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1.
Nanoscale ; 11(18): 9163-9175, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31038150

RESUMO

Diabetes is a chronic metabolic disorder disease characterized by high blood glucose levels and has become one of the most serious threats to human health. In recent decades, a number of insulin delivery systems, including bulk gels, nanogels, and polymeric micelles, have been developed for the treatment of diabetes. Herein, a kind of glucose and H2O2 dual-responsive polymeric nanogel was designed for enhanced glucose-responsive insulin delivery. The polymeric nanogels composed of poly(ethylene glycol) and poly(cyclic phenylboronic ester) (glucose and H2O2 dual-sensitive groups) were synthesized by a one-pot thiol-ene click chemistry approach. The nanogels displayed glucose-responsive release of insulin and the release rate could be promoted by the incorporation of glucose oxidase (GOx), which generated H2O2 at high glucose levels and H2O2 further oxidizes and hydrolyzes the phenylboronic ester group. The nanogels have characteristics of long blood circulation time, a fast response to glucose, and excellent biocompatibility. Moreover, subcutaneous delivery of insulin to diabetic mice with the insulin/GOx-loaded nanogels presented an effective hypoglycemic effect compared to that of injection of insulin or insulin-loaded nanogels. This kind of nanogel would be a promising candidate for the delivery of insulin in the future.


Assuntos
Glucose Oxidase/química , Glucose/metabolismo , Peróxido de Hidrogênio/metabolismo , Hipoglicemiantes/metabolismo , Insulina/metabolismo , Polietilenoglicóis/química , Polietilenoimina/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Química Click , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Portadores de Fármacos/química , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Glucose/química , Glucose Oxidase/metabolismo , Teste de Tolerância a Glucose , Peróxido de Hidrogênio/química , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Insulina/química , Insulina/uso terapêutico , Camundongos , Células NIH 3T3 , Polietilenoglicóis/toxicidade , Polietilenoimina/toxicidade
2.
Colloids Surf B Biointerfaces ; 180: 376-383, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082775

RESUMO

Large amounts of insulin-loaded glucose-responsive micelles based on poly(amino acid)s have been developed for diabetes treatment over last decades, but most of them could not effectively protect insulin from enzymatic degradation in vivo because the micellar core was biodegradable and lacked protective structure for insulin, which would lower the efficacy of insulin to a large extent. In this study, we fabricated a new type of insulin-loaded glucose-responsive complex micelles (CMs), which were self-assembled by a phenylboronic acid (PBA)-modified block copolymer PEG-b-P(Asp-co-AspPBA) and a glucosamine (GA)/nitrilotriacetic acid (NTA)-functionalized block copolymer PNIPAM-b-P(Asp-co-AspGA-co-AspNTA), for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activity in vivo. The CMs possessed mixed shell of PEG/PNIPAM and cross-linked core of PBA/GA complex, which could be disintegrated under the condition of high glucose concentration (5 g/L) while maintaining stable at low glucose concentration (1 g/L). The NTA groups of CMs greatly improved the loading content of insulin by specifically bind insulin via the chelated zinc ions. More importantly, PNIPAM chains in the mixed shell would collapse under 37 °C and form hydrophobic domains around the micellar core, which could significantly protect the micellar core as well as the encapsulated insulin from attacking by external proteases. In a murine model of type 1 diabetes, the CMs with insulin chelated by NTA showed a long hypoglycemic effect, which is superior to insulin-loaded simple micelles without PNIPAM and insulin in PBS buffer (pH 7.4). Therefore, this kind of CMs could be a potential candidate for insulin delivery in diabetes therapy.

