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1.
Transfusion ; 56(11): 2808-2818, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27554133

RESUMEN

BACKGROUND: Missed detection of Staphylococcus epidermidis contamination in platelet (PLT) storage bags by the standard 24-hour-postcollection BacT/ALERT screening test has been documented. A slow growth rate and the strong tendency of this bacterium to adhere to surfaces can contribute to missed detection of the pathogen. STUDY DESIGN AND METHODS: Topography of two different PLT storage bag surfaces, textured (rough) and smooth surfaces of Terumo 80440 bags (designated A15), was studied. Adhesion of biofilm-positive and -negative S. epidermidis strains on these surfaces was evaluated under static conditions. Quality of stored PLTs in A15 bags under blood bank conditions was compared for two different bag orientations (rough vs. smooth surface down) on Days 2, 5, and 7 of storage. PLT adhesion on the surfaces was evaluated after 7 days of storage. RESULTS: Bacterial adhesion and biofilm formation were significantly higher on the rough surfaces of A15 bags compared to the smooth surfaces. After 7 days of storage in A15 bags, PLTs showed similar metabolite levels, pH, and response capacity in the bags with different orientation and more PLT adhesion and aggregation was observed on rough surfaces. CONCLUSION: Higher bacterial adhesion on rough surfaces can contribute to missed detection of bacterial strains that tend to adhere on surfaces. PLT adhesion and aggregation on rough surfaces can affect the quality and safety of PLTs by promoting more bacterial adhesion and biofilm formation on surfaces.


Asunto(s)
Adhesión Bacteriana , Adhesividad Plaquetaria , Embalaje de Productos/normas , Biopelículas/crecimiento & desarrollo , Conservación de la Sangre , Humanos , Agregación Plaquetaria , Staphylococcus epidermidis/citología , Propiedades de Superficie , Factores de Tiempo
2.
J Surg Res ; 205(1): 59-69, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27621000

RESUMEN

BACKGROUND: Efficient and effective perfusion during organ procurement is required for the best prevention of donor organ injury preceding transplantation. However, current organ preservation solutions, including hydroxyethyl starch (HES)-based University of Wisconsin (UW) solution, do not always yield the best outcomes. Our previous study demonstrated that replacing HES with hyperbranched polyglycerol (HPG) reduced donor heart injury during cold storage. The current research was designed to examine the advantages of HPG-based solution for cold kidney perfusion. METHODS: Perfusion efficiency of HPG versus UW solution was tested using mouse kidneys at 4°C. The blood washout was evaluated by using a semiquantitative scoring system and tissue damage by histologic analysis. The interaction of HPG or UW solution with human red blood cells (RBCs) was examined by measuring RBC sedimentation and aggregation. RESULTS: The lower viscosity of HPG solution was correlated with faster and more efficient perfusion through donor kidneys as compared with UW. HPG solution was also more effective than UW in removing RBCs from the kidney and was associated with less tissue damage to donor kidneys. In vitro UW solution caused significant RBC sedimentation and hyperaggregation, whereas HPG showed minimal impact on RBC sedimentation and prevented RBC aggregation. CONCLUSIONS: This experimental study demonstrated that compared with UW, HPG solution was more efficient and effective in the removal of the blood from donor kidneys and offered better protection from donor tissue damage, suggesting that the HPG solution is a promising candidate to supplant standard UW solution for donor kidney perfusion in transplantation.


Asunto(s)
Glicerol , Riñón/patología , Soluciones Preservantes de Órganos , Perfusión/métodos , Polímeros , Animales , Sedimentación Sanguínea , Masculino , Ratones Endogámicos C57BL
3.
Nat Mater ; 11(5): 468-76, 2012 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-22426460

RESUMEN

Phospholipids in the cell membranes of all eukaryotic cells contain phosphatidyl choline (PC) as the headgroup. Here we show that hyperbranched polyglycerols (HPGs) decorated with the 'PC-inverse' choline phosphate (CP) in a polyvalent fashion can electrostatically bind to a variety of cell membranes and to PC-containing liposomes, the binding strength depending on the number density of CP groups per macromolecule. We also show that HPG-CPs can cause cells to adhere with varying affinity to other cells, and that binding can be reversed by subsequent exposure to low molecular weight HPGs carrying small numbers of PCs. Moreover, PC-rich membranes adsorb and rapidly internalize fluorescent HPG-CP but not HPG-PC molecules, which suggests that HPG-CPs could be used as drug-delivery agents. CP-decorated polymers should find broad use, for instance as tissue sealants and in the self-assembly of lipid nanostructures.


