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1.
J Colloid Interface Sci ; 644: 264-274, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37120875

RESUMO

HYPOTHESIS: The design of biodegradable tyrosine-derived polymeric surfactants (TyPS) through the use of calculated thermodynamic parameters could lead to phospholipid membrane surface modifiers capable of controlling cellular properties such as viability. Delivery of cholesterol by TyPS nanospheres into membrane phospholipid domains could provide further controlled modulation of membrane physical and biological properties. EXPERIMENT: Calculated Hansen solubility parameters (∂T) and hydrophile:lipophile balances (HLB) were applied to design and synthesize a small family of diblock and triblock TyPS with different hydrophobic blocks and PEG hydrophilic blocks. Self-assembled TyPS/cholesterol nanospheres were prepared in aqueous media via co-precipitation. Cholesterol loading and Langmuir film balance surface pressures of phospholipid monolayers were obtained. TyPS and TyPS/cholesterol nanosphere effects on human dermal cell viability were evaluated by cell culture using poly(ethylene glycol) (PEG) and Poloxamer 188 as controls. FINDINGS: Stable TyPS nanospheres incorporated between 1% and 5% cholesterol. Triblock TyPS formed nanosphere with dimensions significantly smaller than diblock TyPS nanospheres. In accord calculated thermodynamic parameters, cholesterol binding increased with increasing TyPS hydrophobicity. TyPS inserted into phospholipid monolayer films in a manner consistent with their thermodynamic properties and TyPS/cholesterol nanospheres delivered cholesterol into the films. Triblock TyPS/cholesterol nanospheres increased human dermal cell viability, which was indicative of potentially beneficial TyPS effects on cell membrane surface properties.


Assuntos
Nanosferas , Tensoativos , Humanos , Tensoativos/farmacologia , Tirosina/química , Polímeros/química , Polietilenoglicóis/química , Membrana Celular , Fosfolipídeos
2.
J Colloid Interface Sci ; 623: 247-256, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35588632

RESUMO

HYPOTHESIS: Blending amphiphilic triblock (A-B-A) and diblock (A-B) copolymers comprised of the same hydrophobic tyrosine-derived oligomeric B-block and hydrophilic poly(ethylene glycol) methyl ether (mPEG) A-block can provide highly tunable self-assembled nanosphere particle sizes suitable for biomedical applications. EXPERIMENT: Triblock and diblock copolymers were synthesized via carbodiimide chemistry and were characterized by nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC). The amount of free PEG present in the purified copolymers was determined using a standard addition calibration curve and GPC peak deconvolution methods. Nanospheres were prepared by co-precipitation of each copolymer and of copolymer blends over a range of mole ratios. Nanospheres were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and % polymer recovery post-preparation. FINDING: Precise synthesis control produced triblock and diblock copolymers with narrow molecular weight distributions and minimal residual reactants. Self-assembled nanosphere particle sizes were 33 nm for the triblock and 129 nm for the diblock, and the size of their blends increased continuously as a function of mole ratio within that biomedically relevant range. Addition of unreacted PEG had minimal impact on either triblock or diblock nanosphere particle sizes whereas addition of unreacted oligomeric B-block increased nanosphere sizes.


Assuntos
Nanosferas , Amidas , Ésteres , Micelas , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química , Polímeros/química
3.
J Phys Chem Lett ; 8(17): 4183-4190, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28829138

RESUMO

Solid-state solvation (SSS) is a solid-state analogue of solvent-solute interactions in the liquid state. Although it could enable exceptionally fine control over the energetic properties of solid-state devices, its molecular mechanisms have remained largely unexplored. We use ultrafast transient absorption and optical Kerr effect spectroscopies to independently track and correlate both the excited-state dynamics of an organic emitter and the polarization anisotropy relaxation of a small polar dopant embedded in an amorphous polystyrene matrix. The results demonstrate that the dopants are able to rotationally reorient on ultrafast time scales following light-induced changes in the electronic configuration of the emitter, minimizing the system energy. The solid-state dopant-emitter dynamics are intrinsically analogous to liquid-state solvent-solute interactions. In addition, tuning the dopant/polymer pore ratio offers control over solvation dynamics by exploiting molecular-scale confinement of the dopants by the polymer matrix. Our findings will enable refined strategies for tuning optoelectronic material properties using SSS and offer new strategies to investigate mobility and disorder in heterogeneous solid and glassy materials.

