RESUMO
Glioblastoma multiforme (GBM) is a grade IV malignant brain tumor with a median survival time of approximately 12-16 months. Because of its highly aggressive and heterogeneous nature it is very difficult to remove by surgical resection. Herein we have reported dual stimuli-responsive and biodegradable in situ hydrogels of oligosulfamethazine-grafted gelatin and loaded with anticancer drug paclitaxel (PTX) for preventing the progress of Glioblastoma. The oligosulfamethazine (OSM) introduced to the gelatin backbone for the formation of definite and stable in situ hydrogel. The hydrogels transformed from a sol to a gel state upon changes in stimuli. pH and temperature and retained a distinct shape after subcutaneous administration in BALB/c mice. The viscosity of the sol state hydrogels was tuned by varying the feed molar ratio between gelatin and OSM. The porosity of the hydrogels was confirmed to be lower in higher degree OSM by SEM. Sustained release of PTX from hydrogels in physiological environments (pH 7.4) was further retarded up to 63% in 9th days in tumor environments (pH 6.5). While the empty hydrogels were non-toxic in cultured cells, the hydrogels loaded with PTX showed antitumor efficacy in orthotopic-GBM xenograft mice. Collectively, the gelatin-OSM formed porous hydrogels and released the cargo in a sustained manner in tumor environments efficiently suppressing the progress of GBM. Thus, gelatin-OSM hydrogels are a potential candidate for the direct delivery of therapeutics to the local areas in brain diseases.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos , Gelatina/química , Glioblastoma/tratamento farmacológico , Paclitaxel/farmacologia , Polímeros Responsivos a Estímulos/química , Sulfametazina/química , Temperatura , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Preparações de Ação Retardada , Composição de Medicamentos , Liberação Controlada de Fármacos , Glioblastoma/patologia , Humanos , Hidrogéis , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia , Paclitaxel/química , Porosidade , Fatores de Tempo , Viscosidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The sensitive detection and quantitative separation of toxic heavy metal ions in aqueous media are of great importance. In this study, a thermogelling poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) triblock copolymer (P1) was synthesized, and difluoroboron dipyrromethene (BODIPY) fluorophore integrated with thiosemicarbazide units was attached to the chain ends of P1 through consecutive post-polymerization modifications, leading to P4. P4 exhibited rapid and selective detection of Hg(II) in 100% aqueous media via turn-on fluorescence emission with a limit of detection (LOD) of as low as 0.461 µM. This turn-on emission behavior is attributed to the suppression of CËN isomerization caused by the formation of a coordination complex between P4 and Hg(II) ions. The selective and quantitative removal of Hg(II) among various metal ions was achieved by trapping chelated Hg(II) ions inside the dehydrated P4 gel via thermo-controlled sol-gel-dehydrated gel transitions. Treating the Hg(II) ion-trapped dehydrated gels with sodium sulfide (Na2S) in acetone/water at room temperature led to HgS precipitates, and P4 in solution was dried and recycled. This recyclable thermoresponsive macromolecular probe is promising for not only Hg(II) detection but also its separation and removal from complex aqueous environments.
RESUMO
Lymphoid organs, which are populated by dendritic cells (DCs), are highly specialized tissues and provide an ideal microenvironment for T-cell priming. However, intramuscular or subcutaneous delivery of vaccine to DCs, a subset of antigen-presenting cells, has failed to stimulate optimal immune response for effective vaccination and need for adjuvants to induce immune response. To address this issue, we developed an in situ-forming injectable hybrid hydrogel that spontaneously assemble into microporous network upon subcutaneous administration, which provide a cellular niche to host immune cells, including DCs. In situ-forming injectable hybrid hydrogelators, composed of protein-polymer conjugates, formed a hydrogel depot at the close proximity to the dermis, resulting in a rapid migration of immune cells to the hydrogel boundary and infiltration to the microporous network. The biocompatibility of the watery microporous network allows recruitment of DCs without a DC enhancement factor, which was significantly higher than that of traditional hydrogel releasing chemoattractants, granulocyte-macrophage colony-stimulating factor. Owing to the sustained degradation of microporous hydrogel network, DNA vaccine release can be sustained, and the recruitment of DCs and their homing to lymph node can be modulated. Furthermore, immunization of a vaccine encoding amyloid-ß fusion proteinbearing microporous network induced a robust antigen-specific immune response in vivo and strong recall immune response was exhibited due to immunogenic memory. These hybrid hydrogels can be administered in a minimally invasive manner using hypodermic needle, bypassing the need for cytokine or DC enhancement factor and provide niche to host immune cells. These findings highlight the potential of hybrid hydrogels that may serve as a simple, yet multifunctional, platform for DNA vaccine delivery to modulate immune response.
