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1.
The preparation of pH‐labile polymer‐drug particles via mesoporous silica‐templated assembly for anticancer drug delivery into cancer cells is reported. The polymer‐drug conjugate is synthesized via thiol‐maleimide click chemistry using thiolated poly(methacrylic acid) (PMASH) and a pH‐labile doxorubicin (Dox) derivative. Drug‐loaded polymer particles that are stable under physiological conditions are obtained through infiltration of the conjugates into mesoporous silica particles, followed by cross‐linking the PMASH chains, and subsequent removal of the porous silica templates. The encapsulated Dox is released from the particles through cleavage of the hydrazone bonds between Dox and PMASH at endosomal/lysosomal pH. Cell viability assays show that the assembled PMASH particles have negligible cytotoxicity to LIM1899 human colorectal cancer cells. In comparison, Dox‐loaded PMASH particles cause significant cell death following internalization. The reported particles represent a novel and versatile class of stimuli‐responsive carriers for controlled drug delivery.  相似文献   

2.
A smart drug delivery system integrating both photothermal therapy and chemotherapy for killing cancer cells is reported. The delivery system is based on a mesoporous silica‐coated Pd@Ag nanoplates composite. The Pd@Ag nanoplate core can effectively absorb and convert near infrared (NIR) light into heat. The mesoporous silica shell is provided as the host for loading anticancer drug, doxorubicin (DOX). The mesoporous shell consists of large pores, ~10 nm in diameter, and allows the DOX loading as high as 49% in weight. DOX loaded core–shell nanoparticles exhibit a higher efficiency in killing cancer cells than free DOX. More importantly, DOX molecules are loaded in the mesopores shell through coordination bonds that are responsive to pH and heat. The release of DOX from the core‐shell delivery vehicles into cancer cells can be therefore triggered by the pH drop caused by endocytosis and also NIR irradiation. A synergistic effect of combining chemotherapy and photothermal therapy is observed in our core‐shell drug delivery system. The cell‐killing efficacy by DOX‐loaded core–shell particles under NIR irradiation is higher than the sum of chemotherapy by DOX‐loaded particles and photothermal therapy by core–shell particles without DOX.  相似文献   

3.
Nonviral gene carriers based on electrostatic interaction, encapsulation, or absorption require a large amount of polymer carrier to achieve reasonable transfection efficiencies. With cationic nanoparticles, for example, genes interact only with the surface of the nanoparticles, resulting in a low surface area to volume ratio (SA/V = 3/r). A large volume of carrier, therefore, is required to deliver a small copy number of genes. In this study, it is demonstrated that a nano‐self‐assembly of nucleic acids transfects itself into cells spontaneously, without the need for a gene carrier. The cellular uptake of this nanoassembly occurs through a number of endocytosis mechanisms. Once within the cell, the nanoassembly can escape endolysosomal vesicles and facilitate gene transfection. This nano‐self‐assembly consisting of zinc and plasmid DNA or siRNA, termed the Zn/DNA or Zn/siRNA nanocluster, is formed through the binding of Zn2+ ions to the phosphate groups of nucleic acids. The method described in this paper represents a new platform for carrier‐free gene delivery that can be used to deliver any plasmid DNA or siRNA without the requirement for a specific modification in the nucleic acids or complicated steps to prepare dense particles.  相似文献   

4.
The preparation of mesoporous nanocompartment films composed of both hollow silica capsules and silica particles by using layer‐by‐layer (LbL) adsorption is described. The resultant nanocompartment films exhibit stepwise release of encapsulated water molecules without application of external stimuli. The hollow hierarchic pore structure of the silica capsules, including their internal void and mesoporous walls, is a key factor for the regulation and stepwise release of water, and is probably caused by the non‐equilibrated concurrent evaporation of material from the mesopore and capillary penetration into the mesopores. The number of release steps and rate of release can be tuned by variation of several parameters including water content, ambient temperature, layer multiplicity, and co‐adduct particle size. Application of the mesoporous nanocompartment films for the release of substances, including therapeutic agents and fragrances, indicates that the stepwise material release can be applied for a wide range of liquid substances. The films should lead to a novel material release system useful even for biomedical applications capable of controlled and sustained delivery of drug molecules.  相似文献   

