RESUMEN
Melatonin has been proposed as a potent anticarcinogen presents a short half-life for osteosarcoma (OS). Cell-in-cell (CIC) structures play a role in the development of malignant tumors by changing the tumor cell energy metabolism. This study developed a melatonin-loaded 3D printed magnesium-polycaprolactone (Mg-PCL) scaffold and investigated its effect and molecular mechanism on CIC in OS. Mg-PCL scaffold was prepared by 3D-printing and its characteristic was determined. The effect and molecular mechanism of Mg-PCL scaffold as well as melatonin-loaded Mg-PCL on OS growth and progression were investigated in vivo and in vitro. We found that melatonin receptor 1 (MT1) and CIC expressions were increased in OS tissues and cells. Melatonin treatment inhibit the key CIC pathway, Rho/ROCK, through the cAMP/PKA signaling pathway, interfering with the mitochondrial physiology of OS cells, and thus playing an anti-invasion and anti-metastasis role in OS. The Mg-PCL-MT could significantly inhibit distant organ metastasis of OS in the in vivo model. Our results showed that melatonin-loaded Mg-PCL scaffolds inhibited the proliferation, invasion and metastasis of OS cells through the CIC pathway. The Mg-PCL-MT could be a potential therapeutics for OS.
Asunto(s)
Magnesio/farmacología , Melatonina/farmacología , Osteosarcoma/tratamiento farmacológico , Poliésteres/farmacología , Impresión Tridimensional , Adulto , Animales , Femenino , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , ConejosRESUMEN
The development of polymer-based drug delivery systems provides efficient modalities for cancer therapy. Most of the polymer pharmaceuticals target cancer cells directly, but the insufficient penetration always results in unsatisfactory anticancer efficacy. To break the above bottleneck, strategies of penetration-independent cancer therapy have been developed as advanced treatments for various cancers in the past decade. In this Perspective, we discussed the pros and cons of polymer-mediated biological and physical penetration-independent approaches for cancer therapy and highlighted their further prospects from bench to bedsides.
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Antineoplásicos , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Polímeros , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Polímeros/química , Polímeros/uso terapéuticoRESUMEN
In this study, we report thermosensitive hydrogels based on poly(ethylene glycol)-block-poly(γ-propargyl-l-glutamate) (PEG-PPLG). (13)C NMR spectra, DLS, and circular dichroism spectra were employed to study the mechanism of the sol-gel phase transition. Mouse fibroblast L929 cells were encapsulated and cultured within the hydrogel matrices, and the encapsulated cells were shown to be highly viable in the gel matrices, suggesting that the hydrogels have excellent cytocompatibilities. The mass loss of the hydrogels in vitro was accelerated by the presence of proteinase K compared to the control group. In vivo biocompatibility studies revealed that the in situ formed gels in the subcutaneous layer last for â¼21 days, and H&E staining study suggested acceptable biocompatibility of our materials in vivo. The presence of alkynyl side groups in the PEG-PPLG copolymers allowed convenient further functionalization with azide-modified bioactive molecules, such as biotin and galactose. The biofunctionalized PEG-polypeptide block copolymers showed sol-gel phase transitions similar to the parent copolymers. Interestingly, the incorporation of galactose groups into the hydrogels was found to improve cell adhesion, likely due to the adsorption of fibronectin (FN) in cell-extracellular matrix (ECM). Because bioactive materials have shown unique advantages in biomedical applications, especially tissue engineering and regenerative medicine applications, we believe our novel functionalizable thermosensitive hydrogels have potential to serve as a versatile platform for the development of new biofunctional materials, for example, bioadhesive and bioresponsive hydrogels.