3.
Colloids Surf B Biointerfaces ; 174: 352-359, 2018 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-30472621

RESUMO

Novel artificial enzymes are highly desired to overcome the shortcomings of natural enzymes during industrial or biological applications. Here we designed and prepared nanogel-based artificial enzymes (NAEs) to mimic natural horseradish peroxidase (HRP) using a facile one-pot, scalable method. The poly(N-isopropylacrylamide) (PNIPAM) matrix provided a temperature-responsive and size-controllable scaffold for the NAEs, and 1-vinylimidazole (Vim) moieties stabilized the enzymatic centers (Hemin) through coordination interaction. The feeding ratios of the components to prepare NAEs were subsequently studied and optimized to ensure the NAEs possess the highest catalytic activity and stability. The optimized NAEs were quite stable and can maintain their catalytic activities over a broad range of heat or pH treatments, and a long storage period as well. The NAEs are active to catalytic oxidation of several azo compounds and their activities can easily be switched on/off by changing the surrounding temperature. Taken together, these easily made, highly stable, efficient and activity-switchable NAEs could mimic natural HRP while overcoming their shortcomings and have a potential in wastewater treatment and controllable catalysis.

4.
Langmuir ; 34(40): 12116-12125, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30212220

RESUMO

Insulin plays a significant role in diabetes treatment. Although a huge number of insulin-loaded, glucose-responsive nanocarriers have been developed in past decades, most of them showed a lower loading capacity and efficiency due to the weak interaction between insulin and nanocarriers. In this work, a novel insulin-encapsulated glucose-responsive polymeric complex micelle (CM) is devised, showing (i) enhanced insulin-loading efficiency owing to the zinc ions' chelation by nitrilotriacetic acid (NTA) groups of NTA-functioned glycopolymer and the histidine imidazole of insulin, (ii) the glucose-triggered pulse release of insulin, and (iii) long stability under physiological conditions. This CM was fabricated by the self-assembly of block copolymer PEG- b-P(Asp- co-AspPBA) and glycopolymer P(Asp- co-AspGA- co-AspNTA), resulting in complex micelles with a PEG shell and a cross-linked core composed of phenylboronic acid (PBA)/glucose complexations. Notably, the modified nitrilotriacetic acid (NTA) groups of CM could specifically bind insulin via chelated zinc ions, thus enhancing the loading efficacy of insulin compared to that of nonmodified CM. The dynamic PBA/glucose complexation core of CM dissociates under the trigger of high glucose concentration (>2 g/L) while being quite stable in low glucose concentrations (<2 g/L), as demonstrated by the pulse release of insulin in vitro. Finally, in a murine model of type 1 diabetes, NTA-modified complex micelles loading an insulin (NTA-CM-INS) group exhibited a long hypoglycemic effect which is superior to that of free insulin in the PBS (PBS-INS) group and insulin-loaded complex micelles without an NTA modification (CM-INS) group. This long-term effect benefited from Zn(II) chelation by NTA-modified complex micelles and could avoid hypoglycemia caused by the burst release of insulin. Taken together, this constitutes a highly effective way to encapsulate insulin and release insulin via an on-demand manner for blood glucose control in diabetes.

5.
ACS Appl Mater Interfaces ; 9(15): 13056-13067, 2017 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-28357860

RESUMO

Stimuli-sensitive hydrogels are ideal candidates for biomedical and bioengineering purposes, although applications of hydrogels may be limited, due in part to the limited choice of suitable materials for constructing hydrogels, the complexity in the synthesis of the source materials, and the undesired fast-then-slow drug-release behaviors of usual hydrogels. Herein, we describe the fabrication of a new supramolecular guanosine (G)-quadruplex hydrogel by multicomponent self-assembly of endogenous guanosine (G), 2-formylboronic acid (2-FPBA), and tris(2-aminoethyl)amine (TAEA) in the presence of KCl in an easy and convenient way. The features of the G-quadruplex hydrogel include (1) versatility and commercial availability of building blocks with different functions, (2) dynamic iminoboronate bonds with pH and glucose responsiveness, and (3) zero-order drug-release behavior because of the superficial peel-off of the hydrogel in response to stimuli. The structure, morphology, and properties of the G-quadruplex hydrogel were well-characterized, and satisfactory zero-order drug release was successfully achieved. This kind of supramolecular G-quadruplex hydrogels may find applications in biological fields.

