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The potential toxicity of nanoparticles, especially for clinically applicable ones, has become a critical concern. Technologies that can in situ-evaluate the toxicity of nanoparticles with high sensitivity are urgently needed. In this study, a facile strategy was developed for sensitive detection on the nanotoxicity of nanoparticles with low toxicity or a low dose. A functional nanoprobe loaded with molecular beacons was constructed to realize in situ evaluation of the nanotoxicity through probing multiple miRNAs in nanoparticle-exposed living cells. Being composed of protamine complexed with molecular beacons for miRNA detection and decorated by TAT and KALA peptides, the dual-peptide functionalized nanoprobe can efficiently deliver molecular beacons into living cells to realize the real-time monitoring of early biomarkers (miR-21 and miR-221) to evaluate nanotoxicity. Using mesoporous silica nanoparticles (MSNs) with different surface modifications as typical representatives of low toxic nanoparticles, we demonstrate that our nanoprobe can sensitively detect miRNA changes in cells under diverse exposure conditions, that is, MSN-NH 2 exhibits the strongest capability to upregulate miR-21 and miR-221, and the upregulation is exposure dose- and time-dependent. Our approach is much more sensitive as compared with conventional methods to study cytotoxicity such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell morphology observation, and reactive oxygen species (ROS) assay. This study paves a path for effective and facile nanotoxicity evaluation and provides insights into the biological impacts of MSNs.

Selective amplification of reactive oxygen species (ROS) generation in tumor cells has been recognized as an effective strategy for cancer therapy. However, an abnormal tumor metabolism, especially the mitochondrial glutaminolysis, could promote tumor cells to generate high levels of antioxidants (e.g., glutathione) to evade ROS-induced damage. Here, we developed a tumor-targeted nanoparticle (NP) platform for effective breast cancer therapy via combining inhibition of mitochondrial glutaminolysis and chemodynamic therapy (CDT). This NP platform is composed of bovine serum albumin (BSA), ferrocene, and purpurin. After surface decoration with a tumor-targeting aptamer and then intravenous administration, this NP platform could target tumor cells and release ferrocene to catalyze hydrogen peroxide (H 2 O 2 ) into the hydroxyl radical (·OH) for CDT. More importantly, purpurin could inhibit mitochondrial glutaminolysis to concurrently prevent the nutrient supply for tumor cells and disrupt intracellular redox homeostasis for enhanced CDT, ultimately leading to the combinational inhibition of tumor growth.

The unsatisfactory response rate of immune checkpoint blockade (ICB) immunotherapy severely limits its clinical application as a tumor therapy. Here, we generate a vaccine-based nanosystem by integrating siRNA for Cd274 into the commercial human papillomavirus (HPV) L1 (HPV16 L1) protein. This nanosystem has good biosafety and enhances the therapeutic response rate of anti-tumor immunotherapy. The HPV16 L1 protein activates innate immunity through the type I interferon pathway and exhibits an efficient anti-cancer effect when cooperating with ICB therapy. For both resectable and unresectable breast tumors, the nanosystem decreases 71% tumor recurrence and extends progression-free survival by 67%. Most importantly, the nanosystem successfully induces high response rates in various genetically modified breast cancer models with different antigen loads. The strong immune stimulation elicited by this vaccine-based nanosystem might constitute an approach to significantly improve current ICB immunotherapy.

To enhance the treatment efficiency in tumor therapy, we developed a tumor-targeting protein-based delivery system, DOX&ICG@BSA-KALA/Apt, to efficiently integrate multimodal therapy with tumor imaging and realize synchronous photodynamic therapy/photothermal therapy/chemotherapy. In the delivery system, a chemotherapeutic drug (doxorubicin, DOX) and an optotheranostic agent (indocyanine green, ICG) were co-loaded in bovine serum albumin (BSA) via a hydrophobic-interaction-induced self-assembly to form stable DOX&ICG@BSA nanoparticles. After the decoration of a surface layer composed of a tumor-targeting aptamer (AS1411) and a cell-penetrating peptide (KALA), the obtained DOX&ICG@BSA-KALA/Apt nanoparticles exhibit a significantly improved multimodal cancer therapeutic efficiency due to the enhanced cancer cellular uptake mediated by AS1411 and KALA. In vitro and in vivo studies show that the multimodal theranostic system can efficiently inhibit tumor growth. In addition, the near-infrared fluorescent/photothermal dual-mode imaging enables accurate visualization of the therapeutic action in tumor sites. This study provides a facile strategy to construct self-assembled multimodal theranostic systems, and the functional protein-based theranostic system prepared holds great promise in multimodal cancer therapeutics.

To efficiently deliver CpG oligodeoxynucleotides (ODNs) to macrophages for the reversal of cancer-induced immunosuppression, nanoparticles ODN@MCBSA with mannosylated cationic albumin (MCBSA) as a macrophage targeting vector were constructed. Compared with ODN@CBSA with cationic albumin (CBSA) as a vector, ODN@MCBSA exhibited significantly improved cellular uptake mediated by mannose moieties, resulting in significantly enhanced secretion of proflammatory cytokines including IL-12, IL-6, TNF-α, and iNOS. The modulation of macrophages toward the favorable M1 phenotype was confirmed by the upregulated CD80 expression after being treated by ODN delivery systems. In addition to immune cells, the effects of the ODN delivery system on cancerous HeLa cells were also investigated. The results showed that ODN@MCBSA did not affect the overall tumor cell viability. However, enhanced NF-κB, p-Akt, PIK3R3, Fas, and FasL, as well as upregulated caspases were observed in tumor cells, implying the pleiotropic effects on tumor cells. Our study provides a more in-depth understanding on the immunotherapeutic effects of CpG ODNs and highlights the importance of macrophage targeting delivery to minimize the effects on tumor cells. These results indicate that MCBSA could serve as a promising delivery vector of CpG ODNs to macrophages for cancer immunotherapy.

