Tissue mechanics modulate PCNP expression in oral squamous cell carcinomas with different differentiation.

Background: PEST-containing nuclear protein (PCNP), a novel zinc finger protein, participates in cell cycle regulation. Previous studies have confirmed that PCNP plays a role in mediating cellular development and invasion in a variety of cancer types. However, the relationship between PCNP expression and the occurrence and development of oral squamous cell carcinoma (OSCC) requires further exploration. In this study, we used biological atomic force microscopy to examine the histomorphological and mechanical properties of OSCC to explore the relationship between PCNP expression and differentiation of OSCC. Methods: Seventy-seven OSCC samples with varying degrees of differentiation were selected for hematoxylin and eosin staining, immunohistochemistry, and cellular mechanical measurement. The expression of PCNP and the mechanical properties such as stiffness and roughness of the tissue interface in OSCC samples were investigated. The Kaplan-Meier survival curve was utilized to assess the relationship of PCNP expression with patient survival. Results: The level of PCNP was significantly higher in well-differentiated OSCC than in moderately and poorly differentiated OSCC (P < 0.001). High expression of PCNP was specifically associated with higher tumor differentiation, lack of lymph node metastasis, and lower tumor node metastasis stage (all P < 0.05). Patients with high PCNP expression had a higher survival rate than those with low PCNP expression. The average variation of stiffness within a single tissue ranged from 347 kPa to 539 kPa. The mean surface roughness of highly, moderately, and poorly differentiated OSCC and paraneoplastic tissues were 795.53 ± 47.2 nm, 598.37 ± 45.76 nm, 410.16 ± 38.44 nm, and 1010.94 ± 119.07 nm, respectively. Pearson correlation coefficient demonstrated a positive correlation between PCNP expression and tissue stiffness of OSCC (R = 0.86, P < 0.001). Conclusion: The expression of PCNP was positively correlated with patient survival, tumor differentiation, and mechanical properties of tissue interfaces. PCNP is a potential biomarker for the early diagnosis and staging of OSCC. Furthermore, determination of the mechanical properties of the tissue interface could provide further useful information required for the detection and differentiation of OSCC.

Platelet parameters in Chinese older adults with metabolic syndrome.

PURPOSE: We aimed to examine the associations of platelet parameters with the presence of metabolic syndrome in community-dwelling older Chinese adults. METHODS: Study sample was from the Weitang Geriatric Diseases Study, which included 4338 individuals aged 60 years or above. The mean age of the participants was 68 years. Metabolic syndrome was defined based on the Adult Treatment Panel III criteria. Platelet parameters were assessed using an automated hematology analyzer. Multiple logistic regression models were fitted to examine relationships between the platelet parameters and the presence of metabolic syndrome after adjusting for potential confounders. RESULTS: The adjusted odds ratio (95% CI) of metabolic syndrome for the highest quartile of platelet parameters (platelet count, mean platelet volume, plateletcrit, platelet distribution width, platelet larger cell ratio) when compared to the lowest quartile were 1.32 (1.06, 1.64), 1.00 (0.81, 1.24), 1.37 (1.10, 1.71), 1.45 (1.14, 1.83), 1.11 (0.89, 1.39), respectively. Hypertension and diabetes modified the relationship between platelet distribution width and metabolic syndrome with the associations being significant in hypertensive and non-diabetic groups. The levels of platelet distribution width increased with the risk of metabolic syndrome in men but not in women. CONCLUSION: The levels of platelet count, plateletcrit and platelet distribution width increased in older adults with metabolic syndrome, suggesting that these parameters may be useful biomarkers for further risk appraisal of metabolic syndrome in aged population.

Synthesis and antitumoral activity of gelatin/polyoxometalate hybrid nanoparticles.

