RESUMEN

Since the discovery of metal nanoparticles (NPs) in the 1960s, unknown toxicity, cost and the ethical hurdles of research in humans have hindered the translation of these NPs to clinical use. In this work, we demonstrate that Pt NPs with protein coronas are generated in vivo in human blood when a patient is treated with cisplatin. These self-assembled Pt NPs form rapidly, accumulate in tumors, and remain in the body for an extended period of time. Additionally, the Pt NPs are safe for use in humans and can act as anti-cancer agents to inhibit chemotherapy-resistant tumor growth by consuming intracellular glutathione and activating apoptosis. The tumor inhibitory activity is greatly amplified when the Pt NPs are loaded in vitro with the chemotherapeutic drug, daunorubicin, and the formulation is effective even in daunorubicin-resistant models. These in vivo-generated metal NPs represent a biocompatible drug delivery platform for chemotherapy resistant tumor treatment.

Asunto(s)

Antineoplásicos/sangre , Antineoplásicos/farmacología , Nanopartículas del Metal/química , Platino (Metal)/sangre , Platino (Metal)/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Daunorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Tolerancia a Medicamentos , Femenino , Glutatión/metabolismo , Células Hep G2 , Humanos , Células K562 , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Tamaño de la Partícula , Corona de Proteínas , Factores de Tiempo , Ensayos Antitumor por Modelo de Xenoinjerto , Pez Cebra

RESUMEN

The traditional Chinese medicine Sparganii Rhizoma has a long history in the treatment of gynecological diseases. In our previous work, we found that an extract of Sparganii Rhizoma had antitumor activity, attributed to the aluminum-rich polysaccharide, "SpaTA", which we isolated. SpaTA can selectively regulate the estrogen receptor, but its mechanism of antitumor activity is poorly understood. In the present study, we found that SpaTA naturally exists as a nanoparticle with a regular physical morphology. SpaTA induced apoptosis in human breast cancer cells mainly through interaction with estrogen receptors, ERα and GPR30, followed by activation of the PI3K/Akt and MEK/ERK pathways. Notably, cells also adjusted their cytoskeletal plasticity in response to SpaTA, which inhibited cell motility by suppressing focal adhesion and cytoskeleton reorganization via FAK. On the basis of these antitumor effects, we further modified SpaTA by conjugating it with the near-infrared dye, ICG, and loading the particles with the TGFß inhibitor, LY2157299, to form the tumor-targeting nanomedicine, "SpaTAX". The application of SpaTAX to breast cancer models enables a dual use regimen: a single dose for fluorescence imaging of the tumor site, where SpaTAX accumulates due to the enhanced permeability and retention effect, and a multidose for antitumor treatment through estrogen receptor- and TGFß-related signaling pathways. The synergetic roles of estrogen receptors and TGFß pathways are responsible for SpaTAX-induced reinforced suppression on tumor growth. Finally, we assessed the biosafety of the formulation and found that SpaTAX is highly tolerable and may therefore be considered safe for future clinical theranostic application. Altogether, our results demonstrated a superior tumor targeting ability of SpaTA both in diagnostic imaging and endocrine therapy and also proved SpaTA as a promising nanocarrier with a high therapeutic capacity and a favorable modification potential.

RESUMEN

The biosynthesis of nanoparticles in bioreactors using microbial, plant, or animal cells is at the forefront of nanotechnology. We demonstrated for the first time that luminescent, water-soluble ZnO nanocrystals (bio-ZnO NCs) can be spontaneously biosynthesized in the mammalian blood circulation, not in cells, when animals were fed with Zn(CH3COO)2 aqueous solution. Serum albumin, rather than metallothioneins or glutathione, proved to play the pivotal role in biosynthesis. The bio-ZnO NCs were gradually taken up in the liver and degraded and excreted in the urine. Thus, we propose that in mammals such as rodents, bovinae, and humans, excess metal ions absorbed into the cardiovascular system via the intestine can be transformed into nanoparticles by binding to serum albumin, forming a "provisional metal-pool", to reduce the toxicity of free metal ions at high concentration and regulate metal homeostasis in the body. Furthermore, the bio-ZnO NCs, which showed favorable biocompatibility, were functionalized with the anticancer drug daunorubicin and effectively achieved controlled drug release mediated by intracellular glutathione in tumor xenograft mice.