Asunto(s)
Materiales Biocompatibles/química , Química Clic , Hidrogeles/química , Polietilenglicoles/química , Ácido Poliglutámico/análogos & derivados , Animales , Adhesión Celular , Línea Celular , Matriz Extracelular/metabolismo , Fibronectinas/química , Hidrogeles/metabolismo , Ratones , Péptidos , Transición de Fase , Ácido Poliglutámico/química , Polímeros/química , Ingeniería de TejidosRESUMEN
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
Tumor blockade therapy is a promising penetration-independent antitumor modality, which effectively inhibits the exchange of nutrients, oxygen, and information between the tumor and surrounding microenvironments. However, the current blockade therapy strategies have limited antitumor efficacy due to defects of inadequate tumor obstruction, possible side effects, and short duration. For these reasons, a facilely synthesized versatile polymer 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)-alendronate (DSPE-PEG-ALN, DPA) is developed to initiate the formation of biomineral shell around osteosarcoma as a potent physical barrier. The DSPE moiety shares a similar chemical structure with the cytomembrane, allowing the membrane insertion of DPA. The bisphosphonic acid groups in ALN attract ions to realize biomineralization around cells. After injection in the invasive osteosarcoma tissue, DPA inserts into the cytomembrane, induces continuous mineral deposition, and ultimately builds a physical barrier around the tumor. Meanwhile, ALN in DPA alleviates bone destruction by suppressing the activity of osteoclasts. Through hindering the exchange of necessary substances, the biomineralization coating inhibits the growth of primary osteosarcoma and pulmonary metastasis simultaneously. Therefore, the multifunctional polymer-initiating blockade therapy provides a promising modality for tumor inhibition in clinics with high efficacy and negligible side effects.
Asunto(s)
Neoplasias Óseas , Osteosarcoma , Biomineralización , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Humanos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Polietilenglicoles/química , Polímeros/química , Microambiente TumoralRESUMEN
Novel amphiphilic alternating polyesters, poly((N-phthaloyl-l-glutamic anhydride)-co-(2-(2-(2-methoxyethoxy)ethoxy)methyl)oxirane) (P(PGA-co-ME(2)MO)), were synthesized by alternating copolymerization of PGA and ME(2)MO. The structures of the synthesized polyesters were characterized by (1)H NMR, (13)C NMR, FT-IR, and GPC analyses. Because of the presence of oligo(ethylene glycol) (OEG) side chains, the polyesters could self-assemble into thermosensitive micelles. Dynamic light scattering (DLS) showed that these micelles underwent thermoinduced size decrease without intermicellar aggregation. In vitro methyl thiazolyl tetrazolium (MTT) assay demonstrated that the polyesters were biocompatible to Henrietta Lacks (HeLa) cells, rendering their potential for drug delivery applications. Two hydrophobic drugs, rifampin and doxorubicin (DOX), were loaded into the polyester micelles and observed to be released in a zero-order sustained manner. The sustained release could be accelerated in lower pH or in the presence of proteinase K, due to the degradation of the polyester under these conditions. Remarkably, in vitro cell experiments showed that the polyester micelles accomplished fast release of DOX inside cells and higher anticancer efficacy as compared with the free DOX. With enhanced stability during circulation condition and accelerated drug release at the target sites (e.g., low pH or enzyme presence), these novel polyesters with amphiphilic structures are promising to be used in sustained release drug delivery systems.
Asunto(s)
Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Poliésteres/química , Polietilenglicoles/química , Rifampin/farmacología , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Micelas , Estructura Molecular , Tamaño de la Partícula , Poliésteres/síntesis química , Polietilenglicoles/síntesis química , Rifampin/química , Relación Estructura-Actividad , Propiedades de SuperficieRESUMEN
Tissue engineering is a promising strategy for the repair of large-scale bone defects, in which scaffolds and growth factors are two critical issues influencing the efficacy of bone regeneration. Unfortunately, the broad application of growth factors is limited by their poor stability in the scaffolds. In the present study, the strictly controlled expression of human bone morphogenetic protein-4 (hBMP-4) in the presence of doxycycline is achieved by adding an hBMP-4 gene fragment into a non-viral artificial restructuring plasmid vector (pSTAR) to form the pSTAR-hBMP-4 plasmid (phBMP-4). Furthermore, the controlled release of phBMP-4 is obtained with an electroactive tissue engineering scaffold, generated by combining a triblock copolymer of poly(l-lactic acid)-block-aniline pentamer-block-poly(l-lactic acid) (PLA-AP) with poly(lactic-co-glycolic acid)/hydroxyapatite (PLGA/HA). This PLGA/HA/PLA-AP/phBMP-4 composite scaffold, with controlled gene release and Dox-regulated gene expression upon electrical stimulation, operating synergistically, exhibits an improved cell proliferation ability, enhanced osteogenesis differentiation in vitro, and effective bone healing in vivo in a rabbit radial defect model. Taking these results together, the proposed smart PLGA/HA/PLA-AP/phBMP-4 scaffold lays a solid theoretical and experimental basis for future applications of such multi-functional materials in bone tissue engineering to help patients in need.
