Drug Delivery Research Articles

Enhancing Tumor Targeted Therapy: The Role of iRGD Peptide in Advanced Drug Delivery Systems

Chemotherapy remains the primary therapeutic approach in treating cancer. The tumor microenvironment (TME) is the complex network surrounding tumor cells, comprising various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as ECM components, blood vessels, and signaling molecules. The often stiff and dense network of the TME interacts dynamically with tumor cells, influencing cancer growth, immune response, metastasis, and resistance to therapy. The effectiveness of the treatment of solid tumors is frequently reduced due to the poor penetration of the drug, which leads to attaining concentrations below the therapeutic levels at the site. Cell-penetrating peptides (CPPs) present a promising approach that improves the internalization of therapeutic agents. CPPs, which are short amino acid sequences, exhibit a high ability to pass cell membranes, enabling them to deliver drugs efficiently with minimal toxicity. Specifically, the iRGD peptide, a member of CPPs, is notable for its capacity to deeply penetrate tumor tissues by binding simultaneously integrins ανβ3/ανβ5 and neuropilin receptors. Indeed, ανβ3/ανβ5 integrins are characteristically expressed by tumor cells, which allows the iRGD peptide to home onto tumor cells. Notably, the respective dual-receptor targeting mechanism considerably increases the permeability of blood vessels in tumors, enabling an efficient delivery of co-administered drugs or nanoparticles into the tumor mass. Therefore, the iRGD peptide facilitates deeper drug penetration and improves the efficacy of co-administered therapies. Distinctively, we will focus on the iRGD mechanism of action, drug delivery systems and their application, and deliberate future perspectives in developing iRGD-conjugated therapeutics. In summary, this review discusses the potential of iRGD in overcoming barriers to drug delivery in cancer to maximize treatment efficiency while minimizing side effects.

Biosynthesis of Silver Nanoparticles with Antifungal Potential

Abstract: Metallic nanoparticles, specifically silver nanoparticles, find huge applications in health, medicine, and drug delivery. However, the physical and chemical synthesis methods pose challenges regarding gener, action of toxic by-products, or high energy requirements. Hence biosynthetic approaches have gained interest in the last few years utilizing various sources including yeast, fungi, bacteria, or plant extracts containing reducing and capping agents like quercetin, apocyanin, gallic acid, alkaloids, tannins, etc. The present review would throw light on plant extracts containing such reducing and capping agents for the biosynthesis of silver nanoparticles, including the phytofactors and physicochemical parameters affecting the synthetic methods. Further characterization concerning the polydispersity index (ranging from 0-1) and zeta potential values (stable nanoparticles with ranges >+30 mV or <-30 mV) for improving stability would also be discussed. The potential and applications of silver based nanohybrids or nanocomposites will be described. The antibacterial potential of silver nanoparticles has been shown in previous reviews. Antifungal potential of biosynthetic silver nanoparticles obtained from plant extracts like Croton sparsiflorus morong leaf extract or aqueous extract of Phoenix dactylifera (date palm) pit evaluated on fungal strains will be illustrated in the present review. The underlying mechanism for the antifungal activity of silver nanoparticles will also be discussed. At the conclusion, the list of patents on biosynthetic silver nanoparticles and the limitations and regulatory guidelines for commercial production will be illustrated.

Co-loading Radio-photosensitizer Agents on Polymer and Lipid-based Nanocarriers for Radio-photodynamic Therapy Purposes: Review.

Polymer and lipid-based nanocarriers are a state-of-art in nanomedicine and in co-drug delivery of drugs that could merges various diagnostic and treatment modalities such radiotherapy (RT), photodynamic therapy (PDT) and chemotherapy (CT) in cancer therapy. Among various shapes and nanostructures, polymer and lipid-based nanocarriers have the potential to carry two drugs in same time to cells. However, hydrophobic and hydrophilic drug can be loaded in between layers as well as in the core of these nanocarriers, simultaneously. This advantage of NPs can be employed in combination therapy. Radiosensitizer and photosensitizer agents play a critical role in radio-photodynamic therapy (RT-PDT) of cancer. Co-delivery of these agents to cancerous cells is advantageous to cancer therapy but still remain as a challenge of RT-PDT. However, in this review, we have highlighted the challenges of RT-PDT and role of polymer and lipid-based nanocarriers to codelivery of hydrophobic and hydrophilic agents as radio-photosensitizers. Hence, the different kinds of Poly (lactic-co-glycolic acid) nanoparticles (NPs) have been categorized. Then, the biophysical mechanism of radio- photosensitizer agents with co-loading on polymer and lipid-based nanocarriers in RT-PDT treatment of cancer has been outlined. Finally, attention has been drawn to polymer and lipid-based nanocarriers in codrugs delivery. Taken together, this work presents the latest updates on this area and highlighted the pros and cons of co-delivery for RT-PDT purposes.

