RESUMEN
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.
Asunto(s)
Portadores de Fármacos/química , Micelas , Profármacos/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Portadores de Fármacos/toxicidad , Femenino , Células HT29 , Humanos , Dosis Máxima Tolerada , Ratones , Ratones Desnudos , Polietilenglicoles/química , Polimerizacion , Profármacos/farmacocinética , Profármacos/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
Oral administration is an ideal alternative for drug delivery due to its convenience and safety. However, oral protein delivery is limited by biological barriers such as the mucus barrier and epithelial barrier, which hamper drugs from entering the blood successfully. Here we presented PC6/CS NPs, a thiolated-polymer-based nanodrug delivery system in the form of poly(acrylic acid)-cysteine-6-mercaptonicotinic acid (PAA-Cys-6MNA, PC6), which is a kind of preactivated thiolated polymer, coated on chitosan (CS) nanoparticles (NPs). Its ability to overcome the mucus barrier and epithelial barrier was investigated. The existence of PC6 made the NPs prone to penetrate the mucus layer as well as strengthened the transcellular transport of insulin on epithelial cells. PC6/CS NPs efficiently enhanced the oral bioavailability of insulin to 16.2%. The improvement resulted from the function of PC6: (1) "diluting" mucus to promote nanoparticle penetration, (2) opening a tight junction to help insulin transport via the paracellular pathway, (3) making the nanoparticle more electrically neutral during the penetration process, and (4) uncoating from PC6/CS NPs so that positive CS NPs were adhered and uptaken by epithelial cells. Our study proves that PC6/CS NPs, which can achieve mucus penetration and epithelial permeation efficiently, are a potential nanocarrier for oral protein delivery.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Células Epiteliales/metabolismo , Insulina/administración & dosificación , Moco/metabolismo , Nanopartículas/química , Ácidos Picolínicos/química , Resinas Acrílicas/química , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Quitosano/metabolismo , Cisteína/química , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Células Epiteliales/efectos de los fármacos , Humanos , Insulina/metabolismo , Insulina/farmacocinética , Microscopía Electrónica de Transmisión , Moco/efectos de los fármacos , Nanopartículas/metabolismo , Nanopartículas/toxicidad , Nanopartículas/ultraestructura , Ácidos Nicotínicos/química , Ácidos Picolínicos/metabolismo , Ratas , Compuestos de Sulfhidrilo/química , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismoRESUMEN
To develop a highly efficient strategy against tumors, here, a nanocombination (PDC/P@HCuS) was designed and constructed to actualize chemo-phototherapy with the assistance of fluorescence (FL) and photoacoustic (PA) images. First, a type of organic-inorganic hybrid nanosystem (P@HCuS) was engineered by coupling the fluorescence-labeled amphiphilic fPEDC copolymer on the surface of hollow mesoporous copper sulfide nanoparticle (HCuS), in which HCuS was used as a photothermal and PA agent; fPEDC as a stabilizer, chromophore, and redox/pH-sensitive gatekeeper; and both of them as drug carriers. Then, a peptide-drug conjugate (cRGD-SMCC-DM1, PDC), as a molecular targeted maytansinoid, was loaded inside of P@HCuS to form PDC/P@HCuS. Next, the PDC/P@HCuS was investigated carefully with or without near-infrared (NIR) laser irradiation. In vitro, the nanocombination exhibited stimuli-responsive drug release, obvious cellular uptake, strong cytotoxicity to tumor cells, significant impact on cell cycle, and cytoskeleton and cellular proteomics as well as evident permeability into the tumor sphere, most of which could be boosted by NIR laser irradiation. In vivo, the nanocombinaiton exerted good FL/PA imaging features and photothermal efficiency, achieved the best antitumor efficacy in the presence of NIR laser irradiation, and showed excellent biosafety. Together, it demonstrated that the PDC/P@HCuS, representing a chemo-phototherapy based on a nanocombination associated with peptide-drug conjugate, could achieve the highly efficient antitumor effect.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Péptidos/farmacología , Técnicas Fotoacústicas , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/patología , Colorantes/química , Colorantes/farmacología , Cobre/química , Cobre/farmacología , Doxorrubicina/química , Doxorrubicina/farmacología , Liberación de Fármacos , Femenino , Humanos , Hipertermia Inducida , Células MCF-7 , Maitansina/química , Maitansina/farmacología , Nanopartículas , Péptidos/química , Fototerapia , Sulfuros/química , Sulfuros/farmacologíaRESUMEN
