Temperature-sensitive polypeptide brushes-coated mesoporous silica nanoparticles for dual-responsive drug release

A multifunctional nanohybrid based on mesoporous silica nanoparticle and biocompatible polypeptide was fabricated for targeted and dual-responsive therapy of tumor cells.     

Dual pH and glucose sensitive gel gated mesoporous silica nanoparticles for drug delivery

A low-molecular-weight gel with dual pH and glucose sensitivity was designed as the gate controller for mesoporous silica nanoparticles (MSNs) to fabricate a smart drug delivery system. The smart gel caped MSNs could control the antidiabetic drug release via the detection of glucose and pH levels.     

Mesoporous silica nanoparticles for 19F magnetic resonance imaging,fluorescence imaging,and drug delivery

Multifunctional mesoporous silica nanoparticles (MSNs) are good candidates for multimodal applications in drug delivery, bioimaging, and cell targeting. In particular, controlled release of drugs from MSN pores constitutes one of the superior features of MSNs. In this study, a novel drug delivery carrier based on MSNs, which encapsulated highly sensitive ¹⁹F magnetic resonance imaging (MRI) contrast agents inside MSNs, was developed. The nanoparticles were labeled with fluorescent dyes and functionalized with small molecule-based ligands for active targeting. This drug delivery system facilitated the monitoring of the biodistribution of the drug carrier by dual modal imaging (NIR/¹⁹F MRI). Furthermore, we demonstrated targeted drug delivery and cellular imaging by the conjugation of nanoparticles with folic acid. An anticancer drug (doxorubicin, DOX) was loaded in the pores of folate-functionalized MSNs for intracellular drug delivery. The release rates of DOX from the nanoparticles increased under acidic conditions, and were favorable for controlled drug release to cancer cells. Our results suggested that MSNs may serve as promising ¹⁹F MRI-traceable drug carriers for application in cancer therapy and bio-imaging.     

A dual-responsive hyaluronic acid nanocomposite hydrogel drug delivery system for overcoming multiple drug resistance

Chemotherapy is restricted by efficient drug outflow due to the multiple drug resistance (MDR) in heterogenous nature of tumor. Herein, we present a dual-responsive hyaluronic acid (HA) nanocomposite hydrogel that can not only response to the tumor microenvironment but also enhance chemotherapy. This HA hydrogel consists of a core-shell SiO₂ (GOD@SiO₂-Arg) and mesoporous silica nanoparticles (MSNs) with doxorubicin (DOX) as the cargo (DOX@MSN). It could rapidly release the GOD@SiO₂-Arg nanoparticles at the low pH tumor-specific environment due to the cleavage of imine bond. GOD@SiO₂-Arg activated by over-expressed glutathione (GSH) in tumor cells releases GOD due to the cleavage of disulfide bonds, which could oxidize glucose to produce hydrogen peroxide (H₂O₂) for in situ NO generation via reaction between Arg and H₂O₂. The validity of this study might provide a method to modulate the tumor microenvironment for enhancing chemotherapy.     

Redox‐ and Temperature‐Controlled Drug Release from Hollow Mesoporous Silica Nanoparticles

A controlled drug‐delivery system has been developed based on mesoporous silica nanoparticles that deliver anticancer drugs into cancer cells with minimized side effects. The copolymer of two oligo(ethylene glycol) macromonomers cross‐linked by the disulfide linker N,N′‐bis(acryloyl)cystamine is used to cap hollow mesoporous silica nanoparticles (HMSNs) to form a core/shell structure. The HMSN core is applied as a drug storage unit for its high drug loading capability, whereas the polymer shell is employed as a switch owing to its redox/temperature dual responses. The release behavior in vitro of doxorubicin demonstrated that the loaded drugs could be released rapidly at higher temperature or in the presence of glutathione (GSH). Thus, the dual‐stimulus polymer shell exhibiting a volume phase transition temperature higher than 37 °C can effectively avoid drug leakage in the bloodstream owing to the swollen state of the shell. Once internalized into cells, the carriers shed the polymer shell because of cleavage of the disulfide bonds by GSH, which results in the release of the loaded drugs in cytosol. This work may prove to be a significant development in on‐demand drug release systems for cancer therapy.     

