Effective Drug Delivery Research Articles

A copper-loaded self-assembled nanoparticle for disturbing the tumor redox balance and triple anti-tumor therapy.

Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed using copper ion (Cu2+), doxorubicin (Dox), zinc phthalocyanine (ZnPc) and a trace amount of poly(2-(di-methylamino)ethylmethacrylate)-poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. These triple factor-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radicals (˙OH), thereby enhancing the chemodynamic and photodynamic therapy. Herein, this study provides a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.

Dual stimuli-responsive polymeric nanoparticles combining soluplus and chitosan for enhanced breast cancer targeting.

A dual stimuli-responsive nanocarrier was developed from smart biocompatible chitosan and soluplus graft copolymers. The copolymerization was investigated by differential scanning calorimetry (DSC), thermo-gravimetric analysis (TGA), and Fourier transform infrared (FTIR). The optimized chitosan-soluplus nanoparticles (CS-SP NPs) were further used for the encapsulation of a poorly water-soluble anticancer drug. Tamoxifen citrate (TC) was used as the model drug and it was loaded in CS-SP NPs. TC CS-SP NPs were characterized in terms of particle size, zeta potential, polydispersity, morphology, encapsulation efficiency, and physical stability. The nanoparticles showed homogenous spherical features with a size around 94 nm, a slightly positive zeta potential, and an encapsulation efficiency around 96.66%. Dynamic light scattering (DLS), in vitro drug release, and cytotoxicity confirmed that the created nano-system is smart and exhibits pH and temperature-responsive behavior. In vitro cellular uptake was evaluated by flow cytometry and confocal microscopy. The nanoparticles revealed a triggered increase in size upon reaching the lower critical solution temperature of SP, with 70% of drug release at acidic pH and 40 °C within the first hour and a 3.5-fold increase in cytotoxicity against MCF7 cells incubated at 40 °C. The cellular uptake study manifested that the prepared nanoparticles succeeded in delivering drug molecules to MCF7 and MDA-MB-231 cells. In summary, the distinctive characteristics provided by these novel CS-SP NPs result in a promising nano-platform for effective drug delivery in cancer treatment.

Biomaterial-based combinatorial approach of aescin-comprised zein-coated gelatin nanoparticles alleviates synovial inflammation in experimental inflammatory arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that mostly affects joints. Although RA therapy has made significant progress, difficulties including extensive medication metabolism and its quick clearance result in its inadequate bioavailability. The anti-inflammatory effect of zein was reported with other medications, but it has certain limitations. There are reports on the anti-oxidant and anti-inflammatory effect of aescin, which exhibits low bioavailability for the treatment of rheumatoid arthritis. Also, the combinatorial effect of zein with other effective drug delivery systems is still under investigation for the treatment of experimental collagen-induced rheumatoid arthritis. The focus of this study was to formulate and define the characteristics of zein-coated gelatin nanoparticles encapsulated with aescin (Ze@Aes-GNPs) and to assess and contrast the therapeutic effectiveness of Ze@Aes-GNPs towards collagen-induced RA in Wistar rats. Nanoprecipitation and the layer-by-layer coating process were used to fabricate Ze@Aes-GNPs and their hydrodynamic diameter was determined to be 182 nm. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to further validate the size, shape, and surface morphology of Ze@Aes-GNPs. When tested against foreskin fibroblasts (BJ), these nanoparticles demonstrated significantly high cytocompatibility. Both Aes and Ze@Aes-GNPs were effective in treating arthritis, as shown by the decreased edoema, erythema, and swelling of the joints, between which Ze@Aes-GNPs were more effective. Further, it was demonstrated that Aes and Ze@Aes-GNPs reduced the levels of oxidative stress (articular elastase, lipid peroxidation, catalase, superoxide dismutase and nitric oxide) and inflammatory indicators (TNF-α, IL-1β and myeloperoxidase). The histopathology findings further demonstrated that Ze@Aes-GNPs considerably reduced the infiltration of inflammatory cells at the ankle joint cartilage compared to Aes. Additionally, immunohistochemistry examination showed that treatment with Ze@Aes-GNPs suppressed the expression of pro-inflammatory markers (COX-2 and IL-6) while increasing the expression of SOD1. In summary, the experiments indicated that Aes and Ze@Aes-GNPs lowered the severity of arthritis, and critically, Ze@Aes-GNPs showed better effectiveness in comparison to Aes. This suppression of oxidative stress and inflammation was likely driven by Aes and Ze@Aes-GNPs.

