RESUMEN
The stability of drug-loaded nanoparticles in vivo is related to the success of the drug delivery, which is investigated as a deficiency due to the limitation of traditional experimental methods. In this study, dissipative particle dynamics (DPD), a simulation method suitable for soft matter and fluids, was used to study the stability of amphiphilic nanoparticles in the blood microenvironment. By comparing the morphology alteration of nanoparticles with various molecular topologies in the shear fluid field, we have found that branch degree and geometric symmetry would be the key factors in maintaining the nanoparticle's stability. This research could provide more theoretical guidance for drug delivery system design.
Asunto(s)
Nanopartículas , Simulación por Computador , Sistemas de Liberación de Medicamentos , Preparaciones FarmacéuticasRESUMEN
To alleviate the dilemma of drug administration in Alzheimer's disease (AD) patients, it is of great significance to develop a new drug delivery system. In this study, a subcutaneously implanted microneedle (MN) device with a swellable gelatin methacryloyl (GelMA) needle body and a dissolvable polyvinyl alcohol (PVA) backing layer was designed. The backing layer quickly dissolved once the MN was introduced into the subcutaneous, and the hydrogel needles were implanted in the subcutaneous to enable prolonged drug release. Compared with oral administration, the MN system offers the benefits of a high administration rate, a fast onset of effect, and a longer duration of action. By detecting the concentration of acetylcholine (ACH) and Aß 1-42, it was found that MN administration exhibited a stronger therapeutic effect. The biological safety of the MN system was also assessed, and no obvious signs of hemolysis, cytotoxicity, and inflammatory reaction were observed. Together, these findings suggested that the MN system is a convenient, efficient, and safe method of delivering donepezil hydrochloride (DPH) and may provide AD patients with a novel medicine administration option.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Donepezilo/farmacología , Donepezilo/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Agujas , Sistemas de Liberación de Medicamentos , Alcohol Polivinílico , Administración CutáneaRESUMEN
The drug diffusion issue in microneedles is the focus of its medical application. It will not only affect the distribution of drugs in the needle body but will also have an impact on the drug release performance of the microneedle. The utilization of cross-linked polymer materials to obtain the drug diffusion control has been experimentally verified as a feasible method. However, the mechanism research on the molecular level is still incomplete. In this study, the dissipative particle dynamics (DPD) simulation has been applied to study the effect of the cross-linking reaction on drug diffusion in hyaluronic acid microneedles. We have discovered that when the cross-linking degree reaches 90%, the diffusion coefficient of the drug is 6.45 times lower than that of the uncross-linked system. The main reason for the decline in drug diffusion ability is that the cross-linking reaction varies the conformation of the polymer. The amplification in the cross-linking degree makes the polymer coils more compact and approach each other, finally forming a continuously distributed cross-linked network, which reduces its degradation rate in the body. Simultaneously, these cross-linked networks can also hinder the interaction of soluble drugs with water, thereby preventing the premature release of drugs. The simulation results are consistent with the data collected in the previous microneedle experiment. This work will be an extension of DPD simulation in the application of biological materials.
Asunto(s)
Agujas , Preparaciones Farmacéuticas , Simulación por Computador , Difusión , PolímerosRESUMEN
Hyperlipidemia has been a huge challenge to global health, leading to the cardiovascular disease, hypertension, and diabetes. Atorvastatin calcium (AC), a widely prescribed drug for hyperlipidemia, faces huge challenges with oral administration due to poor water solubility and hepatic first-pass effects, resulting in low therapeutic efficacy. In this work, we designed and developed a hybrid microneedle (MN) patch system constructed with soluble poly(vinyl alcohol) (PVA) and AC-loaded polymeric micelles (AC@PMs) for transdermal delivery of AC to enhance the hyperlipidemia therapy. We first prepared various AC@PM formulations self-assembled from mPEG-PLA and mPEG-PLA-PEG block copolymers using a dialysis method and evaluated the physicochemical properties in combination with experiment skills and dissipative particle dynamics (DPD) simulations. Then, we encapsulated the AC@PMs into the PVA MN patch using a micromold filling method, followed by characterizing the performances, especially the structural stability, mechanical performance, and biosafety. After conducting in vivo experiments using a hyperlipidemic rat model, our findings revealed that the hybrid microneedle-mediated administration exhibited superior therapeutic efficacy when compared to oral delivery methods. In summary, we have successfully developed a hybrid microneedle (MN) patch system that holds promising potential for the efficient transdermal delivery of hydrophobic drugs.
