Ultra-small biocompatible jujube polysaccharide stabilized platinum nanoclusters for glucose detection.

The development of noble ultra-small biocompatible Pt nanoclusters (Pt NCs) for glucose detection has been drawing great attention. Herein, ultra-small biocompatible jujube polysaccharide (JP) stabilized platinum nanoclusters (Ptn-JP NCs) are prepared using natural JP as a reducing and solubilizing agent. Ptn-JP NCs were studied for the colorimetric detection of glucose. Ptn-JP NCs (n = 50, 200 and 400) had an average particle diameter of 1-2 nm. Particularly, the measurements of hydrodynamic sizes of Ptn-JP NCs indicated that they maintained good stability in solution for one week. Pt200-JP NCs showed good biocompatibility, and were not toxic against HeLa cells at a high concentration of 400 µg mL-1. Furthermore, Pt200-JP NCs catalyzed the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) with H2O2 to produce blue oxidized TMB (oxTMB). This reaction followed typical Michaelis-Menten kinetics. More importantly, the glucose concentration could be sensitively detected by the color change, and this process was not interfered by other sugars. The linear range for glucose concentration was from 0.01 to 1 mM with a detection limit of 5.47 µM. The glucose concentrations of real samples of serum using Pt200-JP NCs were 9.2, 4.9 and 6.5 mM, respectively. The prepared Ptn-JP NCs have great potential in various biomedical detection methods.

Gold nanoshell-based betulinic acid liposomes for synergistic chemo-photothermal therapy.

A novel synthesis approach is first developed to fabricate a multifunctional smart nanodrug delivery system: gold nanoshell-coated betulinic acid liposomes (AuNS-BA-Lips) mediated by a glutathione. The AuNS-BA-Lips exhibited good size distribution (149.4±2.4nm), preferable photothermal conversion ability and synergistic chemo-photothermal therapy. Additionally, the absorption wavelength of AuNS-BA-Lips showed a significantly red-shifted to near infrared (NIR) region, which can strongly absorbed NIR laser and efficiently convert it into localized heat, thus providing controlled drug release and antitumor thermotherapy. Moreover, the nanocarriers excited by NIR light significantly promoted cell uptake compared to those without irradiation, resulting in an enhanced intracellular drug accumulation. Upon NIR irradiation, the AuNS-BA-Lips showed highly efficient antitumor effects on tumor-bearing mice with an inhibition rate of 83.02%, thus demonstrating a remarkable synergistic therapeutic effect of chemotherapy and thermotherapy. Therefore, this work provides new insight into developing a multifunctional antitumor drug.

Reducing the cytotoxity of poly(amidoamine) dendrimers by modification of a single layer of carboxybetaine.

The surface primary amines of generation five poly(amido amine) (G5 PAMAM) dendrimer were modified by different amounts of carboxybetaine acrylamide (CBAA). As a result, the fully modified molecules (CBAA-PAMAM-20, obtained from the 20:1 molar ratio of CBAA molecules to amino groups in modification solution) show excellent compatibility with protein and cells. CBAA-PAMAM-20 and fibrinogen (Fg) could coexist in solution without forming aggregation, indicating very weak interaction force between CBAA-PAMAM-20 and fibrinogen. CBAA-PAMAM-20 exhibits almost undetectable hemolytic activity, while other partially modified ones cause severe hemolysis and fibrinogen aggregation. Furthermore, the membrane of human umbilical vascular endothelial cell (HUVEC) remains intact after 24 h incubation with CBAA-PAMAM-20. The cytotoxicity assay of HUVEC cells and KB cells also showed that the CBAA-PAMAM-20 was not cytotoxic up to a 2 mg/mL concentration (>90% cell viability). In short, a thin compact layer of zwitterionic carboxybetaine could reduce the cytotoxicity of PAMAM through minimizing the interaction with protein and cell membranes, which suggest that the carboxybetaine-coated PAMAM could be a useful platform for biocompatible carriers to load contrast agents and drugs.

Zwitterionic Polypeptide-Based Nanodrug Augments pH-Triggered Tumor Targeting via Prolonging Circulation Time and Accelerating Cellular Internalization.

To augment the antitumor efficacy and minimize the significant side effects of chemotherapeutic drugs on health organs, a novel albumin-mimicking nanodrug, which is based on zwitterionic poly(glutamatyl lysine-co-cysteine) peptides scaffold, is developed to enhance pH-triggered tumor targeting via prolonging circulation time and accelerating cellular internalization. Results showed that the internalization of the nanodrug by MCF-7 cells is much faster than that by Doxil and even comparable to that by free doxorubicin (Dox) at tumor microenvironmental pH 6.7, whereas the internalization of the nanodrug is only 27.4 ± 7.6% of the Doxil by RAW-264.7 cells. Moreover, the significantly prolonged circulation time of the "stealthy" nanodrug was also comparable to that of the long circulating Doxil. As a result, the accumulation of the nanodrug in the tumor is much higher than that in the liver and kidney before the circulation half-life, which is significantly different from most other nanodrugs accumulated in the liver and kidney in this time scale. The tumor inhibition rate of the nanodrug was much higher than that of Doxil (93.2 ± 3.0% vs 54.2 ± 6.5%) after 18 day treatment, while the average bodyweight of the mice treated by the nanodrug was 26.9 ± 6.7% higher than that by Doxil. This indicated that the synergetic effect of long circulation time and fast cellular internalization of the nanodrug can significantly augment tumor targeting. This method might rejuvenate the traditional chemotherapeutic treatment.

Ursolic acid liposomes with chitosan modification: Promising antitumor drug delivery and efficacy.