Surfactant-free gelatin/heptamolybdate (HM) hybrid nanoparticles are prepared by a simple and environmentally friendly approach utilizing the electrostatic interaction between anionic HM and the zwitterionic gelatin. The obtained nanoparticles have a tunable size and very high HM loading content up to about 70%. In vitro and in vivo experiments prove that the gelatin/HM hybrid nanoparticles exhibit significantly better antitumor activity than plain ammonium heptamolybdate solution. Therefore, the gelatin/HM hybrid nanoparticles reported here may serve as a prototype platform for polymer/polyoxometalate (POM) hybrid nanoparticles as cancer treatment agents and hence open up more opportunities to maximize the potential of POM-based pharmaceutical agents.

Multifunctional nanocarriers for cell imaging, drug delivery, and near-IR photothermal therapy.

Multifunctional nanocarriers based on chitosan/gold nanorod (CS-AuNR) hybrid nanospheres have been successfully fabricated by a simple nonsolvent-aided counterion complexation method. Anticancer drug cisplatin was subsequently loaded into the obtained hybrid nanospheres, utilizing the loading space provided by the chitosan spherical matrix. In vitro cell experiments demonstrated that the CS-AuNR hybrid nanospheres can not only be utilized as contrast agents for real-time cell imaging but also serve as a near-infrared (NIR) thermotherapy nanodevice to achieve irradiation-induced cancer cell death owing to the unique optical properties endowed by the encapsulated gold nanorods. In addition, an effective attack on the cancer cells by the loaded anticancer drug cisplatin has also been observed, rendering the obtained nanocarriers an all-in-one system possessing drug delivery, cell imaging, and photothermal therapy functionalities.

Dual-functional alginic acid hybrid nanospheres for cell imaging and drug delivery.

An effective and facile approach to prepare gold-nanoparticle-encapsulated alginic acid-poly[2-(diethylamino)ethyl methacrylate] monodisperse hybrid nanospheres (ALG-PDEA-Au) is developed by using monodisperse ALG-PDEA nanospheres as a precursor nanoparticulate reaction system. This approach utilizes particle-interior chemistry, which avoids additional reductant or laborious separation process and, moreover, elegantly ensures that all the gold nanoparticles are located inside the hybrid nanospheres and every nanosphere is loaded with gold nanoparticles. These obtained ALG-PDEA-Au hybrid nanospheres have not only uniform size, similar surface properties, and good biocompatibility but also unique optical properties provided by the embedded gold nanoparticles. It is demonstrated that negatively charged ALG-PDEA-Au hybrid nanospheres can be internalized by human colorectal LoVo cancer cells and hence act as novel optical-contrast reagents in tumor-cell imaging by optical microscopy. Moreover, these hybrid nanospheres can also serve as biocompatible carriers for the loading and delivery of an anti-cancer drug doxorubicin. In vitro cell viability tests reveal that drug-loaded ALG-PDEA-Au hybrid nanospheres exhibit similar tumor cell inhibition to the free drug doxorubicin. Therefore, the obtained hybrid nanospheres successfully combine two functions, that is, cell imaging and drug delivery, into one single system, and may be of great application potential in other biomedical-related areas.

Direct facile approach to the fabrication of chitosan-gold hybrid nanospheres.

Chitosan-gold hybrid nanospheres were prepared through a direct facile approach that utilized cross-linked composite nanospheres consisting of low-molecular-weight chitosan (LWCS) and ethylenediaminetetraacetic acid (EDTA) as a precursor reaction system. EDTA was employed not only to construct the counterion interaction-based composite nanospheres with the cationic chitosan but also as the reductant for subsequent in situ gold salt reduction within the LWCS-EDTA composite nanospheres. This approach elegantly ensured that each and every nanosphere was loaded with gold nanoparticles and no nonembedded free gold nanoparticles would exist in the dispersing medium. Moreover, becauseof the noncovalent interaction between LWCS and EDTA, the EDTA reductant can be easily removed from the cross-linked nanospheres, and "pure" chitosan-gold hybrid nanospheres can be obtained. The obtained chitosan-gold hybrid nanospheres were found to have a tunable size and good dispersing stability within a wide pH range. The embedded gold nanoparticles were in the range from several to several tens of nanometers, which may be useful for sensing and imaging. Morphology studies indicated that most of the loaded gold nanoparticles were located in the interior of the hybrid nanospheres. Taking into account the good biocompatibilities of LWCS, abundant functional (amino) groups in chitosan, and the mild preparation conditions, we find that the chitosan-gold hybrid nanospheres prepared here may have tremendous potential in advanced biomedical applications.

