RESUMEN
Combination of chemotherapy and gene therapy provides an effective strategy for cancer treatment. However, the lack of suitable codelivery systems with efficient endo/lysosomal escape and controllable drug release/gene unpacking is the major bottleneck for maximizing the combinational therapeutic efficacy. In this work, we developed a photoactivatable Pt(IV) prodrug-backboned polymeric nanoparticle system (CNPPtCP/si(c-fos)) for light-controlled si(c-fos) delivery and synergistic photoactivated chemotherapy (PACT) and RNA interference (RNAi) on platinum-resistant ovarian cancer (PROC). Upon blue-light irradiation (430 nm), CNPPtCP/si(c-fos) generates oxygen-independent N3⢠with mild oxidation energy for efficient endo/lysosomal escape through N3â¢-assisted photochemical internalization with less gene deactivation. Thereafter, along with Pt(IV) prodrug activation, CNPPtCP/si(c-fos) dissociates to release active Pt(II) and unpack si(c-fos) simultaneously. Both in vitro and in vivo results demonstrated that CNPPtCP/si(c-fos) displayed excellent synergistic therapeutic efficacy on PROC with low toxicity. This PACT prodrug-backboned polymeric nanoplatform may provide a promising gene/drug codelivery tactic for treatment of various hard-to-tackle cancers.
Asunto(s)
Antineoplásicos , Nanopartículas , Neoplasias Ováricas , Profármacos , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Femenino , Terapia Genética , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Fotoquimioterapia , Platino (Metal) , Polímeros/uso terapéutico , Profármacos/uso terapéuticoRESUMEN
Subunit vaccines are safer but often poorly immunogenic in comparison to traditional vaccines, and thus, adjuvants and delivery vehicles are needed to enhance the immune response. The complement system is a part of the innate immune system, which plays an important role in innate and adaptive immunity. Therefore, the activation of the complement system could be utilized as a potential strategy for vaccine applications. Herein, cysteamine hydrochloride was grafted onto a methoxy poly(ethylene glycol)-block-poly (allyl glycidyl ether)-block-poly(ε-caprolactone) copolymer to synthesize a triblock polymer mPEG5k-PAGE15(NH2)-PCL5k(TPCAH) with amino groups on the side chain. The positive charge of the amino groups could bind with the negatively charged protein (like ovalbumin (OVA)) to form a stable complex by electrostatic interaction. The triblock copolymer TPCAH we designed can easily self-assemble into polymer nanomicelles, and the size of the nanoparticles is similar to that of the pathogens, which was beneficial to the uptake by lymphocytes. Furthermore, the amino groups modified on the side chain can not only integrate with proteins but also activate the complement system, thereby enhancing the immune response of subunit vaccines. The results showed that the complex TPCAH@OVA could efficiently promote powerful anti-OVA-specific antibody production, enhance CD4+ T- and CD8+ T-cell activation, improve the lymphocyte proliferation efficiency, and increase the secretion of different cytokines. In addition, the abundant amino groups on the surface of TPCAH@OVA could effectively activate the complement system to further enhance adaptive immunity. Overall, these results indicated that the triblock copolymer TPCAH as an adjuvant and carrier can effectively improve the ability of innate and adaptive immune responses to resist pathogens, making it a potential candidate for vaccine applications.