Asunto(s)
Regeneración Ósea , Estimulación Eléctrica , Osteogénesis , Andamios del Tejido , Animales , Durapatita , Humanos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Conejos , Ingeniería de TejidosRESUMEN
The in vivo implanted biomaterials are known to induce inflammatory response and recruit immune cells, which could be used as robust adjuvants for immunotherapy. However, the degree of inflammatory response induced by the implanted biomaterials is hard to control. In this work, we reported the application of three kinds of thermogels from the polypeptide methoxy poly(ethylene glycol)-polyalanine (mPEG-PAla) with various chiralities to regulate the levels of inflammatory responses in vivo. The mPEG-PLAla (EG45LA28) and mPEG-PDAal (EG45DA27) thermogels exhibited comparable storage modulus ( G') and loss modulus ( Gâ³), both of which were about two times higher than the values of the racemic mPEG-PAla (EG45RA) thermogel. The component d-alanine in the polypeptide thermogels led to controlled tissue inflammation after subcutaneous injection, and the content of d-alanine could adjust the level of inflammation. The expression of tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in subcutaneous tissue around the injected thermogel EG45DA27 were 3.62, 1.52, and 4.55 times the levels of those after EG45RA thermogel injection and 4.52, 7.38, and 7.96 times the levels of those after EG45LA28 injection, respectively. The results indicated that the chiral polypeptide thermogels could induce a controllable inflammatory response in vivo and exhibit great potential as an efficient adjuvant for immunotherapy.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Geles/química , Péptidos/farmacología , Piel/efectos de los fármacos , Animales , Materiales Biocompatibles/química , Inyecciones Subcutáneas , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ratones , Péptidos/química , Polietilenglicoles/química , Piel/metabolismo , Estereoisomerismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Kidney-sparing surgery is the preferred treatment strategy for low-risk upper tract urothelial carcinoma (UTUC). However, after this procedure, prevention of the carcinoma recurrence in the ureter and supporting the ureter with a ureteral stent are necessary. Biodegradable drug-loaded ureteral scaffolds are able to maintain their long-term effective drug concentrations in the lesion sites without the defects of traditional ureteral stents, which may address both issues simultaneously. The purpose of this study was to reveal the possibility of the controlled delivery of epirubicin (EPI) via gradiently degraded electrospun poly(ε-caprolactone) (PCL)/poly(lactide-co-glycolide) (PLGA) scaffolds to evaluate their antitumor activity against UTUC. The degradable PCL/PLGA scaffolds containing 15.0 and 25.0 wt% PCL and loading of 0, 5.0, and 10.0 wt% EPI were successfully fabricated via electrospinning. In addition, the PCL/PLGA scaffolds showed sustained and controlled degradation and drug release kinetics, that is, their degradation and drug release rates slowed with an increase in the ratio of PCL. The EPI-loaded PCL/PLGA scaffolds showed excellent antitumor activities both in vitro and in vivo without apparent systemic toxicity. Overall, the gradiently-degraded EPI-loaded electrospun polyester scaffolds are potential ureteral stent tubes for the local inhibition of the recurrence of UTUC, where the continued release of EPI can prevent the subsequent proliferation of residual tumor cells, and the gradient degradation is consistent with the repair of the ureter.
Asunto(s)
Poliésteres/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/química , Liberación de Fármacos , Epirrubicina/química , Epirrubicina/metabolismo , Epirrubicina/farmacología , Epirrubicina/uso terapéutico , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Trasplante Heterólogo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
To obtain one biodegradable and electroactive polymer as the scaffold for tissue engineering, the multiblock copolymer PLAAP was designed and synthesized with the condensation polymerization of hydroxyl-capped poly( l-lactide) (PLA) and carboxyl-capped aniline pentamer (AP). The PLAAP copolymer exhibited excellent electroactivity, solubility, and biodegradability. At the same time, as one scaffold material, PLAAP copolymer possesses certain mechanical properties with the tensile strength of 3 MPa, tensile Young 's modulus of 32 MPa, and breaking elongation rate of 95%. We systematically studied the compatibility of PLAAP copolymer in vitro and proved that the electroactive PLAAP copolymer was innocuous, biocompatible, and helpful for the adhesion and proliferation of rat C6 cells. Moreover, the PLAAP copolymer stimulated by electrical signals was demonstrated as accelerating the differentiation of rat neuronal pheochromocytoma PC-12 cells. This biodegradable and electroactive PLAAP copolymer thus possessed the properties in favor of the long-time application in vivo as nerve repair scaffold materials in tissue engineering.