Asunto(s)
Adhesivos/química , Fosforilcolina/química , Adsorción , Animales , Materiales Biocompatibles/química , Células CHO , Cricetinae , Cricetulus , Agregación Eritrocitaria , Eritrocitos/química , Eritrocitos/ultraestructura , Glicerol/química , Humanos , Técnicas In Vitro , Membrana Dobles de Lípidos/química , Ensayo de Materiales , Lípidos de la Membrana/química , Microscopía Electrónica de Rastreo , Modelos Anatómicos , Plasma/química , Polímeros/química , Electricidad Estática
4.
Biomacromolecules ; 14(6): 2052-62, 2013 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-23713758

RESUMEN

Modulation of cell surface properties via functional modification is of great interest in cell-based therapies, drug delivery, and in transfusion. We study the in vivo circulation, immuogenicity, and mechanism of clearance of hyperbranched polyglycerol (HPG)-modified red blood cells (RBCs) as a function of molecular properties of HPGs. The circulation half-life of modified cells can be modulated by controlling the polymer graft concentration on RBCs; low graft concentrations (0.25 and 0.5 mM) showed normal circulation as that of control RBCs. Molecular weight of HPG did not affect the circulation of modified RBCs. HPG grafting on RBCs reduced CD47 self-protein accessibility in a graft concentration-dependent fashion. HPG-grafted RBCs are not immunogenic, as is evident from their similar circulation profile upon repeated administration in mice and monitoring over 100 days. Histological examination of the spleen, liver, and kidneys of the mice injected with modified RBCs revealed distinct differences, such as elevated iron deposits and an increase in the number of CD45 expressing cells at high graft concentration of HPGs (1.5 mM); no changes were seen at low graft concentration. The absence of iron deposits in the white pulp region of the spleen and its presence in the red pulp region indicates that the clearance of functional RBCs occurs in the venous sinuses mechanical filtering system, similar to the clearance of unmodified senescent RBCs. HPG modification at grafting concentrations that yield long circulation in mice produced camouflage of a large number of minor blood group antigens on human RBCs, demonstrating its utility in chronic transfusion. The normal circulation, nonimmunogenic nature, and the potential to modulate the circulation time of modified cells without toxicity make this HPG-based cell surface modification approach attractive for drug delivery and other cell-based therapies.


Asunto(s)
Antígenos/biosíntesis , Polímeros/metabolismo , Animales , Antígenos/inmunología , Ratones
5.
Biomacromolecules ; 14(8): 2611-21, 2013 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-23745838

RESUMEN

Multivalent macromolecular associations are widely observed in biological systems and are increasingly being utilized in bioengineering, nanomedicine, and biomaterial applications. Control over such associations usually demands an ability to reverse the multivalent binding. While in principle this can be done with binding site competitive inhibitors, dissociation is difficult in practice due to limited site accessibility when the macromolecule is bound. We demonstrate here efficient binding reversal of multivalent linear copolymers that adhere to any mammalian cell via the universal mechanism based on choline phosphate (CP) groups binding to phosphatidyl choline (PC)-containing biomembranes. Using a smart linear polymer exhibiting a lower critical solution temperature (LCST), we take advantage of the thermal contraction of the polymer above the LCST, which reduces accessibility of the CP groups to cell membrane PC lipids. The polymer construct can then desorb from the cell surface, reversing all effects of multivalent polymer adhesion on the cell.