Asunto(s)
Inmunidad Adaptativa/efectos de los fármacos , Proteínas del Sistema Complemento/inmunología , Nanopartículas/química , Vacunas de Subunidad/farmacología , Inmunidad Adaptativa/inmunología , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteínas del Sistema Complemento/efectos de los fármacos , Cisteamina/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Humanos , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Micelas , Ovalbúmina/química , Ovalbúmina/farmacología , Poliésteres/síntesis química , Poliésteres/química , Poliésteres/farmacología , Polietilenglicoles/síntesis química , Polietilenglicoles/química , Polietilenglicoles/farmacología , Vacunas de Subunidad/química , Vacunas de Subunidad/inmunologíaRESUMEN
In this paper, we demonstrate a strategy of covalently bonding bioactive molecules onto inorganic hydroxyapatite (HAp) to improve the compatibility between organic and inorganic components and endow the bone composites with sustainable bioactivity. Bone morphogenetic protein-2 (BMP-2) peptide covalently immobilized nano-hydroxyapatite (nHAp-BMP-2) is developed to preserve the bioactivity and slow the release of the BMP-2 peptide. Then nHAp-BMP-2 was further incorporated into an ultraviolet-curable mixture of gelatin methacrylamide (GelMA) and four-armed PEG methacrylamide (four-armed PEGMA) to form a Gel/(nHAp-BMP-2) composite. The hydrogen bonding between gelatin and BMP-2 on nHAp-BMP-2 enhanced the compatibility between inorganic and organic components. The Gel/(nHAp-BMP-2) composite exhibited superior biocompatibility caused by gelatin and nHAp-BMP-2, except in a two-dimensional cell culture, the hydrogel was also capable of a three-dimensional cell culture. In addition, the introduction of nHAp-BMP-2 had a positive influence on bone marrow mesenchymal stem cell proliferation, differentiation, and the subsequent calcification on the composite. After treatment of a rat calvarial defect model for 12 weeks, the Gel/(nHAp-BMP-2) group showed the largest new bone volume and the highest ratio of new bone (50.54 ± 13.51 mm3 and 64.38 ± 17.22%, respectively) compared to those of the other groups. These results demonstrate that this way of controlling BMP-2 release is effective and the Gel/(nHAp-BMP-2) composite has great potential in bone regeneration therapy.
Asunto(s)
Regeneración Ósea , Hidrogeles/química , Nanocompuestos/química , Andamios del Tejido/química , Acrilamidas/química , Animales , Proteína Morfogenética Ósea 2/química , Proliferación Celular , Células Cultivadas , Durapatita/química , Gelatina/química , Hidrogeles/efectos adversos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/fisiología , Nanocompuestos/efectos adversos , Polietilenglicoles/química , Conejos , Ratas , Ratas Sprague-Dawley , Andamios del Tejido/efectos adversosRESUMEN
Carboranes with rich boron content have showed significant applications in the field of boron neutron capture therapy. Biodegradable derivatives of carborane-conjugated polymers with well-defined structure and tunable loading of boron atoms are far less explored. Herein, a new family of amphiphilic carborane-conjugated polycarbonates was synthesized by ring-opening polymerization of a carborane-installed cyclic carbonate monomer. Catalyzed by TBD from a poly(ethylene glycol) macroinitiator, the polymerization proceeded to relatively high conversions (>65%), with low polydispersity in a certain range of molecular weight. The boron content was readily tuned by the feed ratio of the monomer and initiator. The resultant amphiphilic polycarbonates self-assembled in water into spherical nanoparticles of different sizes depending on the hydrophilic-to-hydrophobic ratio. It was demonstrated that larger nanoparticles (PN150) were more easily subjected to protein adsorption and captured by the liver, and smaller nanoparticles (PN50) were more likely to enter cancer cells and accumulate at the tumor site. PN50 with thermal neutron irradiation exhibited the highest therapeutic efficacy in vivo. The new synthetic method utilizing amphiphilic biodegradable boron-enriched polymers is useful for developing more-selective and -effective boron delivery systems for BNCT.
Asunto(s)
Boranos/química , Terapia por Captura de Neutrón de Boro/métodos , Carbonatos/química , Interacciones Hidrofóbicas e Hidrofílicas , Cemento de Policarboxilato/química , Cemento de Policarboxilato/uso terapéutico , Animales , Transporte Biológico , Línea Celular Tumoral , Humanos , Ratones , Nanopartículas/química , Tamaño de la Partícula , Cemento de Policarboxilato/metabolismo , Cemento de Policarboxilato/farmacocinética , Distribución TisularRESUMEN
A tumor is a complicated system, and tumor cells are typically heterogeneous in many aspects. Polymeric drug delivery nanocarriers sensitive to a single type of biosignals may not release cargos effectively in all tumor cells, leading to low therapeutic efficacy. To address the challenges, here, we demonstrated a pH/reduction dual-sensitive charge-conversional polymeric prodrug strategy for efficient codelivery. Reduction-sensitive disulfide group and acid-labile anticancer drug (demethylcantharidin, DMC)-conjugated ß-carboxylic amide group were repeatedly and regularly introduced into copolymer chain simultaneously via facile CuAAC click polymerization. The obtained multifunctional polymeric prodrug P(DMC), mPEG-b-poly(disulfide-alt-demethylcantharidin)-b-mPEG was further utilized for DOX encapsulation. Under tumor tissue/cell microenvironments (pH 6.5 and 10 mM GSH), the DOX-loaded polymeric prodrug nanoparticles (P(DMC)@DOX NPs) performed surface negative-to-positive charge conversion and accelerated/sufficient release of DMC and DOX. The remarkably enhanced cellular internalization and cytotoxicity in vitro, especially against DOX-resistant SMMC-7721 cells, were demonstrated. P(DMC)@DOX NPs in vivo also exhibited higher tumor accumulation and improved antitumor efficiency compared to P(SA)@DOX NPs with one drug and without charge-conversion ability. The desired multifunctional polymeric prodrug strategy brings a new opportunity for cancer chemotherapy.