6.
Biomater Sci ; 5(3): 570-577, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28138672

RESUMO

Artificial enzymes are widely investigated to mimic the active center and the recognition center of natural enzymes. The active center is responsible for the catalytic activity of enzymes, and the recognition center provides enzymes with specificity. Most of the previous studies on artificial enzymes preferred to solve the problem of activity rather than specificity due to the complexity of the enzyme structures related to substrate recognition. Inspired by the multilevel structures of enzymes and the unique net-structures of hydrogels, hemin-micelles immobilized in alginate hydrogels (HM-AH) were constructed by multistep self-assembly. The hemin-micelle was the active center and mimicked the microenvironment of the catalytic site in horseradish peroxidase (HRP). The alginate hydrogel further enhanced the catalytic activity and stability of hemin-micelles and endowed the artificial enzymes with a catalytic capability in harsh water conditions and non-polar organic solvents. The hydrogel also served as the recognition center, which exhibited substrate selectivity owing to the diffusivity differentiations of substrates in hydrogel fibers. It is the first example of constructing a micelle-hydrogel complex system as an artificial enzyme with both catalytic activity and substrate selectivity by the method of multistep self-assembly.


Assuntos
Alginatos/química , Materiais Biomiméticos/química , Hemina/química , Hidrogéis/química , Micelas , Domínio Catalítico , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Peroxidase do Rábano Silvestre/química , Cinética , Oxirredução
7.
Chem Commun (Camb) ; 52(93): 13543-13555, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27709187

RESUMO

Natural porphyrin derivatives possess many interesting functions in biological systems. They are integrated into proteins that are essential for biological activities. Many efforts have been dedicated to mimic the microenvironment and augment the function of porphyrin/protein scaffolds. To achieve such goals, self-assembly has become one of the popular methods to construct porphyrin/protein-mimicking materials owing to its various choices of building blocks and a simple preparation process over chemical modification. Desirable characteristics of building blocks for protein mimicking include high molecular weight, predictable conformations in solution, and appropriate functional residuals. With these aims in mind, polymers are ideal candidates due to their multiple-level hierarchies derived from their chemical and spatial structures. In this review, design strategies for the cooperative self-assembly of porphyrins with polymers and the main efforts towards the implementation of porphyrin/polymer assembly for biomimetic composites with bioactive functions will be addressed.


Assuntos
Materiais Biomiméticos/metabolismo , Polímeros/química , Porfirinas/metabolismo , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Porfirinas/síntese química , Porfirinas/química
8.
Theranostics ; 6(9): 1277-92, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27375779

RESUMO

Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Catequina/administração & dosagem , Doxorrubicina/farmacologia , Portadores de Fármacos/administração & dosagem , Micelas , Nanoestruturas/administração & dosagem , Chá/química , Antibióticos Antineoplásicos/administração & dosagem , Cardiotoxicidade/prevenção & controle , Catequina/análogos & derivados , Catequina/isolamento & purificação , Catequina/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Resistência a Múltiplos Medicamentos , Humanos , Nanoestruturas/química
10.
Biomacromolecules ; 16(4): 1372-81, 2015 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-25803265

RESUMO

Polymeric nanoparticles with glucose-responsiveness are of great interest in developing a self-regulated drug delivery system. In this work, glucose-responsive polymer vesicles were fabricated based on the complexation between a glucosamine (GA)-containing block copolymer PEG45-b-P(Asp-co-AspGA) and a phenylboronic acid (PBA)-containing block copolymer PEG114-b-P(Asp-co-AspPBA) with α-CD/PEG45 inclusion complex as the sacrificial template. The obtained polymer vesicles composed of cross-linked P(Asp-co-AspGA)/P(Asp-co-AspPBA) layer as wall and PEG chains as both inner and outer coronas. The vesicular morphology was observed by transmission electron microscopy (TEM), and the glucose-responsiveness was investigated by monitoring the variations of hydrodynamic diameter (Dh) and light scattering intensity (LSI) in the polymer vesicle solution with glucose using dynamic light scattering (DLS). Vancomycin as a model drug was encapsulated in the polymer vesicles and sugar-triggered drug release was carried out. This kind of polymer vesicle may be a promising candidate for glucose-responsive drug delivery.


