The delivery of therapeutic compounds to target tissues is a central challenge in treating disease. Externally controlled drug release systems hold potential to selectively enhance localized delivery. Here we describe liposomes doped with porphyrin–phospholipid that are permeabilized directly by near-infrared light. Molecular dynamics simulations identified a novel light-absorbing monomer esterified from clinically approved components predicted and experimentally demonstrated to give rise to a more stable porphyrin bilayer. Light-induced membrane permeabilization is enabled with liposomal inclusion of 10 molar % porphyrin–phospholipid and occurs in the absence of bulk or nanoscale heating. Liposomes reseal following laser exposure and permeability is modulated by varying porphyrin–phospholipid doping, irradiation intensity or irradiation duration. Porphyrin–phospholipid liposomes demonstrate spatial control of release of entrapped gentamicin and temporal control of release of entrapped fluorophores following intratumoral injection. Following systemic administration, laser irradiation enhances deposition of actively loaded doxorubicin in mouse xenografts, enabling an effective single-treatment antitumour therapy.
Nanoscale materials have been explored extensively as agents for therapeutic and diagnostic (i.e. theranostic) applications. Research efforts have shifted from exploring new materials in vitro to designing materials that function in more relevant animal disease models, thereby increasing potential for clinical translation. Current interests include non-invasive imaging of diseases, biomarkers and targeted delivery of therapeutic drugs. Here, we discuss some general design considerations of advanced theranostic materials and challenges of their use, from both diagnostic and therapeutic perspectives. Common classes of nanoscale biomaterials, including magnetic nanoparticles, quantum dots, upconversion nanoparticles, mesoporous silica nanoparticles, carbon-based nanoparticles and organic dye-based nanoparticles, have demonstrated potential for both diagnosis and therapy. Variations such as size control and surface modifications can modulate biocompatibility and interactions with target tissues. The needs for improved disease detection and enhanced chemotherapeutic treatments, together with realistic considerations for clinically translatable nanomaterials will be key driving factors for theranostic agent research in the near future.
Biomedical applications of porphyrins and related molecules have been extensively pursued in the context of photodynamic therapy. Recent advances in nanoscale engineering have opened the door for new ways that porphyrins stand to potentially benefit human health. Metalloporphyrins are inherently suitable for many types of medical imaging and therapy. Traditional nanocarriers such as liposomes, dendrimers and silica nanoparticles have been explored for photosensitizer delivery. Concurrently, entirely new classes of porphyrin nanostructures are being developed, such as smart materials that are activated by specific biochemicals encountered at disease sites. Techniques have been developed that improve treatments by combining biomaterials with photosensitizers and functional moieties such as peptides, DNA and antibodies. Compared to simpler structures, these more complex and functional designs can potentially decrease side effects and lead to safer and more efficient phototherapies. This review examines recent research on porphyrin-derived materials in multimodal imaging, drug delivery, bio-sensing, phototherapy and probe design, demonstrating their bright future for biomedical applications.
Hexagonal NaYbF4:Tm3+ upconversion nanoparticles hold promise for use in high contrast near-infrared-to-near-infrared (NIR-to-NIR) in vitro and in vivo bioimaging. However, significant hurdles remain in their preparation and control of their morphology and size, as well as in enhancement of their upconversion efficiency. Here, we describe a systematic approach to produce highly controlled hexagonal NaYbF4:Tm3+ nanoparticles with superior upconversion. We found that doping appropriate concentrations of trivalent gadolinium (Gd3+) can convert NaYbF4:Tm3+ 0.5% nanoparticles with cubic phase and irregular shape into highly monodisperse NaYbF4:Tm3+ 0.5% nanoplates or nanospheres in a pure hexagonal-phase and of tunable size. The intensity and the lifetime of the upconverted NIR luminescence at 800 nm exhibit a direct dependence on the size distribution of the resulting nanoparticles, being ascribed to the varied surface-to-volume ratios determined by the different nanoparticle size. Epitaxial growth of a thin NaYF4 shell layer of ∼2 nm on the ∼22 nm core of hexagonal NaYbF4:Gd3+ 30%/Tm3+ 0.5% nanoparticles resulted in a dramatic 350 fold NIR upconversion efficiency enhancement, because of effective suppression of surface-related quenching mechanisms. In vivo NIR-to-NIR upconversion imaging was demonstrated using a dispersion of phospholipid-polyethylene glycol (DSPE-PEG)-coated core/shell nanoparticles in phosphate buffered saline.