Asunto(s)
Cantaridina/análogos & derivados , Carcinoma Hepatocelular/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Neoplasias Hepáticas/tratamiento farmacológico , Polímeros/química , Profármacos/administración & dosificación , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Cantaridina/administración & dosificación , Cantaridina/farmacología , Doxorrubicina/farmacología , Femenino , Humanos , Concentración de Iones de Hidrógeno , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/química , Profármacos/farmacología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Carborane-conjugated amphiphilic copolymer nanoparticles were designed to deliver anticancer drugs for the combination of chemotherapy and boron neutron capture therapy (BNCT). Poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2(2-dicarba-closo-dodecarborane)propyloxycarbonyl-propyne carbonate) (PLMB) was synthesized via the versatile reaction between decaborane and side alkynyl groups, and self-assembled with doxorubicin (DOX) to form drug-loaded nanoparticles. These DOX@PLMB nanoparticles could not only suppress the leakage of the boron compounds into the bloodstream due to the covalent bonds between carborane and polymer main chains, but also protect DOX from initial burst release at physiological conditions because of the dihydrogen bonds between DOX and carborane. It was demonstrated that DOX@PLMB nanoparticles could selectively deliver boron atoms and DOX to the tumor site simultaneously in vivo. Under the combination of chemotherapy and BNCT, the highest tumor suppression efficiency without reduction of body weight was achieved. This polymeric nanoparticles delivery system could be very useful in future chemoradiotherapy to obtain improved therapeutic effect with reduced systemic toxicity.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Boranos/química , Terapia Combinada/métodos , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos/métodos , Neutrones/uso terapéutico , Neoplasias del Cuello Uterino/terapia , Animales , Antibióticos Antineoplásicos/farmacocinética , Terapia por Captura de Neutrón de Boro/métodos , Doxorrubicina/farmacocinética , Composición de Medicamentos/métodos , Femenino , Enlace de Hidrógeno , Ratones , Nanopartículas/química , Poliésteres/química , Polietilenglicoles/química , Ratas , Ratas Sprague-Dawley , Neoplasias del Cuello Uterino/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Local tumor recurrence remains a major clinical problem following surgical treatment for most cancers such as hepatocellular carcinoma (HCC). An implantable local drug delivery system may be suitable for addressing this unmet clinical need. In this study, asymmetric multilayer polylactide nanofiber (AMPN) mats were prepared and a one-sided and prolonged release profile of hydrophilic dye or oxaliplatin was observed after they were sandwiched between two liver lobes in mice. Covering the surgery site by drug-loaded AMPN mat after tumor resection, in both subcutaneous and orthotopic HCC model in mice, the recurrence of HCC was significantly retarded and the survival time of mice was markedly prolonged. In conclusion, post-surgical therapy at tumor resection margins by drug-loaded AMPN mats may represent a suitable application of nanofiber-based local chemotherapy. FROM THE CLINICAL EDITOR: After cancer surgery, local recurrence remains a significant problem. In this study, the authors designed asymmetric multilayer PLA nanofiber (AMPN) mats and loaded them with anti-tumor drugs. Both in-vitro and in-vivo experiments showed good efficacy in preventing tumor recurrence. This novel product may point a way to the future and improve survival of cancer patients.