5.
A novel and flexible strategy involving hydrothermal transformation of guest‐incorporated zeolite‐seeded mesoporous silica spheres was proposed to prepare guest‐encapsulated hollow zeolite spheres and three‐dimensionally (3D) ordered macroporous zeolite monoliths. The guest species that were pre‐incorporated into the mesopores of silica spheres could be spontaneously encapsulated inside the formed hollow zeolite shells by consuming silica nutrition of the original mesoporous silica cores during the hydrothermal process. A wide range of guest materials with a size ranging from nanometers to micrometers, e.g., Ag and PdO nanoparticles, and mesoporous spheres of carbon and polymer of micrometer size were successfully encapsulated into both discrete hollow zeolite spheres and 3D ordered macroporous zeolite monoliths. Such materials are expected to find a variety of applications such as catalysis, adsorption, and novel microreactors for their special structures with active species inside and zeolitic porous shell outside.  相似文献   

6.
Selective targeting of tumor cells and release of drug molecules inside the tumor microenvironment can reduce the adverse side effects of traditional chemotherapeutics because of the lower dosages required. This can be achieved by using stimuli‐responsive targeted drug delivery systems. In the present work, a robust and simple one‐pot route is developed to synthesize polymer‐gatekeeper mesoporous silica nanoparticles by noncovalent capping of the pores of drug‐loaded nanocontainers with disulfide cross‐linkable polymers. The method offers very high loading efficiency because chemical modification of the mesoporous nanoparticles is not required; thus, the large empty pore volume of pristine mesoporous silica nanoparticles is entirely available to encapsulate drug molecules. Furthermore, the polymer shell can be easily decorated with a targeting ligand for selective delivery to specific cancer cells by subsequent addition of the thiol‐containing ligand molecule. The drug molecules loaded in the nanocontainers can be released by the degradation of the polymer shell in the intracellular reducing microenvironment, which consequentially induces cell death.  相似文献   

7.
The development of a versatile class of silica nanoparticles for cell studies is reported. The particles contain a fluorescent dye‐encoded core and a single‐stranded DNA oligonucleotide‐displaying shell. They are accessible in arbitrary size and color through robust protocols for Stöber‐based colloidal synthesis and sturdy chemical surface functionalization. Silica particles in the size range of 100 nm to 1.5 µm diameter containing fluorescein, Cy3 oder Cy5 dye‐encoded cores are synthesized and functionalized with DNA oligonucleotides. These silica biopebbles are conveniently traceable by microscopy and have a high affinity to live cells, which makes them ideal for cell uptake studies, as demonstrated for MCF7 and A431 cancer cells. The biopebbles can be utilized as building blocks for the self‐assembled formation of arbitrary surface patterns on glass substrates. With these architectures, the privileged internalization of the biopebbles can be exploited for improved adhesion and guidance of cells because the particles are no longer ingested by adhered cells due to their physical connection with the solid support. It is believed that the biopebble approach will be useful for a variety of applications, fundamental studies in cell biology and tissue engineering.  相似文献   

8.
Smart drug delivery systems with on‐demand drug release capability are rather attractive to realize highly specific cancer treatment. Herein, a novel light‐responsive drug delivery platform based on photosensitizer chlorin e6 (Ce6) doped mesoporous silica nanorods (CMSNRs) is developed for on‐demand light‐triggered drug release. In this design, CMSNRs are coated with bovine serum albumin (BSA) via a singlet oxygen (SO)‐sensitive bis‐(alkylthio)alkene (BATA) linker, and then modified with polyethylene glycol (PEG). The obtained CMSNR‐BATA‐BSA‐PEG, namely CMSNR‐B‐PEG, could act as a drug delivery carrier to load with either small drug molecules such as doxorubicin (DOX), or larger macromolecules such as cis‐Pt (IV) pre‐drug conjugated third generation dendrimer (G3‐Pt), both of which are sealed inside the mesoporous structure of nanorods by BSA coating. Upon 660 nm light irradiation with a rather low power density, CMSNRs with intrinsic Ce6 doping would generate SO to cleave BATA linker, inducing detachment of BSA‐PEG from the nanorod surface and thus triggering release of loaded DOX or G3‐Pt. As evidenced by both in vitro and in vivo experiments, such CMSNR‐B‐PEG with either DOX or G3‐Pt loading offers remarkable synergistic therapeutic effects in cancer treatment, owing to the on‐demand release of therapeutics specifically in the tumor under light irradiation.  相似文献   