Glucocorticoids have been confirmed to be effective in the treatment of a variety of inflammatory diseases. However, their application encounters limitations in terms of tissue distribution and bioavailability in vivo. To address these key issues, we designed and developed a nanopreparation by using egg yolk lecithin/sodium glycocholate (EYL/SGC) and utilize such mixed micelles (MMs) to encapsulate dexamethasone palmitate (DMP) for the treatment of rheumatoid arthritis (RA). The prepared DMP-MMs had an average particle size of 49.18 ± 0.43 nm and were compared with an emulsion-based dexamethasone palmitate. Pharmacokinetic and in vivo fluorescence imaging showed that mixed micelles had higher bioavailability and targeting efficiency in inflammatory sites. An arthritis rat model was established via induction by Complete Freund's Adjuvant (CFA), followed by the efficacy studies by the observations of paw volume, histology, spleen index, pro-inflammatory cytokines, and CT images. It was confirmed that intravenous injection of DMP-MMs exhibited advantages in alleviating joint inflammation compared with the emulsion system. Composed of pharmaceutical adjuvants only, the nanoscale mixed micelles seem a promising carrier system for the RA treatment with lipophilic drugs.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Dexametasona/administración & dosificación , Sistemas de Liberación de Medicamentos , Palmitatos/administración & dosificación , Animales , Artritis Experimental/tratamiento farmacológico , Dexametasona/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Emulsiones , Masculino , Micelas , Tamaño de la Partícula , Ratas , Ratas Sprague-DawleyRESUMEN
The objective of this study was to investigate the effect of crystalline state and a formulation of self-nanoemulsifying drug delivery system (SNEDDS) on oral bioavailability of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor, in rats. The crystalline states of W-1 were characterized by scanning electron microscope (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The SNEDDS was formulated by medium-chain lipids, characterized by droplet particle size. The plasma concentrations of W-1 were measured by high performance liquid chromatography (HPLC). The results indicated that W-1 compound were presented as crystalline forms, A and B, the degree of crystallization in form B was higher than that in form A. The SNEDDS of W-1 displayed a significant increase in the dissolution rate than W-1 powder. Furthermore, after oral administration of W-1 (100 mg/kg), the pharmacokinetic parameters of form A, form B, and W-1 SNEDDS were as follows: AUC0-t 526.4 ± 123.5, 305.1 ± 58.5 and 2297 ± 451 ng h/mL (p < .05, when W-1 SNEDDS were compared with either form A or form B), respectively. With SNEDDS formulation, the relative bioavailabilities were enhanced by 4.36-fold and 7.53-fold over the form A and form B of W-1, respectively. In conclusion, the present results suggested that the crystalline states of W-1 might lead to the lower oral bioavailability, and SNEDDS formulation is a promising strategy of improving bioavailability, in spite of that crystalline states usually carry small lot-to-lot variability.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Emulsiones/química , Nanopartículas/química , Uracilo/análogos & derivados , Administración Oral , Animales , Fármacos Anti-VIH/química , Área Bajo la Curva , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Cristalización , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Semivida , Lípidos/química , Masculino , Tasa de Depuración Metabólica , Tamaño de la Partícula , Polietilenglicoles/química , Ratas , Ratas Sprague-Dawley , Tensoactivos/química , Uracilo/administración & dosificación , Uracilo/química , Uracilo/farmacocinética , Difracción de Rayos XRESUMEN
Gold nanoparticles are promising drug delivery vehicles for nucleic acids, small molecules, and proteins, allowing various modifications on the particle surface. However, the instability and low bioavailability of gold nanoparticles compromise their clinical application. Here, we functionalized gold nanoparticles with CPP fragments (CALNNPFVYLI, CALRRRRRRRR) through sulfhydryl PEG to increase their stability and bioavailability. The resulting gold nanoparticles were characterized with transmission electron microscopy (TEM), dynamic light scattering (DLS), UV-visible spectrometry and X-ray photoelectron spectroscopy (XPS), and the stability in biological solutions was evaluated. Comparing to PEGylated gold nanoparticles, CPP (CALNNPFVYLI, CALRRRRRRRR)-modified gold nanoparticles showed 46 folds increase in cellular uptake in A549 and B16 cell lines, as evidenced by the inductively coupled plasma atomic emission spectroscopy (ICP-AES). The interactions between gold nanoparticles and liposomes indicated CPP-modified gold nanoparticles bind to cell membrane more effectively than PEGylated gold nanoparticles. Surface plasmon resonance (SPR) was used to measure interactions between nanoparticles and the membrane. TEM and uptake inhibitor experiments indicated that the cellular entry of gold nanoparticles was mediated by clathrin and macropinocytosis. Other energy independent endocytosis pathways were also identified. Our work revealed a new strategy to modify gold nanoparticles with CPP and illustrated the cellular uptake pathway of CPP-modified gold nanoparticles.