Quantitative Structure-Property Relationship (QSPR) Modeling of Central Nervous System (CNS) Drug Activity using Molecular Descriptors

Background: L-type amino acid transporter-1 is a drug that stimulates the func-tions of the brain’s central nervous system. Membrane transporters have evolved, leading to a distinct approach in L-type amino acid transporter-1 drug delivery. One of the trans-porters used for transporting drugs across biological membranes is the L-type amino acid transporter-1. It is widely discussed in the medicinal field. Objectives: Numerous investigations indicate a close connection between the properties of alkanes and the diversity of central nervous system drugs in the brain, specifically log P and molecular weight. One important study that analyzes structural properties is focused on topological descriptors. Recently, topological indices have found application in the de-velopment of quantitative structure-activity relationships. These indices are correlated with the physicochemical properties of BCNS-acting drugs and their biological activity. Methods: The study employs significant methods of calculating topological indices: the edge set partition method and the Djokovi´c-Winkler relation (cut method) are utilized to calculate the values of these descriptors. Results: The results of distance and degree-based topological descriptors have been de-rived. The strong correlation between topological descriptors and the physicochemical properties of BCNS-acting drugs has been studied. Conclusions: This article identifies important topological features for various CNS medi-cations, aiming to support researchers in understanding the properties of molecules and their biological activity. Furthermore, we demonstrate how strongly these behaviors cor-respond to the physicochemical properties of central nervous system drugs.

In vitro cellular uptake and insulin secretion studies on INS-1E cells of exendin-4-loaded self-nanoemulsifying drug delivery systems

Exendin-4 (ex-4) is a peptide molecule that regulates blood glucose levels without causing hypoglycemia by providing insulin secretion from beta cells in the pancreas. Self-nanoemulsifying drug delivery systems (SNEDDS) attract attention for oral administration of therapeutic peptide/proteins because they protect therapeutic peptide/proteins from the gastric environment, reduce changes due to food effects, are easy to prepare and scale-up. Ex-4 has no commercial form that can be administered orally. In this study, the cytotoxicity, cellular uptake, and insulin secretion of ex-4 and ex-4/chymostatin (chym) SNEDDS were investigated on INS-1E rat pancreatic beta cells. The effect of ex-4 and ex-4/chym SNEDDS on cell viability in INS-1E cells increased when the dilution ratio higher. Ex-4 and ex-4/chym SNEDDS increased insulin levels in 2.8 mM (low-dose) glucose-induced INS-1E cells 2.21-fold and 2.17-fold compared to control, respectively. Ex-4 and ex-4/chym SNEDDS increased insulin levels in 16.7 mM (high dose) glucose-induced INS-1E cells compared to control, respectively. In cellular uptake studies, coumarin-6 solution penetrated the apical membrane of INS-1E cells and remained in the cytoplasm, while coumarin-6 loaded SNEDDS were visualized in the nuclei of the cell. These findings will likely be useful in the development of new formulations for the oral administration of peptides/proteins.

Service Quality and Patient Satisfaction of Internet Hospitals in China: Cross-Sectional Evaluation With the Service Quality Questionnaire.

