Bone-Targeted Mesoporous Silica Nanocarrier Anchored by Zoledronate for Cancer Bone Metastasis

Once bone metastasis occurs, the chances of survival and quality of life for cancer patients decrease significantly. With the development of nanomedicine, nanocarriers loading bisphosphonates have been built to prevent cancer metastasis based on their enhanced permeability and retention (EPR) effects; however, as a passive mechanism, the EPR effects cannot apply to the metastatic sites because of their lack of leaky vasculature. In this study, we fabricated 40 nm-sized mesoporous silica nanoparticles (MSNs) anchored by zoledronic acid (ZOL) for targeting bone sites and delivered the antitumor drug doxorubicin (DOX) in a spatiotemporally controlled manner. The DOX loading and release behaviors, bone-targeting ability, cellular uptake and its mechanisms, subcellular localization, cytotoxicity, and the antimigration effect of this drug delivery system (DDS) were investigated. The results indicated that MSNs–ZOL had better bone-targeting ability compared with that of the nontargeted MSNs. The maximum loading capacity of DOX into MSNs and MSNs–ZOL was about 1671 and 1547 mg/g, with a loading efficiency of 83.56 and 77.34%, respectively. DOX@MSNs–ZOL had obvious pH-sensitive DOX release behavior. DOX@MSNs–ZOL entered into cells through an ATP-dependent pathway and then localized in the lysosome to achieve effective intracellular DOX release. The antitumor results indicated that DOX@MSNs–ZOL exhibited the best cytotoxicity against A549 cells and significantly decreased cell migration in vitro. This DDS is promising for the treatment of cancer bone metastasis in the future

pH and Reduction Dual-Bioresponsive Polymersomes for Efficient Intracellular Protein Delivery

pH and reduction dual-bioresponsive nanosized polymersomes based on poly­(ethylene glycol)-SS-poly­(2-(diethyl amino)­ethyl methacrylate) (PEG-SS-PDEA) diblock copolymers were developed for efficient encapsulation and triggered intracellular release of proteins. PEG-SS-PDEA copolymers with PDEA-block molecular weights ranging from 4.7, 6.8, to 9.2 kg/mol were synthesized in a controlled manner via reversible addition–fragmentation chain transfer (RAFT) polymerization of 2-(diethyl amino)­ethyl methacrylate (DEAEMA) using PEG-SS-CPADN (CPADN = 4-cyanopentanoic acid dithionaphthalenoate; <i>M</i>_n PEG = 1.9 kg/mol) as a macro-RAFT agent. These copolymers existed as unimers in water at mildly acidic pH (<7.2) conditions, but readily formed monodisperse nanosized polymersomes (54.5–66.8 nm) when adjusting solution pH to 7.4. These polymersomes were highly sensitive to intracellular pH and reductive environments, which resulted in fast dissociation and aggregation of polymersomes, respectively. Notably, both fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (FITC-BSA) and cytochrome C (FITC-CC) proteins could facilely be encapsulated into polymersomes with excellent protein-loading efficiencies, likely as a result of electrostatic interactions between proteins and PDEA. The in vitro release studies showed that protein release was minimal (<20% in 8 h) at pH 7.4 and 37 °C. The release of proteins was significantly enhanced at pH 6.0 due to collapse of polymersomes. Notably, the fastest protein release was observed under intracellular-mimicking reductive environments (10 mM dithiothreitol, pH 7.4). MTT assays in RAW 264.7 and MCF-7 cells indicated that PEG-SS-PDEA (9.2 k) polymersomes had low cytotoxicity up to a polymer concentration of 300 μg/mL. Confocal laser scanning microscope (CLSM) observations revealed that FITC-CC-loaded PEG-SS-PDEA (9.2 k) polymersomes efficiently delivered and released proteins into MCF-7 cells following 6 h of incubation. Importantly, flow cytometry assays showed that CC-loaded PEG-SS-PDEA (9.2 k) polymersomes induced markedly enhanced apoptosis of MCF-7 cells as compared to free CC and CC-loaded PEG–PDEA (8.9 k) polymersomes (reduction-insensitive control). These dual-bioresponsive polymersomes have appeared to be highly promising for intracellular delivery of protein drugs

Defect-Related Luminescent Mesoporous Silica Nanoparticles Employed for Novel Detectable Nanocarrier

Uniform and well-dispersed walnut kernel-like mesoporous silica nanoparticles (MSNs) with diameters about 100 nm have been synthesized by a templating sol–gel route. After an annealing process, the as-obtained sample (DLMSNs) inherits the well-defined morphology and good dispersion of MSNs, and exhibits bright white-blue luminescence, higher specific surface area and pore volume, and better biocompatibility. The drug loading and release profiles show that DLMSNs have high drug loading capacity, and exhibit an initial burst release followed by a slow sustained release process. Interestingly, the luminescence intensity of the DLMSNs-DOX system increases gradually with the increase of cumulative released DOX, which can be verified by the confocal laser scanning images. The drug carrier DLMSNs can potentially be applied as a luminescent probe for monitoring the drug release process. Moreover, the DLMSNs-DOX system exhibits potent anticancer effect against three kinds of cancer cells (HeLa, MCF-7, and A549 cells)

Up-Conversion Y₂O₃:Yb³⁺,Er³⁺ Hollow Spherical Drug Carrier with Improved Degradability for Cancer Treatment

