Multifunctional silica nanocomposites prime tumoricidal immunity for efficient cancer immunotherapy.

The tumor immune microenvironment (TIME) has been demonstrated to be the main cause of cancer immunotherapy failure in various malignant tumors, due to poor immunogenicity and existence of immunosuppressive factors. Thus, establishing effective treatments for hostile TIME remodeling has considerable potential to enhance immune response rates for durable tumor growth retardation. This study aims to develop a novel nanocomposite, polyethyleneimine-modified dendritic mesoporous silica nanoparticles loaded with microRNA-125a (DMSN-PEI@125a) to synergistically enhance immune response and immunosuppression reversion, ultimately generating a tumoricidal environment. Our results showed that DMSN-PEI@125a exhibited excellent ability in cellular uptake by murine macrophages and the cervical cancer cell line TC-1, repolarization of tumor associated macrophages (TAMs) to M1 type in a synergistic manner, and promotion of TC-1 immunogenic death. Intratumor injection of DMSN-PEI@125a facilitated the release of more damage-related molecular patterns and enhanced the infiltration of natural killer and CD8+ T cells. Meanwhile, repolarized TAMs could function as a helper to promote antitumor immunity, thus inhibiting tumor growth in TC-1 mouse models in a collaborative manner. Collectively, this work highlights the multifunctional roles of DMSN-PEI@125a in generating an inflammatory TIME and provoking antitumor immunity, which may serve as a potential agent for cancer immunotherapy.

Hollow-core magnetic colloidal nanocrystal clusters with ligand-exchanged surface modification as delivery vehicles for targeted and stimuli-responsive drug release.

The fabrication of hierarchical magnetic nanomaterials with well-defined structure, high magnetic response, excellent colloidal stability, and biocompatibility is highly sought after for drug-delivery systems. Herein, a new kind of hollow-core magnetic colloidal nanocrystal cluster (HMCNC) with porous shell and tunable hollow chamber is synthesized by a one-pot solvothermal process. Its novelty lies in the "tunability" of the hollow chamber and of the pore structure within the shell through controlled feeding of sodium citrate and water, respectively. Furthermore, by using the ligand-exchange method, folate-modified poly(acrylic acid) was immobilized on the surface of HMCNCs to create folate-targeted HMCNCs (folate-HMCNCs), which endowed them with excellent colloidal stability, pH sensitivity, and, more importantly, folate receptor-targeting ability. These assemblages exhibited excellent colloidal stability in plasma solution. Doxorubicin (DOX), as a model anticancer agent, was loaded within the hollow core of these folate-HMCNCs (folate-HMCNCs-DOX), and drug-release experiments proved that the folate-HMCNCs-DOX demonstrated pH-dependent release behavior. The folate-HMCNCs-DOX assemblages also exhibited higher potent cytotoxicity to HeLa cells than free doxorubicin. Moreover, folate-HMCNCs-DOX showed rapid cell uptake apart from the enhanced cytotoxicity to HeLa cells. Experimental results confirmed that the synthesized folate-HMCNCs are smart nanovehicles as a result of their improved folate receptor-targeting abilities and also because of their combined pH- and magnetic-stimuli response for applications in drug delivery.

Curcumin-Loaded TPGS/F127/P123 Mixed Polymeric Micelles for Cervical Cancer Therapy: Formulation, Characterization, and InVitro and InVivo Evaluation.

Cervical cancer is the fourth most common cancer in women worldwide, and existing treatments cause severe side effects and great burdens. Thus, the development of safe, inexpensive therapeutic agents is necessary. Curcumin (Cur), a well-known natural product, exerts promising anti-cancer activities against various cancer types. However, its therapeutic efficacy is severely restrained due to rapid degradation, poor aqueous solubility, and low bioavailability. The objective of this study was to investigate the therapeutic potential of novel curcumin-loaded TPGS/F127/P123 mixed polymeric micelles (Cur@NPT100) for cervical cancer treatment. The Cur@NPT100 exhibited an average size of approximately 19 nm, a zeta potential of around -4 mV, a drug loading of 8.18 ± 0.36%, and an encapsulation efficiency of 79.38 ± 4.65%. Unlike free Cur, Cur@NPT100 are readily dispersed in aqueous medium, showing enhanced stability and a sustained release profile over a 6-day period. In vitro cell culture experiments revealed that TPGS/F127/P123 mixed polymeric micelles (NPT100) based nanocarriers substantially promoted the selective cellular uptake of Cur into HeLa cells rather than by non-cancerous NIH3T3 cells, inducing higher cytotoxicity and greater apoptosis and significantly increasing the percentage of cells arrested at the G2/M phase of the cell cycle. Additionally, the Cur@NPT100 facilitated more Cur accumulation in the mitochondria and decreased the mitochondrial membrane potential. In addition, western blot assays demonstrated that Cur@NPT100 were more potent than free Cur at activating the mitochondria-mediated apoptosis pathway. In vivo results further confirmed that Cur@NPT100 exhibited a much higher antitumor efficacy than free Cur and had excellent biocompatibility. In conclusion, Cur@NPT100 might be an effective therapeutic agent for cervical cancer.