Asunto(s)
Compuestos de Anilina/química , Materiales Biocompatibles/química , Poliésteres/química , Ingeniería de Tejidos , Andamios del Tejido/química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Animales , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/farmacología , Biodegradación Ambiental , Dimetilsulfóxido/química , Estimulación Eléctrica , Calor , Ensayo de Materiales , Neuronas/efectos de los fármacos , Neuronas/fisiología , Células PC12 , Poliésteres/síntesis química , Poliésteres/farmacología , Ratas , SolubilidadRESUMEN
A new kind of electroactive polymers was synthesized by using aniline pentamer (AP) cross-linking chitosan (CS) in acetic acid/DMSO/DMF solution. UV-vis and CV confirmed the electroactivity of polymers in acidic aqueous solution. The amphiphilic polymers self-assembled into 200-300 nm micelles by dialysis against deionized water from the acetic acid buffer solution. Three samples with different weight percentages of AP were used to identify the relationship between the content of AP and the differentiation of rat neuronal pheochromocytoma PC-12 cells without external stimulation. From the results, samples with AP showed an obvious improvement in inducing PC-12 differentiation, while PC-12 on pure CS films had only little neurites on the fifth day; the cells on the films prepared from the samples with 4.9% and 9.5% AP even formed intricate networks. However, the influence of the AP content was the most significant at 4.9 wt % and it decreased when the content increased further.
Asunto(s)
Materiales Biocompatibles/química , Quitosano/química , Reactivos de Enlaces Cruzados/farmacología , Electroquímica/métodos , Ácido Acético/química , Animales , Adhesión Celular , Diferenciación Celular , Proliferación Celular , Micelas , Neuritas/metabolismo , Células PC12 , Polímeros/química , Ratas , Rayos UltravioletaRESUMEN
Novel bioactive glass (BG) nanoparticles/poly(L-lactide) (PLLA) composites were prepared as promising bone-repairing materials. The BG nanoparticles (Si:P:Ca=29:13:58 weight ratio) of about 40nm diameter were prepared via the sol-gel method. In order to improve the phase compatibility between the polymer and the inorganic phase, PLLA (M(n)=9700Da) was linked to the surface of the BG particles by diisocyanate. The grafting ratio of PLLA was in the vicinity of 20 wt.%. The grafting modification could improve the tensile strength, tensile modulus and impact energy of the composites by increasing the phase compatibility. When the filler loading reached around 4 wt.%, the tensile strength of the composite increased from 56.7 to 69.2MPa for the pure PLLA, and the impact strength energy increased from 15.8 to 18.0 kJ m(-2). The morphology of the tensile fracture surface of the composite showed surface-grafted bioactive glass particles (g-BG) to be dispersed homogeneously in the PLLA matrix. An in vitro bioactivity test showed that, compared to pure PLLA scaffold, the BG/PLLA nanocomposite demonstrated a greater capability to induce the formation of an apatite layer on the scaffold surface. The results of marrow stromal cell culture revealed that the composites containing either BG or g-BG particles have much better biocompatibility compared to pure PLLA material.