9.
Targeted delivery remains the major limitation in the development of small interfering RNA (siRNA) therapeutics. The successful siRNA multistep delivery requires precise carriers of substantial complexity. To achieve this, a monodisperse carrier is presented, synthesized by solid‐phase supported chemistry. The sequence‐defined assembly contains two oleic acids attached to a cationizable oligoaminoamide backbone in T‐shape configuration, and a terminal azide functionality for coupling to the atherosclerotic plaque‐specific peptide‐1 (AP‐1) as the cell targeting ligand for interleukin‐4 receptor (IL‐4R) which is overexpressed in a variety of solid cancers. For combined cytosolic delivery with siRNA, different apoptotic peptides (KLK, BAK, and BAD) are covalently conjugated via bioreversible disulfide linkage to the 5′‐end of the siRNA sense strand. siRNA‐KLK conjugates provide the highest antitumoral potency. The optimized targeted carrier is complexed with dual antitumoral siEG5‐KLK conjugates. The functionality of each subdomain is individually confirmed. The lipo‐oligomer confers stable assembly of siRNA conjugates into spherical 150–250 nm sized nanoparticles. Click‐shielding with dibenzocyclootyne‐PEG‐AP‐1 (DBCO‐PEG‐AP‐1) mediates an IL‐4R‐specific cell targeting and gene silencing in tumor cells. Most importantly, formulation of the siEG5‐KLK conjugate displays enhanced apoptotic tumor cell killing due to the combined effect of mitotic arrest by EG5 gene silencing and mitochondrial membrane disruption by KLK.  相似文献   

10.
In order to create advanced functional nanocarriers for efficient gene therapy, novel intracellular microenvironment‐sensitive fluorescence label‐free nanostructured dendrimer‐like silica hybrid nanocarriers are developed for traceable, effective, and safe gene delivery. Dendrimer‐like mesoporous silica nanoparticles (DMSNs) with center‐radial large pores are covalently modified with short polyethyleneimine (PEI) for efficient gene loading and binding. Autofluorescent and biodegradable PEI (AC‐PEI) responsive to the intracellular microenvironment are then coated on the gene‐loaded nanoparticles for inhibiting gene leakage from the carriers. Moreover, AC‐PEI coating not only endows intracellular microenvironment‐responsive gene release property, but also allows monitoring the gene delivery process in the absence of external labelling, owing to the pH‐ and GSH‐responsive autofluorescence and biodegradability of AC‐PEI. The resultant nanocarriers show high gene loading capacity, low cytotoxicity, stimuli‐responsive gene release, label‐free, and simultaneous fluorescence tracking, and high gene silencing capability. Thus, these developed nanocarriers hold substantial and promising potential as effective and safe gene‐delivery carriers for future scientific investigation and practical implications in gene therapy.  相似文献   

11.
Synergistic therapy that combines chemo‐, gene‐, or photothermal means shows great potential for enhancing the therapeutic effects on cancers. Tumor‐targeted nanoparticles based on a doxorubicin (DOX)‐gated mesoporous silica nanocore (MSN) encapsulated with permeability glycoprotein (P‐gp) small interfering RNA (siRNA) and a polydopamine (PDA) outer layer for DOX loading and folic acid decoration are designed. The multifunctional nanoplatform tactfully integrates chemo‐ (DOX), gene‐ (P‐gp siRNA), and photothermal (PDA layer) substances in one system. In vitro results reveal that DOX release behaviors are both pH‐ and thermal‐responsive and the release of co‐delivered P‐gp siRNA is also pH‐dependent due to the pH‐cleavable DOX gatekeeper on MSN. In addition, due to the near‐infrared light‐responsive PDA outer layer and folic acid conjugation, the nanoparticles exhibit outstanding photothermal activity and selective cell targeting ability. Subsequently, in vitro and in vivo antitumor experiments both demonstrate the enhanced antitumor efficacy of the multifunctional nanoparticles, indicating the significance of synergistic therapy combining chemo‐, gene‐, and photothermal treatments in one system.  相似文献   

12.
A new concept is proposed to synthesize mesoporous magnetic nanocomposite particles of great scientific and technological importance. Mesoporous silica coatings were created on micrometer‐sized magnetite (Fe3O4) particles using cetyltrimethylammonium chloride micelles as molecular templates. The characterization by transmission electron microscopy (TEM), nitrogen adsorption–desorption, diffuse‐reflectance Fourier‐transform infrared spectroscopy, and zeta‐potential measurements confirmed the deposition of mesoporous silica thin layers on the magnetite particles. The synthesized particles showed a drastic increase in specific surface area with an average pore size of 2.5 nm. The coating material showed a negligible effect on the saturation magnetization of the original particles that were fully protected by silica coatings. The synthesized mesoporous magnetic nanocomposite particles have a wide range of applications in toxin removal, waste remediation, catalysis, reactive sorbents, and biological cell separations.  相似文献   