Metallo‐Supramolecular Nanogels for Intracellular pH‐Responsive Drug Release

A simple process is developed to fabricate metallo‐supramolecular nanogels (MSNs) by the metallo‐supramolecular‐coordinated interaction between histidine and iron‐meso‐tetraphenylporphin. MSNs are composed of histidine‐modified dextran (DH) and iron‐meso‐tetraphenylporphin (Fe–Por) and exhibit excellent biocompatibility and stability. MSNs show pH responsiveness in the intracellular mildly acidic environment, which has great potential for acid‐triggered drug release delivery. In vitro drug release profiles demonstrate that the pH‐dependent disassembly of MSNs to histidine and Por results in a quicker release rate of loaded‐DOX at pH 5.3, while at pH 7.4 MSNs could hinder the release of loaded‐DOX due to the enhanced stability of MSNs.

     

Application of G-quadruplex aptamer conjugated MSNs to deliver ampicillin for suppressing S. aureus biofilm on mice bone

Staphylococcus aureus is a common bacterial agent of biofilm formation in medical environments. The formed biofilm of this bacterium in bone tissue is one of the main causes of osteomyelitis, which is a serious health issue. Due to the importance of this infection after traumatic injuries or surgical intervention, it is necessary to develop a system that could release the antibiotics at the site of injury, specifically and gradually. The current study aimed to develop a nanosystem composed of single-stranded G-quadreplex DNA aptamer as the bio-recognition element, mesoporous silica nanoparticles (MSNs) as the carrier for gradual drug release, and Ampicillin as the cargo to be delivered to the site of infection. In silico methods were used to select an optimum binding aptamer against protein A of S. aureus. The binding of aptamer was confirmed via gel retardation assay, DLS, and Zeta potential analyses. The loading of the drug was confirmed by the FTIR method, and the drug release investigation showed almost 30 % of drug release via 48 h dialysis assay. The acquired results from the biofilm suppression assay indicated that this system provides a significant inhibitory effect against the S. aureus biofilm and has a high potential for the desired drug release to prevent the formation of biofilm, and could destroy the biofilm on the mice bone. The results of the MTT assay proved that this system does not pose a significant toxicity thread for MCF-7 cell viability, as a model for eukaryotic cells. In vivo studies are required to further confirm the efficacy of this system against S. aureus biofilm on bone.     

Functionalized mesoporous silica nanoparticles templated by pyridinium ionic liquid for hydrophilic and hydrophobic drug release application

Chemotherapy is the most common treatment for all cancer patients but this treatment poses many side effects due to lack of drug’s selectivity. To overcome this problem, utilizing a better and more effective delivery agent is the solution. Mesoporous silica nanoparticles (MSNs) emerged as a promising platform in development of drug delivery agent. This is due to its desirable properties such as tunable pores, large surface area, good biocompatibility and easy functionalization. Furthermore, these properties can be tuned through the utilization of alternative template such as pyridinium ionic liquid. Besides, by employing surface functionalization, the effectiveness of MSNs as drug delivery agent may also increase. This work reported the usage of 1-hexadecylpyridinium bromide ionic liquid as template for MSNs production and the surface of MSNs was then further functionalized via post – grafting method in order to obtain MSN – NH₂, MSN – SH and MSN – COOH as drug carrier, respectively. These functionalized MSNs were then used to study the drug loading and drug release of hydrophilic drug, gemcitabine and hydrophobic drug, quercetin. For quercetin, MSN-NH₂ had the highest drug loading percentage (72%) and slowest release (14%) in 48 h while for gemcitabine, it was found that MSN-COOH had the highest drug loading percentage (45%) and slowest release (15%) in 48 h. Based on the results, it is suggested that mesoporous silica nanoparticle with surface functionalization has suitable properties for controlled drug release which gives constant release behavior over a period of time to avoid repeated administration of drug where the drug is administered at a fixed dosage and regular time interval.     