Asunto(s)
Oro/química , Liposomas/farmacología , Nanopartículas del Metal/química , Péptidos/química , Polietilenglicoles/química , Células A549 , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Endocitosis/efectos de los fármacos , Humanos , Cinética , Liposomas/química , Liposomas/metabolismo , Melanoma Experimental , Nanopartículas del Metal/ultraestructura , Ratones , Tamaño de la Partícula , Péptidos/farmacología , Fosfatidilcolinas/químicaRESUMEN
Most anticancer drugs are poorly soluble and nonspecific, which restricts their clinical application. Drug conjugates, as a prodrug strategy, provide the possibility to overcome these shortcomings, especially combined with nanotechnology. Drug conjugate nanoparticles possess the advantages of high drug loading capacity and passive tumor targeting ability. Here, we prepared doxorubicin drug-drug conjugate nanoparticles (DOX-SS-DOX NPs) based on disulfide-linked doxorubicin drug-drug conjugate (DOX-SS-DOX). Dynamic light scattering (DLS) and transmission electron microscope (TEM) characterization indicated that DOX-SS-DOX NPs were spherical with a uniform size distribution around 89 nm. DLS and in vitro release experiment revealed that DOX-SS-DOX NPs possessed reduction responsive activity. In vitro cellular uptake studies reflected that DOX-SS-DOX NPs could increase the uptake level substantially compared with DOX liposomes. Endocytosis mechanism assay demonstrated that DOX-SS-DOX NPs internalized into cells through a clathrin-mediated endocytosis pathway in an energy-dependent manner. In this manner, the amidase in lysosomes could break the amide bond to release free DOX, which would be helpful to antitumor activity. The in vitro cytotoxicity of DOX-SS-DOX NPs was a bit weaker than that of DOX liposomes, which might be the result of the slow cleavage of the disulfide bridge; but the antitumor efficacy of DOX-SS-DOX NPs evaluated in MCF-7 bearing mice was demonstrated to be higher than that of DOX liposomes. This might be because of the long lasting effect resulting from the slow cleavage of the disulfide bond. In summary, DOX-SS-DOX NPs, prepared nearly totally with drug, provide a good strategy for cancer therapy.
Asunto(s)
Antineoplásicos/química , Disulfuros/química , Doxorrubicina/química , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Animales , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Microscopía ConfocalRESUMEN
Cancer-associated fibroblasts (CAFs) play a vitally important role during tumor progression. Navitoclax (Nav) can specifically induce apoptosis in CAFs. The present study aims to develop a novel CAF-targeted nanoliposome for cancer therapy. Nav-loaded nanoliposomes modified with peptide FH (FH-SSL-Nav), which specifically binds to tenascin C, a protein mainly expressed by CAFs, were formulated and characterized. Several experiments were performed to evaluate CAFs selective apoptosis, targeting and eradicating. Compared with SSL-Nav, FH-SSL-Nav achieved higher cellular uptake, and exhibited stronger cytotoxicity in vitro. The in vivo tumor stroma targeting effect was further confirmed by near infrared imaging. Accordingly, FH-SSL-Nav displayed improved tumor growth inhibition by eradicating CAFs in Hep G2 tumor-bearing nude mice model. In conclusion, FH-SSL-Nav could achieve targeting delivery of Nav to CAFs in vitro and in vivo, and may offer a potential strategy for cancer therapy based on tumor stroma. From the Clinical Editor: The progression of cancer cells often depends on the underlying tumor microenvironment, in which cancer-associated fibroblasts play an important role. In this article, the authors developed targeted therapy against CAFs using liposomes as carriers. This new modality was shown to be more effective in tumor killing both in vitro and in vivo. The finding may open a new era in cancer therapy.
