Chitosan-based hybrid nanospheres for vessel normalization towards enhancing tumor chemotherapy.

Vessel normalization has proved imperative in tumor growth inhibition. In this work, biopolymer-based hybrid nanospheres capable of normalizing blood vessels were designed to improve the therapeutic effect of chemotherapeutic drugs. Zn0.4Fe2.6O4 nanoparticles (ZFO NPs) were synthesized, and were encapsulated in cross-inked chitosan (CS) along with a nitric oxide (NO) precursor, DETA NONOate, forming hybrid ZFO/NO@CS nanospheres highly stable in physiological environment. The structure, morphology and size of the nanospheres were characterized. The ZFO/NO@CS nanospheres could release NO under acidic conditions typical of intratumoral and intracellular environment. The results of related factors expression, wound healing and tube formation assays demonstrated that both the encapsulated ZFO NPs and the released NO were able to inhibit angiogenesis in tumors. The ZFO/NO@CS nanospheres enhanced the antitumor efficacy of the chemotherapeutic drug DOX by normalizing tumor vessels, as evidenced by in vivo experiments for CT26 tumor-bearing mice. By analyzing the contents of Fe in the tumor and different organs, the nanospheres were found to accumulate primarily at the tumor site. The blood analysis showed little side effect of the nanospheres. The ZFO/NO@CS nanospheres have great potential in improving tumor therapeutic effect when used in combination with chemotherapeutic drugs.

Advances in inorganic-based colloidal nanovehicles functionalized for nitric oxide delivery.

Nitric oxide (NO) is an important pharmaceutical agent of considerable therapeutic interest ascribed to its vasodilative, tumoricidal and antibacterial effects. Rapid development of functional nanomaterials has provided opportunities for us to achieve controllable exogenous delivery of NO. In the current review, a variety of functionalized colloidal nanovehicles that have been developed to date for nitric oxide delivery are reported. Specifically, we focus on inorganic nanomaterials such as semiconductor quantum dots, silica nanoparticles, upconversion nanomaterials, carbon/graphene nanodots, gold nanoparticles, iron oxide nanoparticles as the functional or/and supporting materials to carry NO donors. N-diazeniumdiolates, S-nitrosothiols, nitrosyl metal complexes and organic nitrates as main types of NO donors have their own unique properties and molecular structures. Conjugating the NO donors of different forms with appropriate nanomaterials results in NO delivery nanovehicles capable of releasing NO in a dose-controllable or/and on-demand manner. We also consider the therapeutic applications of those NO delivery nanovehicles, especially their applications for cancer therapy. In the end, we discuss possible future directions for developing exogenous NO delivery systems with more desired structure and improved performance. This review aims to offer the readers an overall view of the advances in functionalized colloidal nanovehicles for NO delivery. It will be attractive to scientists and researchers in the areas of material science, nanotechnology, biomedical engineering, chemical biology, etc.

Antimicrobial Efficacy of Liposome-Encapsulated Citral and Its Effect on the Shelf Life of Shatangju Mandarin.

ABSTRACT: Liposome-encapsulated citral was prepared by means of a hot homogenization method. The microstructure, particle size, and zeta potential of the capsules were analyzed by transmission electron microscope and dynamic light scattering, respectively, in which the results showed a good dispersion stability of the citral-loaded liposome. In vitro tests showed that liposome-encapsulated citral significantly (P < 0.05) reduced the populations of Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Penicillium italicum more than free citral. In vivo tests conducted on fresh Shatangju mandarin showed that liposome-encapsulated citral-treated fruit exhibited a decay incidence of 56.67%, which is 42.04% lower than free citral-treated fruit (97.78%) after 26 days of storage at 25°C and 60 to 70% relative humidity. Additionally, fruit treated with citral-loaded liposome significantly reduced weight loss and viable yeast and mold during storage. In summary, liposome-encapsulated citral could be an effective antimicrobial agent to extend the shelf life of the Shatangju mandarin.

Correction: Facile synthesis of CuS mesostructures with high photothermal conversion efficiency.

[This corrects the article DOI: 10.1039/C5RA01835H.].

