos , Polietilenglicoles/química , Vitamina E/química , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Transporte Biológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Portadores de Fármacos/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Espacio Intracelular/metabolismo , Ratones , Micelas , Esferoides Celulares/metabolismo , Vitamina E/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PEGylated liposomes (PEG-Lip) have been widely used as a drug carrier for their good stealth property in blood circulation. However, the second injection of PEG-Lip was reported to result in the accelerated blood clearance (ABC) phenomenon and trigger hypersensitivity reactions in sensitive individuals for its complement activation effect. To avoid adverse immune responses, HA was selected to modify liposomes to afford HA modified liposomes (HA-Lip). Repeated administrations of PEG-Lip and HA-Lip were performed in rats. Our results showed that PEG-Lip induced the ABC phenomenon accompanied by a greatly increased accumulation of PEG-Lip in the liver. In contrast, HA-Lip showed good stealth property without inducing either the ABC phenomenon or an increase in liver uptake. Moreover, HA-Lip did not trigger complement activation in human serum in vitro and in rat blood in vivo. Consequently, HA modification represents a viable strategy to prolong the blood circulation time of liposomes without inducing the ABC phenomenon and adverse immune responses.