The rare earth hollow spheres with up-conversion luminescence properties have shown potential applications in drug delivery and bioimaging fields. However, there have been few reports for the degradation properties of rare earth oxide drug carriers. Herein, uniform and well-dispersed Y₂O₃:Yb³⁺,Er³⁺ hollow spheres (YOHSs) have been fabricated by a general Pechini sol–gel process with melamine formaldehyde colloidal spheres as template. The novel YOHSs with up-conversion luminescence has good drug loading amount and drug-release efficiency; moreover, it exhibits pH-responsive release patterns. In particular, the YOHSs sample exhibits low cytotoxicity and excellent degradable properties in acid buffer. After the sample was loaded with anticancer drug doxorubicin (DOX), the antitumor result <i>in vitro</i> indicates that YOHS-DOX might be effective in cancer treatment. The animal imaging test also reveals that the YOHSs drug carrier can be used as an outstanding luminescent probe for bioimaging <i>in vivo</i> application prospects. The results suggest that the degradable drug carrier with up-conversion luminescence may enhance the delivery efficiency of drugs and improve the cancer therapy in clinical applications

Self-Assembled Peptide Nanofibers Designed as Biological Enzymes for Catalyzing Ester Hydrolysis

The structural arrangement of amino acid residues in a native enzyme provides a blueprint for the design of artificial enzymes. One challenge of mimicking the catalytic center of a native enzyme is how to arrange the essential amino acid residues in an appropriate position. In this study, we designed an artificial hydrolase <i>via</i> self-assembly of short peptides to catalyze ester hydrolysis. When the assembled hydrolase catalytic sites were embedded in a matrix of peptide nanofibers, they exhibited much higher catalytic efficiency than the peptide nanofibers without the catalytic sites, suggesting that this well-ordered nanostructure is an attractive scaffold for developing new artificial enzymes. Furthermore, the cytotoxicity of the assembled hydrolase was evaluated with human cells, and the novel artificial biological enzyme showed excellent biocompatibility

A Carrier-Free Nanostructure Based on Platinum(IV) Prodrug Enhances Cellular Uptake and Cytotoxicity

Flurbiprofen, a hydrophobic COX inhibitor, was coordinated axially with oxoplatin to form a new conjugate, <i>cis</i>,<i>cis</i>,<i>trans</i>-[Pt­(IV)­(NH₃)₂Cl₂(flurbiprofen)₂]. The successful synthesis of this new conjugate was confirmed by ¹H, ¹³C, and ¹⁹⁵Pt NMR. The potential of this conjugate being reduced to cisplatin and subsequently exerting its DNA cross-linking ability was verified using cyclic voltammetry (CV), HPLC, and mass spectrometry (MS). This conjugate showed markedly higher cytotoxicity on many cancer cell lines than cisplatin, flurbiprofen, and their physical mixture (mole ratio, cisplatin:flurbiprofen = 1:2). This is consistent with the result of an apoptosis-inducing assay. This conjugate spontaneously assembles carrier-free nanoparticles in aqueous solution, which is confirmed by DLS, TEM, SEM, and AFM, and thus facilitates cellular uptake and markedly improves its cytotoxicity and apoptosis-inducing ability <i>in vitro</i>

Virus-Inspired Self-Assembled Nanofibers with Aggregation-Induced Emission for Highly Efficient and Visible Gene Delivery

High-efficiency gene transfer and suitably low cytotoxicity are the main goals of gene transfection systems based on nonviral vectors. In addition, it is desirable to track the gene transfer process in order to observe and explain the mechanism. Herein, inspired by viral structures that are optimized for gene delivery, we designed a small-molecule gene vector (TR4) with aggregation-induced emission properties by capping a peptide containing four arginine residues with tetraphenylethene (TPE) and a lipophilic tail. This novel vector can self-assemble with plasmid DNA to form nanofibers in solution with low cytotoxicity, high stability, and high transfection efficiency. pDNA@TR4 complexes were able to transfect a variety of different cell lines, including stem cells. The self-assembly process induces bright fluorescence from TPE, which makes the nanofibers visible by confocal laser scanning microscopy (CLSM). This allows us for the tracking of the gene delivery process

Hybrid Mesoporous Silica-Based Drug Carrier Nanostructures with Improved Degradability by Hydroxyapatite

Potential bioaccumulation is one of the biggest limitations for silica nanodrug delivery systems in cancer therapy. In this study, a mesoporous silica nanoparticles/hydroxyapatite (MSNs/HAP) hybrid drug carrier, which enhanced the biodegradability of silica, was developed by a one-step method. The morphology and structure of the nanoparticles were characterized by TEM, DLS, FT-IR, XRD, N₂ adsorption–desorption isotherms, and XPS, and the drug loading and release behaviors were tested. TEM and ICP-OES results indicate that the degradability of the nanoparticles has been significantly improved by Ca²⁺ escape from the skeleton in an acid environment. The MSNs/HAP sample exhibits a higher drug loading content of about 5 times that of MSNs. The biological experiment results show that the MSNs/HAP not only exhibits good biocompatibility and antitumor effect but also greatly reduces the side effects of free DOX. The as-synthesized hybrid nanoparticles may act as a promising drug delivery system due to their good biocompatibility, high drug loading efficiency, pH sensitivity, and excellent biodegradability

Table S1 -Supplemental material for Quantitative evaluation to efficacy and safety of therapies for psoriasis: A network meta-analysis

<p>Supplemental material, Table S1 for Quantitative evaluation to efficacy and safety of therapies for psoriasis: A network meta-analysis by Jingjing Lv, Dongmei Zhou, Yan Wang, Jingxia Zhao, Zhaoxia Chen, Jinchao Zhang, Tingting Di, Jing Hu, Bo Li, Ping Li and Feng Huang in Molecular Pain</p