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/prevención & control , Preparaciones de Acción Retardada/química , Neoplasias Hepáticas/prevención & control , Nanofibras/química , Recurrencia Local de Neoplasia/prevención & control , Poliésteres/química , Animales , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Sistemas de Liberación de Medicamentos , Hígado/efectos de los fármacos , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Ratones , Nanofibras/ultraestructura , Recurrencia Local de Neoplasia/patologíaRESUMEN
Mesoporous silica nanoparticles (MSN)-polymer hybrid combined with the aliphatic biodegradable polyester caps on the surface were first developed in order to manipulate the smart intracellular release of anticancer drugs. First, poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) was successfully grafted on the surface of MSN via disulfide bonds which could cleave under a reduction environment in tumor cells. The anticancer drug doxorubicin (DOX) was encapsulated into the particle pores. The in vitro drug release profile showed that DOX release was significantly restricted by the polymer caps at pH 7.4, while it was greatly accelerated upon the addition of GSH. Cytotoxicity evaluation showed good biocompatibility with the hybrid particles. Fast endocytosis and intracellular DOX release were observed by confocal laser scanning microscopy (CLSM). The DOX-loaded particles exhibited comparable antitumor activity with free DOX towards HeLa cells and showed in a time-dependent manner. This work developed an extensive method of utilizing aliphatic biodegradable polyesters as polymer caps for MSN to control drug delivery. The paper might offer a potential option for cancer therapy.
Asunto(s)
Nanopartículas/química , Poliésteres/química , Dióxido de Silicio/química , Animales , Antibióticos Antineoplásicos/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/toxicidad , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Células HeLa , Humanos , Lactonas/química , Ratones , Oxidación-Reducción , Poliésteres/síntesis química , Polietilenglicoles/química , PorosidadRESUMEN
As the transport protein for iron, transferrin can trigger cellular endocytosis once binding to its receptor (TfR) on the cell membrane. Using this property, we conjugated transferrin onto the surface of biodegradable polymeric micelles constructed from amphiphilic block copolymers. The core of micelle was either labeled with a near-infrared dye (NIR) or conjugated with a chemotherapeutic drug paclitaxel (PTX) to study the biodistribution or antitumor effect in nude mice bearing subcutaneous TfR-overexpressing cancers. DLS and TEM showed that the sizes of Tf-conjugated and Tf-free micelles were in the range of 85-110 nm. Confocal laser scanning microscopy and flow cytometry experiments indicated that the uptake efficiency of the micelles by the TfR-overexpressing cells was enhanced by Tf conjugation. Semiquantitative analysis of the NIR signals collected from the tumor site showed that the maximum accumulation was achieved at 28 h in the M(NIR) group, while at 22 h in Tf-M(NIR) groups; and the area under the intensity curve in the Tf-M(NIR) groups was more than that in M(NIR) group. Finally, the tumor inhibition effects of targeting micelles were studied with the gastric carcinoma model which overexpressed TfR. The analysis of tumor volumes and the observation of H&E-stained tumor sections showed that Tf-M(PTX) had the best antitumor effect compared with the control groups (saline, PTX, and M(PTX)). The results of this study demonstrated the potential application of Tf-conjugated polymeric micelles in the treatment of TfR-overexpressing cancers.
Asunto(s)
Antineoplásicos Fitogénicos/metabolismo , Antineoplásicos Fitogénicos/farmacología , Receptores de Transferrina/metabolismo , Transferrina/química , Transferrina/metabolismo , Animales , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Micelas , Paclitaxel/química , Paclitaxel/metabolismo , Paclitaxel/farmacología , Polímeros/química , Polímeros/metabolismo , Polímeros/farmacología , Distribución TisularRESUMEN
A biodegradable and amphiphilic copolymer, poly(ethylene glycol)-block-poly(l-lactide-co-2-methyl-2-carboxyl-propylene carbonate) (mPEG-b-P(LA-co-MCC)), which contains pendant carboxyl groups, was chosen as a drug carrier for the active anticancer part (diaminocyclohexane platinum, DACH-Pt) of oxaliplatin to form mPEG-b-P(LA-co-MCC/Pt) complex. A folic acid-conjugated copolymer, folic acid-poly(ethylene glycol)-block-poly(L-lactide) (FA-PEG-PLA), with similar chemical structure was chosen for targeting. Multifunctional micelles were successfully prepared by a coassembling method. In vitro evaluation was performed by using SKOV-3 and MCF-7 cancer cells. In vivo blood clearance of platinum was studied, and the results show that micelles exhibit longer blood circulation after iv injection. Pt biodistribution was studied by measuring its levels in plasma, organs, and tumors, especially in tumor cell DNA, by atomic absorption and inductively coupled plasma mass spectrometry. Antitumor activity was assessed in mice bearing H22 liver cancers, and the results showed that the micelles with FA moieties exhibited greater antitumor efficacy than those without FA or oxaliplatin. Therefore, these novel multifunctional platinum micelles have great potential in future clinical application.