13.
In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. A new nanoparticle construct that is engineered for efficient delivery of siRNA to tumors is now described. The construct comprises a 47‐nm mesoporous silica nanoparticle core coated with a crosslinked polyethyleneimine–polyethyleneglycol copolymer, carrying siRNA against the human epidermal growth factor receptor type 2 (HER2) oncogene, and coupled to the anti‐HER2 monoclonal antibody (trastuzumab). The construct is engineered to increase siRNA blood half‐life, enhance tumor‐specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti‐HER2 nanoparticles produce apoptotic death in HER2 positive (HER2+) breast cancer cells grown in vitro, but not in HER2 negative (HER2?) cells. One dose of the siHER2–nanoparticles reduces HER2 protein levels by 60% in trastuzumab‐resistant HCC1954 xenografts. Administration of multiple intravenous doses over 3 weeks significantly inhibits tumor growth (p < 0.004). The siHER2‐nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch‐to‐batch reproducibility and the production methods are suitable for large‐scale production. These results suggest that this siHER2‐nanoparticle is ready for clinical evaluation.  相似文献   

14.
The successful therapeutic application of small interfering RNA (siRNA) largely relies on the development of safe and effective delivery systems that are able to guide the siRNA therapeutics to the cytoplasm of the target cell. In this report, biodegradable cationic dextran nanogels are engineered by inverse emulsion photopolymerization and their potential as siRNA carriers is evaluated. The nanogels are able to entrap siRNA with a high loading capacity, based on electrostatic interaction. Confocal microscopy and flow cytometry analysis reveal that large amounts of siRNA‐loaded nanogels can be internalized by HuH‐7 human hepatoma cells without significant cytotoxicity. Following their cellular uptake, it is found that the nanogels are mainly trafficked towards the endolysosomes. The influence of two different strategies to enhance endosomal escape on the extent of gene silencing is investigated. It is found that both the application of photochemical internalization (PCI) and the use of an influenza‐derived fusogenic peptide (diINF‐7) can significantly improve the silencing efficiency of siRNA‐loaded nanogels. Furthermore, it is shown that an efficient gene silencing requires the degradation of the nanogels. As the degradation kinetics of the nanogels can easily be tailored, these particles show potential for intracellular controlled release of short interfering RNA.  相似文献   

15.
Two novel porous nitrosamine traps have been synthesized in order to eliminate carcinogens from the environment. A functional mesoporous material, CuO/SBA‐15, has been synthesized by using an in‐situ coating method, with the addition of a guest salt to the reaction system to modify the porous materials before the particles of SBA‐15 were incubated; the synthesis and modification processes were performed in a single step. The resulting mesoporous composites selectively adsorb N‐nitrosopyrrolidine (NPYR), a typical volatile nitrosamine, and are potential cigarette additives that can be used for the removal of nitrosamines from cigarette smoke, thereby protecting public health and the environment. In another reaction, silica gel is modified by being coated with magnesia and then corroded by NaOH solution.The magnesia is dispersed onto the silica by impregnating it with a magnesium acetate solution, followed by calcination. After corrosion of the calcined sample with caustic soda, only the silica particles that are completely covered by magnesia remain. This material exhibits a similar ability to SBA‐15 and zeolite NaY in its selective adsorption of NPYR.  相似文献   

16.
Among the mesoporous silica micellar templated structures (MTSs), MSU‐X silica, obtained through an N0I0 assembly between non‐ionic polyethyleneoxide‐based surfactants (N0) and silica neutral inorganic precursors (I0), exhibits a regular ordered structure with a 3D wormhole porous framework and an easily controlled pore size. These materials have been tested for applications requiring both a narrow mesopore size distribution and isotropic properties. A specific double‐step synthesis that we developed recently for MSU‐X materials has allowed us to prepare mesoporous silica particles with the required shape, size, and properties. Both the particles’ synthesis and comparative HPLC separation tests with a commercial ungrafted silica HPLC powder of identical shape and size are reported.  相似文献   