Large animal models for Huntington's disease research.

Huntington's disease (HD) is a hereditary neurodegenerative disorder for which there is currently no effective treatment available. Consequently, the development of appropriate disease models is critical to thoroughly investigate disease progression. The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin ( HTT) gene, leading to the expansion of a polyglutamine repeat in the HTT protein. Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain, which precipitate selective neuronal loss in specific brain regions. Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets. Due to the marked species differences between rodents and larger animals, substantial efforts have been directed toward establishing large animal models for HD research. These models are pivotal for advancing the discovery of novel therapeutic targets, enhancing effective drug delivery methods, and improving treatment outcomes. We have explored the advantages of utilizing large animal models, particularly pigs, in previous reviews. Since then, however, significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD. In the current review, we provide a comprehensive overview of large animal models of HD, incorporating recent findings regarding the establishment of HD knock-in (KI) pigs and their genetic therapy. We also explore the utilization of large animal models in HD research, with a focus on sheep, non-human primates (NHPs), and pigs. Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

Small extracellular vesicles: Roles and clinical application in prostate cancer.

Prostate cancer is a significant health problem in the United States. It is remarkably heterogenous, ranging from slow growing disease amenable to active surveillance to highly aggressive forms requiring active treatments. Therefore, being able to precisely determine the nature of disease and appropriately match patients to available and/or novel therapeutics is crucial to improve patients' overall outcome and quality of life. Recently small extracellular vesicles (sEVs), a subset of nanoscale membranous vesicles secreted by various cells, have emerged as important analytes for liquid biopsy and promising vehicles for drug delivery. sEVs contain various biomolecules such as genetic material, proteins, and lipids that recapitulate the characteristics and state of their donor cells. The application of existing and newly developed technologies has resulted in an increased depth of knowledge about biophysical structures, biogenesis, and functions of sEVs. In prostate cancer patients, tumor-derived sEVs can be isolated from biofluids, commonly urine and blood. They mediate intercellular signaling within the tumor microenvironment and distal organ-specific sites, supporting cancer initiation, progression, and metastasis. A mounting body of evidence suggests that sEV components can be potent biomarkers for prostate cancer diagnosis, prognosis, and prediction of disease progression and treatment response. Due to enhanced circulation stability and bio-barrier permeability, sEVs can be also used as effective drug delivery carriers to improve the efficacy and specificity of anti-tumor therapies. This review discusses recent studies on sEVs in prostate cancer and is focused on their role as biomarkers and drug delivery vehicles in the clinical management of prostate cancer.

Carbon nanomaterials as carriers for the anti-cancer drug doxorubicin: a review on theoretical and experimental studies.