Asunto(s)
Sistemas de Liberación de Medicamentos , Ácido Fólico/química , Micelas , Compuestos Organoplatinos/farmacología , Polímeros/química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Portadores de Fármacos , Femenino , Humanos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/patología , Espectrometría de Masas , Ratones , Compuestos Organoplatinos/farmacocinética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Oxaliplatino , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Thermosensitive hydrogels based on PEG and poly(l-glutamate)s bearing different hydrophobic side groups were separately synthesized by the ring-opening polymerization (ROP) of l-glutamate N-carboxyanhydrides containing different alkyl protected groups, that is, methyl, ethyl, n-propyl, and n-butyl, using mPEG(45)-NH(2) as macroinitiator. The resulting copolymers underwent sol-gel transitions in response to temperature change. Interestingly, the polypeptides containing methyl and ethyl showed significantly lower critical gelation temperatures (CGTs) than those bearing n-propyl and butyl side groups. Based on the analysis of (13)C NMR spectra, DLS, circular dichroism spectra, and ATR-FTIR spectra, the sol-gel transition mechanism was attributed to the dehydration of poly(ethylene glycol) and the increase of ß-sheet conformation content in the polypeptides. The in vivo gelation test indicated that the copolymer solution (6.0 wt %) immediately changed to a gel after subcutaneous injection into rats. The mass loss of the hydrogel in vitro was accelerated in the presence of proteinase K, and the MTT assay revealed that the block copolymers exhibited no detectable cytotoxicity. The present work revealed that subtle variation in the length of a hydrophobic side group displayed the decisive effect on the gelation behavior of the polypeptides. In addition, the thermosensitive hydrogels could be promising materials for biomedical applications due to their good biocompatibility, biodegradability, and the fast in situ gelation behavior.
Asunto(s)
Hidrogeles/síntesis química , Ácido Poliglutámico/análogos & derivados , Ácido Poliglutámico/síntesis química , Polimerizacion , Anhídridos/síntesis química , Anhídridos/química , Anhídridos/toxicidad , Supervivencia Celular/efectos de los fármacos , Células HeLa , Humanos , Hidrogeles/química , Hidrogeles/toxicidad , Interacciones Hidrofóbicas e Hidrofílicas , Micelas , Peso Molecular , Tamaño de la Partícula , Transición de Fase , Polietilenglicoles/síntesis química , Polietilenglicoles/química , Polietilenglicoles/toxicidad , Ácido Poliglutámico/química , Ácido Poliglutámico/toxicidad , Estructura Secundaria de Proteína , Espectroscopía Infrarroja por Transformada de Fourier , TemperaturaRESUMEN
Biodegradable nucleobase-grafted amphiphilic copolymer, the methoxyl poly (ethylene glycol)-b-poly (L-lactide-co-2-methyl-2(3-(2,3-dihydroxylpropylthio) propyloxycarbonyl)-propylene carbonate/1-carboxymethylthymine) (mPEG-b- P(LA-co-MPT)), was synthesized. (1)H NMR titration and FT-IR spectroscopy indicated that the hydrogen-bonding could be formed between mPEG-b-P(LA-co-MPT) and 9-hexadecyladenine (A-C16). The hydrophobic microenvironment of the amphiphilic copolymer can protect the complementary multiple hydrogen bonds between mPEG-b-P(LA-co-MPT) and A-C16 from water effectively. The addition of A-C16 not only lowered the critical aggregation concentration (CAC) of mPEG-b-P(LA-co-MPT)/A-C16 nanoparticles (NPs) in aqueous solution but also induced different morphologies, which can be observed by transmission electron microscopy (TEM). Meanwhile, dynamic light scattering (DLS) and turbidometry was utilized to evaluate the effect of temperature and pH change on the stability of mPEG-b-P(LA-co-MPT)/A-C16 NPs. Cytotoxicity evaluation showed good biocompatibility of the mPEG-b-P(LA-co-MPT)/A-C16 NPs. The in vitro drug release profile showed that with the increase of A-C16 content, the doxorubiucin (DOX) release at pH 7.4 decreased, while the faster release rate was observed with the addition of A-C16 with a pH of 5.0. Importantly, DOX-loaded NPs exerted comparable cytotoxicity against MDA-MB-231 cells. This work provided a new method to stabilize NP structure using hydrogen-bonds and would have the potential to be applied in controlled drug delivery.