Assuntos
Hidrogéis/química , Animais , Fatores Quimiotáticos/metabolismo , Células Dendríticas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Linfonodos/metabolismo , Vacinação/métodos , Vacinas de DNA/químicaRESUMO
The malignant gliomas are most destructive brain tumor having low drug response. The thermosensitive hydrogel from pluronic F127 (PF127) and N,N,N-trimethyl chitosan (TMC) is developed as a drug delivery system for anticancer drug docetaxel (DTX) to the glioblastoma multiforme. The influence of TMC on morphology, physico-chemical, mechanical, and release properties of PF127 based thermosensitive hydrogel is investigated here. The hydrogels shows porous network as shown by scanning electron microscopy and TMC addition hindered close packing of PF127 layers in the gel system leaving more pores on the surface. TEM images demonstrate micelle formation by PF127-TMC with diameters of about 50 nm. MTT assay result shows that DTX loaded PF127-TMC hydrogel is more capable of killing U87MG cell than free DTX and DTX loaded PF-127. Hydrogels retain sustained release of DTX under different pH conditions more than one month. Furthermore, in vivo experiments are carried out by creating xenograft tumor model on the head of BALB/c nude mice for checking tumor suppression by PF127-TMC/DTX hydrogel. Overall, the hydrogels shows sustained release of DTX on different pH with tumor suppression suggests that it can be used for treating tumor.
Assuntos
Antineoplásicos/uso terapêutico , Quitosana/química , Glioblastoma/tratamento farmacológico , Hidrogéis/química , Poloxâmero/química , Taxoides/uso terapêutico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Quitosana/síntese química , Docetaxel , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Hidrogéis/síntese química , Concentração de Íons de Hidrogênio , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Taxoides/químicaRESUMO
The development of injectable hydrogels with tunable multifunctional properties, for example, adhesive, elastic, swelling, biodegradable, and wound-healing properties that mimic the dynamic-healing process of skin regeneration, is currently a major challenge in tissue regeneration. Here, we report a fillable topical formulation of injectable gelatins (IGs) for the integration of advanced excisional wounds. Bioresorbable temperature-sensitive block copolymer was conjugated to the backbone of gelatins to form a dynamic coordinative network of IGs. The flexible IG precursors transformed to viscoelastic hydrogel at the subcutaneous tissues with cell affinity and tissue adhesive properties. The microporous dynamic network of IGs allows access to nutrients and recruits immune cells that accelerate neovascularization within a hydrogel network. Combined with adhesive and neovascularization properties, the IGs alone exhibit accelerated wound healing in open wounds featured by skin appendages without scar formation. More remarkably, in an excisional wound (1 cm × 1 cm) animal model, the IGs promoted the wound healing as observed by the skin appendages. Furthermore, histological analysis demonstrated that IGs not only accelerate the rate of wound healing but also promoted the quality of wound healing observed by collagen deposition and neovascularization. The in situ forming IGs with a superior adhesive property can be considered as promising wound dressing materials for the treatment of multiple wounds, without the need for the encapsulation of biofactors or antibacterial metals. The IGs prepared in this study can also be employed to repair tissues or organs using minimal invasive administration.
