RESUMEN
Drug delivery systems based on biomimetic peptide nanoparticles are steadily gaining prominence in the treatment of diverse medical conditions. This study focused on the development of peptides that depend on ligand-receptor interactions to load rapamycin (RAPA). Furthermore, a multifunctional peptide was engineered to target oxidized low-density lipoprotein (oxLDL) within atherosclerotic plaques, facilitating the localized delivery of RAPA. The interactions between peptides and RAPA/oxLDL were analyzed by simulations and experimental approaches. Results show that the main amino acid residues on the mammalian target of rapamycin that bind to RAPA are constructed as peptides (P1 and P2), which have specific interactions with RAPA and can effectively improve the loading efficiency of RAPA. The encapsulation and drug loading efficiencies of P1/P2 were 68.0/47.9% and 48.3/36.5%, respectively. In addition, the interaction force of the multifunctional peptide (P3) and oxLDL surpassed that of their interaction with human umbilical vein endothelial cells by a factor of 3.6, conclusively establishing the specific targeting of oxLDL by these nanoparticles. The encapsulation and drug loading efficiencies of P3 for RAPA were determined to be 60.2% and 41.5%. P3 can effectively load RAPA and target oxLDL within the plaque, suggesting that P3 has potential as a therapeutic agent for atherosclerotic disease.
Asunto(s)
Células Endoteliales de la Vena Umbilical Humana , Lipoproteínas LDL , Nanopartículas , Péptidos , Placa Aterosclerótica , Sirolimus , Lipoproteínas LDL/química , Lipoproteínas LDL/metabolismo , Sirolimus/administración & dosificación , Sirolimus/química , Sirolimus/farmacología , Humanos , Placa Aterosclerótica/tratamiento farmacológico , Péptidos/química , Péptidos/farmacología , Péptidos/administración & dosificación , Nanopartículas/química , Nanopartículas/administración & dosificación , Sistemas de Liberación de Medicamentos , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Portadores de Fármacos/químicaRESUMEN
The inhibition of platelet adhesion to collagen in exposed vessels represents an innovative approach to the treatment of atherosclerosis and thrombosis. This study aimed to engineer peptide-based nanoparticles that prevent platelet binding to subendothelial collagen by engaging with collagen with high affinity. We examined the interactions between integrin α2/ glycoprotein VI/ von Willebrand factor A3 domain and collagen, as well as between the synthesized peptide nanoparticles and collagen, utilizing molecular dynamics simulations and empirical assays. Our findings indicated that the bond between von Willebrand factor and collagen was more robust. Specifically, the sequences SITTIDV, VDVMQRE, and YLTSEMH in von Willebrand factor were identified as essential for its attachment to collagen. Based on these sequences, three peptide nanoparticles were synthesized (BPa: Capric-GNNQQNYK-SITTIDV, BPb: Capric-GNNQQNYK-VDVMQRE, BPc: Capric-GNNQQNYK-YLTSEMH), each displaying significant affinity towards collagen. Of these, the BPa nanoparticles exhibited the most potent interaction with collagen, leading to a 75% reduction in platelet adhesion.
Asunto(s)
Adhesividad Plaquetaria , Factor de von Willebrand , Factor de von Willebrand/metabolismo , Colágeno/química , Péptidos/farmacología , Péptidos/metabolismo , Plaquetas/metabolismoRESUMEN
The classical Turing morphogenesis often occurs in nonmetallic solution systems due to the sole competition of reaction and diffusion processes. Here, this work conceives that gallium (Ga) based liquid metals (LMs) possess the ability to alloy, diffuse, and react with a range of solid metals (SMs) and thus should display Turing instability leading to a variety of nonequilibrium spatial concentration patterns. This work discloses a general mechanism for obtaining labyrinths, stripes, and spots-like stationary Turing patterns in the LM-SM reaction-diffusion systems (GaX-Y), taking the gallium indium alloy and silver substrate (GaIn-Ag) system as a proof of concept. It is only when Ga atoms diffuse over Y much faster than X while X reacts with Y preferentially, that Turing instability occurs. In such a metallic system, Ga serves as an inhibitor and X as an activator. The dominant factors in tuning the patterning process include temperature and concentration. Intermetallic compounds contained in the Turing patterns and their competitive reactions have also been further clarified. This LM Turing instability mechanism opens many opportunities for constructing microstructure systems utilizing condensed matter to experimentally explore the general morphogenesis process.
RESUMEN
As nanotechnology is applied clinical medicine, nanoparticle-based therapy is emerging as a novel approach for the treatment of atherosclerosis. Ligand-receptor interaction affects the effectiveness of nanoparticle targeting therapy. In this study, the biomimetic peptide (BP-KFFVLK-WYKDGD) ligand specifically targeting the lysophosphatidylcholine (LPC) receptor in atherosclerotic plaques was constructed. The corresponding ligand-receptor interaction under different pH values was investigated by molecular dynamics simulation and experimental measurements. Results show that the interaction force between the peptide and LPC is greater than that of the peptide and human umbilical vein endothelial cell, clearly demonstrating the specific targeting of the peptide ligand to the LPC receptor. The ligand-receptor binding of peptide and LPC dominantly depends on Coulomb and van der Waals interactions. The YKDG amino acids of the peptide are the main fragment that binds to LPC. Compared with neutral environment at pH 7.4, the interaction forces between the peptide and oxidized low-density lipoprotein (oxLDL) decreased by 18.22 % and 45.87 % under acidic environments at pH 6.5 and 5.5, respectively, because of the change in oxLDL secondary structure and the release of LPC from oxLDL. Nevertheless, the peptide still has a strong binding capacity with oxLDL for the treatment of atherosclerosis.
