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1.
Biomacromolecules ; 24(8): 3545-3556, 2023 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-37449781

RESUMO

Core cross-linked polymeric micelles (CCPMs) are designed to improve the therapeutic profile of hydrophobic drugs, reduce or completely avoid protein corona formation, and offer prolonged circulation times, a prerequisite for passive or active targeting. In this study, we tuned the CCPM stability by using bifunctional or trifunctional cross-linkers and varying the cross-linkable polymer block length. For CCPMs, amphiphilic thiol-reactive polypept(o)ides of polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine) [pSar-b-pCys(SO2Et)] were employed. While the pCys(SO2Et) chain lengths varied from Xn = 17 to 30, bivalent (derivatives of dihydrolipoic acid) and trivalent (sarcosine/cysteine pentapeptide) cross-linkers have been applied. Asymmetrical flow field-flow fraction (AF4) displayed the absence of aggregates in human plasma, yet for non-cross-linked PM and CCPMs cross-linked with dihydrolipoic acid at [pCys(SO2Et)]17, increasing the cross-linking density or the pCys(SO2Et) chain lengths led to stable CCPMs. Interestingly, circulation time and biodistribution in mice of non-cross-linked and bivalently cross-linked CCPMs are comparable, while the trivalent peptide cross-linkers enhance the circulation half-life from 11 to 19 h.


Assuntos
Micelas , Polímeros , Humanos , Animais , Camundongos , Distribuição Tecidual , Polímeros/química , Plasma
2.
Macromol Rapid Commun ; 43(19): e2200318, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35687083

RESUMO

After intravenous administration of nanocarriers, plasma proteins may rapidly adsorb onto their surfaces. This process hampers the prediction of the nanocarriers' pharmacokinetics as it determines their physiological identity in a complex biological environment. Toward clinical translation it is therefore an essential prerequisite to investigate the nanocarriers' interaction with plasma proteins. Here, this work evaluates a highly "PEGylated" squaric ester-based nanogel with inherent prolonged blood circulation properties. After incubation with human blood plasma, the nanogels are isolated by asymmetrical flow-field flow fractionation. Multiangle light scattering measurements confirm the absence of significant size increases as well as aggregation upon plasma incubation. However, proteomic analyses by gel electrophoresis find minor absolute amounts of proteins (3 wt%), whereas label-free liquid chromatography mass spectrometry identify 65 enriched proteins. Interestingly, the relative abundance of these proteins is almost similar to their proportion in pure native plasma. Due to the nanogels' hydrated and porous network morphology, it is concluded that the detected proteins rather result from passive diffusion into the nanogel network than from specific interactions at the plasma particle interface. Consequently, these results do not indicate a classical surface protein corona but rather reflect the highly outer and inner stealth-like behavior of the porous hydrogel network.


Assuntos
Nanopartículas , Coroa de Proteína , Materiais Biocompatíveis , Proteínas Sanguíneas , Portadores de Fármacos/química , Ésteres , Humanos , Hidrogéis , Proteínas de Membrana , Nanogéis , Nanopartículas/química , Polietilenoglicóis , Polietilenoimina , Porosidade , Coroa de Proteína/química , Proteômica
3.
Small ; 16(18): e1907574, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32250017

RESUMO

The current understanding of nanoparticle-protein interactions indicates that they rapidly adsorb proteins upon introduction into a living organism. The formed protein corona determines thereafter identity and fate of nanoparticles in the body. The present study evaluates the protein affinity of three core-crosslinked polymeric nanoparticles with long circulation times, differing in the hydrophilic polymer material forming the particle surface, namely poly(N-2-hydroxypropylmethacrylamide) (pHPMA), polysarcosine (pSar), and poly(ethylene glycol) (PEG). This includes the nanotherapeutic CPC634, which is currently in clinical phase II evaluation. To investigate possible protein corona formation, the nanoparticles are incubated in human blood plasma and separated by asymmetrical flow field-flow fractionation (AF4). Notably, light scattering shows no detectable differences in particle size or polydispersity upon incubation with plasma for all nanoparticles, while in gel electrophoresis, minor amounts of proteins can be detected in the particle fraction. Label-free quantitative proteomics is additionally applied to analyze and quantify the composition of the proteins. It proves that some proteins are enriched, but their concentration is significantly less than one protein per particle. Thus, most of the nanoparticles are not associated with any proteins. Therefore, this work underlines that polymeric nanoparticles can be synthesized, for which a protein corona formation does not take place.