Assuntos
Portadores de Fármacos/química , Glucose/química , Nanopartículas/química , Polietilenoglicóis/química , alfa-Ciclodextrinas/química , Antibacterianos/administração & dosagem , Antibacterianos/química , Ácido Aspártico/química , Ácidos Borônicos/química , Diálise , Polietilenoglicóis/síntese química , Vancomicina/administração & dosagem , Vancomicina/química , alfa-Ciclodextrinas/síntese química
12.
Biomacromolecules ; 15(10): 3634-42, 2014 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-25308336

RESUMO

Exploring ideal nanocarriers for drug delivery systems has encountered unavoidable hurdles, especially the conflict between enhanced cellular uptake and prolonged blood circulation, which have determined the final efficacy of cancer therapy. Here, based on controlled self-assembly, surface structure variation in response to external environment was constructed toward overcoming the conflict. A novel micelle with mixed shell of hydrophilic poly(ethylene glycol) PEG and pH responsive hydrophobic poly(ß-amino ester) (PAE) was designed through the self-assembly of diblock amphiphilic copolymers. To avoid the accelerated clearance from blood circulation caused by the surface exposed targeting group c(RGDfK), here c(RGDfK) was conjugated to the hydrophobic PAE and hidden in the shell of PEG at pH 7.4. At tumor pH, charge conversion occurred, and c(RGDfK) stretched out of the shell, leading to facilitated cellular internalization according to the HepG2 cell uptake experiments. Meanwhile, the heterogeneous surface structure endowed the micelle with prolonged blood circulation. With the self-regulated multifunctional collaborated properties of enhanced cellular uptake and prolonged blood circulation, successful inhibition of tumor growth was achieved from the demonstration in a tumor-bearing mice model. This novel nanocarrier could be a promising candidate in future clinical experiments.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Nanopartículas/química , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Polietilenoglicóis/química , Polímeros/química
13.
Langmuir ; 30(16): 4797-805, 2014 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-24697573

RESUMO

Complexation between 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) and poly(ethylene glycol)-block-poly(L-lysine) (PEG-b-PLL) was performed via electrostatic interaction. Two kinds of primary arrays of TPPS with different supramolecular chirality induced by PLL were obtained in the resultant complex by inverting the mixing procedure of the two components. These arrays could be displaced by poly(sodium-p-styrenesulfonate) (PSS) from the chiral PLL template through competitive electrostatic complexation, and then PSS formed a polyion complex micelle with PEG-b-PLL. The template-removed TPPS arrays preserved their induced chirality and served as primary subunits for the secondary aggregation of TPPS. The morphology of the secondary aggregates was strongly dependent upon the asymmetric primary supramolecular arrangement of TPPS. The rodlike nanostructure that was ∼200 nm in length was composed of the primary arrays that showed opposite exciton chirality between the J- and H-bands. In contrast, the micrometer-sized fibrils observed were composed of the arrays with the same exciton chirality at the J- and H-bands.


