ABSTRACT
We used antioxidant-containing nanoparticles (NPs) to treat acute hearing loss. Alpha-lipoic acid (ALA) served as the antioxidant; we employed Pluronic F127 to fabricate NPs. In vitro, ALA-NPs protected cells of the organ of Corti in HEI-OC1 mice, triggering nuclear translocation of NRF2 and increases in the levels of antioxidant proteins, including Nrf2, HO-1, SOD-1, and SOD-2. In vivo, the hearing of mice that received ALA-NP injections into the middle ear cavity was better preserved after induction of ototoxicity than in control animals. The cochlear Nrf2 level increased in test mice, indicating that the ALA-NPs protected hearing via the antioxidant mechanism observed in vitro. ALA-NPs effectively protected against acute hearing loss by activating the Nrf2/HO-1 pathway.
Subject(s)
Hearing Loss/drug therapy , Nanoparticles/chemistry , Poloxamer/chemistry , Thioctic Acid/administration & dosage , Thioctic Acid/therapeutic use , Tympanic Membrane/pathology , Animals , Antioxidants/pharmacology , Cell Death/drug effects , Cell Line , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Disease Models, Animal , Hearing Loss/pathology , Male , Mice, Inbred C57BL , NF-E2-Related Factor 2/metabolism , Nanoparticles/ultrastructure , Thioctic Acid/pharmacologyABSTRACT
AIM: Colon cancer is one of the leading causes of cancer-related mortality. However, specific biomarkers for its diagnosis or treatment are not established well. METHODS: We developed a colon-cancer specific peptide probe using phage display libraries. We validated the specificity of this probe to colon cancer cells with immunohistochemical staining and FACS analysis using one normal cell and five colon cancer cell lines. RESULTS: This peptide probe maintained binding affinity even after serum incubation. For therapeutic applications, this peptide probe was conjugated to hematoporphyrin, a photosensitizer, which showed a significantly enhanced cellular uptake and high photodynamic effect to kill tumor cells. As another application, we made a nanoparticle modified from the peptide probe. It efficiently delivered SN-38, an anticancer drug, into tumor cells, and its tumor-targeting ability was observed in vivo after intravenous injection to the same xenograft model. CONCLUSION: The noble dodecapeptide probe can be a promising candidate for both colon tumor diagnosis and targeted drug delivery.
ABSTRACT
The objective of the present investigation is to determine the effects of neutral, anionic, and cationic liposomes loaded with doxorubicin with thin-lipid-film-hydration method on the cellular viability and osteogenesis of stem cell spheroids. Spheroid formation and morphology of the three-dimensional spheroid were noted with an inverted microscope. Quantitative cellular viability was assessed using a commercially available kit. Osteogenic potential was evaluated by applying alkaline phosphatase activity and anthraquinone dye of Alizarin Red S. Western blot analysis was performed using collagen I expression. Spheroids were formed in each silicon elastomer-based concave microwell on Day 1. Noticeable changes of the spheroid were seen with a higher concentration of doxorubicin, especially in the cationic liposome group at Days 5 and 7. We found that the application of doxorubicin for 5 days significantly reduced the cellular viability. A higher concentration of doxorubicin produced a significant decrease in alkaline phosphatase activity. Alizarin Red S staining showed that extracellular calcium deposits were evenly noted in each group. An increase of calcium deposits was noted on Day 14 when compared to Day 7. The morphology of the groups with higher concentrations of doxorubicin showed to be more dispersed. We noticed that doxorubicin-loaded cationic liposomes resulted in the highest uptake of the examined cell spheroids and that doxorubicin-loaded liposomes affected the osteogenic differentiation. The implication of this study is that the type of liposome should be selected based on the purpose of the application.