Assuntos
Nanopartículas , Coroa de Proteína , Humanos , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Peptídeos , Polietilenoglicóis , Sarcosina/análogos & derivados
4.
Angew Chem Int Ed Engl ; 56(5): 1416-1421, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-28005299

RESUMO

Novel polymeric cell adhesion inhibitors were developed in which the selectin tetrasaccharide sialyl-LewisX (SLeX ) is multivalently presented on a biocompatible poly(2-hydroxypropyl)methacrylamide (PHPMA) backbone either alone (P1) or in combination with O-sulfated tyramine side chains (P2). For comparison, corresponding polymeric glycomimetics were prepared in which the crucial "single carbohydrate" substructures fucose, galactose, and sialic acid side chains were randomly linked to the PHPMA backbone (P3 or P4 (O-sulfated tyramine)). All polymers have an identical degree of polymerization, as they are derived from the same precursor polymer. Binding assays to selectins, to activated endothelial cells, and to macrophages show that polyHPMA with SLeX is an excellent binder to E-, L-, and P-selectins. However, mimetic P4 can also achieve close to comparable binding affinities in in vitro measurements and surprisingly, it also significantly inhibits the migration of macrophages; this provides new perspectives for the therapy of severe inflammatory diseases.


Assuntos
Macrófagos/metabolismo , Oligossacarídeos/metabolismo , Selectinas/metabolismo , Movimento Celular , Células Cultivadas , Citometria de Fluxo , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50 , Ligantes , Macrófagos/citologia , Microscopia de Fluorescência por Excitação Multifotônica , Nanomedicina , Oligossacarídeos/química , Ácidos Polimetacrílicos/química , Selectinas/química , Antígeno Sialil Lewis X , Ressonância de Plasmônio de Superfície , Tiramina/química
5.
Biomacromolecules ; 17(10): 3305-3317, 2016 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-27673444

RESUMO

Poly(2,3-dihydroxypropyl methacrylamide) (P(DHPMA))-based amphiphilic block copolymers have recently proven to form polymer vesicles (polymersomes). In this work, we further expand their potential by incorporating (i) units for pH-dependent disintegration into the hydrophobic membrane and (ii) mannose as targeting unit into the hydrophilic block. This last step relies on the use of an active ester prepolymer. We confirm the stability of the polymersomes against detergents like Triton X-100 and their low cytotoxicity. The incorporation of 2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methacrylate into the hydrophobic block (lauryl methacrylate) allows a pH-responsive disintegration for cargo release. Efficient decomposition of the polymersome structure is monitored by dynamic light scattering. It is thus possible to include an active enzyme (glucose oxidase), which gets only active (is set free) after vesicle disintegration. In addition, the introduction of mannose as targeting structure allows enhanced and selective targeting of dendritic cells.


Assuntos
Sistemas de Liberação de Medicamentos , Ésteres/química , Metacrilatos/química , Polímeros/química , Dioxolanos/química , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Metacrilatos/síntese química , Octoxinol/química , Polímeros/síntese química
6.
Macromol Rapid Commun ; 37(11): 924-33, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27075781