There are tremendous challenges on antitumor and its therapeutic drugs, and preparation of highly efficient nano-vehicles represents one of the novel topics in antitumor pharmaceutical field. Herein, the novel chitosan-coated ursolic acid (UA) liposome (CS-UA-L) was efficiently prepared with highly tumor targeting, drug controlled release and low side-effect. The CS-UA-L was uniformly spherical particles with diameter of ~130nm, and the size was more easily trapped into the tumor tissues. Chitosan modification can make liposomes carrying positive charges, which were inclined to combine with the negative charges on the surface of tumor cells, and then the CS-UA-L could release UA rapidly at pH5.0 comparing with pH7.4. Meanwhile, the CS-UA-L exhibited obvious anti-proliferative effect (76.46%) on HeLa cells and significantly antitumor activity (61.26%) in mice bearing U14 cervical cancer. The tumor tissues of CS-UA-L treated mice had enhanced cell apoptosis, extensive necrosis and low cell proliferation activity. These results demonstrated that the multifunctional CS-UA-L allowed a precision treatment for localized tumor, and reducing the total drug dose and side-effect, which hold a great promise in new safe and effective tumor therapy.

Development of Robust and Recoverable Ultralow-Fouling Coatings Based on Poly(carboxybetaine) Ester Analogue.

Polyurethane with zwitterionic side chains (PCB-ester-PU) based on a poly(carboxybetaine) ester analogue is developed for marine coatings and biomedical applications by introducing dihydroxy-terminated PCB-ester(OH)2 with different polymerization as the macrodiol, 4,4'-diphenylmethane diisocyanate (MDI) as the diisocyanate, and 1,4-butanediol (1,4-BD) as the chain extender. Robust coatings are obtained and exhibit long-term excellent resistance to nonspecific protein adsorption, bacterial adhesion, and human umbilical vein endothelial cell (HUVEC) attachment after hydrolysis. Tests of adhesion on different substrates and film hardness indicate that the material possesses far more stable mechanic properties than hydrogel coatings. Moreover, such a resistance can be generated not only by alkaline solution, but also by a physiological buffer (such as phosphate-buffered saline (0.15 M pH 7.4 PBS)) or by steam in an autoclave. Ultimately, its excellent long-term nonfouling property, its healing capability through self-regeneration and superior mechanic properties (such as hardness and elasticity), and its good adhesiveness as a paint on both polar and nonpolar substrates make this material an ideal candidate as a coating for marine and medical devices.

Highly hemocompatible zwitterionic micelles stabilized by reversible cross-linkage for anti-cancer drug delivery.

Both blood stability and intelligent-responsiveness after reaching the drug-targeting site are very important features to make desirable nano-drug vehicles (NDVs). Here, a highly nonfouling cross-linked micelle based on a copolymer composed of carboxybetaine methacrylate (CBMA) as hydrophilic segment and 2-(methacryloyloxy)ethyl lipoate (MAEL) as hydrophobic and cross-linked segment is reported. Furthermore, a simple method to evaluate the hemocompatibility of NDVs through examining the activation of a blood-clotting protein (fibrinogen) was introduced. The micelles can encapsulate anticancer drug doxorubicin (DOX) conveniently and release DOX quickly in response to an intracellular reductive environment. With the advantages of excellent stability in fibrinogen (1 mg/mL) PBS solution and 50% fetal bovine serum (FBS), and accelerated intracellular drug release, the biocompatible zwitterionic micelles stabilized by reversible cross-linkage might be a promising drug carrier for cancer chemotherapy.

Investigation of nonfouling polypeptides of poly(glutamic acid) with lysine side chains synthesized by EDC·HCl/HOBt chemistry.

Nonfouling polypeptides with homogenous alternating charges draw peoples' attentions for their potential capability in biodegradation. Homogenous glutamic acid (E) and lysine (K) polypeptides were proposed and synthesized before. In this work, a new polypeptide formed by poly(glutamic acid) with lysine side chains (poly(E)-K) was synthesized by facile EDC·HCl/HOBt chemistry and investigated. Results show that these polypeptides also have good nonspecific protein resistance determined by enzyme-linked immunosorbent assay. The lowest nonspecific adsorption of the model proteins, anti-IgG and fibrinogen (Fg), on the self-assembling monolayers (SAMs) surface of poly(E)-K was only 3.3 ± 1.8 and 4.4 ± 1.6%, respectively, when protein adsorption on tissue culture polystyrene surface was set as 100%. And, the relative nonspecific protein adsorption increases when the polypeptide molecular weight increases due to the repression of low density polymer brushes. Moreover, almost no obvious cytotoxicity and hemolytic activity in vitro were detected. This work suggests that polypeptides with various formats of homogenous balanced charges could achieve excellent nonspecific protein resistance, which might be the intrinsic reason for the coexistence of high concentration serum proteins in blood.

Development of nonstick and drug-loaded wound dressing based on the hydrolytic hydrophobic poly(carboxybetaine) ester analogue.

A novel biocompatible polymer is developed for antimicrobial and nonstick coatings of wound dressing. The polymer is formed by copolymerization of carboxybetaine ester analogue methacrylate (CB-ester) and small partial poly(ethylene glycol) methacrylate (PEGMA) for cross-linking by hexamethylene diisocyanate (HDI), which is highly resistant to nonspecific protein adsorption and mammalian cell attachment after a quick hydrolysis. A small hydrophobic drug, aspirin, can be incorporated into the new polymer and slowly released to inhibit microorganism growth while the new polymer shows very low cytotoxicity. Moreover, the wound dressing, the new polymer coated medical gauze, shows good mechanic properties, such as flexibility and strength, for medical application. After all, this new nonfouling polymer offers great potential for an antimicrobial wound dressing and other applications.