4.
ACS Appl Mater Interfaces ; 9(15): 13369-13379, 2017 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-28350953

RESUMO

Organic light-emitting diode (OLED) displays have been an active and intense area of research for well over a decade and have now reached commercial success for displays from cell phones to large format televisions. A more thorough understanding of the many different potential degradation modes which cause OLED device failure will be necessary to develop the next generation of OLED materials, improve device lifetime, and to ultimately improve the cost vs performance ratio. Each of the different organic layers in an OLED device can be susceptible to unique decomposition pathways, however stability toward excitons is critical for emissive layer (EML) materials as well as any layer near the recombination zone. This study will specifically focus on degradation modes within the hole transport layer (HTL) with the goal being to identify the general decomposition paths occurring in an operating device and use this information to design new derivatives which can block these pathways. Through post-mortem analyses of several aged OLED devices, an apparently common intramolecular cyclization pathway has been identified that was not previously reported for arylamine-containing HTL materials and that operates parallel to but faster than the previously described fragmentation pathways.

5.
J Phys Chem B ; 120(15): 3666-76, 2016 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-27031284

RESUMO

The dissipative particle dynamics (DPD) simulation technique is a coarse-grained (CG) molecular dynamics-based approach that can effectively capture the hydrodynamics of complex systems while retaining essential information about the structural properties of the molecular species. An advantageous feature of DPD is that it utilizes soft repulsive interactions between the beads, which are CG representation of groups of atoms or molecules. In this study, we used the DPD simulation technique to study the aggregation characteristics of ABA triblock copolymers in aqueous medium. Pluronic polymers (PEG-PPO-PEG) were modeled as two segments of hydrophilic beads and one segment of hydrophobic beads. Tyrosine-derived PEG5K-b-oligo(desaminotyrosyl tyrosine octyl ester-suberate)-b-PEG5K (PEG5K-oligo(DTO-SA)-PEG5K) block copolymers possess alternate rigid and flexible components along the hydrophobic oligo(DTO-SA) chain, and were modeled as two segments of hydrophilic beads and one segment of hydrophobic, alternate soft and hard beads. The formation, structure, and morphology of the initial aggregation of the polymer molecules in aqueous medium were investigated by following the aggregation dynamics. The dimensions of the aggregates predicted by the computational approach were in good agreement with corresponding results from experiments, for the Pluronic and PEG5K-oligo(DTO-SA)-PEG5K block copolymers. In addition, DPD simulations were utilized to determine the critical aggregation concentration (CAC), which was compared with corresponding results from an experimental approach. For Pluronic polymers F68, F88, F108, and F127, the computational results agreed well with experimental measurements of the CAC measurements. For PEG5K-b-oligo(DTO-SA)-b-PEG5K block polymers, the complexity in polymer structure made it difficult to directly determine their CAC values via the CG scheme. Therefore, we determined CAC values of a series of triblock copolymers with 3-8 DTO-SA units using DPD simulations, and used these results to predict the CAC values of triblock copolymers with higher molecular weights by extrapolation. In parallel, a PEG5K-b-oligo(DTO-SA)-b-PEG5K block copolymer was synthesized, and the CAC value was determined experimentally using the pyrene method. The experimental CAC value agreed well with the CAC value predicted by simulation. These results validate our CG models, and demonstrate an avenue to simulate and predict aggregation characteristics of ABA amphiphilic triblock copolymers with complex structures.