Asunto(s)
Compuestos de Anilina/administración & dosificación , Nanocápsulas/química , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Péptidos/farmacocinética , Sulfonamidas/administración & dosificación , Tenascina/metabolismo , Animales , Antineoplásicos/administración & dosificación , Femenino , Humanos , Liposomas/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Terapia Molecular Dirigida/métodos , Neoplasias , Resultado del TratamientoRESUMEN
Though combination chemotherapy or antitumor nanomedicine is extensively investigated, their combining remains in infancy. Additionally, enhanced delivery of estrogen or its analogs to tumor with highly-expressed estrogen-receptor (ER) is seldom considered, despite its necessity for ER-positive breast cancer treatment. Here, nanomedicine based combination therapy using QLPVM conjugated liposomal tamoxifen (TAM) and doxorubicin (DOX) was designed and testified, where the penta-peptide was derived from Ku70 Bax-binding domain. Quantitative, semi-quantitative and qualitative approaches demonstrated the enhanced endocytosis and cytotoxicity of QLPVM conjugated sterically stabilized liposomes (QLPVM-SSLs) in vitro and in vivo. Mechanism studies of QLPVM excluded the possible electrostatic, hydrophobic or receptor-ligand interactions. However, as a weak cell-penetrating peptide, QLPVM significantly induced drug release from QLPVM-SSLs during their interaction with cells, which was favorable for drug internalization. These findings suggested that the nanomedicine based combination therapy using QLPVM-SSL-TAM and QLPVM-SSL-DOX might provide a rational strategy for Luminal A breast cancer. FROM THE CLINICAL EDITOR: Breast cancer remains a leading cause of mortality in women worldwide. Although combined therapy using hormonal antagonist and chemotherapy is the norm nowadays, the use of these agents together in a single delivery system has not been tested. Here, the authors investigated this approach using QLPVM conjugated liposomes in in-vitro and in-vivo models. The positive findings may provide a novel direction for breast cancer treatment in the near future.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Péptidos de Penetración Celular/metabolismo , Doxorrubicina/análogos & derivados , Liposomas/metabolismo , Oligopéptidos/metabolismo , Tamoxifeno/administración & dosificación , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mama/efectos de los fármacos , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Péptidos de Penetración Celular/química , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Autoantígeno Ku/química , Autoantígeno Ku/metabolismo , Liposomas/química , Ratones Desnudos , Nanomedicina , Oligopéptidos/química , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Tamoxifeno/uso terapéutico , Proteína X Asociada a bcl-2/metabolismoRESUMEN
The integrity of poly(ethylene glycol)-co-poly(ε-caprolactone) (PEG-PCL) micelles transcellular transported across madin-darby canine kidney(MDCK) epithelial cells was investigated. Fluorescein isothiocyanate isomer I(FITC) was conjugated to PEG-PCL and the product PEG-PCL-FITC was identified by fluorescence spectra. Two micelles were prepared using the thin-film hydration method: 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) co-loaded PEG-PCL micelles (DiO-DiI-M), DiI loaded and PEG-PCL-FITC contained micelles(FITC-DiI-M). The size of the micelles was characterized by dynamic light scattering analysis using a Malvern Zetasizer Nano ZS and it turned out that the particle sizes of both micelles were about 30 nm with identical polydispersity index(PDI). The stability of the micelles in phosphate buffer saline(PBS) was monitored using fluorescence spectra and both micelles were stable within 4 h in PBS. The integrity of PEG-PCL micelles in the transcellular process across MDCK epithelial cell monolayer at 1 and 4 h was investigated using laser confocal scanning microscope and Förster resonance energy transfer(FRET) technology. The Person's coefficient and FRET efficiency of both Transwell layer and Receive layer were recorded. The results show that the FRET efficiency and Person's coefficient of the Receive layer was consistent with that of Transwell layer for both the micelles at 1 h, but decreased at 4 h and FITC-DiI-M decreased more significantly than Di O-DiI-M. The results indicated that the micelles could transport across the MDCK monolayer intactly at 1 h but some of them were disassembled during the 4 h transportation process.