ABSTRACT
For efficient drug delivery, we introduce a click-chemistry-mediated two-step tumor-targeting strategy for nanoparticles (NPs). We modified HER2-binding trastuzumab with trans-cyclooctene (TCO-Trb), and fabricated tetrazine-modified NPs containing the anticancer drug, SN38 (SN38-Tz-NPs). To target tumor cells with the Tz-NPs, the tumor cells are first treated with TCO-Trb. The TCO-Trb binds HER2s and presents multiple TCO groups on the cell surface. Subsequently, the cells are treated with SN38-Tz-NPs that can bind the cell surface via click chemistry between Tz and TCO. This click chemistry-mediated binding resulted in enhanced tumor-targeting of Tz-NPs to the target tumor cells. In our study, this strategy was performed and analyzed in vitro and in vivo, and the results show that this is a promising strategy for tumor-targeted drug delivery by NPs.
Subject(s)
Cyclooctanes/chemistry , Drug Delivery Systems/methods , Irinotecan/chemistry , Nanoparticles/chemistry , Neoplasms, Experimental/drug therapy , Trastuzumab/chemistry , Animals , Cell Line, Tumor , Click Chemistry/methods , Irinotecan/administration & dosage , Irinotecan/pharmacokinetics , Mice, Inbred BALB C , Mice, Nude , Nanoparticles/administration & dosage , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Binding , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Tissue Distribution , Topoisomerase I Inhibitors/administration & dosage , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/pharmacokinetics , Trastuzumab/administration & dosage , Trastuzumab/metabolism , Trastuzumab/pharmacokineticsABSTRACT
Targeting nanoparticle (NP) carriers to sites of disease is critical for their successful use as drug delivery systems. Along with optimization of physicochemical properties, researchers have focused on surface modification of NPs with biological ligands. Such ligands can bind specific receptors on the surface of target cells. Furthermore, biological ligands can facilitate uptake of modified NPs, which is referred to as 'active targeting' of NPs. In this review, we discuss recent applications of biological ligands including proteins, polysaccharides, aptamers, peptides, and small molecules for NP-mediated drug delivery. We prioritized studies that have demonstrated targeting in animals over in vitro studies. We expect that this review will assist biomedical researchers working with NPs for drug delivery and imaging.
ABSTRACT
Herein, we report the development of self-assembled nanoparticles using rhamnolipid, a biosurfactant. Rhamnolipid is produced by Pseudomonas aeruginosa, and has an amphiphilic structure that is suitable for the formation of a nanoparticle shell. These rhamnolipid nanoparticles were loaded with pheophorbide a (Pba), a hydrophobic photosensitizer. The resulting nanoparticles had about 136.1-nm-diameter spherical shapes and had excellent water solubility without aggregation for one month. These nanoparticles showed fast uptake into SCC7 tumor cells and induced photodynamic damage upon laser irradiation. After intravenous injection to SCC7 tumor-bearing mice, their long blood circulation time and high accumulation in tumor tissue were observed in real-time fluorescence imaging. Upon laser irradiation, these rhamnolipid nanoparticles showed complete tumor suppression by photodynamic therapy in vivo. These promising results demonstrate the potential of rhamnolipid nanoparticles for drug delivery, and suggest that further attention to rhamnolipid research would be fruitful.
Subject(s)
Drug Delivery Systems , Glycolipids/chemistry , Nanoparticles/chemistry , Photochemotherapy , Animals , Cell Death/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Chlorophyll/analogs & derivatives , Chlorophyll/chemistry , Chlorophyll/pharmacology , Mice , Nanoparticles/ultrastructure , Singlet Oxygen/chemistry , Tissue Distribution/drug effectsABSTRACT
BACKGROUND: Improving the water solubility of hydrophobic photosensitizer and increasing its accumulation in tumor tissue are essential for in vivo photodynamic therapy (PDT). Considering commercialization or clinical application in future, it will be promising to achieve these purposes by developing new agents with simple and non-toxic structure. RESULTS: We conjugated multiple chlorin e6 (Ce6) molecules to gelatin polymer, synthesizing two types of gelatin-Ce6 conjugates with different amounts of Ce6: gelatin-Ce6-2 and gelatin-Ce6-8. The resulting conjugates remained soluble in aqueous solutions for a longer time than hydrophobic Ce6. The conjugates could generate singlet oxygen and kill tumor cells upon laser irradiation. After intravenous injection into SCC-7 tumor-bearing mice, gelatin-Ce6-2 showed prolonged blood circulation and highly increased accumulation in tumor tissue as observed in real-time imaging in vivo. After laser irradiation, gelatin-Ce6-2 suppressed tumor growth completely and enabled improved PDT compared to free Ce6 and gelatin-Ce6-8. CONCLUSIONS: This work demonstrates that a simple structure based on photosensitizer and gelatin can highly improve water solubility and stability. Superior tumor tissue accumulation and increased therapeutic efficacy of gelatin-Ce6 during in vivo PDT showed its high potential for clinical application.