The incidence of cancer is increasing worldwide in a life-threatening manner. In such a scenario, the development of anti-cancer drugs with minimal side effects and effective drug delivery systems is of paramount importance. Doxorubicin (DOX) is one of the powerful anti-cancer drugs from the chemical family anthracycline, which is used to treat a wide variety of cancers, including breast, prostate, ovarian, and hematological malignancies. However, DOX has been associated with many side effects, including lethal cardiotoxicity, baldness, gastrointestinal disturbances and cognitive function impairment. Even though DOX is administered in liposomal formulations to reduce its toxicity and enhance its therapeutic profile, the liposomal formulations themselves have certain therapeutic profile limitations such as "palmar-plantar erythrodysesthesia (PPE)", which shows severe swelling and redness in the skin, thus restricting the dosage and reducing patient compliance. In contemporary chemotherapy research, there is a great interest in the utilization of nanomaterials for precise and targeted drug delivery applications, especially using carbon-based nanomaterials. This review provides a comprehensive overview of both experimental and theoretical scientific works, exploring diverse forms of carbon-based materials such as graphene, graphene oxide, and carbon nanotubes that function as carriers for DOX. In addition, the review consolidates information on the fate of the carriers after the delivery of the payload at the site of action through different imaging techniques and the various pathways through which the body eliminates these nanomaterials. In conclusion, the review presents a detailed overview of the toxicities associated with these carriers within the human body, contributing to the development of enhanced drug delivery systems.

A novel magnetically guided, oxygen propelled CoPt/Au nanosheet motor in conjugation with a multilayer hollow microcapsule for effective drug delivery and light triggered drug release.

In recent years, nanomotors have been developed and attracted extensive attention in biomedical applications. In this work, a magnetically-guided oxygen-propelled CoPt/gold nanosheet motor (NSM) was prepared and used as an active self-propelled platform that can load, transfer and control the release of drug carrier to cancer cells. As a drug carrier, the microcapsules were constructed by the layer-by-layer (LbL) coating of chitosan and carboxymethyl cellulose layers, followed by incorporation of gold and magnetite nanoparticles. Doxorubicin (DOX) as an anti-cancer drug was loaded onto the synthesized microcapsules with a loading efficiency of 77%. The prepared NSMs can deliver the DOX loaded magnetic multilayer microcapsule to the target cancer cell based on the catalytic decomposition of H2O2 solution (1% v/v) via guidance from an external magnetic force. The velocity of NSM was determined to be 25.1 μm s-1 in 1% H2O2. Under near-infrared irradiation, and due to the photothermal effect of the gold nanoparticles, the proposed system was found to rapidly release more drugs compared to that of an internal stimulus diffusion process. Moreover, the investigation of cytotoxicity of NSMs and multilayer microcapsules clearly revealed that they have negligible side effects over all the concentrations tested.

Tuneable redox-responsive albumin-hitchhiking drug delivery to tumours for cancer treatment.

This paper outlines a novel drug delivery system for highly cytotoxic mertansine (DM1) by conjugating to an albumin-binding Evans blue (EB) moiety through a tuneable responsive disulfide linker, providing valuable insights for the development of effective drug delivery systems toward cancer therapy.

An active transport dual adaptive nanocarrier designed to overcome the corneal microenvironment for neovascularization therapy.

The eyes have a complicated microenvironment with many clearance mechanisms, making it challenging for effective drug delivery to the targeted areas of the eyes. Substrate transport mediated by active transporters is an important way to change drug metabolism in the ocular microenvironment. We designed multifunctional, dual-adaptive nanomicelles (GSCQ@NTB) which could overcome multiple physiological barriers by acting on both the efflux transporter and influx transporter to achieve deep delivery of the P-gp substrate in the cornea. Specifically, an effective "triple" antiangiogenic agent, nintedanib (NTB), was loaded into the biocompatible micelles. The expression of the efflux transporter was reversed by grafting quercetin. The peptide (glycylsarcosine, GS) was modified to target the influx transporter "Peptide Transporter-1" (PepT-1). Quercetin (QRT) and nintedanib (NTB) were transported to the cornea cooperatively, achieving long retention on the ocular surface and high compatibility. In a New Zealand rabbit model, within 8 hours after local administration, GSCQ@NTB was enriched in corneal stromal neovascularization and effectively inhibited the progress of neovascularization. Its effectiveness is slightly better than that in the first-line clinical application of steroids. In this study, we introduce the preparation of a dual adaptive nano-micelle system, which may provide an effective non-invasive treatment for corneal neovascularization.