Assuntos
Polietilenoglicóis/química , Porfirinas/química , Estereoisomerismo
14.
Acc Chem Res ; 47(4): 1426-37, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24694280

RESUMO

In the past decades, polymer based nanoscale polymeric assemblies have attracted continuous interest due to their potential applications in many fields, such as nanomedicine. Many efforts have been dedicated to tailoring the three-dimensional architecture and the placement of functional groups at well-defined positions within the polymeric assemblies, aiming to augment their function. To achieve such goals, in one way, novel polymeric building blocks can be designed by controlled living polymerization methodology and advanced chemical modifications. In contrast, by focusing on the end function, others and we have been practicing strategies of cooperative self-assembly of multiple polymeric building blocks chosen from the vast library of conventional block polymers which are easily available. The advantages of such strategies lie in the simplicity of the preparation process and versatile choice of the constituent polymers in terms of their chemical structure and functionality as well as the fact that cooperative self-assembly based on supramolecular interactions offers elegant and energy-efficient bottom-up strategies. Combination of these principles has been exploited to optimize the architecture of polymeric assemblies with improved function, to impart new functionality into micelles and to realize polymeric nanocomplexes exhibiting functional integration, similar to some natural systems like artificial viruses, molecular chaperones, multiple enzyme systems, and so forth. In this Account, we shall first summarize several straightforward designing principles with which cooperative assembly of multiple polymeric building blocks can be implemented, aiming to construct polymeric nanoassemblies with hierarchal structure and enhanced functionalities. Next, examples will be discussed to demonstrate the possibility to create multifunctional nanoparticles by combination of the designing principles and judiciously choosing of the building blocks. We focus on multifunctional nanoparticles which can partially address challenges widely existing in nanomedicine such as long blood circulation, efficient cellular uptake, and controllable release of payloads. Finally, bioactive polymeric assemblies, which have certain functions closely mimicking those of some natural systems, will be used to conceive the concept of functional integration.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Substâncias Macromoleculares/química , Nanopartículas/química , Polímeros/química , Materiais Biomiméticos , Micelas , Chaperonas Moleculares/química , Permeabilidade , Polímeros/síntese química , Propriedades de Superfície
15.
Biomacromolecules ; 14(10): 3434-43, 2013 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-24063314

RESUMO

Herein, a series of biocompatible, robust, pH/sugar-sensitive, core-cross-linked, polyion complex (PIC) micelles based on phenylboronic acid-catechol interaction were developed for protein intracellular delivery. The rationally designed poly(ethylene glycol)-b-poly(glutamic acid-co-glutamicamidophenylboronic acid) (PEG-b-P(Glu-co-GluPBA)) and poly(ethylene glycol)-b-poly(l-lysine-co-ε-3,4-dihydroxyphenylcarboxyl-L-lysine) (PEG-b-P(Lys-co-LysCA)) copolymers were successfully synthesized and self-assembled under neutral aqueous condition to form uniform micelles. These micelles possessed a distinct core-cross-linked core-shell structure comprised of the PEG outer shell and the PGlu/PLys polyion complex core bearing boronate ester cross-linking bonds. The cross-linked micelles displayed superior physiological stabilities compared with their non-cross-linked counterparts while swelling and disassembling in the presence of excess fructose or at endosomal pH. Notably, either negatively or positively charged proteins can be encapsulated into the micelles efficiently under mild conditions. The in vitro release studies showed that the release of protein cargoes under physiological conditions was minimized, while a burst release occurred in response to excess fructose or endosomal pH. The cytotoxicity of micelles was determined by cck-8 assay in HepG2 cells. The cytochrome C loaded micelles could efficiently delivery proteins into HepG2 cells and exhibited enhanced apoptosis ability. Hence, this type of core-cross-linked PIC micelles has opened a new avenue to intracellular protein delivery.


