RESUMO
High-mobility group box 1 (HMGB1) is a multifunctional protein. Upon injury or infection, HMGB1 is passively released from necrotic and activated dendritic cells and macrophages, where it functions as a cytokine, acting as a ligand for RAGE, a major receptor of innate immunity stimulating inflammation responses including the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Blocking the HMGB1/RAGE axis offers a therapeutic approach to treating these inflammatory conditions. Here, we describe a synthetic antibody (SA), a copolymer nanoparticle (NP) that binds HMGB1. A lightly cross-linked N-isopropylacrylamide (NIPAm) hydrogel copolymer with nanomolar affinity for HMGB1 was selected from a small library containing trisulfated 3,4,6S-GlcNAc and hydrophobic N-tert-butylacrylamide (TBAm) monomers. Competition binding experiments with heparin established that the dominant interaction between SA and HMGB1 occurs at the heparin-binding domain. In vitro studies established that anti-HMGB1-SA inhibits HMGB1-dependent ICAM-1 expression and ERK phosphorylation of HUVECs, confirming that SA binding to HMGB1 inhibits the proteins' interaction with the RAGE receptor. Using temporary middle cerebral artery occlusion (t-MCAO) model rats, anti-HMGB1-SA was found to accumulate in the ischemic brain by crossing the blood-brain barrier. Significantly, administration of anti-HMGB1-SA to t-MCAO rats dramatically reduced brain damage caused by cerebral ischemia/reperfusion. These results establish that a statistical copolymer, selected from a small library of candidates synthesized using an "informed" selection of functional monomers, can yield a functional synthetic antibody. The knowledge gained from these experiments can facilitate the discovery, design, and development of a new category of drug.
Assuntos
Isquemia Encefálica , Proteína HMGB1 , Traumatismo por Reperfusão , Ratos , Animais , Proteína HMGB1/metabolismo , Encéfalo/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Inflamação/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Heparina/metabolismoRESUMO
While the block/graft/branched structures are widely studied to favor the reversible physical gelation, there are no reports regarding the steric hindrance-induced sol-gel transition of PNIPAm-based nanogels above their phase transition temperature (Tp). Generally, the introduction of hydrophobic components into poly (N-isopropylacrylamide) (PNIPAm)-based nanogels only led to collapse and lower viscosity instead of the sol-gel transition upon heating above the Tp. Herein, the results of temperature-variable 1HNMR and FTIR confirm that the introduction of hydrophobic N-tert-butylacrylamide (TBA) with the large steric hindrance of side groups of N-tert-butyl to form NIPAm/TBA copolymer nanogels can dramatically slow down the dehydration of all the hydrophobic alkyl groups, thus resulting in the formation of thermally induced sol-gel transition above the Tp. Furthermore, the N-acrylamido-L-phenylalanine (APhe) monomer composed of a strongly water absorbing carboxyl group and a phenyl group with larger steric hindrance is studied to form P(NIPAm/TBA/APhe) terpolymer nanogels which can self-assemble into colorful colloidal crystals. Surprisingly, owing to the synergistic effect between the water absorbing carboxyl group and the steric hindrance group on the same side group, these colloidal crystals can achieve sol-gel transition above Tp, forming a physically crosslinked colorful hydrogel. This work is expected to greatly advance the design, synthesis, and application of the sol-gel transition of PNIPAm-based nanogel systems.
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Temperature-responsive polymers are often characterized by an abrupt change in the degree of swelling brought about by small changes in temperature. Polymers with a lower critical solution temperature (LCST) in particular, are important as drug and gene delivery vehicles. Drug molecules are taken up by the polymer in their solvent swollen state below their LCST. Increasing the temperature above the LCST, typically physiological temperatures, results in desolvation of polymer chains and microstructure collapse. The trapped drug is released slowly by passive diffusion through the collapsed polymer network. Since diffusion is dependent on many variables, localizing and control of the drug delivery rate can be challenging. Here, we report a fundamentally different approach for the rapid (seconds) tumor-specific delivery of a biomacromolecular drug. A copolymer nanoparticle (NP) was engineered with affinity for melittin, a peptide with potent anti-cancer activity, at physiological temperature. Intravenous injection of the NP-melittin complex results in its accumulation in organs and at the tumor. We demonstrate that by local cooling of the tumor the melittin is rapidly released from the NP-melittin complex. The release occurs only at the cooled tumor site. Importantly, tumor growth was significantly suppressed using this technique demonstrating therapeutically useful quantities of the drug can be delivered. This work reports the first example of an in vivo site-specific release of a macromolecular drug by local cooling for cancer therapy. In view of the increasing number of cryotherapeutic devices for in vivo applications, this work has the potential to stimulate cryotherapy for in vivo drug delivery.
Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Animais , Camundongos , Polímeros/química , Meliteno , Sistemas de Liberação de Medicamentos , Antineoplásicos/uso terapêutico , Temperatura , Nanopartículas/química , Neoplasias/tratamento farmacológicoRESUMO
Three xanthophylls [(3R,3'R,6'R)-lutein (1), (3R,3'S)-zeaxanthin (2), and (3R,3'S)-astaxanthin (3)] were used for the first time as initiators in the ring-opening polymerization (ROP) of ε-caprolactone (CL) catalyzed by tin(ii) 2-ethylhexanoate [Sn(Oct)2] for the synthesis of novel sustainable xanthophyll-containing poly(ε-caprolactone)s (xanthophylls-PCL). The obtained polyesters were characterized by 1H and 13C NMR, FT-IR, DSC, SEC, and MALDI-TOF MS, and their use as additives in green lubricants was evaluated using a sliding friction test under boundary conditions. Xanthophylls-PCL were obtained with good conversions and with molecular weights determined by SEC to be between 2500 and 10 500 Da. The thermal properties of xanthophyll-polyesters showed a crystalline domain, detected by DSC. Lastly, the green lubricant activity of these polymers was evaluated and the results showed that xanthophylls-PCL could be employed as additives for biodegradable lubricant applications since they have better tribological behavior than current additives, which demonstrates their potential as future commercial materials with interesting eco-friendly properties for diverse applications.
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The determination of lactic acid content has a guiding significance for disease diagnosis or food supervision. Herein, a hydrogel-based three-dimensional photonic crystal (PC) sensor for specific detection of lactic acid is introduced. The hydrogel was prepared by one-step copolymerization of N-isopropylacrylamide and acrylamide in the presence of oxamate derivative 2-((6-acrylamidohexyl) amino)-2-oxoacetic acid (AOA). An obvious color change from orange-red to purple and a 45-nm redshift of the reflection peak were obtained in 3 min when lactic acid concentration increased from 0 to 20 mM. The detection limit was confirmed as 0.1 mM, and the prepared sensor can be reused more than 20 times. Moreover, the affinity and selectivity of AOA to lactic acid were proven by both the interaction energy from density functional theory (DFT) study and the comparison to those of pyruvate and propionic acid. This sensor was proven to be cost-effective and convenient with rapid response time, good reusability, and selectivity.
Assuntos
Hidrogéis , Ácido Láctico , Hidrogéis/química , Fótons , Acrilamida , PiruvatosRESUMO
The photonic crystals (PhCs) have a bright structural color, but their angular dependence and naked-eye observation subjectivity only apply for qualitative analysis. The HSB color space is a three-channel color analysis technology based on hue (H)-saturation (S)-brightness (B). We use the HSB color space to analyze the structural color of the AM/NIPAM PhCs hydrogel sensor in response to temperature and organic solvents. We proved that the structural color analysis based on the hue value (H) could achieve an analysis accuracy close to the spectrum analysis. In addition, we have obtained stimulus-responsive PhCs structure color images from references and quantitatively analyzed them through the HSB color space. The results show that the H of the structural color can establish a high correlation with the specified target. In some cases, its best fitness exceeds traditional spectroscopy methods. This analysis method will provide a general and quantitative analysis technology for the structural color of PhCs by consumer-grade computers and smartphones.