RGD peptide-decorated micelles assembled from polymer-paclitaxel conjugates towards gastric cancer therapy.

Development of polymer-drug conjugate capable of controlled drug release is urgently needed for gastric cancer therapy. Herein, arginine-glycine-aspartic acid (RGD)-decorated polyethylene glycol (PEG)-paclitaxel (PTX) conjugates containing disulfide linkage were synthesized. The amphiphilic PEG-PTX conjugates were found to assemble into micelles (RGD@Micelles), which would be decomposed under the reduction of glutathione (GSH) and finally release PTX in weakly acidic conditions characteristic of intracellular environment. The RGD@Micelles were spherical nanoparticles with an average hydrodynamic size of ˜50 nm, which were stable in physiological environment. The release of PTX from the micelles in response to GSH was investigated. In vitro cell assay suggested that the RGD@Micelles could target the gastric cancer cells and inhibit cell proliferation by inducing apoptosis. In vivo experiments indicated that the RGD@Micelles could be delivered to the tumor site and inhibit the tumor growth efficiently by releasing PTX inside the tumor cells. This type of micelles exhibited high therapeutic efficacy and low side effects, providing new insights into targeted drug delivery for gastric cancer therapy.

Preparation, characterization and in vitro release study of drug-loaded sodium carboxy-methylcellulose/chitosan composite sponge.

A sodium carboxy-methylcellulose (CMC)/chitosan (CS) composite sponge as drug carrier was prepared, and its structure and functions were investigated. Samples with different CMC/chitosan ratios and under different pH conditions were synthesized via a freeze-drying method. The microstructure of the dried sponges was analyzed by Scanning Electron Microscope (SEM). Molecule interactions between polymers were confirmed by Fourier transform infrared (FTIR) spectra and Thermal gravimetric analyze (TGA). The swelling degree, weight loss, in vitro drug release behavior and antibacterial property of the sponges were determined as well. The results showed that the CMC/chitosan ratio and the pH value significantly affected the appearance of the blending solution and the microstructure of the final product, and also affected the sponge's degradation behavior, drug-loading capacity and the antibacterial activity. Gentamicin (GEN) as a hydrophilic model drug was remarkably superior to the other two hydrophobic drugs, ibuprofen (IBU) and roxithromycin (ROX), with respect to in vitro releasing. Moreover, higher CMC content and lower pH value of the sponge were confirmed to lead a larger loading for GEN. The bacteriostatic experiment showed a strong antimicrobial ability of GEN-loaded sponges on inhibiting Escherichia coli.

Controllable release of nitric oxide and doxorubicin from engineered nanospheres for synergistic tumor therapy.

NaYF4:Yb,Er upconversion nanoparticles (UCNPs) capped with long-chain carboxylic acid were synthesized and then conjugated with chitosan (CS) in the aid of N-hydroxysuccinimide. The resultant nanocompound was integrated with doxorubicin (DOX) and Roussin's black salt (RBS), a photosensitive nitric oxide (NO) donor to produce stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres as nanocarriers for controllable drug delivery. On the one hand, the encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible photons to trigger NO release. On the other hand, the entrapped DOX can be released at lowered pH from the swollen nanospheres caused by stretched oleoyl-CS chains under acidic conditions. The UCNPs(DOX)@CS-RBS nanospheres exhibit great therapeutic efficacy, which is attributable to the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study highlights the controllable release of NO and DOX from the same nanocarriers and the synergistic therapeutic effect on tumors, which could give new insights into improving cancer nanotherapeutics. STATEMENT OF SIGNIFICANCE: In this paper, core-shell structured UCNPs(DOX)@CS-RBS nanospheres have been designed and synthesized via a step-by-step procedure. The stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres act as nanocarriers for controllable drug delivery towards cancer therapy. The encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible light to trigger NO release. Meanwhile, the entrapped DOX can be released from the swollen nanospheres caused by stretched oleoyl-CS chains at lowered pH typical of intracellular environment. Synergistic cancer therapy will be achieved through the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study provides new drug nanocarriers with high antitumor efficacy for synergistic cancer therapy.