Hydrogel with Aligned and Tunable Pore Via "Hot Ice" Template Applies as Bioscaffold.

An aligned hydrogel with tunable macropore size via hot ice template is described, which exhibits a high porosity, large pore size, easily modified surface, high survival rate as well as a linear arrangement of NIH3T3 cells.

The induction of maturation on dendritic cells by TiO2 and Fe(3)O(4)@TiO(2) nanoparticles via NF-κB signaling pathway.

Nanomaterials are increasingly used in many fields, including drug vectors and vaccine formulation. In this study, nano-TiO(2) and magnetic Fe(3)O(4)@TiO(2) were synthesized and their abilities to activate dendritic cells were investigated. The signaling pathway involved in their effects on the cellular functions was also explored. First, nano-TiO(2) and Fe(3)O(4)@TiO(2) were prepared with diameters of 82nm and 63nm, and zeta potentials of 41.5mV and 30.2mV, respectively. The magnetic property of Fe(3)O(4)@TiO(2) was detected to be 12.9emu/g. Both kinds of nanoparticles were proved to have good biocompatibility in vitro. Second, the exposure of nano-TiO2 and Fe(3)O(4)@TiO(2)caused an increased expression of TNF-α, CD86 and CD80, and besides, Fe(3)O(4)@TiO(2)showed a certain up-regulation on MHC-II. The cellular uptake of Ovalbumin on BMDCs could be strongly improved by nano-TiO2 and Fe(3)O(4)@TiO(2)as detected via flow cytometer and confocal observation. Further investigation revealed that nano-TiO(2) and Fe(3)O(4)@TiO(2)significantly increased the NF-κB expression in the nucleus, indicating that the NF-κB signaling pathway was involved in the dendritic cell maturation. Our results suggested that nano-TiO(2) and Fe(3)O(4)@TiO(2)may function as a useful vector to promote vaccine delivery in immune cells, and Fe(3)O(4)@TiO(2)provided a possibility to deliver and track vaccines via its magnetofection.

Photoionization of oxidized coenzyme Q in microemulsion: laser flash photolysis study in biomembrane-like system.

Photoexcitation to generate triplet state has been proved to be the main photoreaction in homogeneous system for many benzoquinone derivatives, including oxidized coenzyme Q (CoQ) and its analogs. In the present study, microemulsion of CoQ, a heterogeneous system, is employed to mimic the distribution of CoQ in biomembrane. The photochemistry of CoQ(10) in microemulsion and cyclohexane is investigated and compared using laser flash photolysis and results show that CoQ(10) undergoes photoionization via a monophotonic process to generate radical cation of CoQ(10) in microemulsion and photoexcitation to generate excited triplet state in cyclohexane. Meanwhile, photoreactions of duroquinone (DQ) and CoQ(0) in microemulsion are also investigated to analyze the influence of molecular structure on the photochemistry of benzoquinone derivatives in microemulsion. Results suggest that photoexcitation, which is followed by excited state-involved hydrogen-abstraction reaction, is the main photoreaction for DQ and CoQ(0) in microemulsion. However, photoexcited CoQ(0) also leads to the formation of hydrated electrons. The isoprenoid side chain-involved high resonance stabilization is proposed to explain the difference in photoreactions of CoQ(0) and CoQ(10) in microemulsion. Considering that microemulsion is close to biomembrane system, its photoionization in microemulsion may be helpful to understand the real photochemistry of biological quinones in biomembrane system.

One-step bulk preparation of calcium carbonate nanotubes and its application in anticancer drug delivery.