RESUMO

Messenger ribonucleic acids (mRNAs) are considered as promising alternatives for transient gene therapy, but to overcome their poor pharmacokinetic properties, smart carriers are required for cellular uptake and stimuli-responsive release. In this work, a synthetic concept toward reductive decationizable cationic block copolymers for mRNA complexation is introduced. By combination of RAFT block copolymerization with postpolymerization modification, cationic block copolymers are generated with disulfide-linked primary amines. They allow effective polyplex formation with negatively charged mRNA and subsequent release under reductive conditions of the cytoplasm. In first in vitro experiments with fibroblasts and macrophages, tailor-made block copolymers mediate cell-specific mRNA transfection, as quantified by polyplex uptake and mRNA-encoding gene expression. Furthermore, RAFT polymerization provides access to heterotelechelic polymers with orthogonally addressable endgroup functionalities utilized to ligate targeting units onto the polyplex-forming block copolymers. The results exemplify the broad versatility of this reductive decationizable mRNA carrier system, especially toward further advanced mRNA delivery applications.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Polímeros/química , Polímeros/farmacologia , RNA Mensageiro/química , RNA Mensageiro/farmacologia , Células 3T3 , Animais , Camundongos
7.
Macromol Rapid Commun ; 36(11): 1089-95, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25761204

RESUMO

Emission wavelength control in fluorescent nanoparticles (NPs) is crucial for their applications. In the case of inorganic quantum dots or dye-impregnated silica NPs, such a control is readily achieved by changing the size of the particles or choosing appropriate fluorescent dyes, respectively. A similar modular approach for controlling the emission wavelength of fluo-rescent polymer NPs, however, is difficult. This article reports on fluorescent polymer NPs, the synthesis of which provides a platform for a modular approach towards the preparation of fluorescent NPs of desired emission wavelength. Atom-transfer radical polymerization (ATRP) is employed to synthesize reactive ester polymers, which are then easily modified with a commercially available dye and subsequently subjected to nanoprecipitation. The resulting NPs, with low size polydispersity, show an enhanced emission quantum yield when compared with the same dye molecules in solution.


Assuntos
Aminas/química , Nanopartículas/química , Polímeros/síntese química , Ésteres , Corantes Fluorescentes/química , Espectroscopia de Ressonância Magnética , Polimerização , Polímeros/química
8.
Macromol Rapid Commun ; 36(11): 959-83, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25737161

RESUMO

Simple blends of inorganic nanocrystals and organic (semiconducting) polymers usually lead to macroscopic segregation. Thus, such blends typically exhibit inferior properties than expected. To overcome the problem of segregation, polymer coated nanocrystals (nanocomposites) have been developed. Such nanocomposites are highly miscible within the polymer matrix. In this Review, a summary of synthetic approaches to achieve stable nanocomposites in a semiconducting polymer matrix is presented. Furthermore, a theoretical background as well as an overview concerning morphology control of inorganic NCs in polymer matrices are provided. In addition, the morphologic behavior of highly anisotropic nanoparticles (i.e. liquid crystalline phase formation of nanorod-composites) and branched nanoparticles (spatial orientation of tetrapods) is described. Finally, the morphology requirements for the application of inorganic/organic hybrid systems in light emitting diodes and solar cells are discussed, and potential solutions to achieve the required morphologies are provided.


Assuntos
Semicondutores , Coloides/química , Cristais Líquidos/química , Nanopartículas/química , Fosfinas/química , Ácidos Fosforosos/química , Polímeros/síntese química , Polímeros/química , Energia Solar
9.
Macromol Rapid Commun ; 36(11): 1108-14, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25855210

RESUMO

In this paper, the surface modification of CdSe- and CdZnS-based quantum dots (QDs) with a functional silica shell is reported. Functionalized silica shells are prepared by two routes: either by ligand exchange and a modified Stöber process or by a miniemulsion process with amphiphilic poly(oxyethylene) nonylphenylether also know as Igepal CO-520 (IG) as oligomeric amphiphile and modified silica precursors. The polymerizable groups on the functionalized silica shell allow covalent bonding to a polymer matrix and prevent demixing during polymerization and crosslinking. This allows the homogeneous incorporation of QDs in a crosslinked polymer matrix. This paper furthermore demonstrates that the resulting QDs, which are i) shielded with a proper silica shell and ii) functionalized with crosslinkable groups, can be used in two-photon-initiated polymerization processes in combination with different photoresists to obtain highly luminescent 3D structures. The resulting luminescent structures are attractive candidates for photonics and metamaterials research.