Subject(s)
Gelatin/chemistry , Photosensitizing Agents/pharmacology , Porphyrins/pharmacology , Animals , Cell Line, Tumor , Cell Survival , Chlorophyllides , Drug Carriers , Humans , Mice , Neoplasm Transplantation , Phototherapy , Polymers/chemistry , Porphyrins/chemistry , Singlet Oxygen/metabolism , Solubility , Tissue DistributionABSTRACT
Nanoparticles (NPs) play a key role in nanomedicine in multimodal imaging, drug delivery and targeted therapy of human diseases. Consequently, due to the attractive properties of NPs including high stability, high payload, multifunctionality, design flexibility, and efficient delivery to target tissues, nanomedicine employs various types of NPs to enhance targeting and treatment efficacy. In this review, we primarily focus on light-responsive materials, such as fluorophores, photosensitizers, semiconducting polymers, carbon structures, gold particles, quantum dots, and upconversion crystals, for their biomedical applications. Armed with these nanomaterials, NPs represent a growing potential in biophotonic imaging (luminescence, photoacoustic, surface enhanced Raman scattering, and optical coherence tomography) as well as targeted therapy (photodynamic therapy, photothermal therapy, and light-responsive drug release).
Subject(s)
Drug Delivery Systems , Light , Nanostructures/radiation effects , Animals , Diagnostic Imaging , Humans , Nanostructures/administration & dosage , Theranostic NanomedicineABSTRACT
Nanoparticles have been widely used as drug carriers, and finding new materials for them is important for efficient drug delivery. Herein, we developed a new nanoparticle using emulsan and flax seed oil. Emulsan is one of the representative biosurfactants obtained from Acinetobacter calcoaceticus RAG-1. The resulting nanoparticles have an emulsan shell and a hydrophobic oil core, into which pheophorbide a (Pba) was loaded as a model drug. The nanoparticles were about 165.7â¯nm and were stably dispersed in an aqueous condition for more than one week. They demonstrated fast uptake in SCC7 mouse squamous cell carcinoma cells and killed the tumor cells after laser irradiation due to the photodynamic effect of Pba. After injection into SCC7 tumor-bearing mice via the tail vein, the particles showed longer blood circulation and 3.04-fold higher tumor accumulation in tissue than free Pba. These results demonstrate that emulsan-based nanoparticles have promising potential in drug delivery.