Asunto(s)
Fosforilcolina/química , Ácidos Polimetacrílicos/química , Adsorción , Sitios de Unión , Membrana Celular/metabolismo , Eritrocitos/metabolismo , Humanos , Fosfatidilcolinas/metabolismo , Soluciones , Adhesivos Tisulares/química
6.
Pharmaceutics ; 15(3)2023 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-36986628

RESUMEN

Cardiac blood pool imaging is currently performed almost exclusively with 99mTc-based compounds and SPECT/CT imaging. Using a generator-based PET radioisotope has a few advantages, including not needing nuclear reactors to produce it, obtaining better resolution in humans, and potentially reducing the radiation dose to the patient. When the shortlived radioisotope 68Ga is used, it can be applied repeatedly on the same day-for example, for the detection of bleeding. Our objective was to prepare and evaluate a long-circulating polymer functionalized with gallium for its biodistribution, toxicity, and dosimetric properties. A 500 kDa hyperbranched polyglycerol was conjugated to the chelator NOTA and radiolabeled rapidly at room temperature with 68Ga. It was then injected intravenously into a rat, and gated imaging allowed us to easily observe wall motion and cardiac contractility, confirming the suitability of this radiopharmaceutical for cardiac blood pool imaging. Internal radiation dose calculations showed that the radiation doses that patients would receive from the PET agent would be 2.5× lower than those from the 99mTc agent. A complete 14-day toxicology study in rats concluded that there were no gross pathology findings, changes in body or organ weights, or histopathological events. This radioactive-metal-functionalized polymer might be a suitable non-toxic agent to advance for clinical application.

7.
Bioconjug Chem ; 23(3): 372-81, 2012 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-22304718

RESUMEN

Combining various imaging modalities often leads to complementary information and synergistic advantages. A trimodal long-circulating imaging agent tagged with radioactive, magnetic resonance, and fluorescence markers is able to combine the high sensitivity of SPECT with the high resolution of MRI over hours and days. The fluorescence marker helps to confirm the in vivo imaging information at the microscopic level, in the context of the tumor microenvironment. To make a trimodal long-circulating probe, high-molecular-weight hyperbranched polyglycerols (HPG) were modified with a suitable ligand for (111)In radiolabeling and Gd coordination, and additionally tagged with a fluorescent dye. The resulting radiopharmaceutical and contrast agent was nontoxic and hemocompatible. Measured radioactively, its total tumor uptake increased from 2.6% at 24 h to 7.3% at 72 h, which is twice the increase expected due to tumor growth in this time period. Both in vivo MRI and subsequent histological analyses of the same tumors confirmed maximum HPG accumulation at 3 days post injection. Furthermore, Gd-derivatized HPG has an excellent contrast enhancement on T1-weighted MRI at 10× lower molar concentrations than commercially available Galbumin. HPG derivatized with gadolinium, radioactivity, and fluorescence are thus long-circulating macromolecules with great potential for imaging of healthy and leaky blood vessels using overlapping multimodal approaches and for the passive targeting of tumors.


Asunto(s)
Materiales Biocompatibles , Glicerol/metabolismo , Neoplasias/metabolismo , Polímeros/metabolismo , Células Cultivadas , Activación de Complemento , Eritrocitos/citología , Glicerol/farmacocinética , Humanos , Polímeros/farmacocinética , Tromboelastografía , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único
8.
Small ; 7(6): 820-9, 2011 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-21337511

RESUMEN

To study the mechanism of cellular internalization, hyperbranched polyether derivatives consisting of amino-bearing hyperbranched polyglycerols (HPGs) of varied molecular mass and size range are designed and synthesized. HPGs were further fluorescently labelled by conjugating maleimido indocarbocyanine dye (ICC-mal). The conjugates are characterized by UV-vis spectroscopy, fluorescence profile, zeta potential, and dynamic light scattering. The uptake mechanism is studied by fluorescence-activated cell sorting (FACS) analysis, fluorescence spectroscopy, and confocal microscopy with human lung cancer cells A549, human epidermoid carcinoma cells A431, and human umbilical vein endothelial cells (HUVEC) cells. For the first time, the results suggest that the higher-molecular-weight HPGs (40-870 kDa) predominantly accumulate in the cytoplasm much better than their low-molecular-weight counterparts (2-20 kDa). The HPG nanocarriers discussed here have many biomedical implications, particularly for delivering drugs to the targeted site.