Assuntos
Polímeros/síntese química , Pontos Quânticos/química , Fótons , Polimerização , Polímeros/química , Pontos Quânticos/ultraestrutura , Dióxido de Silício/química , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície
10.
Macromol Rapid Commun ; 36(11): 1075-82, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25598387

RESUMO

The synthesis of statistical and block copolymers based on polyacrylonitrile, as a source for carbonaceous materials, and thiol-containing repeating units as inorganic nanoparticle anchoring groups is reported. These polymers are used to coat Au@ZnO multipod heteroparticles with polymer brushes. IR spectroscopy and transmission electron microscopy prove the successful binding of the polymer onto the inorganic nanostructures. Thermogravimetric analysis is applied to compare the binding ability of the block and statistical copolymers. Subsequently, the polymer coating is transformed into a carbonaceous (partially graphitic) coating by pyrolysis. The obtained carbon coating is characterized by Raman spectroscopy and energy-dispersive X-ray (EDX) spectroscopy. The benefit of the conformal carbon coating of the Au@ZnO multipods regarding its application as lithium-ion anode material is revealed by performing galvanostatic cycling, showing a highly enhanced and stabilized electrochemical performance of the carbon-coated particles (still 831 mAh g(-1) after 150 cycles) with respect to the uncoated ones (only 353 mAh g(-1) after 10 cycles).


Assuntos
Fontes de Energia Elétrica , Ouro/química , Lítio/química , Nanopartículas Metálicas/química , Polímeros/química , Óxido de Zinco/química , Resinas Acrílicas/química , Carbono/química , Técnicas Eletroquímicas , Eletrodos , Íons/química , Microscopia Eletrônica de Transmissão , Polímeros/síntese química , Espectrometria por Raios X
11.
Macromol Rapid Commun ; 36(11): 1129-37, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25929974

RESUMO

Many natural materials are complex composites whose mechanical properties are often outstanding considering the weak constituents from which they are assembled. Nacre, made of inorganic (CaCO3 ) and organic constituents, is a textbook example because of its strength and toughness, which are related to its hierarchical structure and its well-defined organic-inorganic interface. Emulating the construction principles of nacre using simple inorganic materials and polymers is essential for understanding how chemical composition and structure determine biomaterial functions. A hard multilayered nanocomposite is assembled based on alternating layers of TiO2 nanoparticles and a 3-hydroxy-tyramine (DOPA) substituted polymer (DOPA-polymer), strongly cemented together by chelation through infiltration of the polymer into the TiO2 mesocrystal. With a Young's modulus of 17.5 ± 2.5 GPa and a hardness of 1.1 ± 0.3 GPa the resulting material exhibits high resistance against elastic as well as plastic deformation. A key feature leading to the high strength is the strong adhesion of the DOPA-polymer to the TiO2 nanoparticles.


Assuntos
Di-Hidroxifenilalanina/química , Nanopartículas Metálicas/química , Polímeros/química , Titânio/química , Carbonato de Cálcio/química , Módulo de Elasticidade , Nanopartículas Metálicas/ultraestrutura , Microscopia de Força Atômica , Polímeros/síntese química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
12.
Biochemistry ; 53(9): 1410-9, 2014 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-24533898

RESUMO

Because a polymer environment might be milder than a detergent micelle, amphiphilic polymers have attracted attention as alternatives to detergents in membrane biochemistry. The polymer poly[N-(2-hydroxypropyl)-methacrylamid] [p(HPMA)] has recently been modified with hydrophobic lauryl methacrylate (LMA) moieties, resulting in the synthesis of amphiphilic p(HPMA)-co-p(LMA) polymers. p(HPMA)-co-p(LMA) polymers with a LMA content of 5 or 15% have unstable hydrophobic cores. This, on one hand, promotes interactions of the hydrophobic LMA moieties with membranes, resulting in membrane rupture, but at the same time prevents formation of a hydrophobic, membrane mimetic environment that is sufficiently stable for the incorporation of transmembrane proteins. On the other hand, the p(HPMA)-co-p(LMA) polymer with a LMA content of 25% forms a stable hydrophobic core structure, which prevents hydrophobic interactions with membrane lipids but allows stable incorporation of membrane proteins. On the basis of our data, it becomes obvious that amphiphilic polymers have to have threshold hydrophobicities should an application in membrane protein research be anticipated.