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The Bacillus thuringiensis (Bt) Cry proteins are widely used in insect pest control. Despite their economic benefits, remaining concerns over potential ecological and health risks warrant their ongoing surveillance. Affinity reagents, most often antibodies, protein scaffolds, and aptamers, are the traditional tools used for protein binding and detection. We report a synthetic antibody (SA) alternative to traditional biological affinity reagents for binding Bt Cry proteins. Analysis of hotspots of the Bt Cry protein-insect midgut cadherin-like receptor complexes was used for the design of the SA. The SA was selected from a small focused library of hydrogel copolymers containing functional monomers complementary to key exposed hotspots of Bt Cry proteins. A directed chemical evolution identified a SA, APhe-NP23, with affinity and selectivity for Bt Cry1Ab/Ac proteins. The putative intermolecular polymer-protein interfaces were identified by the SA's uptake of Bt Cry1Ac pepsin hydrolysates, binding epitope mutation studies, and protein-protein inhibition studies of the toxin binding to its native insect receptor binding domains. The SA inhibitor binds to the same protein domains as the insect's cadherin-like receptors, Bt-R1 and SeCad1b. The SA binds rapidly to Bt Cry1Ab/Ac with high capacity, is pH-responsive, and is synthesized reproducibly. We believe that a hotspot-directed approach is general for creation of abiotic protein affinity reagents that target functional protein domains. Affinity ligands are typically high-information content biologicals. Their structure and function are determined from their amino acid or oligo sequence. In contract, the SA described in this work is a statistical copolymer that lacks sequence specificity. These results are an important contribution to the concept that randomness and biospecificity are not mutually exclusive.
Assuntos
Bacillus thuringiensis , Animais , Bacillus thuringiensis/química , Bacillus thuringiensis/metabolismo , Proteínas de Bactérias/metabolismo , Caderinas/metabolismo , Endotoxinas/química , Proteínas Hemolisinas/metabolismo , Proteínas de Insetos/química , Larva/metabolismo , Ligação Proteica , Domínios ProteicosRESUMO
Synthetic polymer hydrogel nanoparticles (NPs) were developed to function as abiotic affinity reagents for fibrinogen. These NPs were made using both temperature-sensitive N-isopropyl acrylamide (NIPAm) and l-amino acid monomers. Five kinds of l-amino acids were acryloylated to obtain functional monomers: l-phenylalanine (Phe) and l-leucine (Leu) with hydrophobic side chains, l-glutamic acid (Glu) with negative charges, and l-lysine (Lys) and l-arginine (Arg) with positive charges. After incubating the NPs with fibrinogen, γ-globulin, and human serum albumin (HSA) respectively, the NPs that incorporated N-acryloyl-Arg monomers (AArg@NPs) showed the strongest and most specific binding affinity to fibrinogen, when compared with γ-globulin and HSA. Additionally, the fibrinogen-AArg binding model had the best docking scores, and this may be due to the interaction of positively charged AArg@NPs and the negatively charged fibrinogen D domain and the hydrophobic interaction between them. The specific adsorption of AArg@NPs to fibrinogen was also confirmed by the immunoprecipitation assay, as the AArg@NPs selectively trapped the fibrinogen from a human plasma protein mixture. AArg@NPs had a strong selectivity for, and specificity to, fibrinogen and may be developed as a potential human fibrinogen-specific affinity reagent.
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In this paper, soft thermosensitive photonic crystals are immobilized via a reversible temperature-triggered in situ sol-gel transition above their phase transition temperature (Tp), which may be a significant advance in the field. Specifically, a library of thermosensitive poly(N-isopropylacrylamide)/poly(acrylic acid) (PNIPAm/PAA) interpenetrating nanogels (IPNs) is synthesized, which can achieve a reversible temperature-induced sol-gel transition at a low concentration (1.1 wt%). More interestingly, as the temperature is increased above Tp, the photonic crystals assembled by these IPNs do not disappear but are "immobilized" in the in situ formed hydrogel matrix. Moreover, these colorful IPN dispersions exhibit outstanding syringe-injectability, immediately turning from an aqueous solution into an insoluble hydrogel as they are injected into PBS at 37 °C. Plus, a protein-release study showed that these injectable hydrogels show extended release times and slower release rates in comparison with dilute nanogel dispersions. In brief, these in situ formed hydrogels with brilliant structural colors have potential in optical applications, e.g., color displays, crystal immobilization, and biological applications, e.g., 3D cell culture and drug delivery.