Asunto(s)
Portadores de Fármacos/química , Glicerol/química , Polímeros/química , Transporte Biológico , Línea Celular Tumoral , Portadores de Fármacos/metabolismo , Humanos , Estructura Molecular , Espectrometría de Fluorescencia
9.
Biomacromolecules ; 12(10): 3715-27, 2011 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-21902171

RESUMEN

Primary amine containing copolymer, poly(N,N-dimethylacrylamide-co-N-(3-aminopropyl)methacrylamide hydrochloride) (poly(DMA-co-APMA)), brushes were synthesized on Ti surface by surface-initiated atom transfer radical polymerization (SI-ATRP) in aqueous conditions. A series of poly(DMA-co-APMA) copolymer brushes on titanium (Ti) surface with different molecular weights, thicknesses, compositions, and graft densities were synthesized by changing the SI-ATRP reaction conditions. Cysteine-functionalized cationic antimicrobial peptide Tet213 (KRWWKWWRRC) was conjugated to the copolymers brushes using a maleimide-thiol addition reaction after initial modification of the grafted chains using 3-maleimidopropionic acid N-hydroxysuccinimide ester. The modified surfaces were characterized by X-ray photoelectron spectroscopy (XPS), water contact angle measurements, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, atomic force microscopy (AFM), and ellipsometry analysis. The conjugation of the Tet213 onto brushes strongly depended on graft density of the brushes at different copolymer brush compositions. The peptide density (peptides/nm(2)) on the surface varied with the initial composition of the copolymer brushes. Higher graft density of the brushes generated high peptide density (pepetide/nm(2)) and lower number of peptides/polymer chain and vice versa. The peptide density and graft density of the chains on surface greatly influenced the antimicrobial activity of peptide grafted polymer brushes against Pseudomonas aeruginosa.


Asunto(s)
Acrilamidas/química , Antibacterianos/síntesis química , Péptidos Catiónicos Antimicrobianos/síntesis química , Materiales Biocompatibles Revestidos/síntesis química , Proteínas Inmovilizadas/síntesis química , Infecciones por Pseudomonas/prevención & control , Pseudomonas aeruginosa/efectos de los fármacos , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Materiales Biocompatibles Revestidos/farmacología , Humanos , Proteínas Inmovilizadas/farmacología , Pruebas de Sensibilidad Microbiana , Microscopía de Fuerza Atómica , Peso Molecular , Espectroscopía de Fotoelectrones , Polimerizacion , Polímeros/química , Prótesis e Implantes/microbiología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/crecimiento & desarrollo , Espectroscopía Infrarroja por Transformada de Fourier , Relación Estructura-Actividad , Succinimidas/química , Propiedades de Superficie
10.
Biomacromolecules ; 12(1): 145-55, 2011 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-21128674

RESUMEN

Hyperbranched polyglycerols (HPGs) with hydrophobic cores and derivatized with methoxy poly(ethylene glycol) were synthesized and further functionalized with carboxylate groups to bind and deliver cisplatin. Low and high levels of carboxylate were conjugated to HPGs (HPG-C(8/10)-MePEG(6.5)-COOH(113) and HPG-C(8/10)-MePEG(6.5)-COOH(348)) and their structures were confirmed through NMR and FTIR spectroscopy and potentiometric titration. The hydrodynamic diameter of the HPGs ranged from 5-10 nm and the addition of COOH groups decreased the zeta potential of the polymers. HPG-C(8/10)-MePEG(6.5)-COOH(113) bound up to 10% w/w cisplatin, whereas HPG-C(8/10)-MePEG(6.5)-COOH(348) bound up to 20% w/w drug with 100% efficiency. Drug was released from HPG-C(8/10)-MePEG(6.5)-COOH(113) over 7 days at the same rate, regardless of the pH. Cisplatin release from HPG-C(8/10)-MePEG(6.5)-COOH(348) was significantly slower than HPG-C(8/10)-MePEG(6.5)-COOH(113) at pH 6 and 7.4, but similar at pH 4.5. Release of cisplatin into artificial urine was considerably faster than into buffer. Carboxylated HPGs demonstrated good biocompatibility, and drug-loaded HPGs effectively inhibited proliferation of KU-7-luc bladder cancer cells.