To effectively reverse tumor malignization by genome editing, a multi-functional self-assembled nanovector for the delivery of a genome editing plasmid specifically to tumor cells was developed. The nanovector core consisting of protamine and calcium carbonate entrapping the CRISPR-Cas9 plasmid is decorated by aptamer incorporated heparin. Owing to a high affinity between a MUC1 specific aptamer and mucin 1 (MUC1) overexpressed in tumor cells as well as the interaction between AS1411 and nucleolin on the tumor cell surface and cell nuclei, the nanovector can target the nuclei of tumorous cells for the knockout of focal adhesion kinase (FAK). Notably, the genome editing mediated by our delivery systems can effectively modulate cell behaviors and thus reverse tumor malignization. Up-regulated p53, p16, p21, E-cadherin, CD80, MICA, MICB and Fas, together with down-regulated MMP-9, vimentin, VEGF, TGF-β, CD47 and CD133 in genome edited cells indicate that the genome editing system can inhibit cancerous cell growth, prevent tumor invasion and metastasis, reverse tumor-induced immune suppression, and inhibit cancer stemness. More importantly, the edited cells can maintain the modulated cellular function after succeeding subcultures.

Proteins have been extensively explored as versatile nanocarriers for drug delivery due to their complete biocompatibility, ease of surface modification, and lack of toxicity and immunogenicity. In this study, a facile strategy was used to construct aptamer-functionalized albumin-based nanoparticles for effective drug delivery and targeted cancer therapy. A hydrophobic drug, doxorubicin (DOX) was employed to trigger the self-assembly of bovine serum albumin (BSA) to from stable nanoparticles via hydrophobic interaction, and then a tumor targeting aptamer AS1411 was incorporated to the surface of DOX loaded BSA. Due to the specific recognition between AS1411 and its receptor over-expressed on tumor cells, the aptamer-modified nanoparticles show higher cellular uptake and stronger cell inhibitory efficacy against cancerous MCF-7 cells as compared with the nanoparticles without aptamer modification. In addition, DOX loaded aptamer-functionalized nanoparticles can induce more significant down-regulation of Bcl-2 and PCNA as well as up-regulation of pRB, PARP and Bax in MCF-7 cells compared with unmodified nanoparticles, indicating the aptamer modification can induce cell apoptosis more effectively. Besides, aptamer-modified nanoparticles exhibit a significantly improved capability in up-regulating p16, p21 and E-cadherin, and down-regulating EpCAM, vimentin, Snail, MMP-9, CD44 and CD133, implying the favorable effects of drug delivery on the prevention of tumor progression and metastasis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To achieve effective tumor eradication using anti-tumor immunotherapies, a fusion peptide functionalized gene delivery system for macrophage and tumor targeting delivery of the plasmid DNA encoding the IL-12 gene (pDNA IL-12) was prepared for macrophage re-polarization as well as reversal of cancer immunosuppression. A fusion peptide containing the tuftsin sequence that can interact with Fc receptors and neuropilin-1, and hyaluronic acid (HA) that can interact with CD44 were introduced into the delivery system by self-assembly to form peptide/hyaluronic acid/protamine/CaCO3/DNA nanoparticles (PHNP) with both macrophage targeting and tumor targeting capabilities. PHNP provides an efficient immunoregulation on J774A.1 cells to shift the anti-inflammatory M2 phenotype to the anti-tumor M1 phenotype with enhanced secretion of pro-inflammatory cytokines and increased expression of M1 markers. Owing to the improved delivery efficiency caused by the fusion peptide and HA, the transfection mediated by multi-functional PHNP can up-regulate IL-12 as well as down-regulate IL-10 and IL-4 more effectively as compared with the nanoparticles without HA and/or peptide decoration. More importantly, the gene delivery system can also deliver pDNA IL-12 to targeted cancerous HeLa cells to realize the secretion of IL-12. PHNP not only enables tumorous cells to produce pDNA IL-12, but also down-regulates CD47 and up-regulate CD80 and HLA-1 in the malignant cells, indicating that the gene delivery system can effectively reverse tumor induced immunosuppression.

Purpose: To overcome multi-drug resistance (MDR) in tumor chemotherapy, a polymer/inorganic hybrid drug delivery platform with tumor targeting property and enhanced cell uptake efficiency was developed., Method: To evaluate the applicability of our delivery platform for the delivery of different drug resistance inhibitors, two kinds of dual-drug pairs (doxorubicin/buthionine sulfoximine and doxorubicin/tariquidar, respectively) were loaded in heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles to realize simultaneous delivery of an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells., Results: Prepared by self-assembly, the drug loaded hybrid nanovesicles with a mean size less than 210 nm and a negative zeta potential exhibit good stability in serum contained aqueous media. The in vitro cytotoxicity evaluation indicates that hybrid nanovesicles with tumor targeting biotin moieties have an enhanced tumor cell inhibitory effect. In addition, dual-drug loaded hybrid nanovesicles exhibit significantly stronger cell growth inhibition as compared with doxorubicin (DOX) mono-drug loaded nanovesicles due to the reduced intracellular glutathione (GSH) content by buthionine sulfoximine (BSO) or the P-glycoprotein (P-gp) inhibition by tariquidar (TQR)., Conclusions: The tumor targeting nanovesicles prepared in this study, which can simultaneously deliver multiple drugs and effectively reverse drug resistance, have promising applications in drug delivery for tumor treatments. The polymer/inorganic hybrid drug delivery platform developed in this study has good applicability for the co-delivery of different anti-tumor drug/drug resistance inhibitor pairs to overcome MDR. Graphical Abstract A polymer/inorganic hybrid drug delivery platform with enhanced cell uptake was developed for tumor targeting synergistic drug delivery. The heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles prepared in this study can deliver an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells simultaneously to overcome drug resistance efficiently.