Subject(s)
Carcinoma, Squamous Cell/diagnostic imaging , Drug Delivery Systems , Nanoparticles/chemistry , Polysaccharides, Bacterial/chemistry , Skin Neoplasms/diagnostic imaging , Animals , Cell Line, Tumor , Drug Carriers/chemistry , Mice , Mice, Inbred C3H , Optical ImagingABSTRACT
The effects of doxorubicin, particularly doxorubicin liposome, on stem cells have remained to be fully elucidated. The aim of the present study was to evaluate the effects of anionic, cationic and neutral liposomes loaded with doxorubicin on the viability and osteogenic differentiation potential of human gingiva-derived stem cells in two-dimensional culture. Doxorubicin-loaded liposomes were prepared using the traditional thin-lipid-film hydration method. Stem cells were seeded on a culture plate and maintained in osteogenic media. The morphology of the stem cells was observed under an inverted microscope. The number of viable cells was determined using a Cell-Counting Kit-8 assay. The alkaline phosphatase activity was assessed and Alizarin Red S staining was performed to evaluate osteogenic differentiation. A higher concentration of doxorubicin caused noticeable changes in the morphology of the stem cells. Decreases in cellular viability were observed after applying doxorubicin. The application of doxorubicin, particularly at higher concentrations, produced a noticeable decrease in alkaline phosphatase activity and Alizarin Red S staining. The present study indicated that application of doxorubicin with or without liposomes reduced the cellular viability and osteogenic differentiation. Among the different treatments, the doxorubicin-loaded cationic liposomes induced the strongest reduction in the cellular viability and osteogenic differentiation in the stem cell culture.
ABSTRACT
This review summarizes recent advances in the development of nanoparticles (NPs) for efficient photodynamic therapy (PDT), particularly the development and application of various NPs based on organic and inorganic materials. PubMed database was used for literature search with the terms including NP, nanomedicine, PDT, photosensitizer (PSs), and drug delivery. For successful PDT, it is essential to deliver PSs to target disease sites. A number of NPs have been developed and tested as the carriers for both imaging and therapy, an approach termed "nanomedicine". Many studies of NP carriers showed increased water solubility and stability of PSs for in vivo injection, and these NP carriers provided benefits including longer circulation in blood and higher accumulation of PSs at disease sites. This review describes new techniques in PDT such as aggregation-induced emission (AIE) and luminescence-based PDT, and provides insights on NPs and PDT for biomedical researchers working to develop or apply NPs in efficient PDT.
ABSTRACT
The aim of the present study was to evaluate the effects of anionic, cationic and neutral liposomes containing doxorubicin on the cellular viability and osteogenic differentiation of three-dimensional stem cell spheroids. Doxorubicin-loaded liposomes were prepared using the traditional thin-lipid-film-hydration method and were characterized using transmission electron microscopy and a zeta potential analyzer. The doxorubicin release profile from these liposomes was also analyzed in vitro. Three-dimensional cell spheroids were fabricated using silicon elastomer-based concave microwells. Qualitative results of cellular viability were observed using a confocal microscope and quantitative cellular viability was evaluated using a Cell-Counting Kit-8 (CCK-8) assay. Furthermore, the secretion of vascular endothelial growth factor was evaluated. Western blot analysis was performed to assess the expression of collagen I and glyceraldehyde 3-phosphate. Results indicated that the spheroids were well formed in silicon elastomer-based concave microwells on day 1. In general, the shapes of the cells in the in the doxorubicin-loaded anionic, cationic and neutral liposome groups were similar to the control group except for the 10 µg/ml groups on days 3, 5, and 7. No significant changes in cellular viability were noted with the addition of doxorubicin at day 1 but significant decreases in cellular viability were noted with application of doxorubicin at day 5. Notably, higher concentrations of doxorubicin reduced the secretion of vascular endothelial growth factor and stem cell marker expression. To conclude, the present study indicated that doxorubicin-loaded anionic liposomes produced the most sustained release profile and cationic liposomes produced the highest uptake of the stem cell spheroids. These findings suggested that higher concentrations of doxorubicin-loaded liposomes affected cellular viability, the secretion of vascular endothelial growth factor and stem cell marker expression.
ABSTRACT
BACKGROUND: Click chemistry is termed as a group of chemical reactions with favorable reaction rate and orthogonality. Recently, click chemistry is paving the way for novel innovations in biomedical science, and nanoparticle research is a representative example where click chemistry showed its promising potential. Challenging trials with nanoparticles has been reported based on click chemistry including copper-catalyzed cycloaddition, strain-promoted azide-alkyne cycloaddition, and inverse-demand Diels-Alder reaction. MAIN BODY: Herein, we provide an update on recent application of click chemistry in nanoparticle research, particularly nanoparticle modification and its targeted delivery. In nanoparticle modification, click chemistry has been generally used to modify biological ligands after synthesizing nanoparticles without changing the function of nanoparticles. Also, click chemistry in vivo can enhance targeting ability of nanoparticles to disease site. CONCLUSION: These applications in nanoparticle research were hard or impossible in case of traditional chemical reactions and demonstrating the great utility of click chemistry.
