Monodisperse Polyaspartic Acid Derivative Microspheres for Potential Tumor Embolization Therapy.

Polyaspartic acid derivatives are a well-known kind of polypeptide with good biocompatibility and biodegradability, and thus have been widely used as biomedical materials, including drug-loaded nano-scale micelles or macroscopic hydrogels. In this work, for the first time, monodisperse polyaspartic acid derivative microspheres with diameter ranging from 120 to 350 µm for potential tumor embolization therapy are successfully prepared by single emulsion droplet microfluidic technique. The obtained microsphere shows fast cationic anticancer drug doxorubicin hydrochloride loading kinetics with high loading capacity, which is much better than those of the commercial ones. Additionally, drug release behaviors of the drug-loaded microspheres with different diameters in different media are also studied and discussed in detail. These results provide some new insights for the preparation and potential application of polyaspartic acid derivative-based monodisperse microspheres, especially for their potential application as embolic agent.

Drug delivery using reduction-responsive hydrogel based on carboxyethyl-succinoglycan with highly improved rheological, antibacterial, and antioxidant properties.

The development of exopolysaccharide-based polymers is gaining increasing attention in various industrial biotechnology fields for materials such as thickeners, texture modifiers, anti-freeze agents, antioxidants, and antibacterial agents. High-viscosity carboxyethyl-succinoglycan (CE-SG) was directly synthesized from succinoglycan (SG) isolated from Sinorhizobium meliloti Rm 1021, and its structural, rheological, and physiological properties were investigated. The viscosity of CE-SG gradually increased in proportion to the degree of carboxyethylation substitution. In particular, when the molar ratio of SG and 3-chloropropionic acid was 1:100, the viscosity was significantly improved by 21.18 times at a shear rate of 10 s-1. Increased carboxyethylation of SG also improved the thermal stability of CE-SG. Furthermore, the CE-SG solution showed 90.18 and 91.78 % antibacterial effects against Escherichia coli and Staphylococcus aureus and effective antioxidant activity against DPPH and hydroxyl radicals. In particular, CE-SG hydrogels coordinated with Fe3+ ions, which improved both viscosity and rheological properties, while also exhibiting reduction-responsive drug release through 1,4-dithiothreitol. The results of this study suggest that SG derivatives, such as CE-SG, can be used as functional biomaterials in various fields such as food, cosmetics, and pharmaceutical industries.

A chitosan-camouflaged nanomedicine triggered by hierarchically stimuli to release drug for multimodal imaging-guided chemotherapy of breast cancer.

Breast cancer remains one of the most intractable diseases, especially the malignant form of metastasis, with which the cancer cells are hard to track and eliminate. Herein, the common known carbohydrate polymer chitosan (CS) was innovatively used as a shelter for the potent tumor-killing agent. The designed nanoparticles (NPs) not only enhance the solubility of hydrophobic paclitaxel (PTX), but also provide a "hide" effect for cytotoxic PTX in physiological condition. Moreover, coupled with the photothermal (PTT) properties of MoS2, results in a potent chemo/PTT platform. The MoS2@PTX-CS-K237 NPs have a uniform size (135 ± 17 nm), potent photothermal properties (η = 31.5 %), and environment-responsive (low pH, hypoxia) and near infrared (NIR) laser irradiation-triggered PTX release. Through a series of in vitro and in vivo experiments, the MoS2@PTX-CS-K237 showed high affinity and specificity for breast cancer cells, impressive tumor killing capacity, as well as the effective inhibitory effect of metastasis. Benefit from the unique optical properties of MoS2, this multifunctional nanomedicine also exhibited favorable thermal/PA/CT multimodality imaging effect on tumor-bearing mice. The system developed in this work represents the advanced design concept of hierarchical stimulus responsive drug release, and merits further investigation as a potential nanotheranostic platform for clinical translation.

Oral Administration of PLGA Nanoparticles to Deliver Antisense Oligonucleotides to Inflammatory Lesions in the Gastrointestinal Tract.

