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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   

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Photodynamic therapy (PDT) is a well‐established clinical treatment modality for various diseases. However, reactive oxygen species (ROS) generated by photosensitizers(PS) under proper irradiation exhibits the extremely short life span (<200 ns) and severely limited diffusion distance (20 nm), so the damage of ROS to biomolecules, especially DNA, is strongly confined to the immediate vicinity of ROS generation. In this report, an efficient nuclear‐targeted delivery strategy is proposed by using TAT and RGD peptides co‐conjugated mesoporous silica nanoparticles (MSNs) as PS carriers. The conjugation of TAT peptides enable the nuclear penetration of MSNs for efficient accumulation of PS inside nuclei. The intranuclear‐accumulated PS can generate ROS upon irradiation right inside nuclei to destroy DNA instantaneously. For the purpose of in vivo applications, the co‐conjugated RGD peptides endow the nuclear‐targeted delivery system with specific binding and recognition to tumor vasculature and tumor cell membranes for significantly enhanced specificity and reduced side effects. Through intravenous injection of these nanosystems in tumor‐bearing mice at a rather low PS dose of 2 mg/kg, tumor growth is efficiently inhibited by an extremely low irradiation dose of 6 J/cm2. This work presents a new paradigm for specific PDT with high efficacy and low side effects in vivo.  相似文献   

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A series of poly(N‐isopropylacrylamide)‐coated mesoporous silica nanoparticle materials (PNiPAm‐MSNs) has been synthesized by a surface‐initiated living radical polymerization with a reversible addition–fragmentation chain transfer (RAFT) reaction. The structure and the degree of polymerization of the PNiPAm‐MSNs has been characterized by a variety of techniques, including nitrogen sorption analysis, 29Si and 13C solid‐state NMR spectroscopy, transmission electron microscopy (TEM), and powder X‐ray diffraction (XRD). The thermally induced changes of the surface properties of these polymer‐coated core–shell nanoparticles have been determined by examining their partition activities in a biphasic solution (water/toluene) at different temperatures.  相似文献   

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Mesoporous silica nanoparticles (MSN) can load and deliver potentially synergistic anticancer agents such as small molecule cytotoxics (like doxorubicin, DOX) and nucleic acids (like microRNA, miRNA). However, these cargos have different underlying chemical properties so overcoming respective intracellular delivery barriers is a key consideration. Strategies to deliver DOX from MSN frequently employ pH‐driven mechanisms that are restricted to the acidic environment of lysosomes. Conversely, strategies to deliver miRNA make use of approaches that deliberately compromise lysosomal membrane integrity to enable cytosolic delivery of the payload. To reconcile these two needs (lysosomal delivery of DOX and intracellular delivery of miRNA), a new methodology by “weaving” polyethylenimine on the MSN surface through disulfide bonds to achieve superior delivery of chemotherapy (DOX) and miRNA therapy (using miRNA‐145) is developed. Furthermore, an active targeting strategy based on a peptide ligand with affinity to glucose‐regulated protein 78 (GRP78), a cell surface protein overexpressed in colorectal carcinoma, is developed. The active targeting approach results in enhanced synergistic antitumor effect both in vitro and in vivo in an orthotopic murine model of colorectal cancer. Taken together, this work demonstrates the capability and advantages of “smart” MSN delivery systems to deliver anticancer cargo appropriately to targeted cancer cells.  相似文献   