Asunto(s)
Adenina/análogos & derivados , Antibióticos Antineoplásicos/química , Materiales Biocompatibles/síntesis química , Preparaciones de Acción Retardada/síntesis química , Doxorrubicina/química , Polietilenglicoles/síntesis química , Tensoactivos/síntesis química , Timina/análogos & derivados , Timina/síntesis química , Antibióticos Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/farmacología , Doxorrubicina/farmacología , Humanos , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Espectroscopía de Resonancia Magnética , Micelas , Microscopía Electrónica de Transmisión , Estructura Molecular , Nanopartículas/química , Nanopartículas/ultraestructura , Polietilenglicoles/farmacología , Soluciones , Espectroscopía Infrarroja por Transformada de Fourier , Tensoactivos/farmacología , Temperatura , Timina/farmacología , AguaRESUMEN
Anti-seizure medicines constitute a common yet important modality to treat epilepsy. However, some of them are associated with serious side effects including hepatotoxicity and hypersensitivity. Furthermore, the blood-brain barrier (BBB) is an insurmountable obstacle for brain drug delivery. Fortunately, the introduction of the nanoparticles for drug delivery is a feasible approach to overcome these obstacles. Encapsulating drugs into nanoparticles and delivering them to specific sites shows great potential for improving the efficiency of drug delivery and reducing systemic toxicity. Several in vivo studies have investigated the effect of nanoparticle size on biodistribution in mice, but very few have investigated its effects on efficient drug delivery while crossing the BBB. Therefore, we designed a methoxy poly(lactide-co-glycolide)-b-poly(ethylene glycol) methyl ether (mPEG-PLGA) nanoparticle delivery system and explored the cell uptake efficiency of nanoparticles with different sizes and their ability to penetrate the BBB while carrying carbamazepine (CBZ). CBZ-loaded nanoparticles could significantly reduce the cytotoxicity of CBZ to L929 cells at high concentrations. Results from the endocytosis experiment involving human cerebral microvessel endothelial cell/D3 showed that the DiR-loaded mPEG5K-PLGA10K nanoparticles possessed the highest cell uptake efficiency. The endocytosis efficiency was 90% at 30 min, which far exceeded that of the other groups. Moreover, similar results were obtained from subsequent experiments where fluorescence images of the isolated organs of the mice were acquired. To summarize, our study demonstrated that drug delivery to the brain using nanocarriers is size dependent. Nanoparticles with the smallest particle size can be internalized more effectively, and easily penetrate the BBB, and accumulate in the brain.
Asunto(s)
Anticonvulsivantes/farmacocinética , Barrera Hematoencefálica/fisiología , Carbamazepina/farmacocinética , Portadores de Fármacos/química , Nanopartículas/química , Animales , Anticonvulsivantes/química , Encéfalo/citología , Carbamazepina/química , Línea Celular , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidad , Endocitosis/fisiología , Femenino , Humanos , Ratones , Microvasos/citología , Nanopartículas/metabolismo , Nanopartículas/toxicidad , Tamaño de la Partícula , Poliésteres/química , Poliésteres/metabolismo , Poliésteres/toxicidad , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Polietilenglicoles/toxicidadRESUMEN
A series of biodegradable polyurethanes containing free side hydroxyl groups (PUOH) were synthesized successfully in two steps: (1) PLA diol as soft segment, hexamethylene diisocyanate (HDI) as hard segment, and benzalpentaerythritol (BPO) as a chain extender were used to synthesize PUs with protected OH groups; (2) CF(3)COOH was used as a deprotection agent to remove the benzal groups on PU to prepare PUOH. The properties of PU and PUOH were characterized by Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), water contact angle measurement, and gel permeation chromatography (GPC). The benzal groups were removed completely in 15 min without detrimental effect on PU main chains to obtain PUOHs. 4-Azidobenzoic acid was conjugated to PUOH through its esterification with the free OH groups on PUOH. The results of immunofluorescence assay showed that the phenyl azide groups formed were capable of binding mouse IgG under UV (254 nm) irradiation in 3 min; the bound mouse IgG retained its own biological activity and could further bind the FITC-labeled anti(mouse IgG). Therefore, this material has a potential in immunofluorescence assay and related fields.