Improvement of solubility, dissolution, and bioavailability of phenytoin intercalated in Mg-Al layered double hydroxide.

Layered double hydroxides (LDHs) are highly effective drug delivery systems, owing to their capacity to intercalate or adsorb biomaterials, flexible structure, swelling property, high stability, good biocompatibility, and ease of synthesis. Phenytoin (PHT) is an antiseizure BCS (Biopharmaceutics Classification System) class II drug, presenting low aqueous solubility. Therefore, the current study aimed at increasing its solubility, dissolution, and bioavailability. PHT was intercalated to the MgAl-LDH formed in situ and successful intercalation to form MgAl-PHT-LDH was confirmed by FTIR, PXRD, DSC, and TGA. Examination of particle size and morphology (by photon correlation spectroscopy and electron microscopy, respectively) confirmed the formation and intercalation of nanostructured LDH. Intercalation enhanced the saturation solubility of PHT at 25°C in 0.1N HCl and phosphate buffer (pH 6.8) by 6.57 and 10.5 times respectively. The selected drug excipient powder blend for the formulation of MgAl-PHT-LDH tablets exhibited satisfactory properties in both pre-compression parameters (angle of repose, bulk density, tapped density, Carr's index, and Hausner ratio) and tablet characteristics (weight variation, thickness, hardness, friability, content uniformity, and disintegration time). MgAl-PHT-LDH tablets showed better dissolution of PHT compared to unprocessed PHT tablets at all time points. Oral bioavailability of MgAl-PHT-LDH tablets and unprocessed PHT tablets was tested in two groups of Sprague Dawley rats based on analysis of serum levels of both forms of PHT by UPLC-ESI-MS/MS serum. MgAl-PHT-LDH tablets demonstrated a relative bioavailability of 130.15% compared to unprocessed PHT tablets, confirming a significantly higher oral bioavailability of MgAl-PHT-LDH. In conclusion, MgAl-PHT-LDH could provide a strategy for enhancing solubility, dissolution, and thereby bioavailability of PHT, enabling the evaluation of theclinical efficacy of MgAl-PHT-LDH tablets for the treatment of seizures at lower PHT doses.

CNS Drug Delivery in Stroke: Improving Therapeutic Translation From the Bench to the Bedside.

Drug development for ischemic stroke is challenging as evidenced by the paucity of therapeutics that have advanced beyond a phase III trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit. Such knowledge will permit the innate biology of the BBB/neurovascular unit to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. In this review, we will highlight key aspects of BBB/neurovascular unit pathophysiology and describe state-of-the-art approaches for optimization of central nervous system drug delivery (ie, passive diffusion, mechanical opening of the BBB, liposomes/nanoparticles, transcytosis, intranasal drug administration). Additionally, we will discuss how endogenous BBB transporters represent the next frontier of drug delivery strategies for stroke. Overall, this review will provide cutting edge perspective on how central nervous system drug delivery must be considered for the advancement of new stroke drugs toward human trials.

Self-Assembled Aggregated Structures of Natural Products for Oral Drug Delivery.

The self-assembling aggregated structures of natural products have gained significant interest due to their simple synthesis, lack of carrier-related toxicity, and excellent biological efficacy. However, the mechanisms of their assembly and their ability to traverse the gastrointestinal (GI) barrier remain unclear. This review summarizes various intermolecular non-covalent interactions and aggregated structures, drawing on research indexed in Web of Science from 2010 to 2024. Cheminformatics analysis of the self-assembly behaviors of natural small molecules and their supramolecular aggregates reveals assembly-favorable conditions, aiding drug formulation. Additionally, the review explores the self-assembly properties of macromolecules like polysaccharides, proteins, and exosomes, highlighting their role in drug delivery. Strategies to overcome gastrointestinal barriers and enhance drug bioavailability are also discussed. This work underscores the potential of natural products in oral drug delivery and offers insights for designing more effective drug delivery systems.