Asunto(s)
Antineoplásicos , Ácidos Carboxílicos/química , Cisplatino , Preparaciones de Acción Retardada , Glicerol , Nanopartículas/química , Polímeros , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/química , Cisplatino/farmacología , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Glicerol/síntesis química , Glicerol/química , Glicerol/farmacología , Humanos , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Espectroscopía de Resonancia Magnética , Polímeros/síntesis química , Polímeros/química , Polímeros/farmacología , Espectroscopía Infrarroja por Transformada de Fourier , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico
11.
Biomacromolecules ; 12(4): 949-60, 2011 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-21355626

RESUMEN

The objective of this study was to evaluate the tolerability, to establish a dosing regimen, and to evaluate the efficacy of intravesical docetaxel (DTX) formulations in a mouse model of bladder cancer. DTX in commercial formulation (Taxotere, DTX in Tween 80) or loaded in hyperbranched polyglycerols (HPGs) was evaluated. The synthesis and characterization of HPGs with hydrophobic cores and derivatized with methoxy poly(ethylene glycol) in the shell and further functionalized with amine groups (HPG-C(8/10)-MePEG and HPG-C(8/10)-MePEG-NH(2)) is described. Intravesical DTX in either commercial or HPGs formulations (up to 1.0 mg/mL) was instilled in mice with orthotopic bladder cancer xenografts and was well tolerated with no apparent signs of local or systemic toxicities. Furthermore, a single dose of intravesical DTX (0.5 mg/mL) loaded in HPGs was significantly more effective in reducing the tumor growth in an orthotopic model of bladder cancer than the commercial formulation of Taxotere. In addition, DTX-loaded HPG-C(8/10)-MePEG-NH(2) was found to be more effective at lower instillation dose than DTX (0.2 mg/mL)-loaded HPG-C(8/10)-MePEG. Overall, our data show promising antitumor efficacy and safety in a recently validated orthotopic model of bladder cancer. Further research is warranted to evaluate its safety and efficacy in early phase clinical trials in patients refractory to standard intravesical therapy.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Taxoides/farmacología , Neoplasias de la Vejiga Urinaria/patología , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular , Cromatografía en Gel , Modelos Animales de Enfermedad , Docetaxel , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Ratones , Microscopía Confocal , Microscopía Fluorescente , Tamaño de la Partícula , Taxoides/administración & dosificación
12.
J Biomed Mater Res B Appl Biomater ; 109(6): 853-863, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33098184

RESUMEN

Hyperbranched polyglycerol (HPG) is a biocompatible polyether polymer that is a potential colloid component in a preservation solution for suppressing interstitial edema during cold storage of a donor organ. This study evaluated the outcomes of kidney transplants after cold perfusion and storage with a HPG-based preservation solution (HPGS) in a pig model of kidney autotransplantation. The left kidneys of farm pigs (weighing 35-45 kg) were perfused with and stored in either cold HPGS or standard UW solution (UWS), followed by transplantation to the right side after right nephrectomy. The survival and function of transplants were determined by the urine output, and serum creatinine (SCr) and blood urea nitrogen (BUN) of recipients. Transplant injury was examined by histological analysis. Here, we showed that there was no significant difference between HPGS and UWS in the prevention of tissue edema, but HPGS was more effective than UWS for initial blood washout of kidney perfusion and for the prevention of cold ischemia injury during cold storage. After autotransplantation, the kidneys preserved with HPGS (HPG group) had better functional recovery than those with UWS (UW group), indicated by significantly more urine output and lower levels of SCr and BUN. The survived grafts in HPG group had less tissue damage than those in UW group. In conclusion, as compared to the UWS the HPGS has less negative impact on kidney cold ischemia during cold storage, resulting in improving immediate functional recovery after transplantation, suggesting that HPG is a promising colloid for donor kidney preservation.


Asunto(s)
Glicerol/farmacología , Trasplante de Riñón , Riñón , Soluciones Preservantes de Órganos/farmacología , Preservación de Órganos , Perfusión , Polímeros/farmacología , Adenosina/farmacología , Alopurinol/farmacología , Animales , Glutatión/farmacología , Insulina/farmacología , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Rafinosa/farmacología , Porcinos , Trasplante Autólogo
13.
J Am Chem Soc ; 132(10): 3423-30, 2010 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-20166670