Asunto(s)
Vidrio/química , Ácido Láctico/química , Ácido Láctico/metabolismo , Nanopartículas/química , Polímeros/química , Polímeros/metabolismo , Animales , Materiales Biocompatibles/metabolismo , Células de la Médula Ósea/citología , Adhesión Celular , Proliferación Celular , Células Cultivadas , Cristalografía , Espectroscopía de Resonancia Magnética , Nanopartículas/ultraestructura , Poliésteres , Conejos , Silicio , Propiedades de Superficie , Resistencia a la TracciónRESUMEN
A kind of core cross-linked poly(ethylene glycol)-graft-Dextran nanoparticles (CPD NPs) was prepared by a simple chemical cross-linking method for reduction and pH dual response drug delivery. The resultant CPD NPs are of homogeneous spherical structure with sizes from 69±11 to 107±18nm. Doxorubicin (DOX) was then loaded into the CPD NPs in high efficiency, and showing typical reduction and pH dual responsive release profiles. The flow cytometric analysis and confocal laser scanning microscopy (CLSM) confirmed that the DOX-loaded CPD NPs could be internalized into cancer cell efficiently and release DOX in intracellular environment. Furthermore, cell cytotoxicity assays indicated that the CPD NPs had good biocompatibility toward both cancerous and normal cells, while the Dox-loaded CPD NPs exhibited significant inhibition of cell proliferation in various cancer cells. Therefore, this biocompatible CPD NP may have great potential for intracellular drug delivery in clinical cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Reactivos de Enlaces Cruzados/química , Dextranos/química , Doxorrubicina/administración & dosificación , Nanopartículas/química , Polietilenglicoles/química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Propiedades de SuperficieRESUMEN
UNLABELLED: The linear, Y-shaped, and linear-dendritic block copolymers of methoxy poly(ethylene glycol)-block-polyamidoamine-block-poly(l-glutamic acid) (MPEG-b-PAMAM-b-PGA) with one, two, four, and eight PGA arms but similar MPEG/PGA weight ratios (W/W) (named as P1PA, P2PA, P4PA and P8PA, respectively) were synthesized and comparatively investigated for doxorubicin hydrochloride (DOX) delivery. All the obtained block copolymers were highly biocompatible and could efficiently load DOX into nanoparticles (NPs) through electrostatic interaction. The NPs formed by linear (P1PA) or Y-shaped (P2PA) block copolymers and DOX were spherically shaped with smaller sizes, while the NPs formed from linear-dendritic block copolymers (P4PA and P8PA) were irregular in shape and larger in size. The P1PA/DOX and P2PA/DOX NPs exhibited better DOX protection and slower DOX release profile. However, cell cytotoxicity assays indicated that all the DOX-loaded NPs exhibited similar cytotoxicities with free DOX, indicating effective DOX release after cellular uptake. The NPs from linear and Y-shaped block copolymers greatly extended the blood circulation time, and displayed more accumulation in tumor site and less accumulation in the liver and kidney compared with the linear-dendritic counterparts. In addition, the P1PA/DOX and P2PA/DOX NPs also exhibited higher anti-tumor efficacy and less toxicity than the other DOX formulations. All these results indicated that the linear and Y-shaped MPEG-b-PAMAM-b-PGA block copolymers displayed better DOX delivery ability in anti-tumor treatment than the linear-dendritic copolymers. STATEMENT OF SIGNIFICANCE: Polymeric NPs derived from block copolymers have emerged as effective vehicles for drug delivery. However, the majority of the researches in this field have involved simple linear block copolymers and there are very few comparative studies on the self-assembly, in vitro, and in vivo drug delivery by the block copolymers with similar composition but different architectures. In this study, a series of linear, Y-shaped, and linear-dendritic polypeptide-based block copolymers were prepared and thoroughly investigated for DOX delivery. These block polymers loaded DOX into NPs with different sizes and morphologies, and exhibited different anti-tumor capabilities both in vitro and in vivo. The results indicated that the architecture of the block copolymers played an important role in their drug delivery behaviors.