In this study, we prepared antisense oligonucleotide (ASO)-encapsulated nanoparticles (NPs) with a suitable profile for oral administration for the treatment of inflammatory bowel disease (IBD). We chose a water-in-oil-in-water (w/o/w) method to prepare the NPs using poly(lactide-co-glycolide) as a matrix and Pluronic as a stabilizer. The obtained NPs had a suitable diameter (158 nm) for the penetration of the mucus layer, endocytic uptake by enterocytes, and accumulation in inflammatory lesions in the intestine. The amount of ASOs in the NPs was relatively large (6.41% (w/w)). When the NPs were stably dispersed in solutions that mimicked gastrointestinal (GI) juice, minimal leakage of ASOs was demonstrated over the required period. The NPs were administered orally to mice with colitis induced by dextran sodium sulfate, which reduced target gene expression in the colons and rectums of the mice, whereas naked ASO administration caused no reduction in gene expression. Thus, the NPs have the potential of promising oral carriers of ASOs for the treatment of IBD that specifically target inflammatory lesions in the GI tract, thereby reducing the non-specific toxic effects of ASOs.

Advancements in Stimulus-Responsive Co-Delivery Nanocarriers for Enhanced Cancer Immunotherapy.

Cancer immunotherapy has emerged as a novel therapeutic approach against tumors, with immune checkpoint inhibitors (ICIs) making significant clinical practice. The traditional ICIs, PD-1 and PD-L1, augment the cytotoxic function of T cells through the inhibition of tumor immune evasion pathways, ultimately leading to the initiation of an antitumor immune response. However, the clinical implementation of ICIs encounters obstacles stemming from the existence of an immunosuppressive tumor microenvironment and inadequate infiltration of CD8+T cells. Considerable attention has been directed towards advancing immunogenic cell death (ICD) as a potential solution to counteract tumor cell infiltration and the immunosuppressive tumor microenvironment. This approach holds promise in transforming "cold" tumors into "hot" tumors that exhibit responsiveness to antitumor. By combining ICD with ICIs, a synergistic immune response against tumors can be achieved. However, the combination of ICD inducers and PD-1/PD-L1 inhibitors is hindered by issues such as poor targeting and uncontrolled drug release. An advantageous solution presented by stimulus-responsive nanocarrier is integrating the physicochemical properties of ICD inducers and PD-1/PD-L1 inhibitors, facilitating precise delivery to specific tissues for optimal combination therapy. Moreover, these nanocarriers leverage the distinct features of the tumor microenvironment to accomplish controlled drug release and regulate the kinetics of drug delivery. This article aims to investigate the advancement of stimulus-responsive co-delivery nanocarriers utilizing ICD and PD-1/PD-L1 inhibitors. Special focus is dedicated to exploring the advantages and recent advancements of this system in enabling the combination of ICIs and ICD inducers. The molecular mechanisms of ICD and ICIs are concisely summarized. In conclusion, we examine the potential research prospects and challenges that could greatly enhance immunotherapeutic approaches for cancer treatment.

The Application of Nanoparticles Targeting Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAF) are the most abundant stromal cells in the tumor microenvironment (TME), especially in solid tumors. It has been confirmed that it can not only interact with tumor cells to promote cancer progression and metastasis, but also affect the infiltration and function of immune cells to induce chemotherapy and immunotherapy resistance. So, targeting CAF has been considered an important method in cancer treatment. The rapid development of nanotechnology provides a good perspective to improve the efficiency of targeting CAF. At present, more and more researches have focused on the application of nanoparticles (NPs) in targeting CAF. These studies explored the effects of different types of NPs on CAF and the multifunctional nanomedicines that can eliminate CAF are able to enhance the EPR effect which facilitate the anti-tumor effect of themselves. There also exist amounts of studies focusing on using NPs to inhibit the activation and function of CAF to improve the therapeutic efficacy. The application of NPs targeting CAF needs to be based on an understanding of CAF biology. Therefore, in this review, we first summarized the latest progress of CAF biology, then discussed the types of CAF-targeting NPs and the main strategies in the current. The aim is to elucidate the application of NPs in targeting CAF and provide new insights for engineering nanomedicine to enhance immune response in cancer treatment.

