RESUMO
Chronic local inflammation and resulting cellular dysfunction of nucleus pulposus (NP) cells are important pathogenic factors of intervertebral disc degeneration (IDD). Injectable pathological microenvironment-responsive hydrogels hold significant potential for treating IDD by adapting to dynamic microenvironment of IDD. Herein, we proposed an injectable gelatin-based hydrogel drug delivery system that could respond to the pathological microenvironment of IDD for controlled release of anti-inflammatory drug to promote degenerative NP repair. The hydrogel system was prepared by conjugating phenylboronic acid-modified gelatin methacryloyl (GP) with the naturally extracted anti-inflammatory drug epigallocatechin-3-gallate (EGCG) through dynamic boronic esters. The hydrogel exhibited excellent degradability, injectability, antioxidant properties, anti-inflammatory effects, and biocompatibility. It also displayed responsive-release of EGCG under high reactive oxygen species (ROS) levels and acidic conditions. The hydrogel demonstrated remarkable cytoprotective effects on NP cells in both hyperactive ROS environments and inflammatory cytokine-overexpressed environments in vitro. In vivo studies revealed that the hydrogel injected in situ could effectively ameliorate the intervertebral disc degeneration by maintaining the disc height and NP tissue structure in a rat IDD model. The hydrogel system exhibited excellent biocompatibility and responsive-release of diol-containing drugs in pathological microenvironments, indicating its potential application as a drug delivery platform.
Assuntos
Degeneração do Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Ratos , Animais , Degeneração do Disco Intervertebral/patologia , Hidrogéis/química , Espécies Reativas de Oxigênio/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêuticoRESUMO
Meniscus injuries are associated with the degeneration of cartilage and development of osteoarthritis (OA). It is challenging to protect articular cartilage and improve exercise when a meniscus injury occurs. Herein, inspired by the components and functions of the meniscus, we developed a self-lubricating and friction-responsive hydrogel that contains nanoliposomes loaded with diclofenac sodium (DS) and Kartogenin (KGN) for anti-inflammation and cartilage regeneration. When the hydrogel was injected into the meniscus injury site, the drug-loaded nanoliposomes were released from the hydrogel in a friction-responsive manner and reassembled to form hydration layers that lubricate joints during movement. Meanwhile, DS and KNG were constantly released from the nanoliposomes to mitigate inflammation and promote cartilage regeneration. Additionally, this hydrogel exhibited favorable injectability, mechanical properties, fatigue resistance, and prolonged degradation. In vivo experiments demonstrated that injection of the hydrogel effectively improved exercise performance and protected the articular cartilage of rats, suggesting it as a potential therapeutic approach for meniscal injuries.
Assuntos
Cartilagem Articular , Menisco , Ratos , Animais , Hidrogéis/farmacologia , Fricção , Injeções , Diclofenaco/farmacologiaRESUMO
Intervertebral disc (IVD) degeneration occurred with the increasing age or accidents has puzzled peoples in daily life. To seal IVD defect by injectable hydrogels is a promising method for slowing down IVD degeneration. Herein, we reported a rapidly in situ forming injectable chitosan/PEG hydrogel (CSMA-PEGDA-L) through integrating photo-crosslink of methacrylate chitosan (CSMA) with Schiff base reaction between CSMA and aldehyde polyethylene glycol (PEGDA). The CSMA-PEGDA-L possessed a stronger compressive strength than the photo-crosslinked CSMA-L hydrogel and Schiff-base-crosslinked CSMA-PEGDA hydrogel. This chitosan/PEG hydrogel showed low cytotoxicity from incubation experiments of nucleus pulpous cells. When implanted on the punctured IVD of rat's tail, the CSMA-PEGDA-L hydrogel could well retard the progression of IVD degeneration through physical plugging, powerfully proven by radiological and histological evaluations. This work demonstrated the strategy of in situ injectable glue may be a potential solution for prevention of IVD degeneration.
RESUMO
In recent years, epigenetics has attracted great attentions in the field of biomedicine, which is used to denote the heritable changes in gene expression without any variation in DNA sequence, including DNA methylation, histone modification and so on. Inspired by it, a simple and versatile amino acids modification strategy is proposed in this paper to regulate the subcellular distribution of photosensitizer for plasma membrane targeted photodynamic therapy (PDT). Particularly, the plasma membrane anchoring ability and photo toxicity of the photosensitizer against different cell lines could be effectively manipulated at a single amino acid level. Systematic researches indicate that the number and variety of amino acids have a significant influence on the plasma membrane targeting effect of the photosensitizer. Furthermore, after self-assembling into nanoparticles, the obtained nano photosensitizers (NPs) also exhibit a good biocompatibility and plasma membrane targeting ability, which are conducive to enhancing the PDT therapeutic effect under light irradiation. Both in vitro and in vivo investigations confirm a robust tumor inhibition effect of NPs with a good biocompatibility. This epigenetics-inspired photosensitizer modification strategy would contribute to the development of structure-based drug design for tumor precision therapy.