Dynamic covalent linked triblock copolymer micelles for glutathione-mediated intracellular drug delivery.

Redox-responsive linkages dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their niche. In the present work, triblock copolymer PEG-PLA-PEG synthesized and characterized by 1H -NMR and SEC can self-assemble into redox-responsive micelles in aqueous media with nanosized 33nm and 47nm. And the copolymers PEG2000-PLA3000-PEG2000 and PEG2000-PLA5000-PEG2000 present lower CMC with 0.034 and 0.022mg/mL, and higher DLC of 4.28% and 5.14% respectively, compared with that of diblock copolymer. Moreover, drug release from the micelles can be triggered and significantly accelerated in reductive environment. The low cytotoxicity of redox-responsive micelles was confirmed by MTT assay against NIH 3T3 cells. All of these results demonstrated that these polymeric micelles self-assembled from double-disulfide tethered block copolymers are promising carriers for the redox-responsive intracellular delivery of hydrophobic anticancer drugs.

Chitosan-based core-shell nanomaterials for pH-triggered release of anticancer drug and near-infrared bioimaging.

As a naturally-abundant biopolymer, chitosan (CS) exhibit pH-sensitive structural transformation within a narrow pH range. Integrating hydrophobic groups to CS molecules gives modified CS polymers with more adjustable pH responsiveness. In this paper, near-infrared (NIR) photoluminescent Ag2S QDs capped by long-chain carboxylic acid were synthesized and then conjugated with CS via esterification reaction. The anticancer drug doxorubicin (DOX) has an affinity for the hydrophobic oleoyl groups and was entrapped by them to produce Ag2S(DOX)@CS nanospheres. A variety of experiments were performed to characterize the nanospheres. In vitro and in vivo experiments showed that the nanospheres can release DOX at lowered pH in tumor cells and have high antitumor efficacy. In addition, the strong NIR signal derived from the encapsulated Ag2S QDs makes real-time monitoring of the nanosphere distribution in a body possible. This study provides a new CS-based nanocomposite drug carrier for efficient cancer therapy.

Synthesis and evaluations of an acid-cleavable, fluorescently labeled nucleotide as a reversible terminator for DNA sequencing.

An acid-cleavable linker based on a dimethylketal moiety was synthesized and used to connect a nucleotide with a fluorophore to produce a 3'-OH unblocked nucleotide analogue as an excellent reversible terminator for DNA sequencing by synthesis.

Design and synthesis of fluorescence-labeled nucleotide with a cleavable azo linker for DNA sequencing.

A cleavable azo linker was synthesized and reacted with 5-(6)-carboxytetramethyl rhodamine succinimidyl ester, followed by further reactions with di(N-succinimidyl) carbonate and 5-(3-amino-1-propynyl)-2'-deoxyuridine 5'-triphosphate [dUTP(AP3)] to obtain the terminal product dUTP-azo linker-TAMRA as a potential reversible terminator for DNA sequencing by synthesis with no need for 3'-OH blocking.

Facile assembly of oppositely charged silver sulfide nanoparticles into photoluminescent mesoporous nanospheres.

Inorganic mesoporous materials have been attracting increasing attention during the past decade. In the present work, photoluminescent Ag2S nanospheres with mesoporous structures were prepared by assembling Ag2S nanoparticles with opposite charges in aqueous phase. Without structure-directing templates, mesoporous Ag2S with well-ordered face-centered cubic superlattice structures and high specific surface area was obtained. The mesoporous Ag2S nanospheres had the same crystal phase as their precursors Ag2S nanoparticles. Different from their near-infrared emitting precursors, the mesoporous Ag2S nanospheres exhibited cyan emission under ultraviolet excitation. The large number of sulfur-related defects existing in the mesostructures is most likely responsible for the photoluminescence. This work provides new insights into fabricating photoluminescent mesostructured materials via scale-up strategy.

Redox-responsive micelles self-assembled from dynamic covalent block copolymers for intracellular drug delivery.