Visible Light and pH Responsive Polymer‐Coated Mesoporous Silica Nanohybrids for Controlled Release

A visible light and pH responsive anticancer drug delivery system based on polymer‐coated mesoporous silica nanoparticles (MSNs) has been developed. Perylene‐functionalized poly(dimethylaminoethyl methacrylates) sensitive to visible light and pH are electrostatically attached on the surface of MSNs to seal the nanopores. Stimulation of visible light and acid can unseal the nanopores to induce controlled drug release from the MSNs. More interestingly, the release can be enhanced under the combined stimulation of the dual‐stimuli. The synergistic effect of visible light and acid stimulation on the efficient release of anticancer drugs from the nanohybrids endows the system with great potential for cancer therapy.

     

NMR in chiral polypeptide liquid crystals: the problem of amines

It is shown that lyotropic liquid crystal mixtures made of poly-γ-benzyl-l-glutamate (PBLG) dissolved in N,N-dimethylformamide (DMF) are efficient anisotropic NMR solvents to distinguish the enantiomers of chiral amines through the effects of the differential ordering of enantiomers. This type of solvent overcomes problems often encountered when dissolving amines into the more conventional PBLG/CHCl₃ or PBLG/CH₂Cl₂ liquid crystals. Furthermore, it is shown that perdeuterobenzyl chloride is an excellent achiral deuterated derivatizing agent for enantiomeric excess measurements of chiral amines in conjunction with the PBLG/DMF solvent.     

Self‐Propelled Janus Mesoporous Silica Nanomotors with Sub‐100 nm Diameters for Drug Encapsulation and Delivery

The synthesis of an innovative self‐propelled Janus nanomotor with a diameter of about 75 nm that can be used as a drug carrier is described. The Janus nanomotor is based on mesoporous silica nanoparticles (MSNs) with chromium/platinum metallic caps and propelled by decomposing hydrogen peroxide to generate oxygen as a driving force with speeds up to 20.2 μm s^?1 (about 267 body lengths per second). The diffusion coefficient (D) of nanomotors with different H₂O₂ concentrations is calculated by tracking the movement of individual particles recorded by means of a self‐assembled fluorescence microscope and is significantly larger than free Brownian motion. The traction of a single Janus MSN nanomotor is estimated to be about 13.47×10^?15 N. Finally, intracellular localization and drug release in vitro shows that the amount of Janus MSN nanomotors entering the cells is more than MSNs with same culture time and particle concentrations, meanwhile anticancer drug doxorubicin hydrochloride loaded in Janus MSNs can be slowly released by biodegradation of lipid bilayers in cells.     

A pH‐Responsive Hydrogel Based on a Tumor‐Targeting Mesoporous Silica Nanocomposite for Sustained Cancer Labeling and Therapy

A facile strategy is presented to synthesize hyaluronic acid (HA) and a fluorescein isothiocyanate (FITC)‐conjugated mesoporous silica nanocomposite (MSN) with multiple functions of fluorescence, tumor‐cell targeting, pH‐triggered gelation, and enzyme‐responsive drug release. This injectable nanocomposite is able to indicate the entire tumor location and provides a microenvironment with rich anticancer drugs in and around tumor tissue for a long time, to avoid recrudescence. In this design, the mesoporous silica serves as the drug container, the FITC serves as a fluorescent probe, and the anchored HA plays multiple roles as drug‐release cap, tumor‐targeting points, and responsive gel matrix. Owing to the specific affinity between the HA on MSNs and the CD44 antigen over‐expressed on tumor cells, the MSNs can selectively attach to tumor cells. The nanocomposites then exploit the pH‐responsive interactions (hydrogen bonds) among the HA to self‐assemble in situ into a hydrogel around the tumor tissue. The resulting hydrogel gradually releases its payload (doxorubicin, anticancer drugs)‐loaded MSNs upon HA degradation in the presence of hyaluronidase‐1 (Hyal‐1), followed by endocytosis and intracellular drug release. All these properties have distinct benefits for tumor treatment, demonstrating that this device is a promising candidate for oncotherapy applications.