To effectively reverse multiple drug resistance (MDR) in tumor treatments, a functional nano-sized drug delivery system with active targeting function and pH sensitivity was prepared for the co-delivery of multiple drug resistance inhibitors. Buthionine sulfoximine (BSO) to inhibit GSH synthesis and celecoxib (CXB) to down-regulate P-gp expression were co-loaded in polymer/inorganic hybrid nanoparticles to form buthionine sulfoximine/celecoxib@biotin-heparin/heparin/calcium carbonate/calcium phosphate nanoparticles (BSO/CXB@BNP). To investigate the reversal of MDR, the drug resistant cells (MCF-7/ADR) were pretreated by the dual-inhibitor loaded nanoparticles (BSO/CXB@BNP) followed by the treatment of doxorubicin (DOX) loaded nanoparticles (DOX@BNP). The dual-inhibitor loaded nanoparticles (BSO/CXB@BNP) exhibited greatly enhanced efficiency in down-regulation of GSH and P-gp since BSO and CXB had combined effects on the reduction of GSH and P-gp in drug resistant tumor cells. As a result, BSO/CXB@BNP exhibited a significantly improved capability in reversal of MDR compared with mono-inhibitor loaded nanoparticles (CXB@BNP and BSO@BNP). As compared with free drug resistance inhibitors, delivery of drug resistance inhibitors by functional nanocarriers could obviously improve the therapeutic efficiency due to enhanced cellular uptake and increased intracellular drug accumulation. The study on immunostimulatory effects of different treatments showed that BSO/CXB@BNP treatment resulted in the lowest concentration of interleukin 10, a cytokine related to tumor development. These results suggest the nanoparticulate drug delivery platform developed in this study has promising applications in multiple drug delivery to overcome drug resistance in tumor treatments., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The blood-brain barrier (BBB) is the major clinical obstacle in the chemotherapeutic management of brain glioma. Here we synthesized a pH-sensitive dual-targeting doxorubicin (DOX) carrier to compromise tumor endothelial cells, enhance BBB transportation, and improve drug accumulation in glioma cells. The drug delivery system was constructed with polydopamine (PDA)-coated mesoporous silica nanoparticles (NPs, MSNs) and the PDA coating was functionalized with Asn-Gly-Arg (NGR), a ligand with specific affinity for cluster of differentiation 13 (CD13). MSN-DOX-PDA-NGR showed a higher intracellular accumulation in primary brain capillary endothelial cells (BCECs) and C6 cells and greater BBB permeability than the non-targeting NPs (MSN-DOX-PDA) did in vitro. Ex vivo and in vivo tests showed that MSN-DOX-PDA-NGR had a higher accumulation in intracranial tumorous tissue than the undecorated NPs did. Furthermore, the antiangiogenesis and antitumor efficacy of MSN-DOX-PDA-NGR were stronger than that of MSN-DOX-PDA. Therefore, these results indicate that the dual-targeting vehicles are potentially useful in brain glioma therapy.

Fighting metastasis is a major challenge in cancer therapy, and stimulation of the immune system is of particular importance in the treatment of metastatic cancers. Here, an integrated theranostic nanoplatform was developed for the efficient treatment of highly metastatic tumors. Versatile functions including "And" logically controlled drug release, prolonged circulation time, tumor targeting, and anti-metastasis were integrated into doxorubicin (DOX) loaded, highly integrated mesoporous silica nanoparticles (DOX@HIMSNs) for a systemic treatment of highly metastatic triple negative breast cancer (TNBC). It was found that the good therapeutic effect of DOX@HIMSN was only partially attributed to its anticancer cytotoxicity. Most importantly, DOX@HIMSN could induce anticancer immune responses including dendritic cell (DC) maturation and antitumor cytokine release. Compared with the traditional tumor chemotherapy, the integrated theranostic nanoplatform we developed not only improved the tumor specific cytotoxicity but also stimulated antitumor immune responses during the treatment.

The efficiency of dye-sensitized solar cells (DSSCs) is generally limited by the mismatch between the absorption spectrum of the photosensitizer and the solar irradiation spectrum. This work describes the use of a mixture that containing proper proportions of SiO2 coated Au nanospheres (AuNSs@SiO2 ) and Au nanorods (AuNRs@SiO2 ) (the mixture was denoted as AuNCs@SiO2 ) to enhance the sunlight utility in DSSCs. The incorporation of AuNCs@SiO2 into the TiO2 photoanode induced broadband light-harvesting at both low- and long- wavelengths and thus enhanced the photocurrent compared to that of plasmonic solar cells based on either AuNSs@SiO2 or AuNRs@SiO2 . Upon the doping of AuNCs@SiO2 , the overall power conversion efficiency (PCE) increased from 7.39 to 9.12 % for DSSCs based on organic liquid electrolytes., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this work, a ZnO based nanococktail with programmed functions is designed and synthesized for self-synergistic tumor targeting therapy. The nanococktail can actively target tumors via specific interaction of hyaluronic acid (HA) with CD44 receptors and respond to HAase-rich tumor microenvironment to induce intracellular cascade reaction for controlled therapy. The exposed cell-penetrating peptide (R8) potentiates the cellular uptake of therapeutic nanoparticles into targeted tumor cells. Then ZnO cocktail will readily degrade in acidic endo/lysosomes and induce the production of desired reactive oxygen species (ROS) in situ. The destructive ROS not only leads to serious cell damage but also triggers the on-demand drug release for precise chemotherapy, thus achieving enhanced antitumor efficiency synergistically. After tail vein injection of ZnO cocktail, a favorable tumor apoptosis rate (71.2 ± 8.2%) is detected, which is significantly superior to that of free drug, doxorubicin (12.9 ± 5.2%). Both in vitro and in vivo studies demonstrate that the tailor-made ZnO cocktail with favorable biocompatibility, promising tumor specificity, and self-synergistically therapeutic capacity opens new avenues for cancer therapy., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Drug delivery has become an important strategy for improving the chemotherapy efficiency. Here we developed a multifunctionalized nanosized albumin-based drug-delivery system with tumor-targeting, cell-penetrating, and endolysosomal pH-responsive properties. cRGD-BSA/KALA/DOX nanoparticles were fabricated by self-assembly through electrostatic interaction between cell-penetrating peptide KALA and cRGD-BSA, with cRGD as a tumor-targeting ligand. Under endosomal/lysosomal acidic conditions, the changes in the electric charges of cRGD-BSA and KALA led to the disassembly of the nanoparticles to accelerate intracellular drug release. cRGD-BSA/KALA/DOX nanoparticles showed an enhanced inhibitory effect in the growth of αvβ3-integrin-overexpressed tumor cells, indicating promising application in cancer treatments.