Internet hospitals, which refer to service platforms that integrate consultation, prescription, payment, and drug delivery based on hospital entities, have been developing at a rapid pace in China since 2014. However, assessments regarding their service quality and patient satisfaction have not been well developed. There is an urgent need to comprehensively evaluate and improve the service quality of internet hospitals. This study aims to investigate the current status of patients' use of internet hospitals, as well as familiarity and willingness to use internet hospitals, to evaluate patients' expected and perceived service qualities of internet hospitals using the Chinese version of the Service Quality Questionnaire (SERVQUAL-C) with a national representative sample, and to explore the association between service quality of internet hospitals and patients' overall satisfaction toward associated medical platforms. This cross-sectional survey was conducted through face-to-face or digital interviews from June to September 2022. A total of 1481 outpatient participants (635 men and 846 women; mean age 33.22, SD 13.22). Participants reported their use of internet hospitals, and then rated their expectations and perceptions of service quality toward internet hospitals via the SERVQUAL-C, along with their demographic information. Among the surveyed participants, 51.2% (n=758) of participants had used internet hospital service or services. Use varied across age, education level, and annual income. Although the majority of them (n=826, 55.8%) did not know internet hospital services well, 68.1% (n=1009) of participants expressed the willingness to adopt this service. Service quality evaluation revealed that the perceived service quality did not match with the expectation, especially the responsiveness dimension. Important-performance analysis results further alerted that reliable diagnosis, prompt response, clear feedback pathway, and active feedback handling were typically the services awaiting substantial improvement. More importantly, multiple linear regressions revealed that familiarity and willingness to use internet hospital services were significant predictors of satisfaction, above and over tangibles, reliability, and empathy service perspectives, and demographic characteristics such as gender, age, education level, and annual income. In the future, internet hospitals should focus more on how to narrow the gaps between the expected and perceived service quality. Promotion of internet hospitals should also be facilitated to increase patients' familiarity with and willingness to use these services.

A single-particle energy-conserving dissipative particle dynamics approach for simulating thermophoresis of nanoparticles in polymer networks.

The transport of nanoparticles in polymer networks has critical implications in biology and medicine, especially through thermophoresis in response to temperature gradients. This study presents a single-particle energy-conserving dissipative particle dynamics (seDPD) method by integrating a single-particle model into the energy-conserving DPD model to simulate the mesoscopic thermophoretic behavior of nanoparticles in polymer matrices. We first validate the newly developed seDPD model through comparisons with analytical solutions for nanoparticle viscosity, thermal diffusivity, and hydrodynamic drag and then demonstrate the effectiveness of the seDPD model in capturing thermophoretic forces induced by temperature gradients. The results show that nanoparticles driven by the Soret forces exhibit unique transport characteristics, such as drift velocity and diffusivity, leading to a significant acceleration of nanoparticle diffusion in the polymer network, which has been known as the giant acceleration of diffusion. Quantifying how nanoparticles move in flexible polymer networks sheds light on the interaction dynamics of nanoparticles within polymer networks, providing insight into nanoparticle behavior in complex environments that could be leveraged in various applications from drug delivery to material design.

Engineering pH and Temperature-Triggered Drug Release with Metal-Organic Frameworks and Fatty Acids

This study reports the successful synthesis of core-shell microparticles utilizing coaxial electrospray techniques, with zeolitic imidazolate framework-8 (ZIF-8) encapsulating rhodamine B (RhB) in the core and a phase change material (PCM) shell composed of a eutectic mixture of lauric acid (LA) and stearic acid (SA). ZIF-8 is well-recognized for its pH-responsive degradation and biocompatibility, making it an ideal candidate for targeted drug delivery. The LA-SA PCM mixture, with a melting point near physiological temperature (39 °C), enables temperature-triggered drug release, enhancing therapeutic precision. The structural properties of the microparticles were extensively characterized through scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Drug release studies revealed a dual-stimuli response, where the release of RhB was significantly influenced by both temperature and pH. Under mildly acidic conditions (pH 4.0) at 40 °C, a rapid and complete release of RhB was observed within 120 h, while at 37 °C, the release rate was notably slower. Specifically, the release at 40 °C was 79% higher than at 37 °C, confirming the temperature sensitivity of the system. Moreover, at physiological pH (7.4), minimal drug release occurred, demonstrating the system’s potential for minimizing premature drug release under neutral conditions. This dual-stimuli approach holds promise for improving therapeutic outcomes in cancer treatment by enabling precise control over drug release in response to both pH and localized hyperthermia, reducing off-target effects and improving patient compliance.

Evaluation of oral bioavailability and other pharmacy effects on sleep quality by using zaleplon nano emulsifying drug delivery systems carrying

Evaluation of oral bioavailability and other pharmacy effects on sleep quality by using zaleplon nano emulsifying drug delivery systems carrying

Nutritional Glutamine-Modified Iron-Delivery System with Enhanced Endocytosis for Ferroptosis Therapy of Pancreatic Tumors.