Asunto(s)
Administración Cutánea , Atorvastatina , Hiperlipidemias , Micelas , Agujas , Hiperlipidemias/tratamiento farmacológico , Animales , Atorvastatina/química , Atorvastatina/administración & dosificación , Atorvastatina/farmacología , Ratas , Tamaño de la Partícula , Materiales Biocompatibles/química , Polímeros/química , Ensayo de Materiales , Ratas Sprague-Dawley , Sistemas de Liberación de Medicamentos , MasculinoRESUMEN
Block polymer micelles have been proven highly biocompatible and effective in improving drug utilization for delivering atorvastatin calcium. Therefore, it is of great significance to measure the stability of drug-loading nano micelles from the perspective of block polymer molecular sequence design, which would provide theoretical guidance for subsequent clinical applications. This study aims to investigate the structural stability of drug-loading micelles formed by two diblock/triblock polymers with various block sequences through coarse-grained dissipative particle dynamics (DPD) simulations. From the perspectives of the binding strength of poly(L-lactic acid) (PLLA) and polyethylene glycol (PEG) in nanoparticles, hydrophilic bead surface coverage, and the morphological alteration of nanoparticles induced by shear force, the ratio of hydrophilic/hydrophobic sequence length has been observed to affect the stability of nanoparticles. We have found that for diblock polymers, PEG3kda-PLLA2kda has the best stability (corresponding hydrophilic coverage ratio is 0.832), while PEG4kda-PLLA5kda has the worst (coverage ratio 0.578). For triblock polymers, PEG4kda-PLLA2kda-PEG4kda has the best stability (0.838), while PEG4kda-PLLA5kda-PEG4kda possesses the worst performance (0.731), and the average performance on stability is better than nanoparticles composed of diblock polymers.
Asunto(s)
Atorvastatina , Interacciones Hidrofóbicas e Hidrofílicas , Lactatos , Nanopartículas , Polietilenglicoles , Atorvastatina/química , Polietilenglicoles/química , Nanopartículas/química , Portadores de Fármacos/química , Micelas , Poliésteres/química , Composición de Medicamentos , Simulación de Dinámica MolecularRESUMEN
Dissipative Particle Dynamics (DPD) is a mesoscopic simulation program used to simulate the behavior of complex fluids. This work systematically reviews the use of DPD to simulate the self-assembly process of pH-sensitive drug-loaded nanoparticles. pH-sensitive drug-loaded nanoparticles have the characteristics of good targeting and slow release in the body, which is an ideal method for treating cancer and other diseases. As an excellent simulation method, DPD can help people explore the loading and release laws of drugs with complex molecular structures and has extensive applications in other medical fields. This article reviews the self-assembly process of pH-sensitive polymers under neutral conditions and explores the factors that affect the self-assembly structure. It points out that different hydrophilic-hydrophobic ratios, molecular structures, and component distributions will affect the morphology, stability and drug carrying capacity of micelles. This article also introduces the release mechanism of the drug in detail and introduces the factors that affect the release. This article can help relevant researchers to follow the latest advances in the DPD simulation and pH-sensitive drug nano-carrier and insight people to investigate the further application of DPD simulation in biomedical science.
Asunto(s)
Micelas , Polímeros , Portadores de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
By using the prominent merit of poly(N-isopropylacrylamide) (PNIPAm) that can reversibly switch from a linear state to a coiled state with the change in temperature, in this work, gelatin was grafted with carboxylic end-capped PNIPAm as the matrix material to fabricate a physical entanglement crosslinked hydrogel microneedles (MNs) patch that can control drug release after application on the skin. The crystallization of the drug during the fabrication process of MNs was decreased due to the thermo-reversible sol-gel transition of the matrix materials. In addition, to increase the mechanical strength of the MNs and to decrease the application time, the gelatin-g-PNIPAm (GP) MNs patch was mounted onto solid MNs to fabricate a rapidly separating MNs system (RS-GP-MNs). The combination of the rapidly separating technique and the thermosensitive hydrogel provides the combined ability to efficiently deliver drug-loaded MNs into the skin within few seconds and to control drug release within the skin. Through a series of tests, we found that RS-GP-MNs showed suitable lower critical solution temperature and adequate crosslinking speed for practical application. The hypoglycemic effect in diabetic mice was characteristically controlled by insulin release through RS-GP-MNs as compared to the MNs made from unmodified gelatin. The proposed RS-GP-MNs system is potentially applicable to various hydrophilic small molecular and peptide medicines that require frequent dosing, thus providing an effective, noninvasive, and painless administration method with minimal safety concerns. STATEMENT OF SIGNIFICANCE: 1. Hydrogel microneedles that can be reversibly triggered and controllably release drugs at body temperature were fabricated. 2. Hydrogel microneedles prepared from gelatin-g-PNIPAm can avoid the use of a molecular crosslinker that is toxic and difficult to be completely removed. 3. Gelatin-g-PNIPAm with thermosensitive property showed appropriate molecular interactions with the drug and slowed down the crystallization speed of the drug in the solution.