First-principles calculations on monolayer WX2 (X = S, Se) as an effective drug delivery carrier for anti-tuberculosis drugs.

Tuberculosis (TB) remains a major global health concern, necessitating the exploration of novel drug delivery systems to combat the challenges posed by conventional approaches. We investigated the potential of monolayer transition metal dichalcogenides (TMDs) as an innovative platform for efficient and targeted delivery of antituberculosis drugs. Specifically, the electronic and optical properties of prominent TB drugs, isoniazid (INH) and pyrazinamide (PZA), adsorbed on tungsten diselenide (WSe2) and tungsten disulfide (WS2) monolayers were studied using first-principles calculations based on density functional theory (DFT). The investigation revealed that the band gaps of WSe2 and WS2 monolayers remain unaltered upon adsorption of PZA or INH, with negative adsorption energy indicating stable physisorption. We explored different vertical and horizontal configurations, and the horizontal ones were more stable. When INH and PZA drugs were horizontally adsorbed together on WSe2, the most stable configuration was found with an adsorption energy of -2.35 eV. Moreover, the adsorbed drugs could be readily released by light within the visible or near-infrared (NIR) wavelength range. This opened up possibilities for their potential application in photothermal therapy, harnessing the unique properties of these 2D materials. The comprehensive analysis of the band structures and density of states provides valuable insights into how the drug molecules contributed to the conduction and valence bands. The optical responses of anti-TB drugs adsorbed in 2D WSe2 and WS2 were similar to those of pristine 2D WSe2 and WS2. We demonstrated the temperature-dependent release mechanism of our 2D WSe2 and WS2 drug complexes, confirming the feasibility of releasing the discussed anti-tuberculosis drugs by generating heat through photothermal therapy. These findings hold significant promise for developing innovative drug delivery systems that have enhanced efficacy for targeted and low-toxic TB treatment.

Screening of poly-beta amino ester coated emulsion of ketorolac for cartilage delivery.

Osteoarthritis (OA) is a prevalent chronic health condition necessitating effective treatment strategies. Globally, there were 86 million people with incident knee osteoarthritis in 2020. Pain management remains the primary approach to OA as the nature of cartilage poses challenges for drug delivery. An emulsion-based delivery system, using a class of positively charged and hydrolysable polymers (poly-beta-amino-esters) to coat oil droplets containing drugs, has been shown to enhance and prolong drug localization in ex vivo cartilage models. As the properties of the polymers used in this technology strongly depend on the monomers used in the synthesis, this study presents the screening of a wide range of PBAEs as droplet coating agents and using ketorolac as a model of nonsteroidal anti-inflammatory drugs. The emulsions prepared with this PBAE library were characterized, and drug localisation and retention were evaluated in both native and glycosaminoglycan (GAG) depleted cartilage ex vivo models. Optimal candidates were identified and tested in an ex vivo model showing the ability to protect chondrocyte cell viability and increase both GAG and collagen contents in cartilage exposed to cytokine (IL-1α) simulating acute cartilage damage. This work demonstrates the potential of PBAE coated emulsion as a delivery system for effective drug delivery in OA treatment.

Left Sixth Nerve Palsy and Subdural Hygroma Following Intrathecal Morphine Pump Placement: A Case Report

BACKGROUND: An intrathecal (IT) pump is an effective drug delivery system that assists patients with chronic pain management. However, due to the invasive nature of the procedure, a complication that could arise is cerebrospinal overdrainage or leak, which could lead to adverse effects. CASE REPORT: The patient underwent an IT morphine pump implant for treatment of his chronic, intractable low back pain. Following the procedure, he developed persistent headaches and diplopia and was found to have left lateral rectus palsy. Imaging studies showed the development of bilateral subdural hygromas. His condition was resolved with surgical intervention and time. CONCLUSIONS: After an extensive literature search and review, to our knowledge, this is the first reported case of sixth nerve palsy and subdural hygromas following the implant of a drug delivery system. KEY WORDS: Abducens palsy, IT pump, subdural hydrgomas, intrathecal drug delivery system, lateral rectus palsy