Heterogeneous reprogrammed nutrient metabolic networks formed by oncogenes exhibit the potential for exploring novel druggable targets and developing innovative anticancer therapeutics. Herein, based on the heterogeneous metabolic characteristics of glutamine (Gln) addiction in pancreatic cancer cells, an iron-delivery system (IDS) with enhanced endocytosis is designed for efficient ferroptosis therapy. The IDS is characterized by Gln modification and can be recognized as a source of Gln nutrients for efficient endocytic uptake by pancreatic tumor cells. Because the IDS is flexible to combine with amino acid-like components, the IDS with enhanced endocytosis is further produced by loading the Gln transporter inhibitor of V9302. V9302 is capable of suppressing molecular Gln uptake via transporter ASCT2, which generates Gln deprivation to direct metabolic reprogramming of cancer cells and enhances cellular uptake of Gln-modified IDS via RAS-stimulated macropinocytosis. The enhanced endocytosis and high iron content of IDS facilitate ferroptosis in mice pancreatic tumor models; thus, an amino acid-like ferroptosis inducer of l-buthionine sulfoximine (BSO) is further combined. The enhanced endocytosis resulting from the synergism of Gln and V9302 enables the efficient delivery of iron and BSO for ferroptosis tumor therapy. This work provides an alternative approach for enhancing intracellular drug delivery of the tumors with heterogeneous nutrient metabolism by virtue of combining nutrient-modified nanodrugs with the corresponding nutrient transporter inhibitors.

From Preformulative Design to in Vivo Tests: A Complex Path of Requisites and Studies for Nanoparticle Ocular Application. Part 2: In Vitro, Ex Vivo, and In Vivo Studies.

The incidence of ocular pathologies is constantly increasing, as is the interest of the researchers in developing new strategies to ameliorate the treatment of these conditions. Nowadays, drug delivery systems are considered among the most relevant approaches due to their applicability in the treatment of a great variety of inner and outer eye pathologies through painless topical administrations. The design of such nanocarriers requires a deep study of many aspects related to the administration route but also a consideration of the authorities and pharmacopeial requirements, in order to achieve a clinical outcome. On such bases, the scope of this review is to describe the path of the analyses that could be performed on nanoparticles, along with the assessment of their applicability for ophthalmic treatments. Preformulation studies, physicochemical and technological characterization, and preliminary noncellular in vitro studies have been described in part 1 of this review. Herein, first the in vitro cellular assays are described; subsequently, nonocular organotypic tests and ex vivo studies are reported, as to present the various analyses to which the formulations can be subjected before in vivo studies, described in the last part. In each step, the models that could be used are presented and compared, highlighting the pros and cons. Moreover, their reliability and eventual acceptance by regulatory agencies are discussed. Hence, this review provides an overview of the most relevant assays applicable for nanocarriers intended for ophthalmic administration to guide researchers in the experimental decision process.

Sensitive HPLC Method to Support Pre-formulation Studies and to Determine Critical Quality Attributes of Therapeutic Contact Lenses Containing Dorzolamide Hydrochloride

Background: Dorzolamide hydrochloride (DRZ) is a carbonic anhydrase inhibitor used to treat glaucoma and ocular hypertension. Drug-eluting contact lenses, such as Acuvue Theravision ™ with Ketotifen, offer improved drug delivery and reduced side effects compared to eye drops. Drug-loaded nanoparticle-loaded contact lenses can sustain drug release and enhance comfort for extended wear. Objective: High buffer concentration and low pH increase the risk of damage to silica-bonded columns. Therapeutic contact lenses face challenges related to critical lens parameters, including the estimation of drug incorporation and release due to interference of lens matrix leaching. There is currently no analytical method available for estimating DRZ in contact lenses. Method: The HPLC method, which was developed and validated using ICH Q2 (R1) criteria, used a C18 column (250 mm × 4.6 mm, 5 μm) as a stationary phase and methanol:water (70:30 v/v) as the mobile phase. The detecting wavelength was 253 nm. Moreover, to support the efficiency of the developed method, the marketed formulation of DRZ eye drops, drug purity, and loading in contact lenses were analysed. The method was also employed to determine the Critical Quality Attributes (CQAs) of therapeutic contact lenses and drug release and drug leaching during the sterilization process. Result: The developed HPLC method shows Rt for DRZ at 2.881 minutes with good linearity (r2 > 0.998) between 2-32μg/mL, precision (RSD < 2%), accuracy (Recovery > 99.5%), sensitivity, and specificity for quantifying DRZ in marketed formulations and therapeutic contact lenses. The developed method is devoid of any buffer or modifier in the mobile phase, making it safer for the stationary phase. This method mitigates the interference of lens matrix leaching, which induces an overestimation of DRZ. All the result for therapeutic contact lenses was found to be closely aligned with theoretically expected results, confirming the reliability of the developed HPLC method for therapeutic contact lenses. Conclusion: This method is specific, accurate, and precise for quantifying DRZ in commercial formulations and newly developed therapeutic contact lenses. It effectively evaluates the critical quality attributes of these lenses, demonstrating their reliability for assessing their performance and ensuring quality in therapeutic applications.