Assuntos
Antineoplásicos/farmacologia , Reagentes para Ligações Cruzadas/química , Citocromos c/metabolismo , Frutose/farmacologia , Micelas , Polímeros/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ácidos Borônicos/química , Ácidos Borônicos/metabolismo , Catecóis/química , Catecóis/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Íons/química , Íons/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
16.
Colloids Surf B Biointerfaces ; 111: 587-93, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23907047

RESUMO

Lipase is active at the water-oil interface and thus very useful for many applications in non-aqueous media. However, the use of lipase is often limited due to the heat inactivation which is mainly caused by the irreversible aggregation among lipase molecules. The temperature-sensitive polymers can spontaneously form complexes with lipases at higher temperature in the confined spaces of the water in oil microemulsion. With cooling, lipases are released from the complexes and refold into the native state. In this way, the thermal stability of lipase in a microemulsion is effectively improved, and so is the stability of lipase at ambient temperature. Apart from proving the effectiveness and generality of this method, the temperature-sensitive polymers/lipase microemulsion represents a simple and efficient system which could be used in practical applications, since lipase retains the interfacial activity in this system. Moreover, the influences of some factors on the improvement are discussed and the mechanism of this method is suggested after exploring the process by dynamic light scattering and fluorescence measurements.


Assuntos
Lipase/metabolismo , Óleos/química , Polímeros/química , Temperatura Ambiente , Água/química , Resinas Acrílicas/química , Candida/enzimologia , Emulsões , Estabilidade Enzimática , Hidrodinâmica , Espectrometria de Fluorescência
17.
Chemistry ; 19(23): 7437-42, 2013 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-23568708

RESUMO

We have fabricated a mixed-shell polymeric micelle (MSPM) that closely mimics the natural molecular chaperone GroEL-GroES complex in terms of structure and functionality. This MSPM, which possesses a shared PLA core and a homogeneously mixed PEG and PNIAPM shell, is constructed through the co-assembly of block copolymers poly(lactide-b-poly(ethylene oxide) (PLA-b-PEG) and poly(lactide)-b-poly(N-isopropylacryamide) (PLA-b-PNIPAM). Above the lower critical solution temperature (LCST) of PNIPAM, the MSPM evolves into a core-shell-corona micelle (CSCM), as a functional state with hydrophobic PNIPAM domains on its surface. Light scattering (LS), TEM, and fluorescence and circular dichroism (CD) spectroscopy were performed to investigate the working mechanism of the chaperone-like behavior of this system. Unfolded protein intermediates are captured by the hydrophobic PNIPAM domains of the CSCM, which prevent harmful protein aggregation. During cooling, PNIPAM reverts into its hydrophilic state, thereby inducing the release of the bound unfolded proteins. The refolding process of the released proteins is spontaneously accomplished by the presence of PEG in the mixed shell. Carbonic anhydrase B (CAB) was chosen as a model to investigate the refolding efficiency of the released proteins. In the presence of MSPM, almost 93 % CAB activity was recovered during cooling after complete denaturation at 70 °C. Further results reveal that this MSPM also works with a wide spectrum of proteins with more-complicated structures, including some multimeric proteins. Given the convenience and generality in preventing the thermal aggregation of proteins, this MSPM-based chaperone might be useful for preventing the toxic aggregation of misfolded proteins in some diseases.


Assuntos
Resinas Acrílicas/química , Lactatos/química , Chaperonas Moleculares/química , Polietilenoglicóis/química , Polímeros/química , Proteínas/química , Interações Hidrofóbicas e Hidrofílicas , Micelas , Soluções , Temperatura Ambiente
18.
Biomacromolecules ; 14(2): 460-7, 2013 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-23281663

RESUMO

The miserable targeting performance of nanocarriers for cancer therapy arises largely from the rapid clearance from blood circulation and the major accumulation in the organs of the reticuloendothelial system (RES), leading to inefficient enhanced permeability and retention (EPR) effect after intravenous injection (i.v.). Herein, we reported an efficient method to prolong the blood circulation of nanoparticles and decrease their deposition in liver and spleen. In this work, we fabricated a series of mixed shell micelles (MSMs) with approximately the same size, charge and core composition but with varied hydrophilic/hydrophobic ratios in the shell through spontaneously self-assembly of block copolymers poly(ethylene glycol)-block-poly(l-lysine) (PEG-b-PLys) and poly(N-isopropylacrylamide)-block-poly(aspartic acid) (PNIPAM-b-PAsp) in aqueous medium. The effect of the surface heterogeneity on the in vivo biodistribution was systematically investigated through in vivo tracking of the (125)I-labeled MSMs determined by Gamma counter. Compared with single PEGylated micelles, some MSMs were proved to be significantly efficient with more than 3 times lower accumulation in liver and spleen and about 6 times higher concentration in blood at 1 h after i.v.. The results provide us a novel strategy for future development of long-circulating nanocarriers for efficient cancer therapy.