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Mesoporous silica nanoparticles (MSNs) have emerged as promising biomaterials for drug delivery and cell tracking applications, for which MRI is the medical imaging modality of choice. In this contribution, MRI contrast agents (DTPA‐Gd) and polyethylene glycol (PEG) are grafted selectively at the surface of MSNs, in order to achieve optimal relaxometric and drug loading performances. In fact, DTPA and PEG grafting procedures reported until now, have resulted in significant pore obstruction, which is detrimental to the drug delivery function of MSNs. This usually induces a dramatic decrease in surface area and pore volume, thus limiting drug loading capacity. Therefore, these molecules must be selectively grafted at the outer surface of MSNs. In this study, 3D pore network MSNs (MCM‐48‐type) are synthesized and functionalized with a straightforward and efficient grafting procedure in which DTPA and PEG are selectively grafted at the outer surface of MSNs. No pore blocking is observed, and more than 90% of surface area, pore volume and pore diameter are retained. The thus‐treated particles are colloidally stable in SBF and cell culture media, they are not cytotoxic and they have high drug loading capacity. Upon labeling with Gd, the nanoparticle suspensions have strong relaxometric properties (r2/r1 = 1.47, r1 = 23.97 mM?1 s?1), which confers a remarkable positive contrast enhancement potential to the compound. The particles could serve as efficient drug carriers, as demonstrated with a model of daunorubicin submitted to physiological conditions. The selective nanoparticle surface grafting procedures described in the present article represent a significant advance in the design of high colloidal stability silica‐based vectors with high drug loading capacity, which could provide novel theranostic nanocompounds.  相似文献   

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Despite their advantageous morphological attributes and attractive physicochemical properties, mesoporous silica nanoparticles (MSNs) are merely supported as carriers or vectors for a reason. Incorporating various metal species in the confined nanospaces of MSNs (M‐MSNs) significantly enriches their mesoporous architecture and diverse functionalities, bringing exciting potentials to this burgeoning field of research. These incorporated guest species offer enormous benefits to the MSN hosts concerning the reduction of their eventual size and the enhancement of their performance and stability, among other benefits. Substantially, the guest species act through contributing to reduced aggregation, augmented durability, ease of long‐term storage, and reduced toxicity, attributes that are of particular interest in diverse fields of biomedicine. In this review, the first aim is to discuss the current advancements and latest breakthroughs in the fabrication of M‐MSNs, emphasizing the pros and cons, the confinement of various metal species in the nanospaces of MSNs, and various factors influencing the encapsulation of metal species in MSNs. Further, an emphasis on potential applications of M‐MSNs in various fields, including in adsorption, catalysis, photoluminescence, and biomedicine, among others, along with a set of examples is provided. Finally, the advances in M‐MSNs with perspectives are summarized.  相似文献   

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Multifunctional mesoporous silica nanoparticles are developed in order to deliver anticancer drugs to specific cancer cells in a targeted and controlled manner. The nanoparticle surface is functionalized with amino‐β‐cyclodextrin rings bridged by cleavable disulfide bonds, blocking drugs inside the mesopores of the nanoparticles. Poly(ethylene glycol) polymers, functionalized with an adamantane unit at one end and a folate unit at the other end, are immobilized onto the nanoparticle surface through strong β‐cyclodextrin/adamantane complexation. The non‐cytotoxic nanoparticles containing the folate targeting units are efficiently trapped by folate‐receptor‐rich HeLa cancer cells through receptormmediated endocytosis, while folate‐receptor‐poor human embryonic kidney 293 normal cells show much lower endocytosis towards nanoparticles under the same conditions. The nanoparticles endocytosed by the cancer cells can release loaded doxorubicin into the cells triggered by acidic endosomal pH. After the nanoparticles escape from the endosome and enter into the cytoplasm of cancer cells, the high concentration of glutathione in the cytoplasm can lead to the removal of the β‐cyclodextrin capping rings by cleaving the pre‐installed disulfide bonds, further promoting the release of doxorubicin from the drug carriers. The high drug‐delivery efficacy of the multifunctional nanoparticles is attributed to the co‐operative effects of folate‐mediated targeting and stimuli‐triggered drug release. The present delivery system capable of delivering drugs in a targeted and controlled manner provides a novel platform for the next generation of therapeutics.  相似文献   