Asunto(s)
Portadores de Fármacos/química , Transferencia Resonante de Energía de Fluorescencia , Micelas , Animales , Transporte Biológico , Caproatos , Perros , Humanos , Isotiocianatos , Lactonas , Células de Riñón Canino Madin Darby , Tamaño de la Partícula , Poliésteres , PolietilenglicolesRESUMEN
Although transferrin receptor (TfR) is widely accepted as a target for cancer therapy, few studies have elaborated on delivery efficiency of TfR upon interactions with TfR-targeted nanomedicine. Here, a micellar system employing TfR-specific 7peptide (histidine-alanine-isoleucine-tyrosine- proline-arginine-histidine, HAIYPRH, 7pep) as the targeting moiety was constructed; and its endocytosis, intracellular trafficking as well as influence on TfR expression and in vivo tumor targeting were explored in the MCF-7 tumor model. In contrast to unmodified micelles, 7pep modification enhanced the cellular uptake of micelles without altering endocytic pathways, and slowed down the trafficking of micelles to lysosomes without changing the final intracellular colocalization. Interestingly, cellular TfR level was increased by 7pep-modified micelles. Furthermore, receptor saturation and recovery was observed in vivo. In conclusion, this study comprehensively investigated the bionano interaction between TfR positive tumors and 7pep-modified micelles, and provided scientific information for cancer therapy with receptor-mediated nanomedicines.
Asunto(s)
Nanopartículas/química , Receptores de Transferrina/metabolismo , Membrana Celular/metabolismo , Sistemas de Liberación de Medicamentos , Humanos , Células MCF-7 , Micelas , Nanomedicina/métodos , Péptidos/química , Péptidos/metabolismo , Receptores de Transferrina/químicaRESUMEN
Cancer metastasis is difficult to treat, and its outcome becomes dreadful for a patient. Lung is a major metastatic site for many types of cancers, and the need for finding effective treatment for lung metastasis cannot be overemphasized. In a previous study, we showed that camptothecin nanocrystals demonstrated greater anticancer efficacy and achieved significantly higher concentration in lungs than a conventional, solution-based formulation. In this study, we further determined the pharmacokinetics of camptothecin nanocrystals in rats and investigated treatment efficacy in mice against metastatic lung tumors. The results show that camptothecin nanocrystals were capable of eliciting greater antimetastatic efficacy and achieve a longer survival time in the murine model compared with camptothecin salt solution. The study suggests that using engineered, solid nanoparticles may be a feasible approach in the treatment of lung cancer and lung metastatic cancer.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Camptotecina/farmacocinética , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas/química , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Camptotecina/administración & dosificación , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Ratas , Tasa de Supervivencia , Distribución Tisular , Resultado del Tratamiento , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To address the obstacles facing cancer chemotherapeutics, including toxicity, side effects, water insolubility, and lack of tumor selectivity, a novel stimuli-responsive drug-delivery system was developed based on paclitaxel-loaded poly(ethylene glycol)-disulfide-paclitaxel conjugate nanoparticles (PEG-SS-PTX/PTX NPs). The formulation emphasizes several benefits, including polymer-drug conjugates/prodrugs, self-assembled NPs, high drug content, redox responsiveness, and programmed drug release. The PTX-loaded, self-assembled NPs, with a uniform size of 103 nm, characterized by DLS, TEM, XRD, DSC, and (1)H NMR, exhibited excellent drug-loading capacity (15.7%) and entrapment efficiency (93.3%). PEG-SS-PTX/PTX NPs were relatively stable under normal conditions but disassembled quickly under reductive conditions, as indicated by their triggered-aggregation phenomena and drug-release profile in the presence of dithiothreitol (DTT), a reducing agent. Additionally, by taking advantage of the difference in the drug-release rates between physically loaded and chemically conjugated drugs, a programmed drug-release phenomenon was observed, which was attributed to a higher concentration and longer action time of the drugs. The influence of PEG-SS-PTX/PTX NPs on in vitro cytotoxicity, cell cycle progression, and cellular apoptosis was determined in the MCF-7 cell line, and the NPs demonstrated a superior anti-proliferative activity associated with PTX-induced cell cycle arrest in G2/M phase and apoptosis compared to their nonresponsive counterparts. Moreover, the redox-responsive NPs were more efficacious than both free PTX and the non-redox-responsive formulation at equivalent doses of PTX in a breast cancer xenograft mouse model. This redox-responsive PTX drug delivery system is promising and can be explored for use in effective intracellular drug delivery.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/química , Paclitaxel/uso terapéutico , Polietilenglicoles/química , Polímeros/química , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Células MCF-7 , RatonesRESUMEN