     

The synthesis, deprotection and properties of poly(γ-benzyl-l-glutamate)

Diethylamine, di-n-hexylamine, dicyclohexylamine and triethylamine have been used as initiators for the ring-opening polymerization of γ-benzyl-l-glutamate N-carboxyanhydride (BLG NCA) to synthesize poly(γ-benzyl-l-glutamate) (PBLG). The relationship between the molecular weight of PBLG and the molar ratio of monomer and initiator was studied. With dicyclohexylamine as initiator, the influence of monomer concentration, and reaction temperature and time on the polymerization of BLG NCA was examined. Three reagents were used for the deprotection of benzyl groups in PBLG, including hydrobromic acid/acetic acid (33 wt.%), NaOH aqueous solution and trimethylsilyl iodide (TMSI). Through examining the molecular weight of PLGA obtained using different deprotection methods, it was revealed that TMSI could minimize chain cleavage in the process of deprotection and retain the degree of polymerization. The biocompatibilities of PBLG obtained using different initiators were evaluated by a live/dead assay against L929 fibroblast cells. The in vitro cytotoxicities of PLGA obtained using different deprotecting agents were evaluated by a methyl thiazolyl tetrazolium assay. The results revealed that both PBLG and PLGA exhibited good biocompatibilities.     

P(VPBA-DMAEA) as a pH-sensitive nanovalve for mesoporous silica nanoparticles based controlled release

A pH-sensitive controlled release system was proposed in this work, which consists of mesoporous silica nanoparticles(MSNs) functionalized on the pore outlets with poly(4-vinylphenybronic acid-co-2-(dimethylamino)ethyl acrylate) [P(VPBA-DMAEA)]. Four kinds of P(VPBA-DMAEA)-gated MSNs were synthesized and applied for the p H-sensitive controlled release. The results showed that P(VPBADMAEA) can work as a p H-sensitive nanovalve. The release behavior of the hybrid nanoparticles could be adjusted by changing the mole ratio of VPBA and DMAEA. With the increasing of the mole ratio of VPBA,the leakage of the entrapped molecules in the pores of MSNs could be decreased at neutral and alkaline conditions. By altering the p H of buffer from 4.0 to 8.0, the valve could be switched ‘‘on' and ‘‘off'reversibly. In addition, cells viability results indicated that these P(VPBA-DMAEA)-gated MSNs had good biocompatibility. We believe that these MSNs based p H-sensitive controlled release system will provide a promising nanodevice for sited release of drug delivery.     

Enhanced Inhibition of Drug-Resistant Escherichia coli by Tetracycline Hydrochloride-Loaded Multipore Mesoporous Silica Nanoparticles

Drug-resistant bacterial infections exhibit a major threat to public health. Thus, exploring a novel antibacterial with efficient inhibition is urgently needed. Herein, this paper describes three types of MSNs (MSNs-FC2-R1, MSNs-FC2-R0.75, MSNs-FC2-R0.5) with controllable pore size (4–6 nm) and particle size (30–90 nm) that were successfully prepared. The MSNs were loaded with tetracycline hydrochloride (TCH) for effective inhibition of Escherichia coli (ATCC25922) and TCH-resistant Escherichia coli (MQ776). Results showed that the loading capacity of TCH in three types of MSNs was as high as over 500 mg/g, and the cumulative release was less than 33% in 60 h. The inhibitory rate of MSNs-FC2-R0.5 loaded with TCH against E. coli and drug-resistant E. coli reached 99.9% and 92.9% at the concentration of MIC, respectively, compared with the other two types of MSNs or free TCH. Modified MSNs in our study showed a great application for long-term bacterial growth inhibition.     

co-Condensation Synthesis of Salicylaldimine Calcium Complex Containing Mesoporous Silica Nanoparticles as Carriers for Drug Release

A series of functional mesoporous silica nanoparticles（MSNs） was synthesized by a one-step simple synthesis approach involving co-condensation of tetraethoxysilane（TEOS） and salicylaldimine ligand（Sal-Si） in the presence of cetyltrimethylammonium chloride（CTAC） under basic conditions.The target MSNs with different sizes （50,100 and 200 nm,respectively） were obtained.Furthermore,the Ca^2＋ cations were also introduced into MSNs.The prepared nanoparticles were characterized by means of infrared（IR） spectra,thermogravimetric analysis（TGA）,inductively coupled plasma（ICP）,CHN elemental analysis,nitrogen adsorption-desorption,scanning electron microscope（SEM） and transmission electron microscope（TEM）.Ibuprofen（IBU） which contains carboxyl groups was selected as a model drug.The results of drug loading and release reveal that the loading capacities and release behaviors of the model drug are highly dependent on the Ca^2＋ cations in MSNs.The release of IBU from the MSNs functionalized by Ca^2＋ cations is found to be effectively controlled when compared to the release from the MSNs without the functionalization of Ca^2＋ cations,which is due to the ionic interaction between carboxyl groups in IBU and Ca^2＋ cations in MSNs.     