Assuntos
Portadores de Fármacos , Nanopartículas , Polímeros/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Fígado/metabolismo , Micelas , Sistema Fagocitário Mononuclear/metabolismo , Neoplasias/tratamento farmacológico , Baço/metabolismo , Propriedades de Superfície
19.
J Colloid Interface Sci ; 388(1): 80-5, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23021703

RESUMO

Metallo-meso-5,10,15,20-tetrakis-(4-sulfonatophenyl)porphyrins (metallo-TPPSs), such as ZnTPPS, have been widely used as photosensitizers. However, their vulnerability to photodegradation significantly limits their applications. In this contribution, we demonstrate a method to enhance the photostability of metallo-TPPSs while retaining photoactivity via encapsulation inside cores of complex micelles. Poly(ethylene glycol)-b-poly(4-vinylpyridine) (PEG-b-P4VP) and metallo-TPPSs can form complex micelles in acidic solution through electrostatic interactions and then undergo axial coordination with the pyridine moieties of PEG-b-P4VP when the pH is adjusted to 7.4. In this way, metallo-TPPSs are entrapped in the hydrophobic, compact micellar cores, which effectively prevents photodegradation of the metallo-TPPSs that would otherwise occur in aqueous solution. In addition, the photodebromination of 2,3-dibromo-3-phenylpropionic acid (DPP) sensitized with ZnTPPS has been used as a model reaction to study the photosensitive activity of ZnTPPS entrapped in complex micelles. The entrapped ZnTPPSs exhibit pronounced activity and have much higher efficiency and faster photosensitive reaction rates than free ZnTPPS.


Assuntos
Metaloporfirinas/farmacologia , Micelas , Fármacos Fotossensibilizantes/farmacologia , Polietilenoglicóis/farmacologia , Polímeros/farmacologia , Polivinil/farmacologia , Luz , Metaloporfirinas/química , Fotoquímica , Polietilenoglicóis/química , Polivinil/química , Espectrofotometria Ultravioleta
20.
Biomacromolecules ; 13(10): 3409-17, 2012 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-22957842

RESUMO

Polymeric nanoparticles with glucose-responsiveness under physiological conditions are of great interests in developing drug delivery system for the treatment of diabetes. Herein, glucose-responsive complex micelles were prepared by self-assembly of a phenylboronic acid-contained block copolymer PEG-b-P(AA-co-APBA) and a glycopolymer P(AA-co-AGA) based on the covalent complexation between phenylboronic acid and glycosyl. The formation of the complex micelles with a P(AA-co-APBA)/P(AA-co-AGA) core and a PEG shell was confirmed by HNMR analysis. The glucose-responsiveness of the complex micelles was investigated by monitoring the light scattering intensity and the fluorescence (ARS) of the micelle solutions. The complex micelles displayed an enhanced glucose-responsiveness compared to the simple PEG-b-P(AA-co-APBA) micelles and the sensitivity of the complex micelles to glucose increased with the decrease of the amount of P(AA-co-AGA) in the compositions. The cytotoxicity of the polymers and the complex micelles was also evaluated by MTT assay. This kind of complex micelles may be an excellent candidate for insulin delivery and may find application in the treatment of diabetes.


Assuntos
Ácidos Borônicos/química , Glucose/química , Polímeros/química , Ácidos Borônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Micelas , Modelos Moleculares , Estrutura Molecular , Polímeros/síntese química , Polímeros/farmacologia , Relação Estrutura-Atividade
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