A facile strategy to prepare nano-sized drug carriers for co-delivery of multiple types of drugs in combination chemotherapy was developed. Inorganic/organic hybrid alginate/CaCO3 nanoparticles were prepared by co-precipitation in an aqueous solution under very mild conditions. A hydrophilic drug (doxorubicin hydrochloride, DOX) and a hydrophobic drug (paclitaxel, PTX) were co-encapsulated in the hybrid nanoparticles. For comparison, PTX loaded nanoparticles and DOX loaded nanoparticles were also prepared. The measurement based on dynamic light scattering indicated all nanoparticles had a mean size less than 200 nm with a relatively narrow size distribution. The morphology of the nanoparticles was observed by TEM. The in vitro drug release study showed that the release of DOX and PTX from the dual drug loaded nanoparticles could be effectively sustained. The tumor cell inhibitory effect of the drug loaded nanoparticles was evaluated in HeLa cells and MCF-7/ADR cells. The dual drug loaded nanoparticles exhibited significantly enhanced cell uptake and nuclear localization as compared with the single drug loaded nanoparticles. As a result, the dual drug loaded nanoparticles had a significantly enhanced cell inhibitory effect, especially for drug resistant tumor cells. These results indicated that alginate/CaCO3 hybrid nanoparticles have promising applications for the co-delivery of drugs with different physicochemical properties in combination chemotherapy to overcome multidrug resistance., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Ternary nanoparticles, protamine sulfate-calcium carbonate-plasmid DNA (PS-CaCO3-DNA), were prepared for efficient gene delivery. By adding the cationic polypeptide PS in the co-precipitation system of calcium carbonate and DNA, PS-CaCO3-DNA nanoparticles could be formed by self-assembly facilely. The effect of PS on the properties of the ternary nanoparticles was studied by varying the PS amount in the nanoparticles. The size and ζ-potential measurements indicated that the ternary nanoparticles with an appropriate PS amount exhibited a decreased size and an increased ζ-potential. The in vitro gene transfections mediated by different nanoparticles in 293T cells and HeLa cells were carried out in the presence of 10% fetal bovine serum, using pGL3-Luc and pEGFP-C1 as reporter plasmids. As compared with both PS-DNA nanoparticles and CaCO3-DNA nanoparticles, PS-CaCO3-DNA nanoparticles exhibited significantly enhanced gene delivery efficiency, which was higher than that of Lipofectamine 2000-DNA. Confocal microscopy observation showed that PS-CaCO3-DNA nanoparticles could efficiently deliver DNA to cell nuclei. These results indicated that the ternary PS-CaCO3-DNA nanoparticles prepared in this study have promising applications in gene delivery.

A novel type of cellular-uptake-shielding multifunctional envelope-type mesoporous silica nanoparticle (MEMSN) was designed for tumor-triggered targeting drug delivery to cancerous cells. β-Cyclodextrin (β-CD) was anchored on the surface of mesoporous silica nanoparticles via disulfide linking for glutathione-induced intracellular drug release. Then a peptide sequence containing Arg-Gly-Asp (RGD) motif and matrix metalloproteinase (MMP) substrate peptide Pro-Leu-Gly-Val-Arg (PLGVR) was introduced onto the surface of the nanoparticles via host-guest interaction. To protect the targeting ligand and prevent the nanoparticles from being uptaken by normal cells, the nanoparticles were further decorated with poly(aspartic acid) (PASP) to obtain MEMSN. In vitro study demonstrated that MEMSN was shielded against normal cells. After reaching the tumor cells, the targeting property could be switched on by removing the PASP protection layer via hydrolyzation of PLGVR at the MMP-rich tumor cells, which enabled the easy uptake of drug-loaded nanoparticles by tumor cells and subsequent glutathione-induced drug release intracellularly.