Targeted delivery of doxorubicin by SP5-52 peptide conjugated exosome nanoparticles into lung tumor: An in vitro and in vivo study

Here, SP5-52 peptide conjugated exosome nanostructures were developed for targeted delivery of Doxorubicin (DOX) into lung tumor. Exosomes extracted from the serum of Balb/c mice, were characterized in terms of structure and physicochemical properties. Based on the results, the size and zeta potential of exosome NPs were 67 nm and −5 mV, respectively, which was slightly increased after SP5-52 conjugation and DOX loading. The in vitro cell studies displayed that targeted DOX-loaded exosomes had higher cytotoxicity, cellular uptake, and accumulation in LL/2 cell lines compared with non-targeted DOX-loaded exosomes and control groups. Moreover, the therapeutic efficacy of the prepared formulations was evaluated in lung tumor bearing Balb/c mice within 21 days. Accordingly, targeted DOX-loaded exosomes had effectively treated the lung tumor in comparison to other groups. The rate of survival in the mice treated with targeted exosomes was also 35 % higher than other groups; while, the mortality rate was lower. The histopathological evaluation confirmed the accepted off-targeted properties of the targeted exosomes as lower toxicity was observed in different organs rather than lung. This study presents an effective anticancer drug delivery system for specific targeting of induced lung tumor, which could be useful in the treatment of malignant lung cancers in the future.

Data-driven development of an oral lipid-based nanoparticle formulation of a hydrophobic drug.

Due to its cost-effectiveness, convenience, and high patient adherence, oral drug administration normally remains the preferred approach. Yet, the effective delivery of hydrophobic drugs via the oral route is often hindered by their limited water solubility and first-pass metabolism. To mitigate these challenges, advanced delivery systems such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have been developed to encapsulate hydrophobic drugs and enhance their bioavailability. However, traditional design methodologies for these complex formulations often present intricate challenges because they are restricted to a relatively narrow design space. Here, we present a data-driven approach for the accelerated design of SLNs/NLCs encapsulating a model hydrophobic drug, cannabidiol, that combines experimental automation and machine learning. A small subset of formulations, comprising 10% of all formulations in the design space, was prepared in-house, leveraging miniaturized experimental automation to improve throughput and decrease the quantity of drug and materials required. Machine learning models were then trained on the data generated from these formulations and used to predict properties of all SLNs/NLCs within this design space (i.e., 1215 formulations). Notably, formulations predicted to be high-performers via this approach were confirmed to significantly enhance the solubility of the drug by up to 3000-fold and prevented degradation of drug. Moreover, the high-performance formulations significantly enhanced the oral bioavailability of the drug compared to both its free form and an over-the-counter version. Furthermore, this bioavailability matched that of a formulation equivalent in composition to the FDA-approved product, Epidiolex®.

Investigating the influence of lipids on Nano-structured lipid carrier formulation

The study aimed to evaluate the effect of different lipids on the properties of nanostructured lipid carrier (NLC) formulations. The particle size, zeta potential, polydispersity index, entrapment efficiency, and drug release at 24 hours were analyzed for formulations containing various lipid matrices. Among the formulations tested, N3 (Compritol 888 ATO and Softigen) exhibited the most favourable characteristics, including the smallest particle size, highest entrapment efficiency, sustained drug release, and good stability, as indicated by a high zeta potential. Other lipids, such as Witepsol H 32 and Beeswax, also showed desirable properties. The formulations containing Dynasan 114 and Acconon-C-44 EP/NF resulted in larger particle sizes, lower entrapment efficiencies, and slower drug release. Cholesterol exhibited distinct properties, with a lower zeta potential and moderate drug release. The findings highlight the importance of lipid selection in determining the performance and functionality of NLC formulations. Compritol 888 ATO and Softigen were identified as suitable lipids for further optimization of NLC formulations. These lipids contribute to the formation of stable and uniform NLC particles, which are desirable for efficient drug delivery systems. The study provides valuable insights for formulating NLCs with optimized characteristics, facilitating the development of effective drug delivery systems. Future research can focus on optimizing other factors to enhance the performance and therapeutic effectiveness of NLC formulations.