Asunto(s)
Aterosclerosis , Lisofosfatidilcolinas , Humanos , Lisofosfatidilcolinas/metabolismo , Ligandos , Biomimética , Lipoproteínas LDL/metabolismo , Péptidos/farmacologíaRESUMEN
Room temperature liquid metals (LM) such as gallium (Ga) own the potential to react with specific materials which would incubate new application categories. Here, diverse self-organized ring patterns due to nonequilibrium reaction-diffusion and spreading-limitation of Ga-based LM clusters on gold (Au) film are reported, among which diffusion is the controlling step and the self-limiting oxide layer plays the role of kinetic barrier. Such phenomena, classically known as the Liesegang rings, mainly occur in electrolyte media. Unlike existing systems, the present periodic crystallization mechanism enables highly symmetric spatiotemporal periodic Liesegang rings on a smaller scale under ambient conditions. Typically, the Ga-Au and eutectic gallium-indium alloy (EGaIn)-Au reaction-diffusion-spreading systems are constructed, obtaining the revert type and hybrid type concentric Liesegang patterns, respectively. The competitive patterning behavior of the intermediate phase products AuGa2 and AuIn2 in hybrid Liesegang patterns is further analyzed by altering the initial Ga/In mass ratio, first-principles calculations, and molecular dynamic simulations. When the mass ratio of In in GaIn alloy exceeds 15%, it will preferentially react with Au. The discovery of LM Liesegang phenomenon is expected to be a flashpoint for self-organized reaction-diffusion systems and offers promising rules for diverse areas such as materials synthesis and the jewelry design industry.
RESUMEN
Bimetallic nanozymes have been emerging as essential catalysts due to their unique physicochemical properties from the monometallics. However, the access to optimize catalytic performance is often limited by the thermodynamic immiscibility and also heterogeneity. Thus, we present a one-step coreduction strategy to prepare the miscible Cu-Pd bimetallic nanozymes with controllable shape and homogeneously alloyed structure. The homogeneity is systematically explored and luckily, the homogeneous introduction of Cu successfully endows Cu-Pd bimetallic nanozymes with enhanced Fenton-like efficiency. Density functional theory (DFT) theoretical calculation reveals that Cu-Pd bimetallic nanozymes exhibit smaller d-band center compared with Pd nanozymes. Easier adsorption of H2O2 molecular contributed by the electronic structure of Cu significantly accelerate the catalytic process together with the strong repulsive interaction between H atom and Pd atom. In vitro cytotoxicity and intracellular ROS generation performance reveal the potential for in vivo biocatalysis. The strategy to construct kinetically miscible Cu-Pd bimetallic nanozymes will guide the development of bimetallic catalysts with excellent Fenton-like efficiency for biocatalytic nanomedicine.
RESUMEN
Polypeptide nano-carriers with deformation and sustained-release function have gained an attention in anti-tumor treatment. A multifunctional polypeptide with different motifs was discussed and the contribution of each motif to targeted drug release was analyzed by control studies. The transformation and drug release processes of polypeptides were investigated by molecular dynamics method to reveal their dynamics mechanism, and corresponding experiments were performed to verify the simulation results. We observed that the polypeptides could form NPs under the hydrophobic interaction between self-assembly motifs and the electrostatic repulsion between targeting motifs. Affected by the ligand-receptor interaction, the targeting motifs overcame the electrostatic repulsion to approach the ligand proteins, leading to the promotion of the binding of fibrous motifs and the transformation of NPs into NFs for better retention of drugs in the tumor tissues. In addition, the polypeptides with strong hydrophobicity exhibited excellent sustained-release efficiency. These insights allow drawing general conclusions contributed to the design of transformable polypeptide NPs: The decrease in the hydrophobicity of self-assembly motifs is beneficial for the enrichment of doxorubicin in tumor tissues, as well as the similar result can be obtained with the improvement of the hydrophobicity of fibrous motifs and the capability of target.
RESUMEN
Drug-loaded pH-responsive nanoparticles are potential drug carriers in nanotherapeutics delivery because they can remain stable in normal tissues but can disassemble and release drug molecules in tumors. In this study, the mechanisms of self-assembly and disassembly were investigated by analyzing the characteristics of three kinds of biomimetic peptides with different components and sequences. The structural parameters and energy changes during self-assembly and disassembly were calculated by molecular dynamics simulation. Transmission electron microscopy, Fourier transform infrared spectroscopy, and atomic force microscopy were used to observe morphological changes and measure the strength of hydrophobic and hydrophilic interactions between peptides. Results show that the hydrophobic and hydrophilic interactions play crucial roles in the self-assembly and disassembly processes of peptides. The structure of the peptide clusters after self-assembly became tighter as the difference between hydrophobic and hydrophilic interactions increased, whereas a decrease in this difference led to the increased disassembly of the peptides. In general, polyethylene glycol chain modification was necessary in disassembly, and peptides with straight structures had stronger disassembly ability than that with branched structures with the same components. The morphology of peptide clusters can be controlled under different pH values by changing the composition and structure of the peptides for enhanced drug retention and sustained release.