Assuntos
Simulação de Dinâmica Molecular , Polímeros/química , Interações Hidrofóbicas e Hidrofílicas , Polímeros/síntese química , Pirenos/química , Água/química
6.
Pharm Res ; 33(3): 729-38, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26555665

RESUMO

PURPOSE: Polymer-xerogel composite materials have been introduced to better optimize local anesthetics release kinetics for the pain management. In a previous study, it was shown that by adjusting various compositional and nano-structural properties of both inorganic xerogels and polymers, zero-order release kinetics over 7 days can be achieved in vitro. In this study, in vitro release properties are confirmed in vivo using a model that tests for actual functionality of the released local anesthetics. METHODS: Composite materials made with tyrosine-polyethylene glycol(PEG)-derived poly(ether carbonate) copolymers and silica-based sol-gel (xerogel) were synthesized. The in vivo release from the composite controlled release materials was demonstrated by local anesthetics delivery in a rat incisional pain model. RESULTS: The tactile allodynia resulting from incision was significantly attenuated in rats receiving drug-containing composites compared with the control and sham groups for the duration during which natural healing had not yet taken place. The concentration of drug (bupivacaine) in blood is dose dependent and maintained stable up to 120 h post-surgery, the longest time point measured. CONCLUSIONS: These in vivo studies show that polymer-xerogel composite materials with controlled release properties represent a promising class of controlled release materials for pain management.


Assuntos
Anestésicos Locais/química , Materiais Biocompatíveis/química , Bupivacaína/química , Géis/química , Polímeros/química , Animais , Carbonatos/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Cinética , Masculino , Teste de Materiais/métodos , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/química , Tirosina/química
7.
J Control Release ; 194: 103-12, 2014 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-25192941

RESUMO

The clinical application of gene silencing is hindered by poor stability and low delivery efficiency of naked oligonucleotides. Here, we present the in vitro and in vivo behaviors of a rationally designed, ternary, self-assembled nanoparticle complex, consisting of an anionic copolymer, cationic DOTAP liposome, and antisense oligonucleotide (AON). The multifunctional copolymers are based on backbone poly(propylacrylic acid) (PPAA), a pH-sensitive hydrophobic polymer, with grafted poly(alkylene oxides) (PAOs) varying in extent of grafting and PAO chemistry. The nanoparticle complexes with PPAA-g-PAO copolymers enhance antisense gene silencing effects in A2780 human ovarian cancer cells. A greater amount of AON is delivered to ovarian tumor xenografts using the ternary copolymer-stabilized delivery system, compared to a binary DOTAP/AON complex, following intraperitoneal injection in mice. Further, intratumoral injection of the nanoparticle complexes containing 1 mol% grafted PAO reduced tumoral bcl-2 expression by up to 60%. The data for complexes across the set of PAO polymers support a strong role for the hydrophilic-lipophilic balance of the graft copolymer in achieving serum stability and cellular uptake. Based upon these results, we anticipate that this novel nanoparticle delivery system can be extended to the delivery of plasmid DNA, siRNA, or aptamers for preclinical and clinical development.


Assuntos
Resinas Acrílicas/química , Lipossomos/química , Oligonucleotídeos Antissenso/administração & dosagem , Polietilenoglicóis/química , 1,2-Dipalmitoilfosfatidilcolina/química , Acrilamidas , Animais , Cátions/química , Linhagem Celular Tumoral , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Feminino , Inativação Gênica/efeitos dos fármacos , Genes bcl-2/genética , Terapia Genética/métodos , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Nanopartículas , Neoplasias/terapia , Oligonucleotídeos Antissenso/farmacocinética , Oligonucleotídeos Antissenso/farmacologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Expert Opin Investig Drugs ; 22(10): 1295-303, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23902423

RESUMO

INTRODUCTION: Managing burn injury-associated pain and wounds is a major unresolved clinical problem. Opioids, nonsteroidal antiinflammatory drugs (NSAIDs), antidepressants and anticonvulsants remain the most common forms of analgesic therapy to treat burn patients. However, prolonged treatment with these drugs leads to dose escalation and serious side effects. Additionally, severe burn wounds cause scarring and are susceptible to infection. Recent encouraging findings demonstrate that curcumin, a major bioactive component found in turmeric, is a natural pharmacotherapeutic for controlling both severe burn pain and for improved wound healing. AREAS COVERED: This article covers current pr-clinical and clinical studies on the analgesic and wound healing effects. Particular emphasis has been placed on studies aimed at developing improved curcumin delivery vehicles that increase its bioavailability. Based on the available evidence, a hypothesis is proposed that the dual beneficial effects of curcumin, analgesia and enhanced wound healing are mediated through common anti-inflammatory mechanisms. EXPERT OPINION: Emerging studies have demonstrated that curcumin is a promising investigational drug to treat both pain and wounds. The adequate control of severe burn pain, particularly over the long courses required for healing, as well improvements in burn wound healing are unmet clinical needs.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Queimaduras/tratamento farmacológico , Curcumina/uso terapêutico , Dor Nociceptiva/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Queimaduras/imunologia , Ensaios Clínicos como Assunto , Curcumina/administração & dosagem , Curcumina/farmacocinética , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Dor Nociceptiva/imunologia , Cicatrização/imunologia
9.
J Biomed Mater Res A ; 101(9): 2548-58, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23364909