Asunto(s)
Doxorrubicina , Sistemas de Liberación de Medicamentos/métodos , Polietilenglicoles , Ácido Poliglutámico , Animales , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células HeLa , Humanos , Células MCF-7 , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Ácido Poliglutámico/química , Ácido Poliglutámico/farmacocinética , Ácido Poliglutámico/farmacología , Ratas WistarRESUMEN
Polymeric prodrugs formed by the conjugation of drugs onto polymers have shown great promise in cancer therapy because of the enhancement of water solubility, elimination of premature drug release, and the improvement of pharmacokinetics. To integrate the two advantages of upregulated stability during circulation and selective release of drug in cancer cells, a pH and reduction dual-sensitive prodrug nanogel (CLP) was synthesized via a simple one step "click chemistry". CLP was spherically shaped with a uniform diameter of 60.6 ± 13.7 nm and exhibited great stability in size against large volume dilution, high salt concentration, and long-time incubation in phosphate-buffered saline. Owing to the presence of hydrazone-bonded doxorubicin (DOX) and disulfide cross-linker, CLP released minimal amount (7.8%) of drug under normal physiological pH (i.e., 7.4) condition. But it released 85.5% of the loaded DOX at endosomal pH (i.e., 5.5) plus the presence of 5.0 mM GSH in 120 h. CLP could be effectively internalized by tumor cells and subsequently release DOX in the intracellular environment, resulting in effective proliferation inhibition of HeLa and MCF-7 cells. Furthermore, compared with free DOX and non-cross-linked prodrug micelle (NCLP), CLP accumulated more in tumor site but less in the normal organs, so that CLP performed the enhanced antitumor efficiency and reduced side-toxicities toward the MCF-7 human breast cancer xenograft nude mouse model. With convenient fabrication, favorable stability, controlled release properties, optimized biodistribution, and enhanced suppression of tumor growth, CLP held great potential for optimal antitumor therapy.
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Polietilenglicoles , Polietileneimina , Animales , Antibióticos Antineoplásicos , Química Clic , Doxorrubicina , Humanos , Concentración de Iones de Hidrógeno , Nanogeles , Profármacos , Distribución TisularRESUMEN
Recently, polymeric nanocarriers with shielding surfaces, e.g., poly(ethylene glycol) and small molecules, have been widely applied in antitumor drug delivery mainly because of their stealth during blood circulation. However, the shielding shell greatly hinders the tumor penetration, drug release, and cell internalization of the nanocarriers, which leads to unsatisfactory therapeutic efficacy. To integrate the extended blood circulation time and the enhanced drug transmission in one platform, some extracellularly stimuli-mediated shell-sheddable polymeric nanocarriers have been exploited. The systems are stealthy and stable during blood circulation, and as soon as they reach tumor tissue, the shielding matrices are removed, which is triggered by extracellular endogenous stimuli (e.g., pH or enzymes) or exogenous excitations (e.g., light or voltage). This review mainly focuses on recent advances in the designs and emerging antitumor applications of extracellularly reengineered polymeric nanocarriers for directional drug delivery, as well as perspectives for future developments.
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Antineoplásicos/química , Portadores de Fármacos/química , Nanopartículas/química , Polietilenglicoles/química , Polímeros/química , Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Luz , NanotecnologíaRESUMEN
In the pursuit of new strategies for the design and synthesis of high performance, physically associated hydrogels, dynamic materials formed through electrostatic interactions can serve as a powerful model. Here, we introduce a convenient strategy to obtain biodegradable hydrogels from ABA triblock ionic polypeptides formed by mixing poly(L-glutamic acid)-block-poly(ethylene glycol)-block-poly(L-glutamic acid) (PGA-PEG-PGA) with poly(L-lysine)-block-poly(ethylene glycol)-block-poly(L-lysine) (PLL-PEG-PLL). The hydrogels showed tunable physical properties, high strength and reversible response. The reactive function groups in the ionic blocks can conjugate with oppositely charged drugs or proteins and allow for further modification. These ionic ABA triblock polyelectrolytes can also encapsulate intact cells without significantly compromising cell viability, suggesting that the hydrogels have excellent cytocompatibility. In vivo evaluation performed in rats with subcutaneous injection indicated that the gels were formed and degraded, and hematoxylin and eosin staining suggested good biocompatibility in vivo. In addition, these advantages, combined with the synthetic accessibility of the copolymer, make this cross-linking system a flexible and powerful new tool for the development of injectable hydrogels for biomedical applications.