Assuntos
Técnicas de Cultura de Células em Três Dimensões , Hidrogéis , Sistemas de Liberação de Medicamentos , Nanogéis , TemperaturaRESUMO
Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.
Assuntos
Hidrogéis/uso terapêutico , Nanopartículas/uso terapêutico , Sepse/tratamento farmacológico , Animais , Plaquetas/efeitos dos fármacos , Adesão Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Histonas/antagonistas & inibidores , Histonas/metabolismo , Histonas/toxicidade , Hidrogéis/química , Hidrogéis/metabolismo , Hidrogéis/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Nanopartículas/química , Nanopartículas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Ligação Proteica , Sepse/mortalidade , Taxa de SobrevidaRESUMO
This study analyzes the swelling behavior of native, unmodified, spherically uniform, monodisperse poly(lactic-co-glycolic acid) (PLGA) microparticles in a robust high-throughput manner. This work contributes to the complex narrative of PLGA microparticle behavior and release mechanisms by complementing and extending previously reported studies on intraparticle microenvironment, degradation, and drug release. Microfluidically produced microparticles are incubated under physiological conditions and observed for 50 days to generate a profile of swelling behavior. Microparticles substantially increase in size after 15 days, continue increasing for 30 days achieving size dependent swelling indices between 49 and 83%. Swelling capacity is found to correlate with pH. Our study addresses questions such as onset, duration, swelling index, size dependency, reproducibility, and causal mechanistic forces surrounding swelling. Importantly, this study can serve as the basis for predictive modeling of microparticle behavior and swelling capacity, in addition to providing clues as to the microenvironmental conditions that encapsulated material may experience.
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As the most representative family of proteinases related to tumorigenesis, matrix metalloproteinase-9 (MMP-9) represents a key player in cancer cell migration and regulation of the tumor microenvironment. The inhibition of MMP-9 activity has been pursued as a target for anticancer therapy. However, most synthetic MMP-9 inhibitors have failed in clinical trials because of their lack of selectivity. Here, an abiotic mimic based on molecularly imprinted nanoparticles has been designed as an inhibitor for MMP-9. To attain fast mass transfer and facilitate multifunctional roles, we synthesized the imprinted polymer thin layer on the surface of gold nanorods by reversible addition-fragmentation chain transfer polymerization using MMP-9 as the template, which captures MMP-9 selectively and inhibits its activity by providing steric hindrance to the activity-related domain of MMP-9. In vitro cell experiments and in vivo studies in mice demonstrate that the imprinted artificial antibody suppresses the migration and growth of metastatic tumors. The tumor growth inhibition rate reaches up to 54 ± 15%. Compared with the typical photothermal therapy induced by gold nanorods, the use of MMP-9-imprinted synthetic antibody could better inhibit the lung tumor metastasis by quenching the enzyme activity of MMP-9. This study offers a new paradigm in the engineering of imprinted nanoparticles as inhibitors for cancer therapy.
Assuntos
Neoplasias Pulmonares , Inibidores de Metaloproteinases de Matriz , Animais , Movimento Celular , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Microambiente TumoralRESUMO
A biomimetic of endogenous tissue inhibitors of metalloproteinases (TIMPs) was engineered by introducing three binding elements to a synthetic tetrapolymer. We evaluated the contribution of composition, size, and shape of the TIMP-mimicking polymers to the inhibition of BaP1, a P-I class snake venom metalloproteinase (SVMP). Inhibition was achieved when the size of the linear polymer (LP) was comparable to or greater than that of the enzyme, indicating the efficacy requires binding to a significant portion of the enzyme surface in the vicinity of the active site. The efficacy of a low cross-linked polymer hydrogel nanoparticle (NP) of substantially greater molecular weight was comparable to that of the LPs despite differences in size and shape, an important finding for in vivo applications. The abiotic TIMP was effective against two classes of SVMPs in whole snake venom. The results can serve as a design principle for biomimetic polymer inhibitors of enzymes.