Therapeutic Peptides Encapsulated into Lipid-Based Nanovesicles: Scaling from Lab to Plant

Lipid-based peptide-encapsulated nanovesicles represent a cutting-edge approach in drug delivery systems, offering enhanced stability, targeted delivery, and controlled release of therapeutic peptides. This review explores the comprehensive science and techniques behind the robust formulation and analytical methods for these nanovesicles, spanning from lab-scale research to large- scale manufacturing. Critical aspects include lipid selection, detailing how the choice of lipids impacts the stability and efficacy of the nanovesicles, and various peptide encapsulation techniques, emphasizing methods to achieve high encapsulation efficiency and controlled release. Key processes in vesicle formation, such as thin film hydration, sonication, and microfluidics, are discussed to highlight their roles in producing nanovesicles with consistent size and morphology. The importance of stability studies, including physical, chemical, and thermal assessments, is underscored. Analytical techniques such as Dynamic Light Scattering (DLS), Zeta Potential measurement, High-Performance Liquid Chromatography (HPLC), and Mass Spectrometry (MS) are detailed, showcasing their crucial roles in characterizing nanovesicles and ensuring their quality, safety, and efficacy for pharmaceutical use. The review addresses the challenges and solutions associated with scaling up production, including maintaining consistent product quality, optimizing manufacturing processes, and controlling production costs. It also navigates the regulatory landscape, discussing the stringent guidelines set by agencies such as the FDA and EMA and the necessity of strategic regulatory planning to facilitate market approval. This comprehensive review aims to serve as an in-depth resource for experts in the field, aiding in the translation of lipid-based peptide-encapsulated nanovesicle formulations from bench to bedside, ultimately enhancing therapeutic outcomes and expanding treatment options for various disease. Key Words: Peptide, Amino acid, Degradation, Pharmacokinetics, Peptide encapsulation, drug delivery systems, Peptide Characterization

Sodium-Selective Channelrhodopsins

Channelrhodopsins (ChRs) are light-gated ion channels originally discovered in algae and are commonly used in neuroscience for controlling the electrical activity of neurons with high precision. Initially-discovered ChRs were non-selective cation channels, allowing the flow of multiple ions, such as Na+, K+, H+, and Ca2+, leading to membrane depolarization and triggering action potentials in neurons. As the field of optogenetics has evolved, ChRs with more specific ion selectivity were discovered or engineered, offering more precise optogenetic manipulation. This review highlights the natural occurrence and engineered variants of sodium-selective channelrhodopsins (NaChRs), emphasizing their importance in optogenetic applications. These tools offer enhanced specificity in Na+ ion conduction, reducing unwanted effects from other ions, and generating strong depolarizing currents. Some of the NaChRs showed nearly no desensitization upon light illumination. These characteristics make them particularly useful for experiments requiring robust depolarization or direct Na+ ion manipulation. The review further discusses the molecular structure of these channels, recent advances in their development, and potential applications, including a proposed drug delivery system using NaChR-expressing red blood cells that could be triggered to release therapeutic agents upon light activation. This review concludes with a forward-looking perspective on expanding the use of NaChRs in both basic research and clinical settings.