10-Hydroxycamptothecin loaded nanoparticles: preparation and antitumor activity in mice.

10-Hydroxycamptothecin (HCPT) loaded nanoparticles made from poly(caprolactone-co-lactide)-b-PEG-b-poly(caprolactone-co-lactide) (PCLLA-PEG-PCLLA) block copolymer, were prepared by a novel two-step nanoprecipitation method using an interior-chemistry strategy. The satisfactory drug loading content (>13%) as well as high encapsulation efficiency (>85%) was achieved. Cytotoxicity test indicated that the HCPT-loaded nanoparticles had enhanced in vitro cytotoxicity compared to free drug. Progressively, in vivo antitumor activity and HCPT biodistribution in sarcoma-180 (S-180) bearing mice after intravenous injection of the HCPT-loaded nanoparticles show that HCPT-loaded nanoparticles exhibited superior in vivo antitumor effect and remarkably different biodistribution than the commercially available HCPT injection.

Hollow chitosan/poly(acrylic acid) nanospheres as drug carriers.

The preparation, in-vitro release, in-vitro cytotoxicity, and in-vivo drug delivery of doxorubicin (DOX)-loaded chitosan (CS)-poly(acrylic acid) (PAA) hollow nanospheres were investigated. The loading was done by dissolving a certain amount of DOX in non-cross-linked CS-PAA nanospheres aqueous solution followed by cross-linking chitosan with glutaraldehyde. The drug-loading content was up to 4.3% and the size of drug-loaded hollow nanospheres, determined by dynamic light scattering, was 118 nm. The nanospheres showed a continuous release of the entrapped DOX up to 10 days in vitro and showed comparable in-vitro cytotoxicity against HepG2 cells compared to the free DOX. In-vivo DOX delivery of DOX-loaded CS-PAA nanospheres showed that DOX concentration in blood can be maintained for a longer period than free DOX solution, and the DOX concentration in mice liver can be maintained constantly at relatively high level. The interesting feature of DOX-loaded CS-PAA hollow nanopspheres is that the loaded DOX can be delivered into the mice brain. The confocal laser scanning microscopy analysis reveals that fluorescein isothiocyanate (FITC)-labeled CS-PAA can deposit in different organs including liver, spleen, and brain.

Synthesis of alginic acid-poly[2-(diethylamino)ethyl methacrylate] monodispersed nanoparticles by a polymer-monomer pair reaction system.

In this paper, alginic acid-poly(2-(diethylamino)ethyl methacrylate) (ALG-PDEA) nanoparticles were successfully prepared in aqueous medium using a polymer-monomer pair reaction system consisting of the anionic alginic acid (ALG) and the cationic 2-(diethylamino)ethyl methacrylate (DEA), without any aid of surfactants or organic solvents. The ALG-PDEA nanoparticles were monodispersed and stable in aqueous solution. Nanoparticles with desired size could be obtained by varying the amount of initiator or changing the concentration of reactants in solution, which renders this system highly controllable. After the ALG moiety was gelled by Ca(2+), the stability of the nanoparticles in basic or high salt concentration solutions could be notably enhanced. A pH-sensitive anticancer agent, hydroxycamptothecin (HCPT), was encapsulated in ALG-PDEA nanoparticles, and preliminary in vitro release as well as cytotoxicity experiments were carried out. It is found that this system seems to be a very promising carrier for the loading and delivery of labile drugs, taking into account that the preparation procedure is simple, mild, and organic solvent- and surfactant-free. Moreover, the abundant functional groups on the particle surface, such as carboxyls and hydroxyls, allow subsequent chemical modification, which may further unleash the potential of such a system in either biomedical applications or in the construction of other functional mesoscopic architectures.