Assuntos
Polímeros/química , Interações Hidrofóbicas e Hidrofílicas , Metacrilatos/química
13.
Biomacromolecules ; 15(11): 4111-21, 2014 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-25338185

RESUMO

To overcome the poor pharmacokinetic conditions of short double-stranded RNA molecules in RNA interference therapies, cationic nanohydrogel particles can be considered as alternative safe and stable carriers for oligonucleotide delivery. For understanding key parameters during this process, two different types of well-defined cationic nanohydrogel particles were synthesized, which provided nearly identical physicochemical properties with regards to their material composition and resulting siRNA loading characteristics. Yet, according to the manufacturing process using amphiphilic reactive ester block copolymers of pentafluorophenyl methacrylate (PFPMA) and tri(ethylene glycol)methyl ether methacrylate (MEO3MA) with similar compositions but different molecular weights, the resulting nanohydrogel particles differed in size after cross-linking with spermine (average diameter 40 vs 100 nm). This affected their knockdown potential significantly. Only the 40 nm sized cationic nanogel particles were able to generate moderate gene knockdown levels, which lasted, however, up to 3 days. Interestingly, primary cell uptake and colocalization studies with lysosomal compartments revealed that only these small sized nanogels were able to avoid acidic compartments of endolysosomal uptake pathways, which may contribute to their knockdown ability exclusively. To that respect, this size-dependent intracellular distribution behavior may be considered as an essential key parameter for tuning the knockdown potential of siRNA nanohydrogel particles, which may further contribute to the development of advanced siRNA carrier systems with improved knockdown potential.


Assuntos
Técnicas de Silenciamento de Genes , Hidrogéis/química , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoimina/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Cátions , Técnicas de Silenciamento de Genes/métodos , Células HeLa , Humanos , Nanogéis , Estrutura Secundária de Proteína , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/genética
14.
Biomacromolecules ; 15(4): 1526-33, 2014 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-24697603

RESUMO

For systemic siRNA delivery applications, well-defined drug carriers are required that guarantee stability for both carrier and cargo. Among various concepts progressing in market or final development, cationic nanohydrogel particles may serve as novel transport media especially designed for siRNA-in vivo experiments. In this work, the interaction of nanohydrogel particles with proteins and serum components was studied via dynamic light scattering in human blood serum as novel screening method prior to applications in vivo. The formation of larger aggregates mostly caused by charge interaction with albumin could be suppressed by nanogel loading with siRNA affording a neutral zeta potential for the complex. Preliminary in vivo studies confirmed the results inside the light-scattering cuvette. Although both carrier and cargo may have limited stability on their own under physiological relevant conditions, they can form safe and stable complexes at a charge neutralized ratio and thus making them applicable to systemic siRNA delivery.


Assuntos
Portadores de Fármacos/farmacocinética , Polietilenoglicóis/síntese química , Polietilenoglicóis/farmacocinética , Polietilenoimina/síntese química , Polietilenoimina/farmacocinética , Cátions , Portadores de Fármacos/metabolismo , Humanos , Hidrogéis/farmacocinética , Luz , Nanogéis , RNA Interferente Pequeno , Espalhamento de Radiação , Soro/metabolismo
15.
Macromol Rapid Commun ; 35(17): 1522-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24979656

RESUMO

This work provides a detailed insight into the synthesis of N-(2-hydroxypropyl)methacrylamide (HPMA) polymers employing the activated ester approach. In this approach, polypenta fluorophenyl methacrylate (PFPMA)-activated ester polymers are synthesized by the reversible addition-fragmentation chain transfer (RAFT) polymerization and transferred into HPMA-based systems by the use of 2-hydroxypropylamine. To prove quantitative conversion in the absence of side reactions, special attention is devoted to investigate different reaction conditions by different analytical methods ((1) H, (19) F, inverse-gated (13) C NMR, and zeta potential measurements). Furthermore the influence of common solvent impurities, such as water, is investigated. Besides differences in polymer tacticity, the poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA) synthesized under water-free conditions display the same properties like the conventional synthesized control-PHPMA. However, 3% water content in the dimethylsulfoxide are already sufficient to yield PHPMA polymers with a negative zeta potential of -15.8 mV indication the presence of carboxylic groups due to partial hydrolysis of the activated ester.