Zeolites – tabletting ibuprofen with and without zeolites as an excipient

Abstract Introduction Drug delivery via the oral route is a patient and industry-preferred approach. However, maintaining plasma concentrations of the active pharmaceutical ingredient (API) within the therapeutic window can be challenging with immediate-release (IR) tablets. To avoid the plasma peaks and troughs associated with IR tablets, sustained release (SR) formulations have been investigated. Zeolites are microporous aluminosilicate minerals that represent a novel tabletting material with the potential for modifying drug release due to their unique adsorption and ion exchange properties1. Aim This study will investigate the potential for inclusion of zeolites within orally disintegrating tablets (ODTs) and assessment of their ability to modify API release. Methods In-house, 50%w/w ibuprofen (IBU)-loaded ODTs (IHODTs) were prepared from Pearlitol® Flash, magnesium (Mg) stearate and 2 different zeolites (CP814C and CP814E), incorporated at 5%w/w each, using a manual tablet press. Formulations were prepared and mixed for 10 minutes in a cube mixer prior to direct compression (DC) into tablets. Physical characteristics of the tablets were assessed by hardness and friability measurements. Tablet quality was assessed by disintegration and dissolution analysis to British Pharmacopeia (BP) standards2. Release profiles were assessed against various models to determine the effect of zeolites on the release of IBU. Formulations were further examined and characterised using scanning electron microscopy (SEM) and energy-dispersive x-ray (EDX) spectroscopy. An ethics evaluation was completed, and the study was identified as not having any ethical considerations by the University of South Wales. Results The mean weight of blank ODTs was found to be 225.3mg, with a mean thickness of 3.65mm, diameter of 8.10mm, hardness of 43.9±9.2N (mean±SD, n=5) and friability of 0.2±0.2% (mean±SD, n=3). The hardness of IHODTs was found to be 59.98±1.6N, reducing to 54.9±4.3N and 43.4±0.7N (mean±SD, n=3) with the inclusion of CP814C and CP814E, respectively. The friability of IHODTs containing zeolites was 1.76±0.4% and 1.91±0.9N (mean±SD, n=3), for CP814C and CP814E, respectively; conforming to BP specification2. The disintegration time for all in-house tablets, both with and without a zeolite included, was found to be an order of magnitude greater than commercial ODTs (CT) controls, but all remained within the BP specification2. The release of IBU from IHODTs and CTs showed good correlation to the first-order release model (R2 = 0.96 and 0.98, respectively), indicating IR behaviour. Similarly, the release of IBU from IHODTs containing zeolites was shown to correlate best with the first-order release model, R2 = 0.91 for CP814C and R2 = 0.90 for CP814E, respectively. SEM analysis suggested a homogeneous blend of components within IHODTs, whilst EDX analysis indicated the presence of silicon and aluminium from zeolites, and Mg and carbon from Mg stearate and IBU, respectively. Discussion / Conclusion This study investigated the effect of zeolite inclusion on the release properties of ODTs containing IBU. Although the quality of ODTs containing zeolites was not compromised, this study suggests that inclusion of a zeolite by DC only, does not significantly modify the release profile. Future studies are required to ascertain whether zeolites can achieve SR from ODTs using alternative API loading approaches, such as solvent loading1.

Metal–Organic Framework and Biopolymer-Based Composite Hydrogel for Enhanced Encapsulation of Anticancer Drugs: A New Age Transdermal Drug Delivery Vehicle

Metal–Organic Framework and Biopolymer-Based Composite Hydrogel for Enhanced Encapsulation of Anticancer Drugs: A New Age Transdermal Drug Delivery Vehicle

Immunotherapeutic and Targeted Strategies for Managing Brain Metastases from Common Cancer Origins: A State-of-the-Art Review.

This review examines contemporary strategies for managing brain metastases (BM) from common cancers such as lung, breast, and melanoma. We evaluate the efficacy and applicability of targeted therapies and immunotherapies, exploring their potential to cross the blood-brain barrier and improve patient outcomes. Recent studies have shown that tyrosine kinase inhibitors, immune checkpoint inhibitors, and ADCs effectively treat BM. These treatments can overcome the challenges posed by the blood-brain barrier and improve therapeutic outcomes. ADCs are promising because they can deliver cytotoxic agents directly to tumor cells, which reduces systemic toxicity and increases drug delivery efficiency to the brain. Personalized medicine is becoming increasingly significant in treatment decisions, with biomarkers playing an essential role. Advances in molecular genetics and drug development have led to more refined treatments, emphasizing the precision medicine framework. The management of BM is evolving, driven by drug efficacy, resistance mechanisms, and the need for personalized medicine. Integrating ADCs into treatment regimens represents a significant advancement in targeting metastatic brain tumors. Despite these advances, BM management still presents considerable challenges, requiring ongoing research and multi-institutional trials to optimize therapeutic strategies. This review outlines the current state and future directions in treating BM, highlighting the critical need for continued innovation and comprehensive clinical evaluations to improve survival rates and quality of life for affected patients.