RESUMEN

Macromolecular cell surface modification techniques have shown tremendous utility in various biomedical applications. However, a major drawback concerns inefficient cell surface modification caused by the poor association of hydrophilic macromolecules with cell surfaces. Here, a novel, highly efficient, and universal strategy in which nonreactive "additive" macromolecules are used to modulate the grafting efficiency of cell surface reactive, hydrophilic macromolecules is described. Unprecedented enhanced cell surface modifications by up to 10-fold were observed when various concentrations of a suitable "additive" polymer was present with a constant and low concentration of a "reactive" macromolecule. The importance of this increased efficiency and the possible mechanisms involved are discussed. The cell compatible technique is demonstrated in the case of four different cell types--red blood cells (RBC), leukocytes, platelets, and Jurkat cells. A practical application of grafting macromolecules to cell surfaces in concentrated polymer solutions is demonstrated by the enhanced camouflage of RBC surface antigens for the development of RhD null RBC. In principle, the technique can be adapted to various macromolecular systems and cell types, with significant potential for biomedical applications such as live cell based technologies.


Asunto(s)
Plaquetas/química , Membrana Celular/química , Eritrocitos/química , Glicerol/química , Leucocitos/química , Polietilenglicoles/química , Polímeros/química , Succinimidas/química , Eritrocitos/inmunología , Humanos , Células Jurkat , Sistema del Grupo Sanguíneo Rh-Hr , Propiedades de Superficie
14.
Biomacromolecules ; 11(1): 284-93, 2010 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-20000794

RESUMEN

A novel, nonfouling polymer brush, poly-N-[(2,3-dihydroxypropyl)acrylamide] (PDHPA), containing latent aldehyde groups, was synthesized by surface initiated atom transfer radical polymerization (SI-ATRP). The synthetic parameters were adjusted to produce brushes with varying graft densities and molecular weights. High-density PDHPA brushes successfully prevented the nonspecific protein adsorption from single protein solutions as well as from human platelet poor plasma. Patterns of nonfouling PDHPA and reactive PDHPA-aldehyde domains on the brush surface were created by a combination of photo and wet chemical lithography from a single homogeneous PDHPA brush. Successful micropatterning of single proteins and multiple proteins were achieved using this novel substrate. The high-density brush prevented the diffusion of large proteins into the brush, while a monolayer of covalently coupled proteins was formed on the PDHPA-aldehyde domains. Atomic force microscopy (AFM) force measurements using a biotin coupled AFM tip showed that covalently coupled streptavidin retained its activity, while PDHPA domains showed little nonspecific adsorption of streptavidin. The current study avoids tedious and complicated synthetic processes employed in conventional approaches by providing a novel approach to protein micropatterning from a single, multifunctional polymer brush.


Asunto(s)
Aldehídos/química , Polímeros/química , Proteínas/química , Adsorción , Humanos , Microscopía de Fuerza Atómica , Polímeros/síntesis química , Propiedades de Superficie
15.
Biomacromolecules ; 11(10): 2567-75, 2010 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-20804173

RESUMEN

We report the synthesis and characterization of multivalent mannose conjugates based on high molecular weight hyperbranched polyglycerols (HPG). A range of glycoconjugates were synthesized from high molecular weight HPGs (up to 493 kDa) and varying mannose units (22-303 per HPG). Hemagglutination assays using fresh human red blood cells and concanavalin A (Con A) showed that HPG-mannose conjugates exhibited a large enhancement in the relative potency of conjugates (as high as 40000) along with a significant increment in relative activity per sugar (up to 255). The size of the HPG scaffold and the number of mannose residues per HPG were all shown to influence the enhancement of binding interactions with Con A. Isothermal titration calorimetry (ITC) experiments confirmed the enhanced binding affinity and showed that both molecular size and ligand density play important roles. The enhancement in Con A binding to the high molecular weight HPG-mannose conjugates is due to a combination of inter- and intramolecular mannose binding. A few fold increments in the binding constant were obtained over mannose upon covalent attachment to HPG. The binding enhancement is due to the highly favorable entropic contribution to the multiple interactions of Con A to mannose residues on HPG. The high molecular weight HPG-mannose conjugates showed positive cooperativity in binding to Con A. Although carbohydrate density has less of an effect on functional valency of the conjugate compared to the molecular size, it determines the binding affinity.