Novel thermosensitive polymeric micelles for docetaxel delivery.

Targeted delivery of antitumor drugs triggered by hyperthermia has significant advantages in clinical applications, since it is easy to implement and side effects are reduced. To release drugs site-specifically upon local heating often requires the drugs to be loaded into a thermosensitive polymer matrix with a low critical solution temperature (LCST) between 37 and 42 degrees C. However, the LCSTs of most thermosensitive materials were below 37 degrees C, which limits their application in clinic because they would precipitate once injected into human body and lost thermal targeting function. Herein, we prepared a novel thermosensitive copolymer (poly(N-isopropylacrylamide-co-acrylamide)-b-poly (DL-lactide)) that exhibits no obvious physical change up to 41 degrees C when heated. Docetaxel loaded micelles made of such thermosensitive polymer were prepared by dialysis method and the maximum loading content was found to be up to 27%. The physical properties, such as structure, morphology, and size distribution of the micelles with and without docetaxel were investigated by NMR, X-ray diffraction, dynamic light scattering, atomic force microscopy, etc. The efficacy of this drug delivery system was also evaluated by examining the proliferation inhibiting activity against different cell lines in vitro. After hyperthermia, the cytotoxicity of docetaxel-loaded micelles increased prominently. Our results demonstrated that this copolymer could be an ideal candidate for thermal targeted antitumor drug delivery.

Chitosan surface-modified hydroxycamptothecin loaded nanoparticles with enhanced transport across Caco-2 cell monolayer.

This study explored the feasibility of using surface-modified nanoparticulate drug delivery system to enhance the transepithelial transport of antitumor drugs. An antitumor drug, 10-hydroxycamptothecin, was encapsulated into nanoparticles made of biodegradable poly(caprolactone-co-lactide)-PEG-poly(caprolactone-co-lactide) by a novel two-step nano-precipitation method. The obtained nanoparticles had a drug loading content of 10.4% and a size of 256.3 nm, exhibiting a steady and sustained in vitro release profile. By incubation in chitosan containing medium, the drug-loaded nanoparticles could be subsequently surface-modified with chitosan. The surface modification was monitored by dynamic light scattering method, zeta potential observation, and transmission electron microscopy, and its degree could be easily adjusted by varying the concentration of chitosan in the incubation medium. Caco-2 cell monolayer was used as an in vitro model to evaluate the intestinal 10-hydroxycamptothecin absorption. The absorptive transport of 10-hydroxycamptothecin could be improved to some extent by drug loaded nanoparticles and could be further enhanced in the case of surface-modified nanoparticles, suggesting that chitosan surface-modified nanoparticles may be a promising oral delivery system for antitumor drugs.

Synthesis and magnetic properties of biocompatible hybrid hollow spheres.

Magnetic hybrid hollow spheres of about 200 nm were prepared by a core-template-free route, that is, adding Fe3O4 nanoparticles stabilized by poly(vinyl alcohol) (PVA) to an aqueous solution of polymer-monomer pairs composed of a cationic polymer, chitosan (CS), and an anionic monomer, acrylic acid (AA), followed by polymerization of acrylic acid and selective cross-linking of chitosan at the end of polymerization. The obtained hybrid spheres were characterized by dynamic light scattering (DLS) in aqueous solution and observed by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM) in the solid state. Fourier transform infrared spectroscopy (FTIR) and X-ray and electron diffractions revealed that the Fe3O4 nanoparticles were incorporated into the shells of chitosan-poly(acrylic acid) (CS-AA) hollow spheres. Magnetization studies and Mössbauer spectroscopy suggested that the chains (or islands) of iron oxide nanoparticles were most likely formed in the walls of the hollow spheres. The phantom test of magnetic resonance imaging showed that the synthesized hybrid hollow spheres had a significant magnetic resonance signal enhancement in T2-weighted image.