Here we report a facile way of stabilizing large gold nanoparticles (AuNPs) by mixed charged zwitterionic self-assembled monolayers (SAMs). The citrate-capped AuNPs with diameters ranging from 16 nm to even ∼100 nm are well stabilized via a simple place exchange reaction with a 1:1 molar ratio mixture of negatively charged sodium 10-mercaptodecanesulfonic acid (HS-C10-S) and positively charged (10-mercaptodecyl)-trimethyl-ammonium bromide (HS-C10-N4). The 16 nm AuNPs protected by mixed charged zwitterionic SAMs not only show much better stability than the single negatively or positively charged AuNPs, but also exhibit exciting stability as well as those modified by monohydroxy (1-mercaptoundec-11-yl) tetraethylene glycol (HS-C11-EG4). Importantly, 16 nm AuNPs protected by mixed SAMs exhibit good stability in cell culture medium with 10% FBS and strong protein resistance, especially with excellent resistance against plasma adsorption. Moreover, the mixed charged zwitterionic SAMs are also able to well-stabilize larger AuNPs with a diameter of 50 nm, and to help remarkably improve their stability in saline solution compared with HS-C11-EG4 protected ones. When it comes to AuNPs with a diameter of 100 nm, the mixed charged zwitterionic SAM protected nanoparticles retain a smaller hydrodynamic diameter and even better long-term stability than those modified by mercaptopolyethylene glycol (M(w) = 2000, HS-PEG2000). The above results demonstrated that the mixed charged zwitterionic SAMs are able to have a similar effect on stabilizing the large gold nanoparticles just like the single-component zwitterionic SAMs. Concerning its ease of preparation, versatility, and excellent properties, the strategy based on the mixed charged zwitterionic SAM protection might provide a promising method to surface tailoring of nanoparticles for biomedical application.
These results show that VEGF and VEGFR expression in various types of brain tumors differ and are not necessarily parallel.
Surface engineering of nanoparticles plays an essential role in their colloidal stability, biocompatibility and interaction with biosystems. In this study, a novel multidentate zwitterionic biopolymer derivative is obtained from conjugating dithiolane lipoic acid and zwitterionic acryloyloxyethyl phosphorylcholine to the chitosan oligosaccharide backbone. Gold nanoparticles (AuNPs) modified by this polymer exhibit remarkable colloidal stabilities under extreme conditions including high salt conditions, wide pH range and serum or plasma containing media. The AuNPs also show strong resistance to competition from dithiothreitol (as high as 1.5 M). Moreover, the modified AuNPs demonstrate low cytotoxicity investigated by both MTT and LDH assays, and good hemocompatibility evaluated by hemolysis of human red blood cells. In addition, the intracellular fate of AuNPs was investigated by ICP-MS and TEM. It showed that the AuNPs are uptaken by cells in a concentration dependent manner, and they can escape from endosomes/lysosomes to cytosol and tend to accumulate around the nucleus after 24 h incubation but few of them are excreted out of the cells. Gold nanorods are also stabilized by this ligand, which demonstrates robust dispersion stability and excellent hemocompatibility. This kind of multidentate zwitterionic chitosan derivative could be widely used for stabilizing other inorganic nanoparticles, which will greatly improve their performance in a variety of bio-related applications.
BackgroundGlioblastoma is refractory to conventional treatment, which is combined of surgery, chemotherapy and radiotherapy. Recent studies have shown that glioma initiating cells (GICs) contribute to tumorigenesis and radioresistance. Recently, other studies showed that the GICs use the autophagy as the major pathway to survive. Chloroquine, an anti-malarial chemical, is an autophagic inhibitor which blocks autophagosome fusion with lysosome and slows down lysosomal acidification. The aim of this study was to explore the mechanisms of chloroquine on the radiosensitivity of GICs.MethodsHuman glioblastoma cell lines U87 were investigated. MTT and clonogenic survival assay were used to evaluate the cell viability and survival from radiation. The formation of autophagosomes were evaluated by immunofluorescence. Annexin V-FITC/PI staining and flow cytometry were used to quantify the apoptotic cells. The expression levels of proteins were analyzed by Western blot. Cell cycle status was analyzed by checking DNA content after staining with PI. A comet assay was used to assess the DNA repair in the cells. Tumorsphere assay was used for evaluating GICs’ renewal ability.ResultsTreatment of U87 GICs with chloroquine (10–80 nmol/L) alone inhibited the cell growth in a dose-dependent manner. A dose of chloroquine (20 nmol/L) obviously enhanced the radiation sensitivity of U87 GICs., we found more punctate patterns of microtubule-associated protein LC3 immunoreactivity in radiation-treated U87 GICs, and the level of membrane-bound LC3-II was obviously enhanced. A combination of radiation and chloroquine obviously enhanced the U87 GICs’ apoptosis, as demonstrated by the enhanced levels of caspase-3, and reduced level of Bcl-2. In additon, combination of radiation and chloroquine cause G1/G0 cell cycle arrest. what’s more, Chloroquine obviously weakened the repair of radiation-induced DNA damage as reflected by the tail length of the comet. Combination treatment of irradiation and chloroquine has synergistic effects on decreasing the GICs’ tumorsphere number and diameter.ConclusionChloroquine enhances the radiosensitivity of GICs in vitro, suggesting the feasibility of joint treatment with chloroquine with radiation for GBM.
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