Asunto(s)
Glicerol/química , Glicoconjugados/síntesis química , Manosa/química , Polímeros/química , Concanavalina A/metabolismo , Eritrocitos/metabolismo , Glicoconjugados/química , Glicoconjugados/metabolismo , Pruebas de Hemaglutinación , Humanos , Peso Molecular , Unión Proteica
16.
BJU Int ; 103(7): 978-86, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19007363

RESUMEN

OBJECTIVE: To develop paclitaxel incorporated into unimolecular micelles based on hydrophobically derivatized hyperbranched polyglycerols (dHPGs) for use as mucoadhesive intravesical agents against non-muscle-invasive bladder cancer. MATERIALS AND METHODS: Two different types of dHPGs (HPG- C10-polyethylene glycol (PEG) and polyethyleneimine (PEI)-C18-HPG) were synthesized and paclitaxel was loaded into these using a solvent evaporation method. After physicochemical characterization of the resulting nanoparticles, four human bladder cancer cell lines were incubated with various concentrations of paclitaxel incorporated in dHPGs and the results were compared with those of paclitaxel formulated in Cremophor-EL (Taxol(R), Bristol-Myers-Squibb). In vivo, nude mice with orthotopic KU7-luc tumours were intravesically instilled with phosphate buffered saline, Taxol, or paclitaxel/HPG-C10-PEG. RESULTS: dHPGs are mucoadhesive nanoparticles with hydrodynamic radii of <10 nm and incorporation of paclitaxel did not affect their size. The release profiles of paclitaxel from dHPGs were characterized by a rapid-release phase followed by a slower sustained-release phase. While the PEI-C18-HPG formulation released only approximately 40% of the initially incorporated paclitaxel, up to 80% was released from HPG-C10-PEG. Moreover, only paclitaxel/HPG-C10-PEG was stable in acidic urine. In vitro, all paclitaxel formulations potently decreased bladder cancer proliferation although paclitaxel/HPG-C10-PEG was slightly less cytotoxic than standard Taxol. By contrast, in vivo, the mucoadhesive HPG-C10-PEG formulation of paclitaxel was significantly more effective in reducing orthotopic tumour growth than Taxol and was well tolerated. CONCLUSION: Intravesical administration of mucoadhesive nanoparticulate formulations of paclitaxel might be a promising approach for instillation therapy of patients with non-muscle-invasive bladder cancer.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Paclitaxel/administración & dosificación , Polietilenglicoles/administración & dosificación , Polietileneimina/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Administración Intravesical , Animales , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Humanos , Ratones , Ratones Desnudos , Nanopartículas , Paclitaxel/farmacología , Polietilenglicoles/química , Polietileneimina/química
17.
Bioconjug Chem ; 19(11): 2231-8, 2008 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-18847230

RESUMEN

We recently reported the synthesis and testing of a new class of unimolecular micelles based on hyperbranched polyglycerols as second generation synthetic plasma expanders and as general drug delivery vehicles. A detailed biodistribution study of two derivatized hyperbranched polyglycerols of different molecular weights derivatized with hydrophobic groups and short poly(ethylene glycol) chains is reported in this article. In mice, these materials are nontoxic with circulation half-lives as high as 31 h, controllable by manipulating the molecular weight and the degree of PEG derivatization. Organ accumulation is low, presumably due to the "pegylation" effect. Thermal degradation and hydrolysis data suggest that these polymers are highly stable with a long shelf life, a major advantage for a pharmaceutical product. Degradation under acidic conditions has been observed for these polymers.


Asunto(s)
Materiales Biocompatibles/química , Materiales Biocompatibles/farmacocinética , Glicerol/química , Glicerol/farmacocinética , Interacciones Hidrofóbicas e Hidrofílicas , Polímeros/química , Polímeros/farmacocinética , Animales , Materiales Biocompatibles/síntesis química , Femenino , Glicerol/síntesis química , Hidrólisis , Ratones , Ratones Endogámicos BALB C , Micelas , Polímeros/síntesis química , Temperatura , Distribución Tisular , Agua/química
18.
Biomaterials ; 29(11): 1693-704, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18194812

