Hybrid Microneedle-Mediated Transdermal Delivery of Atorvastatin Calcium-Loaded Polymeric Micelles for Hyperlipidemia Therapy.

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.

Assessing the structural stability and drug encapsulation efficiency of poly(ethylene glycol)-poly(L-lactic acid) nanoparticles loaded with atorvastatin calcium: Based on dissipative particle dynamics.

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.

Functional insulin aspart/insulin degludec-based microneedles for promoting postprandial glycemic control.

Insulin aspart (IAsp) and insulin degludec (IDeg), as the third generation of insulin, have a faster onset time or a more durable action period, which may simulate the secretion of insulin under physiological conditions. Microneedles (MNs) are transdermal delivery devices that may allow diabetic patients to easily deploy transdermal insulin therapy while considerably reducing injection pain. In this study, we investigated the combination of dissolving MNs with IAsp or IDeg therapy as an alternative to daily multiple insulin injections, aiming to improve glycemic control and patient compliance. Mechanical properties of the MNs, structural stability of insulin encapsulated in the MNs, and transdermal application characteristics were studied to assess the practicality of insulin-loaded MNs for diabetes therapy. In vivo experiments conducted on diabetic rats demonstrated that the IAsp- and IDeg-loaded MNs have comparable blood glucose control abilities to that of subcutaneous injections. In addition, the therapeutic properties of insulin-loaded MNs under diverse dietary conditions and application strategies were further investigated to provide new information to support future clinical trials. Taken together, the proposed MNs have the potential to improve balances between glycemic control, hypoglycemia risk, and convenience, providing patients with simpler regimens. STATEMENT OF SIGNIFICANCE: 1. The fabricated functional insulin-loaded dissolving microneedles closely matched the glucose rise that occurs in response to meals, demonstrating promising alternatives for multiple daily insulin injections. 2. The hypoglycemic properties of insulin microneedles were investigated under diverse dietary conditions and application strategies, yielding new information to support future clinical trials. 3. Molecular dynamics simulations were utilized to study the interactions between the insulin and microneedle matrix materials, providing a strategy for theoretically understanding drug stability as well as the release mechanism of drug-loaded microneedles.

Improved pharmacodynamics of epidermal growth factor via microneedles-based self-powered transcutaneous electrical stimulation.

Epidermal growth factor is an excellent drug for promoting wound healing; however, its conventional administration strategies are associated with pharmacodynamic challenges, such as low transdermal permeability, reduction, and receptor desensitization. Here, we develop a microneedle-based self-powered transcutaneous electrical stimulation system (mn-STESS) by integrating a sliding free-standing triboelectric nanogenerator with a microneedle patch to achieve improved epidermal growth factor pharmacodynamics. We show that the mn-STESS facilitates drug penetration and utilization by using microneedles to pierce the stratum corneum. More importantly, we find that it converts the mechanical energy of finger sliding into electricity and mediates transcutaneous electrical stimulation through microneedles. We demonstrate that the electrical stimulation applied by mn-STESS acts as an "adjuvant" that suppresses the reduction of epidermal growth factor by glutathione and upregulates its receptor expression in keratinocyte cells, successfully compensating for receptor desensitization. Collectively, this work highlights the promise of self-powered electrical adjuvants in improving drug pharmacodynamics, creating combinatorial therapeutic strategies for traditional drugs.

Evaluation of Nanoparticle Stability under Blood Flow Shear.

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.

Thermosensitive hydrogel microneedles for controlled transdermal drug delivery.

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.

Advances in self-assembling of pH-sensitive polymers: A mini review on dissipative particle dynamics.

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.

Stability and Diffusion Properties of Insulin in Dissolvable Microneedles: A Multiscale Simulation Study.

Microneedle (MN) technology has been proven to be promising to become an effective drug delivery route of insulin for diabetes treatment, with the advantages of high delivery efficiency, convenient management, and minimal risk of infection. However, efforts are still required to verify the insulin activity in MNs for further clinical application. Moreover, it is also essential to study the diffusion properties of insulin to understand the ability of various MN materials to control insulin release. Herein, we have combined all-atom molecular dynamics simulation and coarse-grained dissipative particle dynamics to systematically study insulin's structural stability and diffusion coefficient in polyvinyl alcohol and hyaluronic acid solutions. The all-atom simulation reveals the dissimilarities in the interaction mode between insulin and the two polymers. It also points out that the presence of the two polymers would not irreversibly impact the secondary structure of insulin, thereby ensuring regular insulin expression in vivo. Mesoscopic simulation results manifest that the diffusion coefficient of insulin in hyaluronic acid (HA) solution is greater than that of the polyvinyl alcohol (PVA) system. Meanwhile, through the study of insulin centroid trajectory, we have claimed two different diffusion mechanisms of insulin in polymer solution: The movement of insulin in the HA and water solution follows the Brownian motion rule. In comparison, the hopping effect of insulin has been observed in the PVA solution due to poor intermolecular affinity as well as lower polymer water solubility. By summarizing different diffusion mechanisms, this study can provide theoretical guidance for preparing insulin-loaded dissolvable MNs.