Degradation behavior of poly(epsilon-caprolactone)-b-poly(ethylene glycol)-b-poly(epsilon-caprolactone) micelles in aqueous solution.

Poly(epsilon-caprolactone)-b-poly(ethylene glycol)-b-poly(epsilon-caprolactone) triblock copolymers were synthesized by the ring-opening polymerization of epsilon-caprolactone in the presence of hydroxyl-terminated poly(ethylene glycol) with different molecular weights, using stannous octoate catalyst. Micelles prepared by the precipitation method with these triblock copolymers exhibit a core-shell structure. The degradation behaviors of these core-shell micelles in aqueous solution were investigated by FT-IR, 1H NMR, GPC, DLS, TEM, and AFM. It was found that the degradation behavior of micelles in aqueous solution was quite different from that of bulk materials. The size of the micelles increased in the initial degradation stages and decreased gradually when the degradation period was extended. The caprolactone/ethylene oxide (CL/EO) ratio in micelles measured by NMR also shows an increase at the initial degradation stage and a decrease at later stages. The morphology of these micelles became more and more irregular during the degradation period. We explain the observed behavior by a two-stage degradation mechanism with interfacial erosion between the cores and the shells followed by core erosion.

Camptothecin derivative-loaded poly(caprolactone-co-lactide)-b-PEG-b-poly(caprolactone-co-lactide) nanoparticles and their biodistribution in mice.

Triblock copolymers of poly(caprolactone-co-lactide)-b-PEG-b-poly(caprolactone-co-lactide) (PCLLA-PEG-PCLLA) were synthesized by ring opening copolymerization of caprolactone and lactide in the presence of poly(ethylene glycol) (PEG). With such triblock copolymers, PCLLA-PEG-PCLLA nanoparticles entrapping 10-hydroxycamptothecin-10,20-diisobutyl dicarbonate (HCPT-1), a derivative of the antitumor drug 10-hydroxycamptothecin (HCPT), were prepared by nano-precipitation method and characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The investigations on drug loading, in vitro release and body distribution in mice after intravenous (i.v.) administration were also carried out. It is found that the obtained nanoparticles showed smooth surface and spherical shape with the controllable size in the range of 70-180 nm, and drug loading content varied from 3.3% to 7.0% depending on the copolymer composition and preparation conditions. The in vitro release behavior exhibited a sustaining release manner and was affected by particle size as well as copolymer composition. The results of body distribution study in mice show that the blood concentration of HCPT-1 could be maintained for a long period and the tissue distribution was influenced by the particle size to some extent. These results suggest that the PCLLA-PEG-PCLLA nanoparticles seem to be a promising delivery system for poorly soluble antitumor drugs or their derivatives.

Preparation and drug release behaviors of nimodipine-loaded poly(caprolactone)-poly(ethylene oxide)-polylactide amphiphilic copolymer nanoparticles.

Amphiphilic block copolymers, poly(caprolactone)-poly(ethylene glycol)-poly(lactide) (PCELA), were synthesized by ring opening polymerization of caprolactone and lactide initiated with the hydroxyl groups of poly(ethylene glycol) (PEG). These copolymers could form micelle-like nanoparticles due to their amphiphilic characteristic. From the observation of transmission electron microscopy (TEM), the nanoparticles exhibited a regular spherical shape with core-shell structure. The critical micelle concentrations (CMC) of these nanoparticles in water were decreased as molecular weight of PEG decreased. The particle sizes obtained by dynamic light scattering of these nanoparticles were in the range of 100-200 nm, and increased as the hydrophobic property of the nanoparticles increased. Nimodipine as a model drug was loaded in these nanoparticles to investigate the drug release behavior. It was found that the chemical composition of the nanoparticles was a key factor in controlling nanoparticle size, nanoparticle yields, drug-entrapment efficiency, and drug release behavior. When the PEG content is about 2% (wt), the release profile of PCELA nanoparticles appeared to follow zero-order kinetics.