Asunto(s)

Nanopartículas , Animales , Daunorrubicina , Humanos , Luminiscencia , Ratones , Nanotecnología , Óxido de Zinc

RESUMEN

Rapid diagnosis and targeted drug treatment require agents that possess multiple functions. Nanomaterials that facilitate optical imaging and direct drug delivery have shown great promise for effective cancer treatment. In this study, we first modified near-infrared fluorescent indium phosphide quantum dots (InP QDs) with a vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody to afford targeted drug delivery function. Then, a miR-92a inhibitor, an antisense microRNA that enhances the expression of tumor suppressor p63, was attached to the VEGFR2-InP QDs via electrostatic interactions. The functionalized InP nanocomposite (IMAN) selectively targets tumor sites and allows for infrared imaging in vivo. We further explored the mechanism of this active targeting. The IMAN was endocytosed and delivered in the form of microvesicles via VEGFR2-CD63 signaling. Moreover, the IMAN induced apoptosis of human myelogenous leukemia cells through the p63 pathway in vitro and in vivo. These results indicate that the IMAN may provide a new and promising chemotherapy strategy against cancer cells, particularly by its active targeting function and utility in noninvasive three-dimensional tumor imaging.

Asunto(s)

Neoplasias , Anticuerpos Monoclonales , Humanos , MicroARNs , Puntos Cuánticos , Factor A de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular

RESUMEN

Because they generate excellent images, nanoparticles (NPs), especially biosynthesized NPs, provide a new solution for tumor imaging. In this research, we unveil a novel type of biosynthesized NPs featuring multicolor fluorescence. These NPs exhibit little cytotoxicity to cells. The explored NPs, designated Zn-ZFP-GST NPs (Zinc NPs in abbreviation), are generated from leukemia cells treated with a Zn2+ solution, while zinc-finger protein and glutathione S-transferase (GST) were also identified in the Zinc NPs. Under near-UV illumination, the Zinc NPs simultaneously emit green, yellow, and red fluorescence. In addition, the intensity of the fluorescence increases with the existence of sulfides. Besides, the NPs are encapsulated by microvesicles (MVs) shed from the plasma membrane. As observed in whole-body research of nude mice, the NP-MVs migrate via blood circulation and are distinguished by their fluorescent signals. Furthermore, the folic acid (FA) &AVR2 (human VEGF antibody)-coated NP-MVs are exploited to target the tumor location, and the feasibility of this approach has been confirmed empirically. The Zinc NPs shed light on an alternative solution to tumor detection.

Asunto(s)

Colorantes/química , Leucemia/diagnóstico por imagen , Nanopartículas/química , Zinc/química , Animales , Línea Celular Tumoral , Membrana Celular/química , Fluorescencia , Ácido Fólico/química , Humanos , Ratones , Ratones Desnudos , Sulfuros/química

RESUMEN

A polysaccharide named SpaTA, as novel selective estrogen receptor modulator, was isolated from water extraction of traditional Chinese herbal medicine Sparganii Rhizoma. SpaTA had a backbone consisting of 2-O-grailsine-ß-xylose (4→6)-α-glucose (1→4) -ß-mannose osamine. There is an aluminium element combined with nitrogen on both grailsine and mannose osamine in repeating unit of SpaTA. The anticancer effect of SpaTA was assessed using ZR-75-1 human breast cancer cells. The results showed that SpaTA induced sequential increases in proliferation and apoptosis through a time- and concentration-dependent manner. Further studies revealed that SpaTA regulated the expression and nuclear translocation of ERα, then modulated the downstream estrogen signaling pathway. Moreover, knock-down ERα in ZR-75-1 cells and overexpress ERα in MDA-MB-231 cells also provided evidences that SpaTA activated the apoptosis-related caspase -3, -8, -9 and PARP in an ERα-dependent manner. Taken together, these results indicated that SpaTA can induce the apoptosis of breast cancer cells through regulating ERα. Therefore, SpaTA may be considered as an effective agent against human breast cancer.