Mesoscopic Simulation for the Effect of Cross-Linking Reactions on the Drug Diffusion Properties in Microneedles.

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.

Simulation study of the pH sensitive directed self-assembly of rheins for sustained drug release hydrogel.

The hydrogel formed by the directed self-assembled rhein molecules at an appropriate pH value for sustained drug release has been reported recently. Although the application in drug therapy has been experimentally verified, the research on the mechanism of the self-assembly by rhein is still incomplete. In this study, we provide a new insight of the pH-induced self-assembly mechanism employing the dissipative particle dynamics (DPD) as well as multiscale molecular simulations. It comes to the conclusion that protonated rheins incline to aggregate, so spherical, columnar, and membrane-shaped aggregated micelles can be observed with the mounting drug concentrations. However, the thermodynamic solubility of these structures is relatively weak, which ultimately causes the system to precipitate. While, driven by the better hydrophilicity and charge effect of the deprotonated rheins, the self-assembly conformation of deprotonated rheins grows through a sphere, wormlike, long wormlike manner, resulting in a host of discontinuous and highly dispersive morphologies. Those structures, having good thermodynamic solubility though, cannot provide the required mechanical properties, thus the rhein system can only exist in the aqueous solution state. Only when the value of pH is moderate (the corresponding degree of deprotonation is 36 %-60 %), could a continuous network self-assembled structure be obtained, leading to the formation of hydrogel to meet the clinical requirements.

Dissipative Particle Dynamics Aided Design of Drug Delivery Systems: A Review.

A nanocarrier drug delivery system, effectively assisting to improve the solubility, bioavailability, and targeting of drugs in the human body, is a crucial means for treating cancer and other diseases. However, drug carriers usually possess multiple components and complex microstructures, and studies on the formation mechanism and internal structural details of nanocarriers are still incomplete by experimental methods. In order to overcome this adversity, the dissipative particle dynamics (DPD) simulation has been widely used owing to its unique simulation time-space scale and satisfying computing efficiency. In the past decades, more and more kinds of complex nanocarriers with various structures have been successfully characterized, and influencing factors in mounting numbers have also been parametrized. Not only emphasizing on the self-assembly structure of nanocarriers, but the application area of DPD simulation has also become a complete system covering from the synthesis and preparation to interaction with the biomembrane. This article reviews the application of DPD simulations in drug delivery systems. We have established the connection between existing studies and proposed some outlooks for the further combination between DPD simulation and the design of a drug delivery system.

Clinical study of the predictors to neoadjuvant chemotherapy in patients with advanced gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the predictive value of seven gastric cancer-associated factors on neoadjuvant chemotherapy in patients with advanced gastric cancer.</p><p><b>METHODS</b>Expressions of C-met, EGFR, HER2, Ki-67, MMP7, P53 and TOPOII were detected by immunohistochemistry in gastric cancer tissues of 53 cases before and after mFOLFOX7 neoadjuvant chemotherapy. Chemotherapy efficacy was evaluated according to RECIST 1.1 standard combined with histopathology, and the relationship between various genes and chemotherapy efficacy was analyzed by univariate and logistic multivariate regression analyses.</p><p><b>RESULTS</b>The clinical response rate was 52.8% (28/53) in neoadjuvant chemotherapy, including complete response in none, partial response in 28 cases (52.8%), stable disease in 24 cases (45.3%) and progressive disease in 1 case (1.9%). The expressions of all the genes were not significantly different before and after neoadjuvant chemotherapy (P>0.05). Neoadjuvant chemotherapy efficacy was 83.3% (10/12) in the patients of HER2 positive expression and 43.9% (18/41) in the patients of HER2 negative expression. The former was significant higher than the latter (P=0.016). Response rate of patients with P53 positive expression was 35.7% (10/28), significantly lower than 72.0% (18/25) of those with P53 negative expression (P=0.008). Six patients with both HER2 positive expression and P53 negative expression showed better efficacy. The expressions of C-met, EGFR, Ki-67, MMP7 and TOPOII were not associated with response to neoadjuvant chemotherapy (P>0.05). HER2 and P53 were independent influencing factors of neoadjuvant chemotherapy (P<0.05).</p><p><b>CONCLUSION</b>Expressions of HER2 and P53 have great value in the prediction of mFOLFOX7 neoadjuvant chemotherapy efficacy, suggesting that as independent factors, HER2 and P53 may be used to predict the efficacy before chemotherapy.</p>