RESUMEN

There is a huge clinical demand for Human Serum Albumin (HSA), with a world market of approximately $1.5B/year. Concern over prion and viral transmission in the blood supply has led to a need for safer substitutes and offers the opportunity for development of materials with enhanced properties over the presently available plasma expanders. We report here the synthesis and testing of a new synthetic plasma expander that can replace not only the osmotic and volume expansion properties of HSA but, uniquely, its binding and transport properties. We have synthesized several hyperbranched polyglycerols derivatized with hydrophobic groups and short poly(ethylene glycol) (PEG) chains. The hydrophobic groups provide regions for binding fatty acids and other hydrophobic materials while PEG imparts the necessary protection from host defense systems and enhances circulation longevity. These polymers, being hyperbranched, have only a small effect on plasma viscosity. We have shown in vitro that our materials bind 2-3 moles palmitic acid per mole, do not activate the platelet, coagulation or complement systems and do not cause red cell aggregation. In mice these materials are non-toxic with circulation half-lives as high as 34h, controllable by manipulating the molecular weight and the degree of PEG derivatization.


Asunto(s)
Glicerol/química , Interacciones Hidrofóbicas e Hidrofílicas , Polímeros/química , Albúmina Sérica , Animales , Materiales Biocompatibles/metabolismo , Proteínas Sanguíneas/química , Femenino , Glicerol/metabolismo , Glicerol/farmacocinética , Glicerol/toxicidad , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Activación Plaquetaria/efectos de los fármacos , Polímeros/metabolismo , Polímeros/farmacocinética , Polímeros/toxicidad , Pruebas de Toxicidad , Viscosidad
19.
Biomacromolecules ; 9(3): 886-95, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18247528

RESUMEN

This paper discusses the binding and release properties of hydrophobically modified hyperbranched polyglycerol-polyethylene glycol copolymers that were originally developed as human serum albumin (HSA) substitutes. Their unimolecular micellar nature in aqueous solution has been proven by size measurements and other spectroscopic methods. These polymers aggregate weakly in solution, but the aggregates are broken down by low shear forces or by encapsulating a hydrophobic ligand within the polymer. The small molecule binding properties of these polymers are compared with those of HSA. The preliminary in vitro paclitaxel release studies showed very promising sustained drug release characteristics achieved by these unimolecular micelles.


Asunto(s)
Dendrímeros/química , Glicerol/química , Micelas , Polímeros/química , Albúmina Sérica/química , Preparaciones de Acción Retardada , Ácidos Grasos/química , Colorantes Fluorescentes/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Imitación Molecular , Paclitaxel/administración & dosificación , Paclitaxel/química , Polietilenglicoles/química , Pirenos/química
20.
Adv Healthc Mater ; 7(5)2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28961393

RESUMEN

Platelets have a limited shelf life, due to the risk of bacterial contamination and platelet quality loss. Most platelet storage bags are made of a mixture of polyvinyl chloride with a plasticizer, denoted as pPVC. To improve biocompatibility of pPVC with platelets and to inhibit bacterial biofilm formation, an antifouling polymer coating is developed using mussel-inspired chemistry. A copolymer of N,N-dimethylacrylamide and N-(3-aminopropyl)methacrylamide hydrochloride is synthesized and coupled with catechol groups, named DA51-cat. Under mild aqueous conditions, pPVC is first equilibrated with an anchoring polydopamine layer, followed by a DA51-cat layer. Measurements show this coating decreases fibrinogen adsorption to 5% of the control surfaces. One-step coating with DA51-cat does not coat pPVC efficiently although it is sufficient for coating silicon wafers and gold substrates. The dual layer coating on platelet bags resists bacterial biofilm formation and considerably decreases platelet adhesion. A cationic antimicrobial peptide, E6, is conjugated to DA51-cat then coated on silicon wafers and introduces bactericidal activity to these surfaces. Time-of-flight second ion-mass spectroscopy is successfully applied to characterize these surfaces. pPVC is widely used in medical devices; this method provides an approach to controlling biofouling and bacterial growth on it without elaborate surface modification procedures.


Asunto(s)
Biopelículas/crecimiento & desarrollo , Incrustaciones Biológicas/prevención & control , Plaquetas/metabolismo , Conservación de la Sangre , Materiales Biocompatibles Revestidos/química , Indoles/química , Polímeros/química , Staphylococcus epidermidis/fisiología , Adulto , Péptidos Catiónicos Antimicrobianos/química , Adhesión Bacteriana , Plaquetas/microbiología , Conservación de la Sangre/instrumentación , Conservación de la Sangre/métodos , Catecoles/química , Femenino , Humanos , Masculino
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