17.
Periodic mesoporous organosilica nanoparticles emerge as promising vectors for nanomedicine applications. Their properties are very different from those of well‐known mesoporous silica nanoparticles as there is no silica source for their synthesis. So far, they have only been synthesized from small bis‐silylated organic precursors. However, no studies employing large stimuli‐responsive precursors have been reported on such hybrid systems yet. Here, the synthesis of porphyrin‐based organosilica nanoparticles from a large octasilylated metalated porphyrin precursor is described for applications in near‐infrared two‐photon‐triggered spatiotemporal theranostics. The nanoparticles display unique interconnected large cavities of 10–80 nm. The framework of the nanoparticles is constituted with J‐aggregates of porphyrins, which endows them with two‐photon sensitivity. The nanoparticle efficiency for intracellular tracking is first demonstrated by the in vitro near‐infrared imaging of breast cancer cells. After functionalization of the nanoparticles with aminopropyltriethoxysilane, two‐photon‐excited photodynamic therapy in zebrafish is successfully achieved. Two‐photon photochemical internalization in cancer cells of the nanoparticles loaded with siRNA is also performed for the first time. Furthermore, siRNA targeting green fluorescent protein complexed with the nanoparticles is delivered in vivo in zebrafish embryos, which demonstrates the versatility of the nanovectors for biomedical applications.  相似文献   

18.
Naturally derived nanovesicles secreted from various cell types and found in body fluids can provide effective platforms for the delivery of various cargoes because of their intrinsic ability to be internalized for intercellular signal transmission and membrane recycling. In this study, the versatility of bioengineered extracellular membranous nanovesicles as potent carriers of small‐interfering RNAs (siRNAs) for stem cell engineering and in vivo delivery has been explored. Here, exosomes have been engineered, one of the cell‐derived vesicle types, to overexpress exosomal proteins fused with cell‐adhesion or cell‐penetrating peptides for enhanced intracellular gene transfer. To devise a more effective delivery system with potential for mass production, a new siRNA delivery system has also been developed by artificially inducing the outward budding of plasma membrane nanovesicles. Those nanovesicles have been engineered by overexpressing E‐cadherin to facilitate siRNA delivery to human stem cells with resistance to intracellular gene transfer. Both types of engineered nanovesicles deliver siRNAs to human stem cells for lineage specification with negligible cytotoxicity. The nanovesicles are efficient in delivering siRNA in vivo, suggesting feasibility for gene therapy. Cell‐derived, bioengineered nanovesicles used for siRNA delivery can provide functional platforms enabling effective stem cell therapeutics and in vivo gene therapy.  相似文献   

19.
Considering the problems of small interfering RNA (siRNA) delivery using traditional viral and nonviral vehicles, a new siRNA delivery system to enhance efficiency and safety needs to be developed. Here human ferritin‐based proteinticles are genetically engineered to simultaneously display various functional peptides on the surface of proteinticles: cationic peptide to capture siRNA, tumor cell targeting and penetrating peptides, and enzymatically cleaved peptide to release siRNA inside tumor cell. In the in vitro treatment of poly‐siRNA‐proteinticle complex, both of the tumor cell targeting and penetrating peptides are important for efficient delivery of siRNA, and the red fluorescent protein (RFP) expression in RFP‐expressing tumor cells is notably suppressed by the delivered siRNA with the complementary sequence to RFP mRNA. It seems that the human ferritin‐based proteinticle is an efficient, stable, and safe tool for siRNA delivery, having a great potential for application to in vivo cancer treatment. The unique feature of proteinticles is that multiple and functional peptides can be simultaneously and evenly placed and also easily switched on the proteinticle surface through a simple genetic modification, which is likely to make proteinticles appropriate for targeted delivery of siRNA to a wide range of cancer cells.  相似文献   

20.
Recently, we demonstrated the possibility of synthesizing ordered nanowires of diluted magnetic II/VI semiconductors inside the channels of mesoporous silica host structures. Here, we expand this procedure from mesoporous powders to mesoporous thin films. Diluted magnetic semiconductors Cd1–xMnxS were synthesized within the pores of mesoporous thin‐film silica host structures by a wet‐impregnation technique using an aqueous solution of the respective metal acetates, followed by drying steps and a conversion to sulfide by thermal H2S treatment. The presence of Cd1–xMnxS nanoparticles inside the pores was proved by powder X‐ray diffraction, infrared and Raman spectroscopy, and transmission electron microscopy. Photoluminescence excitation measurements clearly demonstrate the quantum size effect of the incorporated nanostructured guest species. The quality of the nanoparticles incorporated into the mesoporous films is comparable to that of those inside the mesoporous powders.  相似文献   

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