Assuntos
Membrana Celular/metabolismo , Epigênese Genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Células 3T3 , Aminoácidos/metabolismo , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/farmacologia , Protoporfirinas/uso terapêutico , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Distribuição Tecidual/efeitos dos fármacosRESUMO
Targeted delivery of the drug to its therapeutically active site with low immunogenicity and system toxicity is critical for optimal tumor therapy. In this paper, exosomes as naturally-derived nano-sized membrane vesicles are engineered by chimeric peptide for plasma membrane and nucleus targeted photosensitizer delivery and synergistic photodynamic therapy (PDT). Importantly, a dual-stage light strategy is adopted for precise PDT by selectively and sequentially destroying the plasma membrane and nucleus of tumor cells. Briefly, plasma membrane-targeted PDT of chimeric peptide engineered exosomes (ChiP-Exo) could directly disrupt the membrane integrity and cause cell death to some extent. More interestingly, the photochemical internalization (PCI) and lysosomal escape triggered by the first-stage light significantly improve the cytosolic delivery of ChiP-Exo, which could enhance its nuclear delivery due to the presence of nuclear localization signals (NLS) peptide. Upon the second-stage light irradiation, the intranuclear ChiP-Exo would activate reactive oxygen species (ROS) in situ to disrupt nuclei for robust and synergistic PDT. Based on exosomes, this dual-stage light guided subcellular dual-targeted PDT strategy exhibits a greatly enhanced therapeutic effect on the inhibition of tumor growth with minimized system toxicity, which also provides a new insight for the development of individualized biomedicine for precise tumor therapy.
Assuntos
Exossomos/transplante , Neoplasias/terapia , Peptídeos/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/patologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos/administração & dosagem , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagemRESUMO
An abnormal pH microenvironment results from the development of tumors, and also affects the therapeutic efficiency of anti-tumor drugs. In this work, a Förster resonance energy transfer (FRET)-based theranostic fluorescent nanoprobe was constructed for simultaneous ratiometric pH sensing and tumor-targeted photodynamic therapy. Based on the FRET process between rhodamine B and protoporphyrin IX (PpIX), the fabricated nanoprobe exhibited excellent pH responsiveness in both solutions and live cells with the ratiometric fluorescence changes. Moreover, this ratiometric pH fluorescent nanoprobe also possessed the capability for pH-responsive singlet oxygen (1O2) generation under light irradiation, guiding robust photodynamic therapy in a pH-dependent manner. Benefiting from the enhanced permeability and retention (EPR) effect, the nanoprobe could significantly inhibit tumor growth and metastasis via targeted photodynamic therapy in vivo. This work presents a novel paradigm for precise tumor theranostics by ratiometric pH fluorescence imaging-guided photodynamic therapy.
Assuntos
Nanoestruturas/química , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Microscopia Confocal , Neoplasias/diagnóstico por imagem , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , Rodaminas/química , Oxigênio Singlete/metabolismo , Transplante HeterólogoRESUMO
Mitochondria and cell membrane play important roles in maintaining cellular activity and stability. Here, a single-agent self-delivery chimeric peptide based nanoparticle (designated as M-ChiP) was developed for mitochondria and plasma membrane dual-targeted photodynamic tumor therapy. Without additional carrier, M-ChiP possessed high drug loading efficacy as well as the excellent ability of producing reactive oxygen species (ROS). Moreover, the dual-targeting property facilitated the effective subcellular localization of photosensitizer protoporphyrin IX (PpIX) to generate ROS in situ for enhanced photodynamic therapy (PDT). Notably, plasma membrane-targeted PDT would enhance the membrane permeability to improve the cellular delivery of M-ChiP, and even directly disrupt the cell membrane to induce cell necrosis. Additionally, mitochondria-targeted PDT would decrease mitochondrial membrane potential and significantly promote the cell apoptosis. Both in vitro and in vivo investigations indicated that this combinatorial PDT in mitochondria and plasma membrane could achieve the therapeutic effect maximization with reduced side effects. The single-agent self-delivery system with dual-targeting strategy was demonstrated to be a promising nanoplatform for synergistic tumor therapy.
Assuntos
Membrana Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Peptídeos/química , Fármacos Fotossensibilizantes/administração & dosagem , Protoporfirinas/administração & dosagem , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Camundongos , Mitocôndrias/metabolismo , Nanopartículas/química , Neoplasias/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/farmacocinética , Protoporfirinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismoRESUMO
In this paper, a self-delivery chimeric peptide PpIX-PEG8 -KVPRNQDWL is designed for photodynamic therapy (PDT) amplified immunotherapy against malignant melanoma. After self-assembly into nanoparticles (designated as PPMA), this self-delivery system shows high drug loading rate, good dispersion, and stability as well as an excellent capability in producing reactive oxygen species (ROS). After cellular uptake, the ROS generated under light irradiation could induce the apoptosis and/or necrosis of tumor cells, which would subsequently stimulate the anti-tumor immune response. On the other hand, the melanoma specific antigen (KVPRNQDWL) peptide could also activate the specific cytotoxic T cells for anti-tumor immunity. Compared to immunotherapy alone, the combined photodynamic immunotherapy exhibits significantly enhanced inhibition of melanoma growth. Both in vitro and in vivo investigations confirm that PDT of PPMA has a positive effect on anti-tumor immune response. This self-delivery system demonstrates a great potential of this PDT amplified immunotherapy strategy for advanced or metastatic tumor treatment.
Assuntos
Antígenos de Neoplasias/farmacologia , Sistemas de Liberação de Medicamentos , Imunoterapia , Melanoma Experimental/terapia , Peptídeos/farmacologia , Fotoquimioterapia , Animais , Antígenos de Neoplasias/imunologia , Células COS , Chlorocebus aethiops , Imunidade Celular/efeitos dos fármacos , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologiaRESUMO
An azobenzene-based heteromeric prodrug (hNDP) was prepared for targeted chemotherapy against hypoxic tumor. hNDP could divert the parent drug from nucleus to cytoplasm with lower toxicity, while the azoreduction of hNDP in hypoxia would activate the drug with a robust anti-tumor effect by initiating the apoptosis-related biochemical cascades.