Asunto(s)

Apoptosis , Medicamentos Herbarios Chinos/farmacología , Polisacáridos/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Plerocercoide/química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Humanos , Rizoma/química

RESUMEN

The title polymer, [Zn(3)(C(8)H(8)O(5))(2)(C(3)H(3)N(2))(2)(C(3)H(4)N(2))(2)](n), was formed by the reaction of zinc acetate with imidazole and 7-oxabicyclo-[2.2.1]heptane-2,3-dicarboxylic anhydride (norcan-tharidine). One of the two crystallographically unique Zn(II) atoms is four-coordinated by three N atoms of three imidazole ligands, two of which are deprotonated, and by one carboxyl-ate O atom of the demethyl-cantharate anion. The second Zn(II) atom is situated on an inversion centre and is six-coordinated by the bridging O atoms of two symmetry-related demethyl-cantharate anions and by four carboxyl-ate O atoms of the corresponding carboxyl-ate groups. The polymeric crystal structure is additionally stabilized by N-H⋯O hydrogen bonding between the imidazole ligands and carboxyl-ate O atoms.

RESUMEN

In the crystal structure of the title complex, [Cd(C(8)H(8)O(5))(C(3)H(4)N(2)S)(3)]·2H(2)O, the Cd(II) atom exhibits a slightly distorted octa-hedral CdO(3)N(3) coordination, defined by the bridging O atom of the bicyclo-heptane unit, two O atoms from the carboxyl-ate groups and by three N atoms from three 2-amino-thia-zole ligands. Uncoordinated lattice water mol-ecules are also present in the crystal structure. N-H⋯O and O-H⋯O hydrogen-bonding inter-actions link the components into a three-dimensional structure.

RESUMEN

<p><b>OBJECTIVE</b>To investigate the methodology of mimic resection system on liver.</p><p><b>METHODS</b>Hepatic arteries, portal vein, inferior cava vein, hepatic veins and biliary ducts of liver with integrate hepatic portal were perfused with filling materials in different colors. And then the sample was embedded, frozen and slice-cut to obtain serial sectional images. After image registration and segmentation, the 3D reconstruction model which contained the liver's surface and its internal structures was constructed with MIMICS 9.0. Based on the freeform modeling system and its accessories (the software GHOST and the force-feedback equipment PHANTOM), the virtual hepatectomy system was established which could manipulate the virtual scalpel to perform optional resection on virtual liver model.</p><p><b>RESULTS</b>After slice-cutting the cast liver, 910 serial cross-section images were obtained sharply and clearly. The 3D reconstructed liver model looked like the liver sample exactly, and could be magnified, contracted and rotated. In the virtual surgery system with good interaction, powerful immersion and great imagination, the virtual scalpel could be manipulated to perform optional resection on 3D liver model with the haptic device (PHANTOM).</p><p><b>CONCLUSIONS</b>The 3D visualized liver and the virtual hepatectomy system has been satisfactorily developed using the hepatic serial sectional images. The process of simulation operation was consistent with clinical practice.</p>

Asunto(s)

Adulto , Humanos , Anatomía Transversal , Hepatectomía , Métodos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Hígado , Cirugía General , Modelos Anatómicos , Modelos Biológicos , Interfaz Usuario-Computador