Assuntos
Polímeros/química , Ácidos Polimetacrílicos/química , Ésteres , Hidrólise , Cinética , Espectroscopia de Ressonância Magnética , Polimerização , Água/química
16.
Macromol Rapid Commun ; 35(19): 1685-91, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25179514

RESUMO

The morphology or dispersion control in inorganic/organic hybrid systems is studied, which consist of monodisperse CdSe tetrapods (TPs) with grafted semiconducting block copolymers with excess polymers of the same type. Tetrapod arm-length and amount of polymer loading are varied in order to find the ideal morphology for hybrid solar cells. Additionally, polymers without anchor groups are mixed with the TPs to study the effect of such anchor groups on the hybrid morphology. A numerical model is developed and Monte Carlo simulations to study the basis of compatibility or dispersibility of TPs in polymer matrices are performed. The simulations show that bare TPs tend to form clusters in the matrix of excess polymers. The clustering is significantly reduced after grafting polymer chains to the TPs, which is confirmed experimentally. Transmission electron microscopy reveals that the block copolymer-TP mixtures ("hybrids") show much better film qualities and TP distributions within the films when compared with the homopolymer-TP mixtures ("blends"), representing massive aggregations and cracks in the films. This grafting-to approach for the modification of TPs significantly improves the dispersion of the TPs in matrices of "excess" polymers up to the arm length of 100 nm.


Assuntos
Polímeros/química , Semicondutores , Compostos de Cádmio/química , Microscopia Eletrônica de Transmissão , Método de Monte Carlo , Compostos de Selênio/química
17.
Macromol Rapid Commun ; 35(24): 2057-64, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25323454

RESUMO

Well-defined nanogels have become quite attractive as safe and stable carriers for siRNA delivery. However, to avoid nanoparticle accumulation, they need to provide a stimuli-responsive degradation mechanism that can be activated at the payload's site of action. In this work, the synthetic concept for generating well-defined nanohydrogel particles is extended to incorporate disulfide cross-linkers into a cationic nanonetwork for redox-triggered release of oligonucleotide payload as well as nanoparticle degradation under reductive conditions of the cytoplasm. Therefore, a novel disulfide-modified spermine cross-linker is designed that both allows disassembly of the nanogel as well as removal of cationic charge from residual polymer fragments. The degradation process is monitored by scanning electron microscopy (SEM) and fluorescence correlation spectroscopy (FCS). Moreover, siRNA release is analyzed by agarose gel electrophoresis and a fluorescent RNA detection assay. The results exemplify the versatility of the applied nanogel manufacturing process, which allows alternative stimuli-responsive core cross-linkers to be integrated for triggered oligonucleotide release as well as effective biodegradation for reduced nanotoxicity.


Assuntos
Hidrogéis/química , Polietilenoglicóis/química , Polietilenoimina/química , RNA Interferente Pequeno/metabolismo , Cátions , Dissulfetos/síntese química , Espectroscopia de Ressonância Magnética , Nanogéis , Espermidina/química
18.
Mol Pharm ; 10(10): 3769-75, 2013 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-24004321

RESUMO

Immediately after administration, polymer therapeutics are exposed to complex biological media like blood which may influence and alter their physicochemical properties due to interactions with proteins or serum components. Among such interactions those leading to larger sized aggregates can be sensitively detected by dynamic light scattering (DLS) as a pre in vivo screening method. Random copolymers from N-(2-hydroxypropyl)methacrylamide and lauryl methacrylate p(HPMA-co-LMA) and copolymers loaded with the model drug domperidone were characterized by DLS in isotonic salt solution and in blood serum. The bare amphiphilic copolymer micelles (Rh=30 nm in isotonic salt solution) formed large aggregates in serum of over 100 nm radius which were shown to originate from interactions with very low density lipoproteins (VLDLs). Encapsulation of the hydrophobic drug domperidone resulted, at first, in drug-copolymer formulations with larger hydrodynamic radii (39 nm