RESUMO

Peptides have enormous potential as therapeutic agents for the treatment of infection, in immunomodulation and for other medical applications, but their hydrolytic degradation in biological fluids is a serious limitation to their in vivo performance. Here we demonstrate the potential utility of polyelectrolyte nanoparticle complexes of novel self-assembling anionic graft copolymers for protecting peptides from degradation in human plasma. The anionic graft copolymers are synthesized by covalently attaching pendent polyetheramine chains to poly(alkylacrylic acid) backbones by carbodiimide coupling. The peptide:copolymer nanocomplexes' particle size, zeta-potential, peptide binding, and controlled release of the peptide are shown to be dependent upon the pendent chain graft density, polymer backbone alkyl groups (propyl vs. methyl), and the nanocomplexes' electrostatic charge ratio. The nanocomplexes can provide substantial protection to the bound peptides from degradation in human plasma for at least 24 h and, in standard microbiological assays are shown to retain some or all of the peptide's antimicrobial activity against a clinically relevant strain of Staphylococcus aureus.


Assuntos
Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos , Polímeros/química , Peptídeos Catiônicos Antimicrobianos/sangue , Eletrólitos/química , Humanos , Teste de Materiais , Nanopartículas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Staphylococcus aureus/efeitos dos fármacos
10.
Integr Biol (Camb) ; 4(12): 1498-507, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23146945

RESUMO

Heterotopic ossification (HO) associated with traumatic neurological or musculoskeletal injuries remains a major clinical challenge. One approach to understanding better and potentially treating this condition is to silence one or more genes believed to be responsible for osteogenesis by small interfering RNA (siRNA) post-injury. Improved methods of delivering siRNA to myoprogenitor cells as well as relevant cell culture models of HO are needed to advance this approach. We utilize a model of HO featuring C2C12 myoprogenitor cells stimulated to the osteogenic phenotype by addition of BMP-2. For siRNA delivery, we utilize a nanocomposite consisting of DOTAP-based cationic liposomes coated with a graft copolymer of poly(propylacrylic acid) grafted with polyetheramine (Jeffamine), as this system has been shown previously to deliver antisense oligonucleotides safely into cells and out of endosomes for gene silencing in vitro and in vivo. Delivery of siRNA targeting Runx2, a transcription factor downstream of BMP-2, to stimulated C2C12 cells produced greater than 60% down-regulation of the Runx2 gene. This level of gene silencing was sufficient to inhibit alkaline phosphatase activity over the course of several days and calcium phosphate deposition over the course of 2 weeks. These results show the utility of the BMP-2/C2C12 model for capturing the cellular cell-fate decision in HO. Further, they suggest DOTAP/PPAA-g-Jeffamine as a promising delivery system for siRNA-based therapy for HO.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/antagonistas & inibidores , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Ossificação Heterotópica/prevenção & controle , Osteogênese/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Acrilatos/química , Fosfatase Alcalina/antagonistas & inibidores , Animais , Sequência de Bases , Proteína Morfogenética Óssea 2/administração & dosagem , Calcificação Fisiológica/genética , Fosfatos de Cálcio/metabolismo , Linhagem Celular , Sistemas de Liberação de Medicamentos , Ácidos Graxos Monoinsaturados/administração & dosagem , Ácidos Graxos Monoinsaturados/química , Lipossomos/administração & dosagem , Lipossomos/química , Camundongos , Modelos Biológicos , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/efeitos dos fármacos , Mioblastos Esqueléticos/metabolismo , Nanocompostos/administração & dosagem , Nanocompostos/química , Ossificação Heterotópica/genética , Ossificação Heterotópica/patologia , Poliaminas/química , Polímeros/química , Compostos de Amônio Quaternário/administração & dosagem , Compostos de Amônio Quaternário/química , Biologia de Sistemas
11.
Acc Chem Res ; 45(7): 1057-66, 2012 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-22260518