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Nanoparticle-based combination therapy strategy of photothermal therapy (PTT) and immunotherapy is an attractive cancer treatment for ablating tumors and eliciting host immune responses. However, this strategy is often hampered by tedious treatment process and limited immune response, and usually needs to be combined with checkpoint blockades to enhance therapeutic effect. Herein, a nanoplatform with mesoporous silica nanoparticles (MSNs) as a vector, which integrated photothermal agent polydopamine (PDA), model antigen ovalbumin (OVA), and antigen release promoter ammonium bicarbonate (ABC) in an easy way for melanoma PTT-immunotherapy is designed. The formulated MSNs-ABC@PDA-OVA nanovaccine exhibits excellent photothermal properties and effectively eliminates primary tumors. Under laser irradiation, the MSNs-ABC@PDA-OVA nanovaccine realizes rapid antigen release and endosome escape, enhances dendritic cells activation and maturation, facilitates migration to tumor-draining lymph nodes, and induces robust antitumor immune responses. Impressively, single injection of MSNs-ABC@PDA-OVA combines with single round of PTT successfully eradicates melanoma tumors with a cure rate of 75% and generates strong immunological memory to inhibit tumor recurrence and lung metastasis. Hence, the research offers a simple and promising strategy of synergistic PTT-immunotherapy to effectively treat cancer.  相似文献   

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Mesoporous silica nanoparticles (MSNs) have been well‐demonstrated as excellent carriers for anticancer drug delivery. Presented here is a cancer‐targeted MSNs drug delivery system that allows the direct fluorescence monitoring of the cellular uptake and localization of theranostic agents in cancer cells. Specifically, the anticancer action mechanisms of RGD peptide‐functionalized MSNs carrying ruthenium polypyridyl complexes (RuPOP@MSNs) are elucidated in detail. RGD peptide surface decoration significantly enhances the cellular uptake of the nanoparticles through receptor‐mediated endocytosis, and increases the selectivity between cancer and normal cells. RuPOP@MSNs exhibits unprecedented enhanced cytotoxicity toward cancer cells overexpressing integrin receptor, which is significantly higher than that of free RuPOP, through induction of apoptosis. The important contribution of extrinsic pathway to cell apoptosis is confirmed by increase in expression levels of death receptors, activation of caspase‐8 and truncation of Bid. The internalized nanoparticles release free RuPOP into the cytoplasm, where they modulate the phosphorylation of p53, AKT, and MAPKs pathways to promote cell apoptosis. Moreover, the strong autofluorescence of RuPOP permits the direct monitoring of drug delivery, and extends the power of theranostics to subcellular level. Taken together, this study provides an effective strategy for the design and development of cancer‐targeted theranostic agents.  相似文献   

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In recent years, nanomedicine has emerged at the forefront of nanotechnology, generating great expectations in the biomedical field. Researchers are developing novel nanoparticles for both diagnostic applications using imaging technology and treatment purposes through drug delivery technologies. Among all the available nanoparticles, inorganic mesoporous silica nanoparticles are the newcomers to the field, contributing with their unique and superlative properties. A brief overview of the most recent progress in the synthesis of mesoporous silica nanoparticles and their use as drug delivery nanocarriers is provided. The latest trends in this type of nanoparticles and their use in modern medicine are discussed, highlighting the significant impact that this technology might have in the near future.  相似文献   

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Great efforts have been devoted so far to combine nano‐magnetic hyperthermia and nano‐photothermal therapy to achieve encouraging additive therapeutic performance in vitro and in vivo with limitation to direct intratumoral injection and no guidance of multimodality molecular imaging. In this study, a novel multifunctional theranostic nanoplatform (MNP@PES‐Cy7/2‐DG) consisting of magnetic nanoparticles (MNPs), poly(3,4‐ethylenedioxythiophene):poly(4‐styrenesulfonate) (PES), Cyanine7 (Cy7), and 2‐deoxyglucose (2‐DG)‐polyethylene glycol is developed. They are then applied to combined photo‐magnetic hyperthermia therapy under intravenous administration that is simultaneously guided by trimodality molecular imaging. Remarkably, nanoparticles are found aggregated mainly in the cytoplasm of tumor cells in vitro and in vivo, and exhibit stealth‐like behavior with a long second‐phase blood circulation half‐life of 20.38 ± 4.18 h. Under the guidance of photoacoustic/near‐infrared fluorescence/magnetic resonance trimodality imaging, tumors can be completely eliminated under intracellular photo‐magnetic hyperthermia therapy with additive therapeutic effect due to precise hyperthermia. This study may promote a further exploration of such a platform for clinical applications.  相似文献   