ABSTRACT
To develop efficient carriers for inner ear drug delivery, we prepared four kinds of phospholipid-based nanoparticles: neutral, anionic, cationic, and cationic-PEG (polyethyleneglycol) particles. PEG was used to maintain long-term particle circulation in the perilymph, avoiding non-specific binding of particles to proteins. All four nanoparticles were about 200 nm in diameter, and their zeta potentials were -4.32, -26.0, +25.8, and -0.28, respectively, for neutral, anionic, cationic, and cationic-PEG nanoparticles. To test particle efficacy in vitro, we used an artificial mucosa 100⯵m in thickness to model the round window membrane (RWM) and HEI-OC1 cells, which were treated with particles containing Nile Red dye. Based on the levels of particle penetration and cellular uptake in this model system, we selected an optimal particle for further study. We also observed the movement of particles in ex vivo organotypic cultures of the organ of Corti. In mice, we analyzed the biodistribution of dexamethasone (Dex) in the inner ear after intratympanic injection of Dex-loaded nanoparticles. Then, we tested the therapeutic utility of the Dex-loaded nanoparticles in a mouse model of ototoxicity. In the auditory brainstem response (ABR) test, particle provided improved hearing loss recovery at all tested frequencies, more so than did the Dex sodium phosphate (Dex-SP) solution in current clinical use. Furthermore, quantitative PCR showed that nanoparticles reduced the levels of pro-inflammatory cytokines, exhibiting anti-inflammatory effects superior to those of Dex-SP. Thus, the surface properties of nanoparticles play pivotal roles in particle penetration and distribution after intratympanic injection. Our in vitro screening system using an artificial mucosa will also be valuable in the development of carriers for inner ear drug delivery.
Subject(s)
Drug Delivery Systems , Ear, Inner/pathology , Nanoparticles/chemistry , Phospholipids/chemistry , Animals , Cell Death/drug effects , Cell Line , Dexamethasone/administration & dosage , Dexamethasone/pharmacology , Disease Models, Animal , Drug Carriers/chemistry , Ear, Inner/drug effects , Humans , Male , Mice, Inbred C57BL , Nanoparticles/ultrastructure , Polyethylene Glycols/chemistryABSTRACT
Targeted drug delivery has been an important issue for tumor therapy including photodynamic therapy (PDT). The purpose of our study is to increase the targeting efficiency of photosensitizer (PS) using folate-modified nanoparticles (NPs) to tumor site in vivo. Folate receptor is over-expressed on the surface of many human cancer cells. We prepared poly (lactic-co-glycolic acid) (PLGA) NPs containing pheophorbide a (Pba), a PS that is used in PDT and generates free radical for killing cancer cells. The surface of NPs was composed of phospholipids modified with polyethylene glycol (PEG) and folate (FA). The size of the resulting FA-PLGA-Pba NPs was about 200â¯nm in PBS at pH 7.4 and they were stable for long time. They showed faster cellular uptake to MKN28 human gastric cancer cell line than control PLGA-Pba NPs by high-affinity binding with folate receptors on cell surface. In MTT assay, FA-PLGA-Pba NPs also showed enhanced tumor cell killing compared to control PLGA-Pba NPs. In vivo and ex vivo imaging showed high accumulation of FA-PLGA-Pba NPs in tumor site during 24â¯h after intravenous injection to MKN28 tumor-bearing mice model. These results demonstrate that our FA-PLGA-Pba NPs are useful for tumor-targeted delivery of PS for cancer treatment by PDT.