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Conventional chemotherapy is bothered by systematic toxicity and confined therapeutic effects. Gas therapy has emerged as a potent tumor treatment, and hydrogen sulfide (H2S), a traditional gasotransmitter, has been found to show a tumor inhibition effect. Therefore, we established a mesoporous organosilica-based H2S nanogenerator (MON-TPGS-DOX). Tetrasulfide bond-incorporated mesoporous organosilica nanoparticles were modified with d-α-tocopheryl polyethylene glycol succinate (TPGS), namely, MON-TPGS, and then loaded with doxorubicin (DOX) to obtain the nanogenerator. Tetrasulfide bonds in the nanogenerator could be triggered by glutathione (GSH) to release H2S, further resulting in the degradation of nanogenerator and DOX release. GSH consumption and H2S release led to oxidative stress in 4T1 cells, activation of apoptotic signaling cascades, and enhanced cell-killing effect. Furthermore, the nanogenerator effectively suppressed tumor growth in a tumor-bearing mice model with good biosafety, providing a promising approach for H2S-enhanced tumor chemotherapy. [ABSTRACT FROM AUTHOR]

The development of stimuli‐responsively degradable porous carriers for both controlled drug release and high biosafety is vitally important to their clinical translation, but still challenging at present. A new type of porphyrin–iron metal organic framework (Fe‐MOF) nanocrystals is engineered here as acid‐degradable drug carrier and hydrogen donor by the coordination between porphyrin and zero‐valence Fe atom. Fe‐MOF nanocrystals exhibit excellent acid‐responsive degradation for H2 generation and simultaneous release of the loaded drug for combined hydrogen‐chemotherapy of cancer multidrug resistance (MDR) and metastasis and for local hydrogen eradication of the off‐target induced toxic side effects of the drug to normal cells/tissues. Mechanistically, released H2 assists chemotherapeutic drug to efficiently inhibit cancer metastasis by immunoactivating intratumoral M1‐phenotype macrophages and consequently downregulating the expression of metastasis‐related matrix metalloproteinase‐2 (MMP‐2) and can also downregulate the expressions of both P‐glycoprotein (P‐gp) protein and adenosine triphosphate (ATP) in MDR cancer cells to sensitize chemotherapeutic drug for enhanced damage to mitochondria and DNA. High anti‐MDR/antimetastasis efficacies and high biocompatibility endow Fe‐MOF nanocrystals and the Fe‐MOF‐based nanomedicine with high potential for clinical translation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mesoporous silica nanoparticles (MSN) were coated by pH-responsive polymer chitosan-poly (methacrylic acid) (CS-PMAA). This nano drug delivery system showed good application prospects and the polymer-coated microspheres were promising site-specific anticancer drug delivery carriers in biomedical field. A continuous detection of pH-responsive drug delivery system in cells in situ, utilizing MSN/CS-PMAA composite microspheres, was proposed. Two kinds of different cell lines, tumor cell line (Hela) and normal somatic cells (293T), were used to investigate the behaviours of the drug loaded system in the cells. Conclusions could be drawn from the fluorescent images obtained by confocal laser scanning microscopy (CLSM), modified drug-loaded microspheres (MSN/CS-PMAA) were ingested into cells more easily, the uptake of DOX@FITC-MSN/CS-PMAA by HeLa/293T cells were performed at pH 7.4/pH 6.8, DOX was released during the ingestion process, fluorescence intensity decreased with time because of efflux transport and photo-bleaching. Fluoresence detection by flow cytometry was performed as comparison. The continuous fluorescent observation in situ could be widely used in the pH-responsive releasing process of drug delivery system in the cells. [ABSTRACT FROM AUTHOR]