RESUMO
Sustained delivery of protein therapeutics is limited owing to the fragile nature of proteins. Despite its great potential, delivery of proteins without any loss of bioactivity remains a challenge in the use of protein therapeutics in the clinic. To surmount this shortcoming, we report a pH- and temperature-responsive in situ-forming injectable hydrogel based on comb-type polypeptide block copolymers for the controlled delivery of proteins. Polypeptide block copolymers, composed of hydrophilic polyethylene glycol (PEG), temperature-responsive poly(γ-benzyl-l-glutamate) (PBLG), and pH-responsive oligo(sulfamethazine) (OSM), exhibit pH- and temperature-induced sol-to-gel transition behavior in aqueous solutions. Polypeptide block copolymers were synthesized by combining N-carboxyanhydride-based ring-opening polymerization and post-functionalization of the chain-end using N-hydroxy succinimide ester activated OSM. The physical properties of polypeptide-based hydrogels were tuned by varying the composition of temperature- and pH-responsive PBLG and OSM in block copolymers. Polypeptide block copolymers were non-toxic to human embryonic kidney cells at high concentrations (2000 µg mL-1). Subcutaneous administration of polypeptide block copolymer sols formed viscoelastic gel instantly at the back of Sprague-Dawley (SD) rats. The in vivo gels exhibited sustained degradation and were found to be bioresorbable in 6 weeks without any noticeable inflammation at the injection site. Anionic characteristics of hydrogels allow efficient loading of a cationic model protein, lysozyme, through electrostatic interaction. Lysozyme-loaded polypeptide block copolymer sols readily formed a viscoelastic gel in vivo and sustained lysozyme release for at least a week. Overall, the results demonstrate an elegant approach to control the release of certain charged proteins and open a myriad of therapeutic possibilities in protein therapeutics.
Assuntos
Plásticos Biodegradáveis/síntese química , Portadores de Fármacos/síntese química , Hidrogel de Polietilenoglicol-Dimetacrilato/síntese química , Ácido Poliglutâmico/análogos & derivados , Animais , Plásticos Biodegradáveis/efeitos adversos , Portadores de Fármacos/efeitos adversos , Elasticidade , Células HEK293 , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/efeitos adversos , Concentração de Íons de Hidrogênio , Masculino , Muramidase/administração & dosagem , Muramidase/farmacocinética , Polietilenoglicóis/química , Ácido Poliglutâmico/química , Ratos , Ratos Sprague-Dawley , Sulfametazina/química , Temperatura , ViscosidadeRESUMO
Stimuli-responsive polypeptides are a promising class of biomaterials due to their tunable physicochemical and biological properties. Herein, a series of novel pH- and thermo-responsive block copolymers based on polypeptides were synthesized by ring-opening polymerization of γ-benzyl-l-glutamate-N-carboxyanhydride in the presence of poly(ethylene glycol)-diamine macroinitiator followed by aminolysis. The resulting polypeptide-based triblock copolymer, poly[(2-(dibutylamino)ethyl-l-glutamate)-co-(γ-benzyl-l-glutamate)]-poly(ethylene glycol)-b-poly[(2-(dibutylamino)ethyl-l-glutamate)-co-(γ-benzyl-l-glutamate)] (PNLG-co-PBLG-b-PEG-b-PBLG-co-PNLG), exists as a low viscous sol at low pH and temperature (≤pH 6.4, 25 °C) but it transforms to a soft gel under physiological conditions (pH 7.4 and 37 °C). The physical properties of the polypeptide gel can be tuned by controlling the ratio between hydrophobic PBLG and pH-sensitive PNLG blocks. The polypeptide-based copolymer did not show any noticeable cytotoxicity to fibroblast cells in vitro. It was found that subcutaneous injection of the polypeptide copolymer solution into the dorsal region of Sprague-Dawley (SD) rats formed a gel instantly without major inflammation. The gels were completely biodegraded in six weeks and found to be bioresorbable. Human growth hormone (hGH)-loaded polypeptide-based biodegradable copolymer sols readily formed a viscoelastic gel that inhibited an initial burst and prolonged the hGH release for one week. Overall, due to their bioresorbable and sustained release protein characteristics, polypeptide hydrogels may serve as viable platforms for therapeutic protein delivery and the surface tunable properties of polypeptide hydrogels can be exploited for other potential therapeutic proteins.