A liposome system modified with chlorotoxin (ClTx), a scorpion venom peptide previously utilized for targeting brain tumors, was established. Its targeting efficiency and antimetastasis behavior against metastatic breast cancer highly expressed MMP-2, the receptor of ClTx, were investigated. 4T1, a metastatic breast cancer cell line derived from a murine breast tumor, was selected as the cell model. As results, the ClTx-modified liposomes displayed specific binding to 4T1 as determined by flow cytometry and confocal imaging. The cytotoxicity assay revealed that the ClTx modification increased the toxicity compared with nonmodified liposomes. In addition, the modified liposomes also exhibited high in vivo targeting efficiency in the BALB/c mice bearing 4T1 tumors. Importantly, this system inhibited the growth of metastatic tumor and prevented the incidence of lung metastasis in mice bearing 4T1 tumors with only low systemic toxicity. The data obtained from the in vitro and in vivo studies confirmed that the ClTx-modified liposomes increased the drug delivery to metastatic breast cancers. This study proved that the ClTx-modified liposomes had targeting ability to metastatic breast cancer in addition to brain cancer, and displayed an obvious antimetastasis effect. Generally, it may provide a promising strategy for metastatic breast cancer therapy.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Liposomas/química , Venenos de Escorpión/química , Venenos de Escorpión/uso terapéutico , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Femenino , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The aimed of this study was to prepare stabilized thiomers to overcome the poor stability character of traditional thiomers. Poly(acrylic acid)-cysteine (PAA-Cys) was synthesized by conjugating cysteine with poly(acrylic acid) and poly(acrylic acid)-cysteine-6-mercaptonicotinic acid (PAA-Cys-6MNA, stabilized thiomers) was synthesized by grafting a protecting group 6-mercaptonicotinic acid (6MNA) with PAA-Cys. The free thiol of PAA-Cys was determined by Ellmann's reagent method and the ratio of 6MNA coupled was determined by glutathione reduction method. The study of permeation enhancement and stabilized function was conducted by using Franz diffusion cell method, with fluorescein isothiocyanate dextran (FD4) used as model drug. The influence of polymers on tight junctions of Caco-2 cell monolayer was detected with laser scanning confocal fluorescence microscope. The results indicated that both PAA-Cys and PAA-Cys-6MNA could promote the permeation of FD4 across excised rat intestine, and the permeation function of PAA-Cys-6MNA was not influence by the pH of the storage environment and the oxidation of air after the protecting group 6MNA was grafted. The distribution of tight junction protein of Caco-2 cell monolayer F-actin was influenced after incubation with PAA-Cys and PAA-Cys-6MNA. In conclusion, stabilized thiomers (PAA-Cys-6MNA) maintained the permeation function compared with the traditional thiomers (PAA-Cys) and its stability was improved. The mechanism of the permeation enhancement function of the polymers might be related to their influence on tight junction relating proteins of cells.
Asunto(s)
Resinas Acrílicas/química , Cisteína/química , Ácidos Nicotínicos/química , Compuestos de Sulfhidrilo/química , Actinas/metabolismo , Animales , Células CACO-2 , Dextranos , Fluoresceína-5-Isotiocianato/análogos & derivados , Glutatión , Humanos , Absorción Intestinal , Mucosa Intestinal/efectos de los fármacos , RatasRESUMEN
Conventional treatments of uveitis are not ideal because of the short period of therapeutic efficacy. In the present study, biodegradable polylactic-glycolic acid microspheres loaded with triamcinolone acetonide (TA) were prepared to achieve sustained drug release and their therapeutic efficacy was investigated on a rabbit model of uveitis. TA-loaded microspheres (TA-MS) were prepared by the solvent evaporation method and characterized for encapsulation efficiency, particle size, morphology and in vitro release. The therapeutic efficacy was studied on the rabbit experimental uveitis model based on scoring of the inflammation, aqueous leukocyte counting, aqueous protein determination and histological examination. The TA-MS exhibited smooth and intact surfaces with an average diameter of 50.87 µm. The drug-loading coefficient and encapsulation efficiency were 15.2 ± 0.6 % and 91.24 ± 3.77 %, respectively. The drug release from TA-MS lasted up to 87 days, but only 46 days for TA suspension. The change in surface morphology also showed sustained drug release from TA-MS. TA-MS exhibited improved therapeutic efficacy in lipopolysaccharide -induced uveitis compared to TA suspension, especially in regard to the inhibition of inflammation. The TA-MS had a longer-term therapeutic effect on intraocular inflammation in LPS-induced uveitis in rabbits compared to TA suspension. The results suggested that TA-MS can be developed as a potential sustained-release system for the treatment of uveitis.