Graphical abstract Biodegradable phosphorylcholine-based zwitterionic polymer nanogels with charge-conversion ability at tumor extracellular pH were fabricated by one-step reflux precipitation polymerization, leading to the enhanced tumor cellular uptake and controlled drug release. Abstract Zwitterionic polymer nanocarriers have attracted much attention in recent years due to their desirable biocompatibility and anti-fouling properties. However, the super-hydrophilic and neutral charge of zwitterionic polymer results in weak interactions with negatively charged cell membranes, which leads to suboptimal uptake by tumor cells. Herein, a series of biodegradable poly(2-methacryloyloxyethyl phosphorylcholine- s-s -vinylimidazole) (PMV) nanogels with uniform spherical shape was fabricated by one-step reflux precipitation polymerization, which was clean and efficient. The PMV nanogels remained in zwitterionic state at physiological pH (pH 7.4) and were converted rapidly to positive charged state at tumor extracellular pH (pH 6.5). Proton nuclear magnetic resonance spectra and acid-base titration experiment proved that the charge-conversion ability of PMV nanogels was attributed to protonation of the imidazole ring in an acidic environment. Protein stability experiment showed that PMV nanogels exhibited a protein-adsorption resistance at pH 7.4 for as long as 7 days while adsorbed protein rapidly at pH 6.5. Moreover, PMV nanogels showed a reducing-labile property, which was able to degrade into short linear polymer chains in the presence of reduction agents. Therefore, the doxorubicin (DOX) release profile was controlled finely with a low DOX leakage under physiological conditions (7.8% in 48 h) and a rapid DOX release in 10 mM glutathione at pH 7.4 (78.9% in 48 h). Confocal laser scanning microscope and flow cytometry showed that the PMV nanogels exhibit an enhanced cellular uptake by tumor cells at pH 6.5 compared with pH 7.4, which allows for a severe cytotoxic effect of DOX-loaded PMV nanogels against tumor cells. [ABSTRACT FROM AUTHOR]

The strategy to efficiently deliver antitumor drugs via nanocarriers to targeted tumor sites and achieve controllable drug release is attracting great research interest in cancer therapy. In this study, a novel type of disulfide-bonded poly(vinylcaprolactam) (PVCL)-based nanogels with tunable volume phase transition temperature and excellent redox-labile property are prepared. The nanogels are hydrophilic and swell at 37 °C, whereas under hyperthermia (e.g., 41 °C), the nanogels undergo sharp hydrophilic/hydrophobic transition and volume collapse, which enhances the cellular uptake and drug release. The incorporation of disulfide bond linkers endows the nanogels with an excellent disassembly property in reducing environments, which greatly facilitates drug release in tumor cells. Nanogels loaded with doxorubicin (DOX) (DOX-NGs) (DOX-NGs) are stable in physiological conditions with low drug leakage (15% in 48 h), while burst release of DOX (92% in 12 h) can be achieved in the presence of 10 × 10−3 m glutathione and under hyperthermia. The DOX-NGs possess improved cell killing efficiency under hyperthermia (IC50 decreased from 1.58 μg mL−1 under normothermia to 0.5 μg mL−1). Further, the DOX-NGs show a pronounced tumor inhibition rate of 46.6% compared with free DOX, demonstrating that this new dual-responsive nanogels have great potential as drug delivery carriers for cancer therapy in vivo. [ABSTRACT FROM AUTHOR]

Multifunctional nanoparticles for selectively targeting tumor cells and effectively delivering multiple drugs are urgently needed in cancer therapy. Here, a dual-drug delivery system is prepared, based on functionalized hollow mesoporous silica nanoparticles (HMSNs). Doxorubicin (DOX) hydrochloride is loaded into the hollow core, and dichloro(1,2-diaminocyclohexane)platinum (II) (DACHPt) is stored in the pores of the shell by the coordination interaction with the carboxyl groups modified on the pore walls, which also serves as barriers to control the DOX release. Detailed studies in vitro indicate that the DACHPt release is triggered by Cl− through the cleavage of the coordination interaction, and the DOX release depends on the release rate of DACHPt and the environmental pH value. The surface of the mechanized nanoparticles is also modified by transferrin (Tf) to achieve the tumor specificity. Compared with individual drug delivery systems, the dual-drug delivery system shows synergistic efficacy on the cell cytotoxicity (combination index = 0.30), resulting in improved tumor cell killing. The present dual-drug delivery system provides a promising strategy to develop controlled and targeted combination therapies for efficient cancer treatment. [ABSTRACT FROM AUTHOR]

Highlights: [•] Monodisperse core–shell nanocomposites with fluorescent solid SiO2 core mesoporous silica shell. [•] DOX release study for F-nSiO2/mSiO2 with different shell thickness as carrier. [•] Smaller nanoparticles will be uptaken by HeLa cells easier. [ABSTRACT FROM AUTHOR]