Bulk fabrication of ordered hollow structural particles (HSPs) with large surface area and high biocompatibility simultaneously is critical for the practical application of HSPs in biosensing and drug delivery. In this article, we describe a smart approach for batch synthesis of calcium carbonate nanotubes (CCNTs) based on supported liquid membrane (SLM) with large surface area, excellent structural stability, prominent biocompatibility, and acid degradability. The products were characterized by transmission electron micrograph, X-ray diffraction, Fourier transform infrared spectra, UV-vis spectroscopy, zeta potential, and particle size distribution. The results showed that the tube-like structure facilitated podophyllotoxin (PPT) diffusion into the cavity of hollow structure, and the drug loading and encapsulation efficiency of CCNTs for PPT are as high as 38.5 and 64.4 wt.%, respectively. In vitro drug release study showed that PPT was released from the CCNTs in a pH-controlled and time-dependent manner. The treatment of HEK 293T and SGC 7901 cells demonstrated that PPT-loaded CCNTs were less toxic to normal cells and more effective in antitumor potency compared with free drugs. In addition, PPT-loaded CCNTs also enhanced the apoptotic process on tumor cells compared with the free drugs. This study not only provides a new kind of biocompatible and pH-sensitive nanomaterial as the feasible drug container and carrier but more importantly establishes a facile approach to synthesize novel hollow structural particles on a large scale based on SLM technology.

Mesoporous biocompatible and acid-degradable magnetic colloidal nanocrystal clusters with sustainable stability and high hydrophobic drug loading capacity.

Fabrication of magnetic particles (MPs) with high magnetization and large surface area simultaneously is critical for the application of MPs in bioseparation and drug delivery but remains a challenge. In this article, we describe an unprecedented approach to synthesize mesoporous magnetic colloidal nanocrystal clusters (MCNCs) stabilized by poly(γ-glutamic acid) (PGA) with high magnetization, large surface area (136 m(2)/g) and pore volume (0.57 cm(3)/g), excellent colloidal stability, prominent biocompatibility, and acid degradability. This result provides the important step toward the construction of a new family of MCNCs and demonstrates its capacity in a "magnetic motor" drug delivery system. Here, as an example, we explore the applicability of as-prepared mesoporous MCNCs as hydrophobic drug delivery vehicles (paclitaxel as model drug), and the resultant loading capacity is as high as 35.0 wt %. The antitumor efficacy measured by MTT assay is significantly enhanced, compared with free drugs. Thus, combined with their inherent high magnetization, the mesoporous MCNCs pave the way for applying magnetic targeting drug carriers in antitumor therapeutics.

MFalpha signal peptide enhances the expression of cellulase eg1 gene in yeast.

Ethanol production from lignocellulose by recombinant yeast with high level expression of heterologous cellulase genes has been a major anticipation. The native secretion signal sequence of the cellulase endoglucanase I (eg1) gene was replaced by Saccharomyces cerevisiae mating factor alpha prepro-leader sequence (MFalpha). The transformants containing native secretion signal (Y(1)) and MFalpha secretion signal (Y(2)) were characterized with respect to gene expression and growth on cellulose substrate. Increased enzyme activity and cellulose utilization were observed. The enzyme activity of Y(2) was 0.084 U/ml, 61.5% higher than Y(1) (0.052 U/ml). The sufficiency parameter (S value) was raised from 0.6 to 0.84. MFalpha signal peptide was more efficient than the native signal peptide of eg1 gene, suggesting that signal peptide replacement is an efficient way to enhance the cellulase expression level in yeast, for cellulose-derived ethanol production.

Comparative transmembrane transports of four typical lipophilic organic chemicals.

Transmembrane transports of four kinds of lipophilic organic chemicals (LOCs) on suspending multilamellar liposomes (SML) and Escherichia coli (E. coli) were investigated, where both anthracene and phenanthrene were accorded to the lipid-water partition law and Sudan I and III to the Langmuir isothermal adsorption. Less than half of phenanthrene is transported into E. coli, where more than 60% are located in the cytoplasm. About 60% of anthracene entered the E. coli where only 10% was released into the cytoplasm. The partition coefficients of phenanthrene and anthracene partitioning from the extracellular liquid into membrane are 502 and 1190L/kg but their inverse partition coefficients are only 0.180 and 0.018kg/L. Over 60% of Sudan I and less than 40% of Sudan III accumulated on E. coli where most of them remained on the membrane. The transmembrane impedance effect (TMIE) is proposed for evaluating the cell-transport of polar LOCs.