Asunto(s)
Anticuerpos Antiidiotipos/metabolismo , Materiales Biocompatibles/síntesis química , Inmunoensayo/métodos , Inmunoglobulina G/metabolismo , Poliuretanos/síntesis química , Animales , Anticuerpos Antiidiotipos/inmunología , Azidas/química , Materiales Biocompatibles/metabolismo , Biodegradación Ambiental , Rastreo Diferencial de Calorimetría , Cromatografía en Gel , Cianatos/química , Fluoresceína-5-Isotiocianato/análisis , Hidróxidos/química , Inmunoglobulina G/inmunología , Isocianatos , Espectroscopía de Resonancia Magnética , Ratones , Poliuretanos/metabolismo , Glicoles de Propileno/química , Unión Proteica , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Poly(ε-lysine) (ε-PL)-analogous click polypeptides with not only similar α-amino side groups but also similar main chain to ε-PL were chemically synthesized for the first time through click polymerization from aspartic (or glutamic)-acid-based dialkyne and diazide monomers. With microwave-assisting, the reaction time of click polymerization was compressed into 30 min. The polymers were fully characterized by NMR, ATR-FTIR, and SEC-MALLS analysis. The deprotected click polypeptides had similar pK(a) value (7.5) and relatively low cytotoxicity as ε-PL and could be used as substitutes of ε-PL in biomedical applications, especially in endotoxin selective removal. Poly(ethylene glycol) (PEG)-containing alternating copolymers with α-amino groups were also synthesized and characterized. After deprotection, the polymers could be used as functional gene vector with PEG shadowing system and NCA initiator to get amphiphilic graft polymers.
Asunto(s)
Microondas , Polilisina/síntesis química , Polímeros/síntesis química , Aminoácidos , Endotoxinas/aislamiento & purificación , Humanos , Polietilenglicoles , Polilisina/uso terapéutico , Polimerizacion , Polímeros/uso terapéuticoRESUMEN
Immune checkpoint blockade (ICB) therapy in combination with immunogenic death (ICD) triggered by photothermal therapy (PTT) and oxaliplatin (OXA) treatment was expected to elicit both innate and adaptive immune responses for tumor control and metastasis prevention. In this study, a photothermal agent (IR780), a folic acid (FA) linked oxaliplatin (OXA) prodrug, and PD-L1 inhibitors (BMS-1) were integrated into a liposomal system. The FA tumor-targeting and enhanced permeability and retention (EPR) effect of the liposomal system prolonged circulating times and increased accumulation in tumors, resulting in an enhanced photothermal effect and less systemic toxicity. In addition, PTT and OXA had a considerable synergistic effect in the induction of a combined ICD. The PD-1/PD-L1 checkpoint, which is a negative immune regulatory mechanism, could be blocked by the thermosensitive released BMS-1. Finally, ICD was harnessed to synergize with a small molecule PD-L1 inhibitor for activation of the immune system in the treatment of tumor relapse and metastasis.
Asunto(s)
Muerte Celular Inmunogénica , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico , Liposomas , Neoplasias/tratamiento farmacológico , Terapia FototérmicaRESUMEN
Immunotherapy has shown encouraging results in various cancers, but the response rates are relatively low due to the complex tumor immunosuppressive microenvironment (TIME). The presence of tumor-associated macrophages (TAMs) and tumor hypoxia correlates significantly with potent immunosuppressive activity. Here, a hemoglobin-poly(ε-caprolactone) (Hb-PCL) conjugate self-assembled biomimetic nano red blood cell (nano-RBC) system (V(Hb)) is engineered to deliver chemotherapeutic doxorubicin (DOX) and oxygen for reprogramming TIME. The Hb moiety of V(Hb)@DOX can bind to endogenous plasma haptoglobin (Hp) and specifically target the M2-type TAMs via the CD163 surface receptor, and effectively kill the cells. In addition, the O2 released by the Hb alleviates tumor hypoxia, which further augments the antitumor immune response by recruiting fewer M2-type macrophages. TAM-targeting depletion and hypoxia alleviation synergistically reprogram the TIME, which concurrently downregulate PD-L1 expression of tumor cells, decrease the levels of immunosuppressive cytokines such as IL-10 and TGF-ß, elevate the immunostimulatory IFN-γ, enhance cytotoxic T lymphocyte (CTL) response, and boost a strong memory response. The ensuing TAM-targeted chemo-immunotherapeutic effects markedly inhibit tumor metastasis and recurrence. Taken together, the engineered endogenous TAM-targeted biomimetic nano-RBC system is a highly promising tool to reprogram TIME for cancer chemo-immunotherapy.