Abstract: pH-sensitive poly(l-glutamic acid) grafted mesoporous silica nanoparticles (MSN-PLGA) were prepared by the surface-initiated N-carboxyanhydride polymerization method. The resultant MSN-PLGA was well dispersed in aqueous medium and showed high drug loading efficiency, superior stability, and significantly higher drug release rates. The cumulative release of doxorubicin hydrochloride (DOX) from DOX-loaded MSN-PLGA (DOX@MSN-PLGA) was pH-dependent and the release rate was much higher at pH 5.5 than that at pH 7.4. The cytotoxicity results indicated that the blank MSN-PLGA was biocompatible and the DOX@MSN-PLGA had potent in vitro cytotoxicity effect similar to free DOX. Overall, these results demonstrate that MSN-PLGA is a promising platform to build pH controlled drug delivery systems for cancer therapy. [Copyright &y& Elsevier]

Abstract: pH-responsive composite microspheres, consisting of a core of Fe3O4 nanoparticle, a sandwiched layer of mesoporous silica and a shell of crosslinked poly (methacrylic acid) (PMAA), were successfully synthesized via distillation precipitation polymerization. The pKa of the composite microsphere increased with the increase in the crosslinking density. Doxorubicin hydrochloride (DOX) was applied as a model drug, and the behavior of drug storage/release was investigated. The cumulative release of DOX-loaded composite microsphere in vitro showed that the drug release rate was much faster below its pKa than that of above its pKa. Because pH of most tumor tissues was lower than that of normal tissues, the pH-responsive composite microspheres are promising drug delivery system especially for cancer therapy. [Copyright &y& Elsevier]

Abstract: pH-responsive polymer shell chitosan/poly (methacrylic acid) (CS-PMAA) was coated on mesoporous silica nanoparticles (MSN) through the facile in situ polymerization method. The resultant composite microspheres showed a flexible control over shell thickness, surface charges and hydrodynamic size by adjusting the feeding amount of MSN and the molar ratio of [–NH2]/MAA. The MSN/CS-PMAA composite microspheres were stable in the pH range of 5–8 as well as in the physiological saline (0.15M NaCl). Doxorubicin hydrochloride (DOX) was applied as a model drug to investigate the drug storage and release behavior. The results demonstrated that DOX could be effectively loaded into the composite microspheres. The cumulative release of DOX-loaded composite microspheres was pH dependent and the release rate was much faster at low pH (5.5) than that of pH 7.4. The cytotoxicity test by MTT assay showed that the blank carrier MSN/CS-PMAA microspheres were suitable as drug carriers. The cellular uptake of composite microspheres was investigated by confocal laser scanning microscopy (CLSM), which indicated that MSN/CS-PMAA could deliver the drugs into HeLa cell. The above results imply that the composite microspheres are a promising drug delivery system for cancer therapy. [Copyright &y& Elsevier]

Long blood circulation is the basic requirement of advanced drug delivery systems for tumor treatment, which leads to enhanced tumor therapeutic efficiency and reduced side effects. However, the pharmacokinetics of the current nanoparticles in vivo is still unsatisfactory, which leads to limited success to translate nanoparticles into clinical applications. Inspired by the natural cell membrane-coating strategy, a series of zwitterionic polymer membranes are firstly developed and coated onto different kinds of nanoparticles in this work. Intriguingly, the zwitterionic polymer membrane shows stronger protein adsorption resistance and reduced macrophage uptake compared with the corresponding zwitterionic polymer brush or the red blood cell (RBC) membrane, which results in longer blood circulation time and higher tumor accumulation of the coated nanoparticles. Combined with the photothermal effect of model nanoparticles, Fe 3 O 4 , zwitterionic polymer membrane-coated Fe 3 O 4 shows enhanced photothermal therapy (PTT) efficacy on A549 tumors compared with the corresponding zwitterionic polymer brush or RBC membrane-coated Fe 3 O 4. Notably, Fe 3 O 4 coated by carboxybetaine-based biomimic membranes exhibits the ultra-long blood circulation (t 1/2 = 96.0 h) and strongest PTT efficacy compared with those coated by phosphorylcholine-based or sulfobetaine-based biomimic membranes. In addition, the zwitterionic biomimic membrane exhibits rapid glutathione-triggered degradation with the products of low molecular weight (<2000 g mol−1). Therefore, the biodegradable zwitterionic biomimic membrane coating offers a universal platform for the design and application of long-circulating biomedical nanoparticles, which may pave the way for the clinical applications of biomedical nanoparticles in tumor therapy. [ABSTRACT FROM AUTHOR]