In this study, a facile strategy to effectively improve the delivery efficiency of nano-sized drug delivery systems was developed. Calcium phosphate/carboxymethyl chitosan (Ca-P/CMC) hybrid nanoparticles were prepared by the precipitation of calcium phosphate in the aqueous solution containing CMC. The obtained Ca-P/CMC nanoparticles were characterized by SEM, XPS and TGA. Doxorubicin hydrochloride (DOX), a water-soluble anticancer drug, was loaded in the nanoparticles with high encapsulation efficiency. The in vitro drug release showed that the release of DOX from the nanoparticles could be effectively sustained. After drug loading, the nanoparticles were decorated by peptide KALA by self-assembly through the electrostatic interaction between the positively charged KALA and the negatively charged CMC chains to obtain drug loaded Ca-P/CMC/KALA nanoparticles. The size and size distribution of the nanoparticles were measured by a particle size analyzer. The KALA decorated nanoparticles exhibited a larger size and an increased zeta potential. The effect of KALA content on the HeLa cell inhibition was studied. The in vitro study showed that the cell inhibition effect could be significantly enhanced by the presence of KALA., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A facile method to prepare inorganic/organic hybrid heparin/CaCO(3)/CaP nanoparticles for drug delivery was developed. The heparin/CaCO(3)/CaP nanoparticles were prepared by the co-precipitation of Ca(2+) ions with carbonate and phosphate ions in the presence of heparin. The effects of ion concentrations on the particle size and properties of the nanoparticles were investigated. The dynamic light scattering (DLS) particle size analysis and scanning electron microscopy (SEM) observation showed that the mean size of the hybrid nanoparticles could be controlled at less than 50 nm in the dried state through adjusting the concentrations of the inorganic ions. Fourier transform infrared (FTIR) spectroscopy indicated that the crystallization of CaCO(3) could be suppressed with the presence of phosphate ions in the co-precipitation system. X-ray photoelectron spectroscopy (XPS) showed that the heparin content in the surface layer of heparin/CaCO(3)/CaP hybrid nanoparticles decreased with the increasing ion concentrations during the nanoparticle preparation. The drug loading and release properties of the hybrid nanoparticles with different sizes and different compositions were studied. The in vitro cellular cytotoxicity indicated that blank hybrid nanoparticles had good biocompatibility, whereas doxorubicin hydrochloride (DOX) loaded nanoparticles exhibited a strong cell inhibition effect, indicating that the heparin/CaCO(3)/CaP hybrid nanoparticles could be promising carriers for drug delivery., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In this study, a facile strategy to effectively improve the gene and drug delivery efficiencies of calcium carbonate based nanoparticles was developed by introducing a cell-penetrating peptide, KALA, into the delivery systems. To evaluate the effect of KALA on the gene delivery efficiency, luciferase reporter gene plasmid was encapsulated in CaCO(3)-KALA-DNA nanoparticles. The measurements of a Zetasizer showed that the size and the zeta potential of CaCO(3)-KALA-DNA nanoparticles increased with increasing KALA amount because of the addition of positively charged KALA. Due to the existence of KALA, the gene expressions could be significantly enhanced in both HeLa and 293T cells. Confocal microscopy observation showed that the cellular uptake of CaCO(3)-KALA-DNA nanoparticles was obviously enhanced compared to CaCO(3)-DNA nanoparticles. To investigate the gene and drug co-delivery property, p53 expression plasmid and doxorubicin hydrochloride (DOX) were loaded in CaCO(3)-KALA-p53-DOX nanoparticles. The in vitro cell growth inhibition effect of CaCO(3)-KALA-p53-DOX nanoparticles was evaluated by MTT assay. Compared with CaCO(3)-p53-DOX nanoparticles, CaCO(3)-KALA-p53-DOX nanoparticles exhibited enhanced delivery efficiency, which led to a stronger inhibition effect on HeLa cells. These results indicated that the addition of KALA, which facilitated the cellular uptake of various agents, could improve both gene and drug delivery efficiencies. The KALA modified CaCO(3) based nanoparticles have promising applications in cancer treatments.

In this study, a facile strategy for efficient codelivery of gene and drug was developed. Using a coprecipitation method, doxorubicin hydrochloride (DOX), an antitumor drug, and p53 expression plasmid were encapsulated in alginate/CaCO(3)/DNA/DOX nanoparticles with high encapsulation efficiency. The in vitro cell inhibition effect of the alginate/CaCO(3)/DNA/DOX nanoparticles was evaluated by MTT assay in HeLa cells. The alginate/CaCO(3)/DNA/DOX nanoparticles exhibited a high cell inhibition rate about 80%, indicating that the alginate/CaCO(3)/DNA/DOX nanoparticles could effectively mediate gene transfection and deliver the drug to the cells. Compared with the codelivery of gene and drug, the treatments by alginate/CaCO(3)/DOX nanoparticles and alginate/CaCO(3)/DNA nanoparticles separately led to much lower cell inhibition rates. Compared with the CaCO(3)/DNA/DOX nanoparticles without alginate modification, the alginate/CaCO(3)/DNA/DOX nanoparticles with a decreased particle size exhibited enhanced delivery efficiency. The alginate/CaCO(3)/DNA/DOX nanoparticles have promising applications in cancer treatments.

Poly(alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide])-folate (PHEA-FA) was synthesized by linking FA to a poly(alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide]) (PHEA) backbone. The chemical structure of PHEA-FA was characterized by (1)H-NMR and FT-IR. The molecular weights of the polymers were determined by combined size-exclusion chromatography and multiangle laser light scattering (SEC-MALLS) analysis. Due to the incorporation of FA, PHEA-FA exhibited pH-sensitive aggregation behavior in aqueous media. As characterized by UV-Vis spectroscopy and fluorescence spectroscopy, PHEA-FA could self-assemble to form aggregates in acidic and neutral aqueous solutions, and became soluble in a basic solution. The potential application of PHEA-FA in drug delivery was explored. Drug-loaded PHEA-FA nanoparticles were fabricated and the in vitro drug release of the drug-loaded nanoparticles was investigated. Transmission electron microscopy (TEM) showed that the nanoparticles exhibited a spherical morphology with particle sizes <100 nm. The in vitro study showed PHEA-FA exhibited enhanced cell uptake on the folate-receptor-positive cells because of the folate-mediated targeting.

Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH sensitivity were developed for oral delivery of protein drugs, using bovine serum albumin (BSA) as a model drug. The composite drug-loaded microparticles with a mean particle size less than 200mum were prepared by a convenient shredding method. Since the microparticles were formed by tripolyphosphate cross-linking, electrostatic complexation by alginate and/or pectin, as well as ionotropic gelation with calcium ions, the microparticles exhibited an improved pH-sensitive drug release property. The in vitro drug release behaviors of the microparticles were studied in simulated gastric (pH 1.2 and pH 5.0), intestinal (pH 7.4) and colonic (pH 6.0 and pH 6.8 with enzyme) media. For the composite microparticles with suitable compositions, the releases of BSA at pH 1.2 and pH 5.0 could be effectively sustained, while the releases at pH 7.4, pH 6.8 and pH 6.0 increased significantly, especially in the presence of pectinase. These results clearly suggested that the microparticles had potential for site-specific protein drug delivery through oral administration.

A series of biocompatible and stimuli-sensitive poly(N-isopropylacrylamide-co-propyl acrylic acid) (P(NIPAAm-co-PAAc)) nanogels were synthesized by emulsion polymerization. In addition, polyethyleneimine (PEI) was further grafted to modify the PNIPAAm-based nanogels. The P(NIPAAm-co-PAAc)-g-PEI nanogels exhibited good thermosensitivity as well as pH sensitivity. Transmission electron microscopy (TEM) showed that the P(NIPAAm-co-PAAc)-g-PEI and P(NIPAAm-co-PAAc) nanogels displayed well dispersed spherical morphology. The mean sizes of the nanogels measured by dynamic light scattering (DLS) were from 100 nm to 500 nm at different temperatures. The cytotoxicity study indicated P(NIPAAm-co-PAAc) nanogels exhibited a better biocompatibility than both PNIPAAm nanogel and P(NIPAAm-co-PAAc)-g-PEI nanogel although all the three kinds of nanogels did not exhibit apparent cytotoxicity. The drug-loaded nanogels, especially the PEI-grafted nanogels, showed temperature-trigged controlled release behaviors, indicating the potential applications as an intelligent drug delivery system.

Novel thermo-sensitive magnetomicelles that consist of a magnetic core, Fe(3)O(4)-oleic acid (Fe(3)O(4)-OA), and an amphiphilic surface layer of thermo-sensitive poly(oleic acid-co-N-isopropylacrylamide) P(OA-co-NIPAAm) co-polymer were prepared. Fe(3)O(4) magnetic cores functionalized with double bonds of oleic acid were prepared by suspension-oxidation reaction. Subsequently, by the co-polymerization of hydrophilic NIPAAm, hydrophobic OA and the Fe(3)O(4)-OA magnetic core, the thermo-sensitive amphiphilic polymers (P(OA-co-NIPAAm)) were grafted to obtain Fe(3)O(4)-OA-g-P(OA-co-NIPAAm) nanoparticles. The surface polymeric layer of Fe(3)O(4)-OA-g-P(OA-co-NIPAAm) nanoparticles would self-assemble in aqueous media to form a micellar structure attributed to the amphiphilic P(OA-co-NIPAAm) polymers. The model drug, prednisone acetate, was loaded in the magnetomicelles and in vitro release behavior of loaded drug in magnetomicelles was further investigated, which showed a thermo-sensitive release behavior due to the thermo-sensitive structural changes of the micellar surface layer.

A novel pH-sensitive nanogel based on pectin cross-linked with glutaraldehyde (PT-GA) was designed and synthesized for drug delivery. Transmission electron microscope observation shows that the nano-sized gel particles exhibit a spherical morphology. The optical absorbance study of nanogel suspension reveals its pH sensitivity. Cytotoxicity study shows that the nanogel has no apparent inhibitory effect on cells. The in vitro drug-release behavior of the drug-loaded nanogel particles in three kinds of media, i.e., simulated gastric fluid, simulated intestine fluid and simulated colon fluid, was studied. PT-GA nanogel exhibits a faster release at a high pH, and the release could be further accelerated in the presence of pectinolytic enzyme, indicating that the nanogel may be used for colon-specific drug delivery.

An amphiphilic AB block copolymer composed of poly(N-isopropylacrylamide) as a hydrophilic segment and poly(10-undecenoic acid) as a hydrophobic segment was synthesized. Cytotoxicity study of this copolymer exhibited no significant cytotoxicity. The lower critical solution temperature (LCST) of the copolymer was 30.8 degrees C, as determined by the turbidity method. The block copolymer forms micelles in an aqueous medium at the temperature lower than the LCST. Transmission electron microscopy images showed that these micelles were regularly spherical in shape. The micelle size determined by size analysis was around 160 nm. The anti-inflammation drug prednisone acetate was incorporated into the micelles and the release profiles of prednisone acetate showed a dramatic thermoresponsive switching behavior and a unique pH responsive behavior. Moreover, the pH responsive behavior was in relation to the thermoresponsive behavior. That is, the micelles were not pH sensitive at the temperature below the LCST, but the aggregates were pH sensitive at the temperature above the LCST. Based on these results, the thermo- and pH responsive micelles have great potential to be a novel carrier for drug delivery.