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Biomimética , Polímeros , Inibidores Teciduais de Metaloproteinases , Domínio Catalítico , Venenos de SerpentesRESUMO
We describe an approach for the discovery of protein affinity reagents (PARs). Abiotic synthetic hydrogel copolymers can be "tuned" for selective protein capture by the type and ratios of functional monomers included in their polymerization and by the polymerization conditions (i.e., pH). By screening libraries of hydrogel nanoparticles (NPs) containing charged and hydrophobic groups against a protein target (IgG), a stimuli-responsive PAR is selected. The robust carbon backbone synthetic copolymer is rapidly synthesized in the chemistry laboratory from readily available monomers. The production of the PAR does not require living cells and is free from biological contamination. The capture and release of the protein by the copolymer NP is reversible. IgG is sequestered from human serum at pH 6.5 and following a wash step, the purified protein is released by elevating the pH to 7.3. The binding and release of the protein occur without denaturation. The abiotic material functions as a selective PAR for the F(ab')2 domain of IgG for pull-down and immunoprecipitation experiments and for isolation and purification of proteins from complex biological mixtures.
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Nanopartículas , Polímeros , Humanos , Hidrogéis , Interações Hidrofóbicas e Hidrofílicas , Imunoglobulina GRESUMO
We report a metal free synthetic hydrogel copolymer with affinity and selectivity for His6-tagged peptides and proteins. Small libraries of copolymers incorporating charged and hydrophobic functional groups were screened by an iterative process for His6 peptide affinity. The monomer selection was guided by interactions found in the crystal structure of an anti-His tag antibody-His6 peptide antigen complex. Synthetic copolymers incorporating a phenylalanine-derived monomer were found to exhibit strong affinity for both His6-containing peptides and proteins. The proximity of both aromatic and negatively charged functional groups were important factors for the His6 affinity of hydrogel copolymers. His6 affinity was not compromised by the presence of enzyme cleavage sequences. The His6-copolymer interactions are pH sensitive: the copolymer selectively captured His6 peptides at pH 7.8 while the interactions were substantially weakened at pH 8.6. This provided mild conditions for releasing His6-tagged proteins from the copolymer. Finally, a synthetic copolymer coated chromatographic medium was prepared and applied to the purification of a His6-tagged protein from an E. coli expression system. The results establish that a synthetic copolymer-based affinity medium can function as an effective alternative to immobilized metal ion columns for the purification of His6-tagged proteins.
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Escherichia coli , Polímeros , Cromatografia de Afinidade , Escherichia coli/genética , Metais , Proteínas , Proteínas RecombinantesRESUMO
Peptide-polymer complementary pairs can provide useful tools for isolating, organizing, and separating biomacromolecules. We describe a procedure for selecting a high affinity complementary peptide-polymer nanoparticle (NP) pair using phage display. A hydrogel copolymer nanoparticle containing a statistical distribution of negatively charged and hydrophobic groups was used to select a peptide sequence from a phage displayed library of >1010 peptides. The NP has low nanomolar affinity for the selected cyclic peptide and exhibited low affinity for a panel of diverse proteins and peptide variants. Affinity arises from the complementary physiochemical properties of both NP and peptide as well as the specific peptide sequence. Comparison of linear and cyclic variants of the peptide established that peptide structure also contributes to affinity. These findings offer a general method for identifying polymer-peptide complementary pairs. Significantly, precise polymer sequences (proteins) are not a requirement, a low information statistical copolymer can be used to select for a specific peptide sequence with affinity and selectivity comparable to that of an antibody. The data also provides evidence for the physiochemical and structural contributions to binding. The results confirm the utility of abiotic, statistical, synthetic copolymers as selective, high affinity peptide affinity reagents.
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Materiais Biocompatíveis/química , Nanopartículas/química , Peptídeos/química , Polímeros/química , Teste de Materiais , Tamanho da PartículaRESUMO
We describe a process for engineering a synthetic polymer nanoparticle (NP) that functions as an effective, broad-spectrum metalloproteinase inhibitor. Inhibition is achieved by incorporating three functional elements in the NP: a group that interacts with the catalytic zinc ion, functionality that enhances affinity to the substrate-binding pocket, and fine-tuning of the chemical composition of the polymer to strengthen NP affinity for the enzyme surface. The approach is validated by synthesis of a NP that sequesters and inhibits the proteolytic activity of snake venom metalloproteinases from five clinically relevant species of snakes. The mechanism of action of the NP mimics that of endogenous tissue inhibitors of metalloproteinases. The strategy provides a general design principle for synthesizing abiotic polymer inhibitors of enzymes.