Enigmatic exosomal connection in lung cancer drug resistance.

Lung cancer remains a significant global health concern with limited treatment options and poor prognosis, particularly in advanced stages. Small extracellular vesicles such as exosomes, secreted by cancer cells, play a pivotal role in mediating drug resistance in lung cancer. Exosomes have been found to facilitate intercellular communication by transferring various biomolecules between cancer cells and their microenvironment. Additionally, exosomes can transport signaling molecules promoting cancer cell survival and proliferation conferring resistance to chemotherapy. Moreover, exosomes can modulate the tumor microenvironment by inducing phenotypic changes hindering drug response. Understanding the role of exosomes in mediating drug resistance in lung cancer is crucial for developing novel therapeutic strategies and biomarkers to overcome treatment limitations. In this review, we summarize the current knowledge on conventional and emerging drug resistance mechanisms and the involvement of exosomes as well as exosome-mediated factors mediating drug resistance in lung cancer.

Communities of Care Approach: Developing a Place-based Model of Care and Building Partnerships in the Communities in Central Singapore.

The population in Singapore is ageing, adding pressure to community care as the health and social needs of its residents increase. This has accelerated the pace at which Regional Health Systems adopt and deliver its population health strategies from early prevention, chronic disease management, crisis care to end-of-life care. To this end, the Central Health Integrated Care Network (ICN) began its journey to develop Communities of Care (CoCs) with other health and social care partners to meet the needs of residents in the Central Zone of Singapore. This paper describes the processes and steps taken by Central Health ICN to build partnerships with other agencies and organisations to build place-based models of care in the local neighbourhoods. The faciliating factors and the barriers faced in the implementation of CoCs were described to allow sharing of such learnings on large scale change. Strategies in overcoming some of the challenges were also presented to demonstrate the iterative processes required in building integrated place-based models of care to meet the needs of the residents in different communities.

The Effect of Coordinating the Outpatient Treatment across Medical Specialities for Patients With Multimorbidity.

Introduction: Patients with multimorbidity attend multiple outpatient clinics. We assessed the effects on hospital use of scheduling several outpatient appointments to same-day visits in a multidisciplinary outpatient pathway (MOP). Methods: This study used a quasi-experimental design. Eligible patients had multimorbidity, were aged ≥18 years and attended ≥2 outpatient clinics in five different specialties. Patients were identified through forthcoming appointments from August 2018 to March 2020 and divided into intervention group (alignment of appointments) and comparison group (no alignment). We used patient questionnaires and paired analyses to study care integration and treatment burden. Using negative binomial regression, we estimated healthcare utilisation as incidence rates ratios (IRRs) at one year before and one year after baseline for both groups and compared IRR ratios (IRRRs). Results: Intervention patients had a 19% reduction in hospital visits (IRRR: 0.81, 95% CI: 0.70-0.96) and a 17% reduction in blood samples (IRRR: 0.83, 0.73-0.96) compared to comparison patients. No effects were found for care integration, treatment burden, outpatient contacts, terminated outpatient trajectories, hospital admissions, days of admission or GP contacts. Conclusion: The MOP seemed to reduce the number of hospital visits and blood samples. These results should be further investigated in studies exploring the coordination of outpatient care for multimorbidity. Research question: Can an intervention of coordinating outpatient appointments to same-day visits combined with a multidisciplinary conference influence the utilisation of healthcare services and the patient-assessed integration of healthcare services and treatment burden among patients with multimorbidity?

Extracellular vesicles and their therapeutic applications: a review article (part1).