RESUMO

The advancement of gene-based therapeutics to the clinic is limited by the ability to deliver physiologically relevant doses of nucleic acids to target tissues safely and effectively. Over the last couple of decades, researchers have successfully employed polymer and lipid based nanoassemblies to deliver nucleic acids for the treatment of a variety of diseases. Results of phase I/II clinical studies to evaluate the efficacy and biosafety of these gene delivery vehicles have been encouraging, which has promoted the design of more efficient and biocompatible systems. Research has focused on designing carriers to achieve biocompatibility, stability in the circulatory system, biodistribution to target the disease site, and intracellular delivery, all of which enhance the resulting therapeutic effect. The family of poly(alkylene oxide) (PAO) polymers includes random, block, and branched structures, among which the ABA type triblocks copolymers of ethylene oxide (EO) and propylene oxide (PO) (commercially known as Pluronic) have received the greatest consideration. In this Account, we highlight examples of polycation-PAO conjugates, liposome-PAO formulations, and PAO micelles for nucleic acid delivery. Among the various polymer design considerations, which include molecular weight of polymer, molecular weight of blocks, and length of blocks, the overall hydrophobic-lipophilic balance (HLB) is a critical parameter in defining the behavior of the polymer conjugates for gene delivery. We discuss the effects of varying this parameter in the context of improving gene delivery processes, such as serum stability and association with cell membranes. Other innovative macromolecular modifications discussed in this category include our work to enhance the serum stability and efficiency of lipoplexes using PAO graft copolymers, the development of a PAO gel-based carrier for sustained and stimuli responsive delivery, and the development of biodegradable PAO-based amphiphilic block copolymers.


Assuntos
Ácidos Nucleicos/metabolismo , Polímeros/química , Animais , Células COS , Chlorocebus aethiops , Lipossomos/química , Camundongos , Micelas , Células NIH 3T3 , Ácidos Nucleicos/genética , Poloxâmero/química , Polietilenoglicóis/química , Transfecção
13.
Biomaterials ; 31(24): 6336-43, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20510447

RESUMO

Many polymers and composites have been used to prepare active wound dressings. These materials have typically exhibited potentially toxic burst release of the drugs within the first few hours followed by a much slower, potentially ineffective drug release rate thereafter. Many of these materials also degraded to produce inflammatory and cytotoxic products. To overcome these limitations, composite active wound dressings were prepared here from two fully biodegradable and tissue compatible components, silicon oxide sol-gel (xerogel) microparticles that were embedded in tyrosine-poly(ethylene glycol)-derived poly(ether carbonate) copolymer matrices. Sustained, controlled release of drugs from these composites was demonstrated in vitro using bupivacaine and mepivacaine, two water-soluble local anesthetics commonly used in clinical applications. By systematically varying independent compositional parameters of the composites, including the hydrophilic:hydrophobic balance of the tyrosine-derived monomers and poly(ethylene glycol) in the copolymers and the porosity, weight ratio and drug content of the xerogels, drug release kinetics approaching zero-order were obtained. Composites with xerogel mass fractions up to 75% and drug payloads as high as 13% by weight in the final material were fabricated without compromising the physical integrity or the controlled release kinetics. The copolymer-xerogel composites thus provided a unique solution for the sustained delivery of therapeutic agents from tissue compatible wound dressings.