A facile strategy for the fabrication of multi-functional polymer/inorganic hybrid nanoparticles for efficient gene and drug co-delivery was developed. A therapeutic gene (p53 plasmid) and a chemotherapy drug (doxorubicin hydrochloride, DOX) were co-loaded simultaneously in hybrid nanoparticles during co-precipitation with high encapsulation efficiency. The prepared heparin-biotin/heparin/ CaCO3/calcium phosphate/ DNA/ DOX ( HPB/ HP/ CaCO3/ CaP/ DNA/ DOX) nanoparticles exhibited pH sensitivity and tumor-targeting property due to the presence of the CaCO3/ CaP inorganic component and biotin moiety in the polymer chain, respectively. For comparison, HPB/ HP/ CaCO3/ CaP/ DOX hybrid nanoparticles for drug delivery were also fabricated. The cell inhibition effects of different nanoparticles on HeLa cells were evaluated using methylthiazole tetrazolium assay. In vitro study indicated that the gene and drug co-delivery system ( HPB/ HP/ CaCO3/ CaP/ DNA/ DOX) showed a stronger cell growth inhibition effect as compared with the drug delivery system ( HPB/ HP/ CaCO3/ CaP/ DOX), indicating that HPB/ HP/ CaCO3/ CaP/ DNA/ DOX hybrid nanoparticles could effectively mediate gene transfection and deliver the drug. The hybrid nanoparticles with good biocompatibility have great promise for gene and drug co-delivery. © 2014 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

A facile and rapid approach for detecting low concentration of iron ion (Fe) with improved sensitivity was developed on the basis of plasmon enhanced fluorescence and subsequently amplified fluorescence quenching. AuAg@SiO nanoparticles were synthesized and dispersed into fluorescein isothiocyanate (FITC) solution. The fluorescence of the FITC solution was improved due to plasmon enhanced fluorescence. However, efficient fluorescence quenching of the FITC/AuAg@SiO solution was subsequently achieved when Fe, with a concentration ranging from 17 nM to 3.4 μM, was added into the FITC/AuAg@SiO solution, whereas almost no fluorescence quenching was observed for pure FITC solution under the same condition. FITC/AuAg@SiO solution shows a better sensitivity for detecting low concentration of Fe compared to pure FITC solution. The quantized limit of detection toward Fe was improved from 4.6 μM for pure FITC solution to 20 nM for FITC/AuAg@SiO solution. [ABSTRACT FROM AUTHOR]

Novel thermo-sensitive magnetomicelles that consist of a magnetic core, Fe3O4-oleic acid (Fe3O4-OA), and an amphiphilic surface layer of thermo-sensitive poly(oleic acid-co-N-isopropylacrylamide) P(OA-co-NIPAAm) co-polymer were prepared. Fe3O4 magnetic cores functionalized with double bonds of oleic acid were prepared by suspension–oxidation reaction. Subsequently, by the co-polymerization of hydrophilic NIPAAm, hydrophobic OA and the Fe3O4-OA magnetic core, the thermo-sensitive amphiphilic polymers (P(OA-co-NIPAAm)) were grafted to obtain Fe3O4-OA-g-P(OA-co-NIPAAm) nanoparticles. The surface polymeric layer of Fe3O4-OA-g-P(OA-co-NIPAAm) nanoparticles would self-assemble in aqueous media to form a micellar structure attributed to the amphiphilic P(OA-co-NIPAAm) polymers. The model drug, prednisone acetate, was loaded in the magnetomicelles and in vitro release behavior of loaded drug in magnetomicelles was further investigated, which showed a thermo-sensitive release behavior due to the thermo-sensitive structural changes of the micellar surface layer. [ABSTRACT FROM AUTHOR]

Photothermal immunotherapy emerges as a promising strategy for treating tumors. However, the majority of current photothermal immunotherapy approaches do not yet show significant potential for clinical translation. In this study, lyophilized polydopamine (PDA) nanoparticles combined with Bacillus Calmette–Guérin (BCG) are investigated for photothermal immunotherapy against colorectal cancer. By simply mixing with two lyophilized powders, PDA nanoparticles can covalently bond onto BCG to form BCG@PDA. This combination demonstrates a potent photothermal cytotoxic effect on tumor cells by utilizing PDA nanoparticles. In addition, a heightened immune response triggered by the BCG vaccine, as evidenced by the secretion of important pro‐inflammatory cytokines and the activation of antigen‐presenting cells, is observed. In vivo testing on a murine colon cancer model demonstrates that the combined treatment significantly inhibits tumor growth. Further, the lyophilized PDA nanoparticles can be stored at −20 °C for up to 1 year with stable photothermal properties. Therefore, this study not only presents a reliable method for storing the therapeutic PDA nanoparticles but also demonstrates the potential application of BCG@PDA in photothermal immunotherapy for colorectal cancer. [ABSTRACT FROM AUTHOR]

A simple two-step procedure, which involves the synthesis of the Zn 0.33 Mn 0.67 CO 3 microspheres through a hydrothermal process and the subsequent calcination, has been used to synthesize the ZnMn 2 O 4 microspheres with a hierarchical porous morphology consisting of the ZnMn 2 O 4 sub-nanoparticles. When evaluated as anode materials for lithium ion batteries (LIBs), these hierarchical porous ZnMn 2 O 4 microspheres could exhibit a stable reversible capability of ∼723.7 mAh g −1 at the current density of 400 mA g −1 , which is much higher than those of the ZnMn 2 O 4 based materials reported previously, indicating the great potential of using them as the anode for the LIBs. This is further supported by their better rate capability and higher cycling stability. Careful analysis has shown that the unique porous structure of the hierarchical porous ZnMn 2 O 4 microspheres which consists of the ZnMn 2 O 4 sub-nanoparticles plays an important role in their higher electrochemical performance, since it allows the accommodation of the volume expansion during the repeated discharge–charge cycles, preventing them from the structural destruction, and increase the accessibility of the electrode material to the Li + storage, making a better utilization of active materials and an easy diffusion of electrolytes in and out of the electrode material. [ABSTRACT FROM AUTHOR]