Extracellular vesicles (EVs) have emerged as a captivating field of study in molecular biology with diverse applications in therapeutics. These small membrane-bound structures, released by cells into the extracellular space, play a vital role in intercellular communication and hold immense potential for advancing medical treatments. EVs, including exosomes, microvesicles, and apoptotic bodies, are classified based on size and biogenesis pathways, with exosomes being the most extensively studied. The aim of this study was to examine the molecular secretory pathway of exosomes and to discuss the medical applications of exosomes and the methods for employing them in laboratory models. The therapeutic potential of EVs has garnered significant attention. Their unique properties, such as stability, biocompatibility, and capacity to traverse biological barriers, make them promising vehicles for targeted drug delivery. By engineering EVs to carry specific cargo molecules, such as therapeutic proteins, small interfering Ribonucleic Acid (RNAs) (siRNAs), or anti-cancer drugs, researchers can enhance drug stability and improve their targeted delivery to specific cells or tissues. This approach has the potential to minimize off-target effects and increase therapeutic efficacy, offering a more precise and effective treatment strategy. EVs represent a captivating and rapidly evolving field with significant therapeutic implications. Their role in intercellular communication, targeted drug delivery, and regenerative medicine makes them valuable tools for advancing medical treatments. As our understanding of EV biology and their therapeutic applications continues to expand, we can expect remarkable advancements that will revolutionize the field of medicine and lead to more personalized and effective therapies.

Comparative study of nasal cavity drug delivery efficiency with different nozzles in a 3D printed model.

Background: Nasal sprays are widely used in treating nasal and sinus diseases; however, there are very few studies on the drug delivery efficiency of nasal sprays. In this study, the drug delivery efficiency of three different nasal spray devices was evaluated in vitro using a 3D printed cast model of nasal cavity. Methods: Three nasal spray devices with different nozzles and angles of administration were used in the 3D model of the nasal cavity and paranasal sinuses. The spraying area (SA), maximal spraying distance (MSD), and spraying distribution scores on the nasal septum and lateral nasal wall were recorded. Results: Different nasal spray devices have their own characteristics, including volume of each spray, SA, and plume angle. The SA of the three nozzles on the nasal septum increased with an increasing angle of administration. When the angle of administration was 50°, each nozzle reached the maximal SA. There was no statistically significant difference in MSD among the three nozzles at the three angles. The total scores for each nozzle using the three different spraying angles were as follows: nozzle A, 40° > 30° > 50°; nozzle B, 30° > 40° > 50°; and nozzle C, 30° > 40° > 50°. The total scores for different nozzles using the same angle were statistically significantly different and the scores for nozzle C were the highest. Nozzle C had the minimum plume angle. None of the three nozzles could effectively delivered drugs into the middle meatus at any angle in this model. Conclusions: The design of the nozzle affects drug delivery efficiency of nasal spray devices. The ideal angle of administration is 50°. The nozzle with smaller plume angle has higher drug delivery efficiency. Current nasal spray devices can easily deliver drugs to most areas of the nasal cavity, such as the turbinate, nasal septum, olfactory fissure, and nasopharynx, but not the middle meatus. These findings are meaningful for nozzle selection and device improvements.

Protein click chemistry and its potential for medical applications.

A revolution in chemical biology occurred with the introduction of click chemistry. Click chemistry plays an important role in protein chemistry modifications, providing specific, sensitive, rapid, and easy-to-handle methods. Under physiological conditions, click chemistry often overlaps with bioorthogonal chemistry, defined as reactions that occur rapidly and selectively without interfering with biological processes. Click chemistry is used for the posttranslational modification of proteins based on covalent bond formations. With the contribution of click reactions, selective modification of proteins would be developed, representing an alternative to other technologies in preparing new proteins or enzymes for studying specific protein functions in different biological processes. Click-modified proteins have potential in diverse applications such as imaging, labeling, sensing, drug design, and enzyme technology. Due to the promising role of proteins in disease diagnosis and therapy, this review aims to highlight the growing applications of click strategies in protein chemistry over the last two decades, with a special emphasis on medicinal applications.

Lessons From the Field From a Volunteer Telehealth Ambassador Program to Enhance Video Visits Among Low-Income Patients: Qualitative Improvement Study.