RESUMEN

<p><b>OBJECTIVE</b>To study the three-dimensional (3D) reconstruction and 3D visualization of the pancreas and create anatomy of the digitalized visual pancreas so as to construct a concrete basis for virtual operation and surgical operation on pancreas.</p><p><b>METHODS</b>The digital imaging data of pancreas, duodenum, common bile duct, arteries and veins were obtained from the Virtual Chinese Human-Female 1 (VCH-F1) and processed using ACDSee and Photoshop so as to reconstruct 3D pancreas digitally and realize 3D visualization of pancreas.</p><p><b>RESULTS</b>We successfully 3D reconstructed and visualized the pancreas and the peri-pancreatic structures: the duodenum, the common bile duct, the inferior vena cava, the portal vein vessels, the aorta, the ceoliac trunk vessels. The 3D and visualized pancreas manifested itself with its complete structure as well as its adjacency to other tissues.</p><p><b>CONCLUSIONS</b>The 3D reconstruction and 3D visualization of the pancreas based on the digital data of VCH-F1 produces a digitally visualized pancreas, which promises us a novel method for virtual operation on pancreas, clinical operation on pancreas and anatomy of 3D visualized pancreas.</p>

Asunto(s)

Femenino , Humanos , Anatomía Transversal , China , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Páncreas , Diagnóstico por Imagen , Tomografía Computarizada por Rayos X , Proyectos Humanos Visibles

RESUMEN

<p><b>OBJECTIVE</b>To study digitized virtual hepatic three-dimensional reconstruction and virtual hepatic surgery.</p><p><b>METHODS</b>The whole series of hepatic images taken from the database of digitized Virtual Chinese Human Female Number 1 (VCH-F1) was employed to reconstruct a three-dimensional (3D) liver. First, studied some algorithms for registration of human liver tissue images, and then, segmented the regions of liver, vein, bile duct, and gallbladder from the images. Based on them, the 3D visualization human liver model was reconstructed. Finally, a 3D visualization demo system of liver was developed based on personal computer and Windows operation system.</p><p><b>RESULTS</b>This demo system of liver provided a graphics user interface to rotate, scale the 3D liver to observe the 3D hepatic structure, and a virtual liver simulation system of resection with primary function.</p><p><b>CONCLUSIONS</b>The study may be beneficial to the future research on digitized virtual hepatic and virtual hepatic surgery, and the 3D visualization demo system of liver may be beneficial to the research on the hepatic structure.</p>

Asunto(s)

Femenino , Humanos , Anatomía Transversal , China , Hepatectomía , Imagenología Tridimensional , Métodos , Hígado , Interfaz Usuario-Computador

RESUMEN

<p><b>OBJECTIVE</b>To establish the modal of perfusing and casting in hepatic duct system and explore the methods of three dimensional reconstruction with CT scanning image after filling hepatic duct.</p><p><b>METHODS</b>All canal of livers with integral porta hepatic were perfused with various filling material after pretreatment, then fixed and casted. Hepatic preparations that had been perfused were put into the model of modelling abdominal cavity and scanned with thin slice. The three dimensional duct structures of hepatic with three methods of MIP, SSD and computerized treatment.</p><p><b>RESULTS</b>Fourteen hepatic samples were filled and casted. Nine hepatic samples were scanned with slice height 1.0 mm, all 2514 slice images and average 279 images. Five hepatic samples were scanned with slice height 3.0 mm, all 512 slice images and average 102 images. Intrahepatic vein and portal vein system of three dimensional reconstruction were seen clearly with MIP method. The three dimensional established three dimensional images with SSD method was shown much stronger than that of MIP method. The three dimensional images of hepatic solid and hepatic vein system were established with method of comperized treatment. Vary three dimensional shape of hepatic solid and hepatic vein was obtained through different direction rotational.</p><p><b>CONCLUSIONS</b>The modal filled and casted hepatic duct system were practise. The images established three dimensional with methods of MIP, SSD and comperized treatment were seen clearly. The modal and images of thin slice CT scanning are a better method for researching hepatic duct system.</p>

Asunto(s)

Humanos , Imagenología Tridimensional , Métodos , Técnicas In Vitro , Hígado , Diagnóstico por Imagen , Tomografía Computarizada por Rayos X