Asunto(s)
Materiales Biomiméticos/química , Hemoglobinas/química , Nanoestructuras/química , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígeno B7-H1/metabolismo , Materiales Biomiméticos/metabolismo , Línea Celular Tumoral , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Humanos , Inmunoterapia/métodos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/terapia , Oxígeno/metabolismo , Poliésteres/química , Unión Proteica , Receptores de Superficie Celular/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/citologíaRESUMEN
Correction for 'Combining PD-L1 inhibitors with immunogenic cell death triggered by chemo-photothermal therapy via a thermosensitive liposome system to stimulate tumor-specific immunological response' by Jie Yu et al., Nanoscale, 2021, DOI: .
Asunto(s)
Liposomas , Neoplasias , Doxorrubicina , Humanos , Inhibidores de Puntos de Control Inmunológico , Muerte Celular Inmunogénica , Neoplasias/tratamiento farmacológico , Terapia FototérmicaRESUMEN
BACKGROUND: The application of polyethylenimine (PEI) in gene delivery has been severely limited by significant cytotoxicity that results from a nondegradable methylene backbone and high cationic charge density. It is therefore necessary to develop novel biodegradable PEI derivates for low-toxic, highly efficient gene delivery. METHODS: A series of novel cationic copolymers with various charge density were designed and synthesized by grafting different kinds of oligoethylenimine (OEI) onto a determinate multi-armed poly(L-glutamic acid) backbone. The molecular structures of multi-armed poly(L-glutamic acid)-graft-OEI (MP-g-OEI) copolymers were characterized using nuclear magnetic resonance, viscosimetry and gel permeation chromatography. Moreover, the MP-g-OEI/DNA complexes were measured by a gel retardation assay, dynamic light scattering and atomic force microscopy to determine DNA binding ability, particle size, zeta potential, complex formation and shape, respectively. MP-g-OEI copolymers were also evaluated in Chinese hamster ovary and human embryonic kidney-293 cells for their cytotoxicity and transfection efficiency. RESULTS: The particle sizes of MP-g-OEI/DNA complexes were in a range of 109.6-182.6 nm and the zeta potentials were in a range of 29.2-44.5 mV above the N/P ratio of 5. All the MP-g-OEI copolymers exhibited lower cytotoxicity and higher gene transfection efficiency than PEI25k in the absence and presence of serum with different cell lines. Importantly, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that the cytotoxicity of MP-g-OEI copolymers varied with their molecular weight and charge density, and two of MP-g-OEI copolymers (OEI600-MP and OEI1800-MP) could achieve optimal transfection efficiency at a similar low N/P ratio as that for PEI25k. CONCLUSIONS: MP-g-OEI copolymers demonstrated considerable potential as nonviral vectors for gene therapy.
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Técnicas de Transferencia de Gen , Vectores Genéticos/genética , Polietileneimina/química , Ácido Poliglutámico/química , Animales , Células CHO , Muerte Celular , Supervivencia Celular , Cricetinae , Cricetulus , Ensayo de Cambio de Movilidad Electroforética , Fluoresceína-5-Isotiocianato , Humanos , Espacio Intracelular/metabolismo , Espectroscopía de Resonancia Magnética , Microscopía de Fuerza Atómica , Tamaño de la Partícula , Espectroscopía Infrarroja por Transformada de Fourier , Transfección , Virus/genética , ViscosidadRESUMEN
Multifunctional poly(glycidyl methacrylate) (PGMA) microspheres containing magnetic, fluorescent, and cancer cell-specific moieties were prepared in four steps: (i) preparation of parent PGMA microspheres by dispersion polymerization and their reaction with ethylenediamine to obtain amino groups, (ii) precipitation of iron ions (Fe(2+) and Fe(3+)) to form Fe(3)O(4) nanoparticles within the microspheres, (iii) consecutive reactions of folic acid with the amino groups on PGMA, and (iv) incorporation of fluorescein isothiocyanate into the microspheres. The microspheres were superparamagnetic, highly monodispersive, intensively fluorescent, and capable of recognizing and binding cancer cells that overexpress folic acid receptors. It was demonstrated that with these microspheres, HeLa cells could be captured from their suspension and easily moved in the direction of the externally applied magnetic field.