BACKGROUND: The prevalence of telehealth video use across the United States is uneven, with low uptake in safety-net health care delivery systems, which care for patient populations who face barriers to using digital technologies. OBJECTIVE: This study aimed to increase video visit use in an urban safety-net delivery system. We piloted a telehealth ambassador program, in which volunteers offered technical support to patients with access to digital technologies to convert primary care visits already scheduled as telehealth audio-only visits to telehealth video visits. METHODS: We used a descriptive approach to assess the feasibility, efficacy, and acceptability of the pilot telehealth ambassador program. Feasibility was quantified by the percentage of eligible patients who answered calls from telehealth ambassadors. Program efficacy was measured in two ways: (1) the percentage of patients with access to digital technology who interacted with the navigators and were successfully prepared for a telehealth video visit, and (2) the percentage of prepared patients who completed their scheduled video visits. Program acceptability was ascertained by a structured telephone survey. RESULTS: Telehealth ambassadors attempted to contact 776 eligible patients; 43.6% (338/776) were reached by phone, among whom 44.4% (150/338) were provided digital support between March and May 2021. The mean call duration was 8.8 (range 0-35) minutes. Overall, 67.3% (101/150) of patients who received support successfully completed a telehealth video visit with their provider. Among the 188 patients who were contacted but declined video visit digital support, 61% (114/188) provided a reason for their decline; 42% (48/114) did not see added value beyond a telehealth audio-only visit, 20% (23/114) had insufficient internet access, and 27% (31/114) declined learning about a new technology. The acceptability of the telehealth ambassador program was generally favorable, although some patients preferred having in-real-time technology support on the day of their telehealth video visit. CONCLUSIONS: This high-touch program reached approximately one-half of eligible patients and helped two-thirds of interested patients with basic video visit capability successfully complete a video visit. Increasing the program's reach will require outreach solutions that do not rely solely on phone calls. Routinely highlighting the benefits of video visits, partnering with community-based organizations to overcome structural barriers to telehealth use, and offering in-real-time technology support will help increase the program's efficacy.

Multifunctional Ionic Hydrogel-Based Transdermal Delivery of 5-Fluorouracil for the Breast Cancer Treatment.

Transdermal drug delivery systems (TDDS) are a promising and innovative approach for breast cancer treatment, offering advantages such as noninvasiveness, potential for localized and prolonged drug delivery while minimizing systemic side effects through avoiding first-pass metabolism. Utilizing the distinctive characteristics of hydrogels, such as their biocompatibility, versatility, and higher drug loading capabilities, in the present work, we prepared ionic hydrogels through synergistic interaction between ionic liquids (ILs), choline alanine ([Cho][Ala]), and choline proline ([Cho][Pro]) with oleic acid (OA). ILs used in the study are biocompatible and enhance the solubility of 5-fluorouracil (5-FU), whereas OA is a known chemical penetration enhancer. The concentration-dependent (OA) change in morphological aggregates, that is, from cylindrical micelles to worm-like micelles to hydrogels was formed with both ILs and was characterized by SANS measurement, whereas the interactions involved were confirmed by FTIR spectroscopy. The hydrogels have excellent mechanical properties, which studied by rheology and their morphology through FE-SEM analysis. The in vitro skin permeation study revealed that both hydrogels penetrated 255 times ([Cho][Ala]) and 250 times ([Cho][Pro]) more as compared to PBS after 48 h. Those ionic hydrogels exhibited the capability to change the lipid and keratin arrangements within the skin layer, thereby enhancing the transdermal permeation of the 5-FU. Both ionic hydrogels exhibit excellent biocompatibility with normal cell lines (L-132 cells) as well as cancerous cell lines (MCF-7 cells), demonstrating over 92% cell viability after 48 h in both cell lines. In vitro, the cytotoxicity of the 5-FU-loaded hydrogels was evaluated on MCF-7 and HeLa cell lines. These results indicate that the investigated biocompatible and nontoxic ionic hydrogels enable the transdermal delivery of hydrophilic drugs, making them a viable option for effectively treating breast cancer.