MOF- or ZIF-derived carbon (MDC/ZDC) has attracted significant attention especially in catalysis applications, because well-dispersed metal or oxide nanoparticles over the MDC/ZDC matrix with retained MOF/ZIF porosity can be obtained with direct pyrolysis. Although it seems to be a facile approach, pyrolysis parameters could significantly alter the MDC/ZDC properties. However, an in-depth study on the pyrolytic factors has not been discussed. Herein, we manipulated ZIF structure, pyrolytic atmosphere, temperature, incubation time, and ramping/cooling rates for ZDC structural analyses. Compared to pure ZIF-67 derived carbon with only Co metal nanoparticles, it was observed that the carbonization process in core-shell ZIF-8@ZIF-67 (Z8@Z67) initiated the interdiffusion of reduced metal ions at the core-shell interface, which triggered the unique Zn-Co alloying behavior forming Zn 3 Co when they were in close proximity. The resultant intermetallic Zn 3 Co compound is unstable and has never been experimentally observed. By employing the in situ powder X-ray diffraction (PXRD) technique, we observed the fast-heating plus cooling process arrested or circumvented the phase segregation, and kept the metastable intermetallic Zn 3 Co. For the first time, we report a method to maintain it at ambient conditions, protected by the porous MOF derivative from ZIF pyrolysis. [Display omitted] • Well-dispersed Co nanoparticles is observed during Zn-Co core-shell ZIF pyrolysis. • Metastable phase Zn 3 Co is formed and preserved after core-shell ZIF pyrolysis. • The existence of Zn 3 Co can be controlled by ZIF pyrolytic ramping/quenching rates. [ABSTRACT FROM AUTHOR]

Abstract For effective regulation of cell behaviors and prevention of tumor development by genome editing, we constructed multi-functional self-assembled nanoparticles based on natural polymers to deliver CRISPR-Cas9 plasmid to tumorous cells. The CRISPR based gene editing plasmid to knockout CDK11 gene was complexed with protamine sulfate, and then the complex was decorated by a multi-functional outer layer composed of an endosomolytic peptide (KALA) and aptamer AS1411 incorporated carboxymethyl chitosan. The resultant multi-functional nanoparticles, which exhibit significantly enhanced delivery efficiency, can specifically deliver the plasmid into tumor cell nuclei owing to the favorable effects of KALA in cellular uptake and endosomal escape, together with the cancer cell and cell nucleus targeting capability of AS1411 ligands. The genome editing mediated by the nanoparticles leads to a dramatic decrease (>75%) in CDK11 expression, which results in further modulation of cancer cells with significant down-regulation of the proteins (MMP-9 and VEGF) involved in tumor development and metastasis as well as up-regulation of the tumor suppressor protein p53. More importantly, the detection of immune-related proteins after genome editing shows that the significantly enhanced Fas, CD80, MICA, MICB, and HLA-1 expression and decreased CD47 and MUC1 expression, indicating the genome editing is favorable for reversal of tumor-induced immunosuppression and prevention of tumor development. Graphical abstract A natural polymer based multi-functional delivery system can efficiently deliver CRISPR-Cas9 plasmid into targeted tumor cell nuclei to regulate cell behaviors and prevent tumor development. Unlabelled Image [ABSTRACT FROM AUTHOR]

Highlights: [•] A facile strategy to modify CaCO3 based gene delivery systems was developed. [•] CaCO3/CaP/DNA nanoparticles were prepared by a facile co-precipitation method. [•] CaCO3/CaP/DNA nanoparticles exhibited significantly improved delivery efficiency. [ABSTRACT FROM AUTHOR]

[Display omitted] • A facile synthesis of dendritic PdAgPt nanorings was reported. • Dendritic PdAgPt nanorings possess multiple crystal defects as active sites. • The superior EOR performance of PdAgPt nanorings over Pt/C and Pd/C are achieved. Metallic ring-shaped nanostructures are of particular interest in electrocatalysis for both interior and exterior surfaces are exposed to the reactants. However, it still remains a great challenge to synthesize such trimetallic ring-shaped nanostructure with nanodendrites. Herein, a facile synthesis of dendritic PdAgPt nanorings with abundant crystal defects was reported. The enhanced ethanol oxidation reaction (EOR) activity and stability by PdAgPt nanorings was obtained due to the synergistic effect among trimetallic alloys and the special morphology. The mass activity of PdAgPt nanorings reached 3663 mA mg-1 Pt+Pd , which was much higher than that of Pt/C and Pd/C. [ABSTRACT FROM AUTHOR]

Abstract: In this study a two-dimensional graphene sheet (GS) doped with palladium (Pd) nanoparticles was physically mixed with a superactivated carbon (AC) receptor and used as a hydrogen adsorbent. The hydrogen adsorption/desorption isotherm of the Pd-doped GS catalyst/AC composite (Pd-GS/AC) is determined using a static volumetric measurement at room temperature (RT) and pressure up to 8 MPa. The experiments show that the H2 uptake capacity of 0.82wt.% for Pd-GS/AC is obviously enhanced, measuring 49% more than the 0.55wt.% for Pd-free GS/AC at RT and 8 MPa. Highly reversible behavior of Pd-GS/AC is also observed. Moreover, the isosteric heat of adsorption for Pd-GS/AC (−14 to −10 kJ/mol) is higher than that for pristine AC (−8 kJ/mol). An increase in H2 uptake in the Pd-GS/AC suggests the occurrence of a relatively strong interaction between the spilt-over H and the receptor sites due to the spillover effect. [Copyright &y& Elsevier]

Abstract: A four-arm star block copolymer, comprised of a hydrophobic PMMA arm and an average of three hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) arms were designed and synthesized from the molecular level. The amphiphilic star block copolymer is capable of self-assembling into micelles in water, which was confirmed by FT-IR, 1H NMR and fluorescence spectroscopy. Transmission electron microscopy images showed that these nanoparticles were regularly spherical in shape. The micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 34°C, observed by optical absorbance measurements. Resulted polymeric micelles loaded with prednisone acetate showed a much improved drug release behavior due to the special micellar structure. [Copyright &y& Elsevier]