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Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.  相似文献   

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A high‐performance molecular gating system for efficient capping and delivery of hydrophilic cargo is reported. It integrates a mesoporous silica nanoparticle core and a lipid bilayer (LB) shell by covalent tethering via a hyperbranched polyethylenimine (PEI) cushion. When using calcein as a general model for hydrophilic drug molecules, a high payload is loaded into the porous structure due to greatly enhanced concentration of amino groups on the pore walls. Surprisingly, LB non‐disruptively resides on the porous surface in this system, despite the strong positive charge from PEI, originating from the covalent tethering of the inner leaflet, as well as preferential spanning over the pore openings facilitated by the stretching of PEI chains on the particle surface. An unprecedented high retention of negatively charged hydrophilic guest molecules after up to 1 week is consequently achieved, even in the presence of a membrane disrupting agent. Furthermore, a PEI‐induced charge conversion at neutral pH is conferred to the particles using a zwitterionic PC lipid as the outer leaflet of LB. Interestingly, the corresponding nanocarriers are able to promote cargo escape from endosomes. Subsequent delivery of the loaded hydrophilic cargo to the cytoplasm is observed despite the tight retention under extracellular conditions.  相似文献   

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We synthesized mesoporous silica nanoparticles (MSN) with different densities of surface positive charges. The positive surface charge was generated by incorporating trimethylammonium (TA) functional groups into the framework of MSN (MSN–TA) via direct co‐condensation of a TA‐silane and tetraethoxysilane (TEOS) in the presence of a base as a catalyst. These MSN–TA samples have well‐defined hexagonal structures with an average particle diameter of 100 nm, pore size of 2.7 nm, and surface area of about 1000 m2 g?1. Anionic drug molecules, Orange II (a fluorescent tracing molecule), and sulfasalazine (an anti‐inflammatory prodrug used for bowel disease), were effectively loaded into these MSN–TA samples and remained inside of the MSN–TA under acidic environment (pH 2–5). The amounts of loading of both Orange II and sulfasalazine were increased with increasing positive charge densities resulting from the increasing number of TA groups. When these drug‐loaded MSN–TA nanoparticles were placed in physiological buffer solution (pH 7.4), a partial negative surface charge on the MSN–TA was generated due to the deprotonation of silanol groups, and the strong electrostatic repulsion triggered a sustained release of the loaded molecules. MSN–TA as a nanovehicle for pH‐dependent loading and controllable release of anionic drug molecules can be used as an oral delivery drug systems targeting at intestine. These drugs can be remained trapped in the nanovehicle when passing through the stomach's acidic environment and be released in intestine where the environmental pH is close to neutral.  相似文献   

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Photodynamic therapy (PDT) is a noninvasive and site‐specific therapeutic technique for the clinical treatment of various of superficial diseases. In order to tuning the operation wavelength and improve the tissue penetration of PDT, rare‐earth doped upconversion nanoparticles (UCNPs) with strong anti‐stokes emission are introduced in PDT recently. However, the conventional Yb3+‐sensitized UCNPs are excited at 980 nm which is overlapped with the absorption of water, thus resulting in strong overheating effect. Herein, a convenient but effective design to obtain highly emissive 795 nm excited Nd3+‐sensitized UCNPs (NaYF4:Yb,Er@NaYF4:Yb0.1Nd0.4@NaYF4) is reported, which provides about six times enhanced upconversion luminescence, comparing with traditional UCNPs (NaYF4:Yb,Er@NaYF4). A colloidal stable and non‐leaking PDT nanoplatform is fabricated later through a highly PEGylated mesoporous silica layer with covalently linked photosensitizer (Rose Bengal derivative). With as‐prepared Nd3+‐sensitized UCNPs, the nanoplatform can produce singlet oxygen more effective than traditional UCNPs. Significant higher penetration depth and lower overheating are demonstrated as well. All these features make as‐prepared nanocomposites excellent platform for PDT treatment. In addition, the nanoplatform with uniform size, high surface area, and excellent colloidal stability can be extended for other biomedical applications, such as imaging probes, biosensors, and drug delivery vehicles.  相似文献   

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