Telehealth Utilization for Opioid Use Disorder: A Nationwide Analysis Before and After the COVID-19 Public Health Emergency Declaration.

Introduction: The COVID-19 pandemic has led to the rapid and widespread adoption of telehealth services. Telehealth may aid in bridging gaps in access to care. The specific impact of telehealth on opioid use disorder (OUD) and its treatment remains uncertain. Methods: A retrospective review of commercial insurance claim records within the United States was conducted to investigate the association between the COVID-19 pandemic and changes in the rates of(a) OUD treatments with and without telehealth support and (b) prescriptions for medications for opioid use disorder (MOUD) with and without telehealth support among individuals diagnosed with OUD. Results: In a study population of 1,340,506 individuals, OUD diagnosis rates were 5 per 1,000 in-person and 1 per 1,000 via telehealth. COVID-19 decreased in-person OUD diagnoses by 0.89 per 1,000, while telehealth diagnoses increased by 0.83 per 1,000. In-person MOUD treatment rates increased by 0.07 per 1,000 during COVID-19, while telehealth rates remained low. The onset of COVID-19 saw a 1.13 per 1,000 higher increase in telehealth-supported MOUD treatment compared to solely in-person treatment. Conclusions: A retrospective review of commercial insurance claim records within the United States was conducted to investigate the association between the COVID-19 pandemic and changes in the rates of (a) OUD treatments with and without telehealth support and (b) prescriptions for MOUD with and without telehealth support among individuals diagnosed with OUD.

Microfluidic Platform Enables Shearless Aerosolization of Lipid Nanoparticles for mRNA Inhalation.

Leveraging the extensive surface area of the lungs for gene therapy, the inhalation route offers distinct advantages for delivery. Clinical nebulizers that employ vibrating mesh technology are the standard choice for converting liquid medicines into aerosols. However, they have limitations when it comes to delivering mRNA through inhalation, including severe damage to nanoparticles due to shearing forces. Here, we introduce a microfluidic aerosolization platform (MAP) that preserves the structural and physicochemical integrity of lipid nanoparticles, enabling safe and efficient delivery of mRNA to the respiratory system. Our results demonstrated the superiority of the MAP over the conventional vibrating mesh nebulizer, as it avoided problems such as particle aggregation, loss of mRNA encapsulation, and deformation of the nanoparticle morphology. Notably, aerosolized nanoparticles generated by the microfluidic device led to enhanced transfection efficiency across various cell lines. In vivo experiments with mice that inhaled these aerosolized nanoparticles revealed successful lung-specific mRNA transfection without observable signs of toxicity. This MAP may represent an advancement for the pulmonary gene therapy, enabling precise and effective delivery of aerosolized nanoparticles.

Solid self-emulsifying casein carrier for the improvement on the oral bioavailability of simvastatin.

Simvastatin (SV) is a statin drug that can effectively control cholesterol and prevent cardiovascular diseases. However, SV is water-insoluble, and poor oral bioavailability (<5 %). Solid self-emulsifying carrier system is more stable than liquid emulsions, facilitating to improve the solubility and bioavailability of poorly soluble drugs. In the present study, a solid self-emulsifying carrier stabilized by casein (Cas-SSE) was successfully used to load SV to improve its solubility in water, by formulation selection and emulsification process optimization. Compared with oral tablets, the release of SV from Cas-SSE was significantly enhanced in artificial intestinal fluid. Furthermore, everted gut sac experiments indicated some water-soluble dispersing agents such as hydroxyethyl starch (HES), were not conducive to drug absorption. Pharmacokinetic studies suggested Cas-SSE without dispersing agent has much higher relative bioavailability (184.1 % of SV and 284.5 % of simvastatin acid) than SV tablet. The present work suggests Cas-SSE is a promising drug delivery platform with good biocompatibility for improving oral bioavailability of poorly water-soluble drugs.

Hyaluronic acid functionalized citric acid dendrimer/UiO-66-COOH as a stable and biocompatible platform for daunorubicin delivery.