Nanoparticles for Triple Drug Release for Combined Chemo- and Photodynamic Therapy

A pH-responsive drug delivery system (DDS) based on mesoporous silica nanoparticles (MSNs) has been prepared for the delivery of three anticancer drugs with different modes of action. The novelty of this system is its ability to combine synergistic chemotherapy and photodynamic therapy. A photoactive conjugate of a phthalocyanine (Pc) and a topoisomerase I inhibitor (topo-I), namely camptothecin (CPT), linked by a poly(ethylene glycol) (PEG) chain has been synthesized and then loaded into the mesopores of MSNs. Doxorubicin (DOX), which is a topoisomerase II inhibitor (topo-II), has also been covalently anchored to the outer surface of the MSNs through a dihydrazide PEG linker. In the acidic environment of tumor cells, selective release of the three drugs takes place. In vitro studies have demonstrated the endocytosis of the system into HeLa and HepG2 cells, and the subsequent release of the three drugs into the cytoplasm and nucleus. Furthermore, the cytotoxic effect of DOX, CPT and Pc has been assessed in vitro before and upon light irradiation.     

A study of the conformational stability of poly(β-benzyl l-aspartate), poly(γ-benzyl l-glutamate) and poly(β-benzyl l-aspartate)/poly(γ-benzyl l-glutamate) blend in the solid state by variable-temperature C CP/MAS NMR

¹³C CP/MAS NMR experiments on polypeptides, poly(β-benzyl l-aspartate) (PBLA), poly(γ-benzyl l-glutamate) (PBLG) and PBLA/PBLG blend have been carried out, in order to elucidate the conformational stability of the polypeptides in the solid state over a wide range of temperatures and its blending effect. The PBLA/PBLG blend with a mixture ratio of 1/1 is prepared by adding trifluoroacetic acid (TFA) solution to alkaline water (TFA-alkaline treatment). From these experimental results, it is found that the conformation of PBLA in the PBLA/PBLG blend sample is changed from left-handed helix (α_L-helix and/or ω_L-helix) form to the α_R-helix form, and then the origin of the formation of the α_R-helix form in PBLA comes from the existence of PBLG. Further, from the variable-temperature ¹³C CP/MAS NMR experiments results, it is shown that the conformational behavior of PBLA in the PBLA/PBLG blend is similar to that of the TFA-alkaline treated PBLA, and also the conformational behavior of PBLG in the PBLA/PBLG blend is similar to that of the TFA-alkaline treated PBLG.     

荧光介孔二氧化硅纳米粒子的合成及药物运输

合成了荧光介孔二氧化硅纳米粒子（MSNs-FITC）,并研究了其在持续药物释放和生物示踪成像方面的应用。首先,采用一步法合成出MSNs-FITC,结合SEM、TEM、FT-IR、XRD和氮气吸附脱附等表征技术进行表征。其次,将抗癌药物阿霉素（DOX）负载到MSNs-FITC中。载药粒子的药物释放行为具有明显的pH依赖性,酸性环境加速释放速率。同时,体外细胞毒性测试表明MSNs-FITC具有良好的生物相容性。激光共聚焦扫描显微镜（CLSM）图像表明,MSNs-FITC可以进入细胞并具有剂量依赖性,流式细胞术分析（FCM）进一步证明了这一结果。     

A Selective Release System Based on Dual‐Drug‐Loaded Mesoporous Silica for Nanoparticle‐Assisted Combination Therapy

A selective release system was demonstrated with a dual‐cargo loaded MSNs. When stimulated by different signals (UV or H⁺), this system could selectively release different kinds of cargoes individually. Furthermore, this system has been used to provide a combination of chemotherapy and biotherapy for cancer treatment. This controlled release system could be an important step in the development of more effective and sophisticated nanomedicine and nanodevices, due to the possibility of selective release of a complex multi‐drug.