Assuntos
Lipoproteínas LDL/sangue , Polímeros/metabolismo , Humanos , Lipoproteínas VLDL/sangue , Micelas
19.
Langmuir ; 29(9): 3080-8, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23387936

RESUMO

Scale formation, the deposition of certain minerals such as CaCO3, MgCO3, and CaSO4·2H2O in industrial facilities and household devices, leads to reduced efficiency or severe damage. Therefore, incrustation is a major problem in everyday life. In recent years, double hydrophilic block copolymers (DHBCs) have been the focus of interest in academia with regard to their antiscaling potential. In this work, we synthesized well-defined blocklike PAA-PAMPS copolymers consisting of acrylic acid (AA) and 2-acrylamido-2-methyl-propane sulfonate (AMPS) units in a one-step reaction by RAFT polymerization. The derived copolymers had dispersities of 1.3 and below. The copolymers have then been investigated in detail regarding their impact on the different stages of the crystallization process of CaCO3. Ca(2+) complexation, the first step of a precipitation process, and polyelectrolyte stability in aqueous solution have been investigated by potentiometric measurements, isothermal titration calorimetry (ITC), and dynamic light scattering (DLS). A weak Ca(2+) induced copolymer aggregation without concomitant precipitation was observed. Nucleation, early particle growth, and colloidal stability have been monitored in situ with DLS. The copolymers retard or even completely suppress nucleation, most probably by complexation of solution aggregates. In addition, they stabilize existing CaCO3 particles in the nanometer regime. In situ AFM was used as a tool to verify the coordination of the copolymer to the calcite (104) crystal surface and to estimate its potential as a growth inhibitor in a supersaturated CaCO3 environment. All investigated copolymers instantly stopped further crystal growth. The carboxylate richest copolymer as the most promising antiscaling candidate proved its enormous potential in scale inhibition as well in an industrial-filming test (Fresenius standard method).


Assuntos
Resinas Acrílicas/química , Carbonato de Cálcio/química , Polímeros/química , Ácidos Sulfônicos/química , Precipitação Química , Cristalização , Microscopia de Força Atômica , Água/química
20.
Biomacromolecules ; 14(9): 3091-101, 2013 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-23962188

RESUMO

Polymeric drug carriers aim to selectively target tumors in combination with protecting normal tissue. In this regard polymer structure and molecular weight are key factors considering organ distribution and tumor accumulation of the polymeric drug delivery system. Four different HPMA based copolymer structures (random as well as block copolymers with lauryl methacrylate as hydrophobic block) varying in molecular weight, size and resulting architecture were analyzed in two different tumor models (AT1 prostate carcinoma and Walker-256 mammary carcinoma) in vivo. Polymers were labeled with (18)F and organ/tumor uptake was followed by µPET imaging and ex vivo biodistribution. Vascular permeability was measured by dextran extravasation and vascular density by immunohistochemistry. Cellular polymer uptake was determined in vitro using fluorescence-labeled polymers. Most strikingly, the high molecular weight HPMA-LMA random copolymer demonstrated highest tumor uptake and blood pool concentration. The molecular structure (e.g., amphiphilicity) is holding a higher impact on desired in vivo properties than polymer size. The results also revealed pronounced differences between the tumor models although vascular permeability was almost comparable. Accumulation in Walker-256 carcinomas was much higher, presumably due to a better cellular uptake in this cell line and a denser vascular network in the tumors. These investigations clearly indicate that the properties of the individual tumor determine the suitability of polymeric drug carriers. The findings also illustrate the general necessity of a preclinical screening to analyze polymer uptake for each individual patient (e.g., by noninvasive PET imaging) in order to individualize polymer-based chemotherapy.


Assuntos
Carcinoma 256 de Walker/diagnóstico por imagem , Metacrilatos/química , Nanopartículas , Ácidos Polimetacrílicos/química , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos , Animais , Masculino , Nanopartículas/química , Transplante de Neoplasias , Tamanho da Partícula , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição Tecidual , Imagem Corporal Total
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