Assuntos
Bandagens , Preparações de Ação Retardada/farmacologia , Géis/farmacologia , Polietilenoglicóis/farmacologia , Polímeros/farmacologia , Dióxido de Silício/farmacologia , Bupivacaína/farmacologia , Hidrólise/efeitos dos fármacos , Cinética , Mepivacaína/farmacologia , Peso Molecular , Polietilenoglicóis/química , Porosidade/efeitos dos fármacos , Solubilidade/efeitos dos fármacos , Tirosina/química
14.
J Control Release ; 140(2): 134-40, 2009 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-19699243

RESUMO

Antisense technology holds tremendous potential in the research and clinical settings. However, successful delivery of antisense oligodeoxynucleotides (ODNs) to the intracellular site of action requires the passage of many barriers, including survival against extracellular serum nucleases and escape from endolysosomal degradation. Previous work has shown that the effectiveness of antisense delivery by the cationic liposome, dioleoyl-3-trimethylammonium-propane (DOTAP), is enhanced substantially by the incorporation of a pH-sensitive polymer, poly (propylacrylic acid) (PPAA), in serum-free media. To improve this system for application in serum-containing media conditions, PPAA was modified in this work by grafting onto it either poly(ethylene oxide) (PEO) or a more hydrophobic analog, poly (oxyalkylene amine), known as Jeffamine. The ternary formulation of DOTAP/ODN/PPAA-g-Jeffamine resulted in 8-fold increased uptake of fluorescently-labeled ODNs compared to DOTAP/ODN/PPAA and ~80% silencing of green fluorescent protein (GFP) expression in CHO-d1EGFP cells treated in the presence of 10% FBS-containing media. In contrast, the carrier systems that contained PPAA or PPAA-g-PEO failed to display any significant antisense activity in the presence of serum, even though all of the delivery systems displayed moderate to high levels of antisense activity in serum-free conditions. The results reveal that the carrier system with the Jeffamine graft copolymer effectively mediates specific gene silencing in the presence of serum, while the system with the PEO graft copolymer fails to do so. While the pH-dependent lytic functionality of PPAA was found to be lost upon grafting with PEO or Jeffamine, the hydrophobicity of the latter was sufficient to mediate cellular internalization and endosomal escape. Thus, the PPAA-g-Jeffamine copolymers hold substantial promise as agents for controlled therapeutic delivery of antisense oligonucleotides.


Assuntos
Acrilatos/química , Aminas/química , Ácidos Graxos Monoinsaturados/química , Inativação Gênica , Oligonucleotídeos Antissenso/metabolismo , Polietilenoglicóis/química , Polímeros/química , Compostos de Amônio Quaternário/química , Soro/metabolismo , Transfecção , Acrilatos/toxicidade , Animais , Transporte Biológico , Células CHO , Cricetinae , Cricetulus , Endossomos/metabolismo , Genes Reporter , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Hemólise/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Oligonucleotídeos Antissenso/química , Polietilenoglicóis/toxicidade , Polímeros/toxicidade
15.
Biomacromolecules ; 8(3): 998-1003, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17274654

RESUMO

We have obtained structure-activity relations for nanosphere drug delivery as a function of the chemical properties of a tunable family of self-assembling triblock copolymers. These block copolymers are synthesized with hydrophobic oligomers of a desaminotyrosyl tyrosine ester and diacid and hydrophilic poly(ethylene glycol). We have calculated the thermodynamic interaction parameters for the copolymers with anti-tumor drugs to provide an understanding of the drug binding by the nanospheres. We find that there is an optimum ester chain length, C8, for nanospheres in terms of their drug loading capacities. The nanospheres release the drugs under dialysis conditions, with release rates strongly influenced by solution pH. The nanospheres, which are themselves non-cytotoxic, deliver the hydrophobic drugs very effectively to tumor cells as measured by cell killing activity in vitro and thus offer the potential for effective parentarel in vivo delivery of many hydrophobic therapeutic agents.