Redox-responsive micelles self-assembled from dynamic covalent block copolymers with double disulfide linkage in the backbone have been developed successfully. The amphiphilic block copolymers PEG-PLA associated with complementary H-bonding sequences can self-assemble into spherical micelles in aqueous media with sizes from 34 nm to 107 nm with different molar mass of PEG and PLA. Moreover, in vitro drug release analyses indicate that reductive environment can result in triggered drug release profiles. The glutathione (GSH) mediated intracellular drug delivery was investigated against HeLa human cervical carcinoma cell line. Flow cytometry and fluorescence microscopy measurements demonstrated that the micelles exhibited faster drug release in glutathione monoester (GSH-OEt) pretreated HeLa cells than that in the nonpretreated cells. Cytotoxicity assay of DOX-loaded micelles indicated the higher cellular proliferation inhibition against 10 mM of GSH-OEt pretreated HeLa cells than that of the nonpretreated ones. These reduction-responsive, biodegradable and biocompatibility micelles could provide a favorable platform to construct excellent drug delivery systems for cancer therapy.

A new strategy for synthesizing AgInS2 quantum dots emitting brightly in near-infrared window for in vivo imaging.

A new strategy for fabricating water-dispersible AgInS2 quantum dots (QDs) with bright near-infrared (NIR) emission is demonstrated. A type of multidentate polymer (MDP) was synthesized and utilized as a compact capping ligand for the AgInS2 QDs. Using silver nitrate, indium acetate and sulfur-hydrazine hydrate complex as the precursors, MDP-capping AgInS2 QDs were synthesized in aqueous solution at room temperature. Characterization indicates that the MDP-capping AgInS2 QDs are highly photoluminescent in NIR window and possess good photostability. Also, the QDs are stable in different media and have low cytotoxicity. Nude mice photoluminescence imaging shows that the MDP-capping AgInS2 QDs can be well applied to in vivo imaging. These readily prepared NIR fluorescent nanocrystals have huge potential for biomedical applications.

Visible light-triggered nitric oxide release from near-infrared fluorescent nanospheric vehicles.

Bifunctional Ag2S QDs@CS-RBS nanospheres with ultralow toxicity for biomedical use were fabricated. These are capable of releasing NO under irradiation of visible light and emitting in near-infrared (NIR) region fluorescence excited by NIR laser under physiological environment. Glutathiose (GSH)-capped Ag2S QDs were synthesized and encapsulated by chitosan (CS) to form NIR fluorescent Ag2S QDs@CS nanospheres. A type of iron/sulfur/-nitrosyl cluster, Roussin's black salt anion Fe4S3(NO)7(-) (RBS) was conjugated with the Ag2S QDs@CS to obtain Ag2S QDs@CS-RBS nanospheres. A variety of characterization methods were employed to analyze the nanospheres. In vitro cell imaging and in vivo mice imaging experiments demonstrated that the Ag2S QDs@CS-RBS nanospheres could emit readily observable NIR fluorescence and deliver NO in living cells and small animals. The NIR imaging of the Ag2S QDs@CS nanospheres would not interfere with the light-triggered NO release from them, as the excitation lasers needed for these two functions are in different wavelength regions. This work provides new perspectives for the application of multifunctional nano-structured materials in diagnostics and bioimaging.

Aqueous synthesis of multidentate-polymer-capping Ag2Se quantum dots with bright photoluminescence tunable in a second near-infrared biological window.

A new strategy for fabricating water-dispersible Ag2Se quantum dots (QDs) is presented. A multidentate polymer (MDP) was synthesized and used as a capping agent for Ag2Se QDs. The MDP-capping Ag2Se QDs were synthesized in aqueous solution at room temperature, which are highly photoluminescent in a second near-infrared (NIR-II) biological window and possess good photostability. These readily prepared NIR-II fluorescent nanoprobes have great potential for biomedical applications, especially useful for in vivo imaging.

Nitric oxide release triggered by two-photon excited photoluminescence of engineered nanomaterials.

A new strategy toward controllable release of NO for therapeutic purpose is described. Mn(2+)-doped ZnS quantum dots with NIR-II to visible upconversion properties were encapsulated by chitosan, with which photochemical NO precursors were conjugated to generate nanostructured materials capable of releasing NO under NIR-II irradiation.