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Biomimética , Metaloproteases/antagonistas & inibidores , Nanopartículas/química , Polímeros/química , Inibidores Teciduais de Metaloproteinases/farmacologia , Catálise , Zinco/químicaRESUMO
The affinity of a synthetic polymer nanoparticle (NP) to a target biomacromolecule is determined by the association and dissociation rate constants (kon, koff) of the interaction. The individual rates and their sensitivity to local environmental influences are important factors for the on-demand capture and release a target biomacromolecule. Positively charged NPs for small interfering RNA (siRNA) delivery is a case in point. The knockdown efficacy of siRNA can be strongly influenced by the binding kinetics to the NP. Here, we show that kon and koff of siRNA to NPs can be individually engineered by tuning the chemical structure and composition of the NP. N-Isopropylacrylamide-based NPs functionalized with hydrophobic and amine monomers were used. koff decreased by increasing the amount of amine groups in the NP, whereas kon did not change. Importantly, NPs showing a low koff at pH 5.5 together with a high koff at pH 7.4 showed high knockdown efficiency when NP/siRNA complexes were packaged in lipid nanoparticles. These results provide direct evidence for the premise that the efficacy of an siRNA delivery vector is linked with the strong affinity to the siRNA in the endosome and low affinity in the cytoplasm.
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Técnicas de Transferência de Genes , Nanopartículas/química , RNA Interferente Pequeno/metabolismo , Acrilamidas/química , Animais , Linhagem Celular Tumoral , Citoplasma/metabolismo , Endossomos/metabolismo , Técnicas de Silenciamento de Genes/métodos , Camundongos , RNA Interferente Pequeno/genética , Polímeros Responsivos a Estímulos/químicaRESUMO
A wearable silk fibroin/cellulose composite is reported. It is structurally dyed and functionalized by embedding three-dimensional (3D) or two-dimensional poly(methyl methacrylate) and polystyrene nanocolloidal arrays to form opal and inverse opal silk methylcellulose photonic crystal films (SMPCF). The brilliant color of SMPCF is utilized for naked-eye detection of humidity and a trace amount (0.02%) of H2O content in organic solvents. Volatile organic compounds gases of 5 types were detected. By alternately exposed to organic solvents of methanol, acetonitrile, acetone, ethanol, isopropanol, n-butanol, carbon tetrachloride, and toluene, 3D inverse opal SMPCF displayed an excellent sensing performance with instantaneously color changes from green to red. The organic solvent sensitive SMPCF are wearable by integrated into a rubber glove. This composite has the potential to be used in wearable real-time sensing materials.
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Corantes/química , Fibroínas/química , Metilcelulose/química , Nanotecnologia/métodos , Dispositivos Eletrônicos Vestíveis , Gases/química , Umidade , Análise em Microsséries , Solventes/química , Compostos Orgânicos Voláteis/análise , Água/análiseRESUMO
Stimuli-responsive polymers are an efficient means of targeted therapy. Compared to conventional agents, they increase bioavailability and efficacy. In particular, polymer hydrogel nanoparticles (NPs) can be designed to respond when exposed to a specific environmental stimulus such as pH or temperature. However, targeting a specific metabolite as the trigger for stimuli response could further elevate selectivity and create a new class of bioresponsive materials. In this work we describe an N-isopropylacrylamide (NIPAm) NP that responds to a specific metabolite, characteristic of a hypoxic environment found in cancerous tumors. NIPAm NPs were synthesized by copolymerization with an oxamate derivative, a known inhibitor of lactate dehydrogenase (LDH). The oxamate-functionalized NPs (OxNP) efficiently sequestered LDH to produce an OxNP-protein complex. When exposed to elevated concentrations of lactic acid, a substrate of LDH and a metabolite characteristic of hypoxic tumor microenvironments, OxNP-LDH complexes swelled (65%). The OxNP-LDH complexes were not responsive to structurally related small molecules. This work demonstrates a proof of concept for tuning NP responsiveness by conjugation with a key protein to target a specific metabolite of disease.