This work aimed to prepare a new system for daunorubicin (DNR) delivery to improve therapeutic efficiency and decrease unwanted side effects. Typically, at first, a carboxylic acid functional group containing metal-organic framework (UiO-66-COOH) was synthesized in a simple way. Then, a third generation of citric acid dendrimer (CAD G3) was grown on it (UiO-66-COOH-CAD G3). Finally, the system was functionalized with pre-modified hyaluronic acid (UiO-66-COOH-CAD-HA). SEM analysis displayed that the synthesized particles have a spherical shape with an average particle size ranging from 260 to 280 nm. An increase in hydrodynamic diameter from 223 nm for UiO-66-COOH to 481 nm for UiO-66-COOH-CAD-HA is a sign of success in the performed reactions. Also, the average pore size was calculated at about 4.04 nm. The DNR loading efficiency of UiO-66-COOH-CAD-HA was evaluated at ~74 % (DNR@UiO-66-COOH-CAD-HA). It was observed that the drug release rate at a lower pH is more than higher pH. The maximum hemolysis of <3 % means that the UiO-66-COOH-CAD-HA is hemocompatible. The use of DNR-loaded UiO-66-COOH-CAD-HA led to cell-killing of 77.9 % for MDA-MB 231. These results specified the great potential of UiO-66-COOH-CAD-HA for tumor drug delivery, so it could be proposed as a new carrier for anticancer agents to minimize adverse effects and improve therapeutic efficacy.

Acetazolamide encapsulation in elastin like recombinamers using a supercritical antisolvent (SAS) process for glaucoma treatment.

Glaucoma, the second most common cause of blindness worldwide, requires the development of new and effective treatments. This study introduces a novel controlled-release system utilizing elastin-like recombinamers (ELR) and the Supercritical Antisolvent (SAS) technique with supercritical CO2. Acetazolamide (AZM), a class IV drug with limited solubility and permeability, is successfully encapsulated in an amphiphilic ELR at three different ELR:AZM ratios, yielding up to 62 %. Scanning electron microscopy (SEM) reveals spherical microparticles that disintegrate into monodisperse nanoparticles measuring approximately 42 nm under physiological conditions. The nanoparticles, as observed via Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM), do not exhibit aggregates, a fact confirmed by the zeta potential displaying a value of -33 mV over a period of 30 days. Transcorneal permeation tests demonstrate a 10 % higher permeation level compared to the control solution, which increases to 30 % after 2 h. Ocular irritation tests demonstrate no adverse effects or damage. Intraocular pressure (IOP) tests conducted on hypertensive rabbits indicate greater effectiveness for all three analyzed formulations, suggesting enhanced drug bioavailability during treatment. Consequently, the combination of recombinant biopolymers and high-pressure techniques represents a promising approach for advancing glaucoma therapy, emphasizing its potential clinical significance.

Deciphering the monocyte-targeting mechanisms of PEGylated cationic liposomes by investigating the biomolecular corona.

Cationic liposomes specifically target monocytes in blood, rendering them promising drug-delivery tools for cancer immunotherapy, vaccines, and therapies for monocytic leukaemia. The mechanism behind this monocyte targeting ability is, however, not understood, but may involve plasma proteins adsorbed on the liposomal surfaces. To shed light on this, we investigated the biomolecular corona of three different types of PEGylated cationic liposomes, finding all of them to adsorb hyaluronan-associated proteins and proteoglycans upon incubation in human blood plasma. This prompted us to study the role of the TLR4 co-receptors CD44 and CD14, both involved in signalling and uptake pathways of proteoglycans and glycosaminoglycans. We found that separate inhibition of each of these receptors hampered the monocyte uptake of the liposomes in whole human blood. Based on clues from the biomolecular corona, we have thus identified two receptors involved in the targeting and uptake of cationic liposomes in monocytes, in turn suggesting that certain proteoglycans and glycosaminoglycans may serve as monocyte-targeting opsonins. This mechanistic knowledge may pave the way for rational design of future monocyte-targeting drug-delivery platforms.