Engineering the Mechanical Stability of a Therapeutic Complex between Affibody and Programmed Death-Ligand 1 by Anchor Point Selection.

Protein-protein complexes can vary in mechanical stability depending on the direction from which force is applied. Here, we investigated the mechanical stability of a complex between a binding scaffold called Affibody and an immune checkpoint protein Programmed Death-Ligand 1 (PD-L1). We used AFM single-molecule force spectroscopy with bioorthogonal clickable peptide handles, shear stress bead adhesion assays, molecular modeling, and steered molecular dynamics (SMD) to understand the pulling point dependency of the mechanostability of the Affibody:(PD-L1) complex. We observed a wide range of rupture forces depending on the anchor point. Pulling from residue #22 on Affibody generated an intermediate state attributed to partially unfolded PD-L1, while pulling from Affibody's N-terminus generated a force-activated catch bond. Pulling from residue #22 or #47 on Affibody generated high rupture forces, with the complex breaking at up to ∼190 pN under loading rates of ∼104-105 pN/s, representing a ∼4-fold increase as compared with low-force N-terminal pulling. SMD simulations showed relative tendencies in rupture forces that were consistent with experiments and, through visualization of force propagation networks, provided mechanistic insights. These results demonstrate how the mechanical properties of protein-protein interfaces can be controlled by informed choice of site-specific bioconjugation points within molecules, with implications for optimal bioconjugation strategies in drug delivery vehicles.

Efficient Loading into and Controlled Release of Lipophilic Compound from Liposomes by Using Cyclodextrin as Novel Trapping Agent.

Lipid bilayer vesicles, liposomes are representative drug delivery carriers. High encapsulation efficiency and release control of drugs are essential for clinical application of liposomes. For efficient drug loading into liposomes, remote loading method using driving force like transmembrane gradients of pH and ions are utilized. Ions are called as "trapping agents," which are also critical for the controlled release of drugs loaded into liposomes inside. It is difficult to apply ions as trapping agents to various drugs because of limited physicochemical compatibility between drugs and ions. Cyclodextrins (CDs) with hydrophobic cavity can make inclusion complexes with various hydrophobic compounds. Therefore, we aimed to evaluate the potential of CDs as a novel trapping agent using sulfobutylether-β-cyclodextrin (SBE-β-CD) and ibuprofen (IB), a weak acid hydrophobic drug. Encapsulation efficiency of IB in liposomes with pH gradient was approximately 27%, and it was enhanced by intraliposomal SBE-β-CD inclusion in addition to pH gradient, which was SBE-β-CD concentration-dependent. In liposomes with pH gradient, a large fraction of IB was released in a short time. This early-stage rapid IB release was significantly suppressed by the inclusion of SBE-β-CD inside liposomes. Thus, novel remote loading technology by intraliposomal SBE-β-CD enabled the efficient encapsulation of the hydrophobic drug into the aqueous phase of liposomes as well as their controlled release. This technology should be applied to various drugs that can be included into CDs in order to enhance their therapeutic benefits.

Micro/nanorobots for gastrointestinal tract

The application of micro/nanomotors (MNMs) in the gastrointestinal tract has become a Frontier in the treatment of gastrointestinal diseases. These miniature robots can enter the gastrointestinal tract through oral administration, achieving precise drug delivery and therapy. They can traverse mucosal layers and tissue barriers, directly targeting tumors or other lesion sites, thereby enhancing the bioavailability and therapeutic effects of drugs. Through the application of nanotechnology, these MNMs are able to accomplish targeted medication release, regulating drug release in response to either external stimuli or the local biological milieu. This results in reduced side effects and increased therapeutic efficacy. This review summarizes the primary classifications and power sources of current MNMs, as well as their applications in the gastrointestinal tract, providing inspiration and direction for the treatment of gastrointestinal diseases with MNMs.