Unraveling the Molecular Mechanisms of Alcohol-Mediated Skin Permeation Enhancement: Insights from Molecular Dynamics Simulations.

The application of alcohols as permeation enhancers in pharmaceutical and cosmetic formulations has attracted considerable attention, owing to their skin permeation-enhancing effect. Nonetheless, the elucidation of the fundamental mechanisms underlying the skin permeation-enhancing effect remains elusive. In this study, molecular dynamics (MD) simulations were employed to investigate the effect of 1,2-propanediol (1,2-PDO), 1,2-butanediol (1,2-BDO), and ethanol (EtOH) on the stratum corneum (SC) model membrane. The results showed that the effect of alcohols on the SC model membrane displayed a concentration-dependent nature. The alcohols can interact with SC lipids and exhibit a remarkable ability to selectively extract free fatty acid (FFA) molecules from the SC model membrane and make the SC looser. Meanwhile, 1,2-BDO and EtOH can penetrate into SC lipid bilayers at higher concentrations, leading to the formation of continuous hydrophilic defects in SC. The FFA extraction and the formation of continuous hydrophilic defects induced ceramide (CER) tail chains to become more disordered and fluid and also weakened the hydrogen bonding (H-bonding) network among SC lipids. Both the FFA extraction and the continuous hydrophilic defect formation endowed alcohols with the permeation-enhancing effect. The constrained simulations revealed that the free energy barriers decreased for the permeation of the hydrophilic model molecule (COL) across the SC model membranes containing alcohols, particularly for 1,2-BDO and EtOH. The possible permeation-enhancing mechanisms of alcohols were proposed correspondingly. This work not only provided a deep understanding of the transdermal permeation-enhancing behavior of alcohols at the molecular level but also provided necessary reference information for designing effective transdermal drug delivery systems in applications.

CD4+ T cell-targeting immunoliposomes for treatment of latent HIV reservoir

Active targeting nano-delivery is a promising approach to enhance therapeutic efficacy and specificity to the target cells. Liposomes (LPs) have been widely studied for the active targeting delivery due to their low toxicity, biodegradability, biocompatibility, and feasibility of surface medication to provide the interactions with cell receptors. One of the strategies is to functionalize the surface of LPs with monoclonal antibodies (mAbs) to obtain immunoliposomes (imLPs) that recognize specific receptors on target cells. Among several target cells, CD4+ T cells are known for playing a pivotal role in controlling the immune system in several diseases, including cancers, inflammatory diseases, and viral infections, particularly HIV-1. Here, we demonstrate two methods for conjugating αCD4 mAb with imLPs for specific targeting of CD4+ T cells that can harbor viral genome and serve as a predominant latent HIV reservoir. LPs conjugated with αCD4 mAb via neutravidin-biotin linkage were used for selectively targeting CD4+ J-Lat 10.6 cells. We demonstrate, via flow cytometry, the importance of the conjugation step, mAb density, and the presence of polyethylene glycol (PEG) for effective drug delivery to CD4+ T cells. The cellular uptake of imLPs is substantially higher if the imLPs are functionalized with the pre-conjugated αCD4 mAb-neutravidin complex. Furthermore, imLPs loaded with HIV-1 latency reversing agent, suberoylanilide hydroxamic acid (SAHA), could reactivate the J-Lat 10.6 cells, suggesting that the αCD4-imLPs could be potentially used as a targeted drug delivery system for HIV-1 latency reactivation or other CD4-targeted immunotherapies.