Asunto(s)
Hidrogeles , Ensayo de Materiales , Polietilenglicoles , Ácido Poliglutámico , Polilisina , Animales , Línea Celular , Hidrogeles/síntesis química , Hidrogeles/química , Hidrogeles/farmacología , Ratones , Polietilenglicoles/química , Polietilenglicoles/farmacología , Ácido Poliglutámico/química , Ácido Poliglutámico/farmacología , Polilisina/química , Polilisina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The reversible PEGylation endows antitumor drugs with various fascinating advantages, including prolonged circulation time in blood, enhanced accumulation in tumor tissue, increased cellular uptake, and promoted intracellular drug release, to improve the therapeutic efficacy and security. Here, the obtained succinic anhydride (SA)-functionalized DOX (SAD) (i.e., insensitive succinic anhydride-functionalized doxorubicin (DOX)) and aconitic anhydride (CA)-modified DOX (CAD) (i.e., acid-sensitive cis-aconitic anhydride-modified DOX) are conjugated to the terminal of poly(ethylene glycol) (PEG) yielding the unresponsive SAD-PEG-SAD and pH-responsive CAD-PEG-CAD prodrugs, respectively. The prepared prodrugs can self-assemble into micelles in aqueous solution. Both micelles are sufficiently stable at normal physiological pH (i.e., 7.4), while CAD-PEG-CAD micelle gradually swells and finally disassembles at intratumoral (i.e., 6.8) and especially endosomal pHs (i.e., 5.5). DOX release from CAD-PEG-CAD at pH 7.4 is efficiently inhibited, whereas it is significantly accelerated by the rapid cleavage of amide bond at pH 5.5. In addition, CAD-PEG-CAD exhibits more efficient cellular uptake and potent cytotoxicity in vitro, as well as improved tissue distribution and superior tumor suppression in vivo than free DOX and SAD-PEG-SAD. More importantly, the PEGylated DOX exhibits favorable security in vivo. In brief, the smart CAD-PEG-CAD with enhanced antitumor efficacy and decreased side effects shows as a promising powerful platform for the clinical chemotherapy of malignancy.
Asunto(s)
Antineoplásicos/farmacología , Concentración de Iones de Hidrógeno , Polietilenglicoles/química , Antineoplásicos/química , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacología , HumanosRESUMEN
In the past few decades, the in situ sustained drug delivery platforms present fascinating potential in sentinel chemotherapy of various solid tumors. In this work, doxorubicin (DOX), a model antitumor drug, was loaded into the thermogel of poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide). The moderate mechanical property of DOX-loaded hydrogel was confirmed by rheological test. In vitro degradation revealed the good biodegradability of thermogel. The DOX-loaded hydrogel exhibited the sustained release profiles up to 30days without and even with elastase. The improved in vivo tumor inhibition and reduced side-effects were observed in the DOX-incorporated hydrogel group compared with those in free DOX group. The excellent in vivo results were further confirmed by the histopathological evaluation or terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. The thermogel with great prospect may be used as an ideal controlled drug delivery platform for the designated and long-term antitumor chemotherapy.
Asunto(s)
Antineoplásicos/química , Preparaciones de Acción Retardada/química , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Animales , Antineoplásicos/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Hidrogel de Polietilenoglicol-Dimetacrilato/administración & dosificación , Masculino , Ratones , Elastasa Pancreática/metabolismo , Poliésteres/química , Polietilenglicoles/químicaRESUMEN
The reduction-responsive polymeric nanocarriers have attracted considerable interest because of a significantly higher concentration of intracellular glutathione in comparison with that outside cells. The smart nanovehicles can selectively transport the antitumor drugs into cells to improve efficacies and decrease side effects. In this work, a facilely prepared glutathione-degradable nanogel was employed for targeting intracellular delivery of an antitumor drug (ie, doxorubicin [DOX]). DOX was loaded into nanogel through a sequential dispersion and dialysis approach with a drug loading efficiency of 56.8 wt%, and the laden nanogel (noted as NG/DOX) showed an appropriate hydrodynamic radius of 56.1±3.5 nm. NG/DOX exhibited enhanced or improved maximum tolerated dose on healthy Kunming mice and enhanced intratumoral accumulation and dose-dependent antitumor efficacy toward H22 hepatoma-xenografted mouse model compared with free drug. In addition, the upregulated antitumor efficacy of NG/DOX was further confirmed by the histopathological and immunohistochemical analyses. Furthermore, the excellent in vivo security of NG/DOX was confirmed by the detection of body weight, histopathology, and biochemical indices of corresponding organs and serum. With controllable large-scale preparation and fascinating in vitro and in vivo properties, the reduction-responsive nanogel exhibited a good prospect for clinical chemotherapy.