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Antiinflamatorios/administración & dosificación , Portadores de Fármacos/administración & dosificación , Triamcinolona Acetonida/administración & dosificación , Uveítis/tratamiento farmacológico , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Glicolatos , Inyecciones Intravítreas , Ácido Láctico , Microesferas , Poliésteres , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Polímeros , Conejos , Uveítis/patologíaRESUMEN
Cancer vaccine gains great attention with the advances in tumor immunology and nanotechnology, but its long-term efficacy is restricted by the unsustainable immune activity after vaccination. Here, we demonstrate the vaccine efficacy is negatively correlated with the tumor burden. To maximum the vaccine-induced immunity and prolong the time-effectiveness, we design a priming-boosting vaccination strategy by combining with radiofrequency ablation (RFA), and construct a bisphosphonate nanovaccine (BNV) system. BNV system consists of nanoparticulated bisphosphonates with dual electric potentials (BNV(+&-)), where bisphosphonates act as the immune adjuvant by blocking mevalonate metabolism. BNV(+&-) exhibits the spatial and temporal heterogeneity in lymphatic delivery and immune activity. As the independent components of BNV(+&-), BNV(-) is drained to the lymph nodes, and BNV(+) is retained at the injection site. The alternately induced immune responses extend the time-effectiveness of antitumor immunity and suppress the recurrence and metastasis of colorectal cancer liver metastases after RFA. As a result, this trinity system integrated with RFA therapy, bisphosphonate adjuvant, and spatiotemporal immune effect provides an orientation for the sustainable regulation and precise delivery of cancer vaccines.
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Vacunas contra el Cáncer , Ablación por Catéter , Neoplasias Colorrectales , Neoplasias Hepáticas , Ablación por Radiofrecuencia , Humanos , Nanovacunas , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Vacunas contra el Cáncer/uso terapéutico , Difosfonatos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológicoRESUMEN
Extracellular vesicles (EVs) are an effective tool to elucidate the bioeffect of nanomedicines. To clarify the interaction between oral nanomedicines and intestinal epithelial cells, and their bioeffects on downstream cells, polystyrene nanoparticles (PS-NPs) with different sizes were used as the model nanomedicines for EVs induction. Caco-2 monolayers were selected as the model of the intestinal epithelium and DLD-1 cells as the colorectal cancer model proximal to the gastrointestinal tract. It is found that compared with small-sized (25, 50, 100 nm) PS-NPs, the large-sized (200 and 500 nm) exhibited higher co-localization with multivesicular bodies and lysosomes, and more significant reduction of lysosomal acidification in Caco-2 cells. Proteomic and western-blotting analysis showed that the EVs remodeled by large-sized PS-NPs exhibited a higher extent of protein expression changes. The in vitro and in vivo signaling pathway detection in DLD-1 cells and DLD-1 cell xenograft nude mice showed that the remodeled EVs by large-sized PS-NPs inhibited the activation of multiple signaling pathways including Notch3, EGF/EGFR, and PI3K/Akt pathways, which resulted in the inhibition of tumor cell migration. These results primarily clarify the regulation mechanisms of nanomedicines-EVs-receptor cells chain. It provides a new perspective for the rational design and bioeffect evaluation of oral drug nanomaterials and sets up the fundamental knowledge for novel tumor therapeutics in the future.
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Vesículas Extracelulares , Nanopartículas , Animales , Ratones , Humanos , Células CACO-2 , Proteómica/métodos , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Mucosa Intestinal/metabolismo , Vesículas Extracelulares/metabolismo , Nanopartículas/metabolismo , Movimiento CelularRESUMEN
Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.