Assuntos
Sistemas de Liberação de Medicamentos , Nanotubos/química , Polímeros/química , Tirosina/química , Cromatografia Líquida de Alta Pressão , Portadores de Fármacos/química , Concentração de Íons de Hidrogênio , Substâncias Macromoleculares/química , Modelos Químicos , Peso Molecular , Nanoestruturas , Paclitaxel/química , Polietilenoglicóis/química , Relação Estrutura-Atividade
16.
Biomacromolecules ; 7(5): 1502-8, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16677032

RESUMO

The use of antisense oligodeoxynucleotides (ODNs) to inhibit the expression of specific mRNA targets represents a powerful technology for control of gene expression. Cationic lipids and polymers are frequently used to improve the delivery of ODNs to cells, but the resulting complexes often aggregate, bind to serum components, and are trafficked poorly within cells. We show that the addition of a synthetic, pH-sensitive, membrane-disrupting polyanion, poly(propylacrylic acid) (PPAA), improves the in vitro efficiency of the cationic lipid, DOTAP, with regard to oligonucleotide delivery and antisense activity. In characterization studies, ODN complexation with DOTAP/ODN was maintained even when substantial amounts of PPAA were added. The formulation also exhibited partial protection of phosphodiester oligonucleotides against enzymatic digestion. In Chinese hamster ovary (CHO) cells, incorporation of PPAA in DOTAP/ODN complexes improved 2- to 3-fold the cellular uptake of fluorescently tagged oligonucleotides. DOTAP/ODN complexes containing PPAA also maintained high levels of uptake into cells upon exposure to serum. Addition of PPAA to DOTAP/ODN complexes enhanced the antisense activity (using GFP as the target) over a range of PPAA concentrations in both serum-free, and to a lesser extent, serum-containing media. Thus, PPAA is a useful adjunct that improves the lipid-mediated delivery of oligonucleotides.


Assuntos
Acrilatos , Ácidos Graxos Monoinsaturados/química , Lipídeos , Oligonucleotídeos Antissenso/farmacocinética , Polímeros , Compostos de Amônio Quaternário/química , Animais , Sequência de Bases , Transporte Biológico , Células CHO , Núcleo Celular/metabolismo , Cricetinae , DNA/genética , Endossomos/metabolismo , Inativação Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Cinética , Transfecção
17.
Biomacromolecules ; 6(5): 2726-31, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16153112

RESUMO

We describe the synthesis and characterization of a family of biocompatible ABA-triblock copolymers that comprised of hydrophilic A-blocks of poly(ethylene glycol) and hydrophobic B-blocks of oligomers of suberic acid and desaminotyrosyl-tyrosine esters. The triblock copolymers spontaneously self-assemble in aqueous solution into nanospheres, with hydrodynamic diameters between 40 and 70 nm, that do not dissociate under chromatographic and ultracentrifugation conditions. These nanospheres form strong complexes with hydrophobic molecules, including the fluorescent dye 5-dodecanoylaminofluorescein (DAF) and the antitumor drug, paclitaxel, but not with hydrophilic molecules such as fluorescein and Oregon Green. The nanosphere-paclitaxel complexes retain in vitro the high antiproliferative activity of paclitaxel, demonstrating that these nanospheres may be useful for delivery of the hydrophobic drugs.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Polímeros/química , Materiais Biocompatíveis/química , Caprilatos/química , Cromatografia , Cromatografia em Gel , Ácidos Dicarboxílicos/química , Relação Dose-Resposta a Droga , Ésteres , Fluoresceína/farmacologia , Fluoresceínas/farmacologia , Humanos , Modelos Químicos , Peso Molecular , Nanotecnologia , Nanotubos/química , Neoplasias/terapia , Paclitaxel/farmacologia , Fosfatos/química , Polietilenoglicóis/química , Fatores de Tempo , Tirosina/química , Ultracentrifugação
18.
J Am Chem Soc ; 126(1): 42-3, 2004 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-14709050

RESUMO

The reduction of ZrCl4(PR3)2 with Li powder, in the presence of a stoichiometric amount of trans-1,4-diphenyl-1,3-butadiene, affords the Zr(II) diene complexes (1) in 90-93% yields. This reaction consists of a rate-limiting step for the formation of the chloride-bridged Zr(III) dimer (2) and a fast diene-driven disproportionation of 2 to 1 and ZrCl4(PR3)2 that re-enters the reduction cycle. The reaction of 1 with Li2{Me2Si(2-Me-4-Ph-Ind)2} in toluene produces quantitatively the desired racemic, divalent ansa-zirconocene (3) that is a highly active isospecific propylene polymerization catalyst upon activation with common activators.

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