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Eye, Cell Line, Endothelial Cells, Animals, Rabbits, Humans, Guinea Pigs, Silicic Acid, Drug Carriers, Cell Culture Techniques, Cell Survival, Particle Size, Surface Properties, Porosity, Silica Gel, Intravitreal Injections, In Vitro Techniques, Drug Liberation, Intravitreal drug delivery, rabbit and guinea pig eyes, silica pore size and ocular toxicity, silicic acid cytotoxicity, sol-gel mesoporous silica, Pharmacology and Pharmaceutical Sciences, and Pharmacology & Pharmacy

Mesoporous silica has attracted significant attention in the drug delivery area; however, impurities can be a source of toxicity. The current study used commercial microparticles produced at large scale in a well-controlled environment. Micrometer sized mesoporous silica particles were acquired through a commercial vendor and pore structures were characterized by SEM. The three silica particle formulations had a diameter of 15 micrometers and three different pore sizes of 10 nm, 30 nm, and 100 nm. The fourth formulation had particle size of 20-40 micrometers with 50 nm pores. Before in vivo tests, an in vitro cytotoxicity test was conducted with silicic acid, derived from the sol-gel particles, on EA.hy926 cells. Low concentration (2.5 µg/mL) of silicic acid showed no cytotoxicity; however, high concentration (25 µg/mL) was cytotoxic. In vivo intravitreal injection demonstrated that 15 um silica particles with 10 nm pore were safe in both rabbit and guinea pig eyes and the particles lasted in the vitreous for longer than two months. Formulations of with larger pores demonstrated variable localized vitreous cloudiness around the sol-gel particle depot and mild inflammatory cells in the aqueous humor. The incidence of reaction trended higher with larger pores (10 nm: 0%, 30 nm: 29%, 50 nm: 71%, 100 nm: 100%, p

Gastric Juice, Humans, Delayed-Action Preparations, Tablets, Chemistry, Pharmaceutical, Proton Pump Inhibitors, Drug Liberation, and Bioengineering

Many solid-dose oral drug products are engineered to release their active ingredients into the body at a certain rate. Techniques for measuring the dissolution or degradation of a drug product in vitro play a crucial role in predicting how a drug product will perform in vivo. However, existing techniques are often labor-intensive, time-consuming, irreproducible, require specialized analytical equipment, and provide only "snapshots" of drug dissolution every few minutes. These limitations make it difficult for pharmaceutical companies to obtain full dissolution profiles for drug products in a variety of different conditions, as recommended by the US Food and Drug Administration. Additionally, for drug dosage forms containing multiple controlled-release pellets, particles, beads, granules, etc. in a single capsule or tablet, measurements of the dissolution of the entire multi-particle capsule or tablet are incapable of detecting pellet-to-pellet variations in controlled release behavior. In this work, we demonstrate a simple and fully-automated technique for obtaining dissolution profiles from single controlled-release pellets. We accomplished this by inverting the drug dissolution problem: instead of measuring the increase in the concentration of drug compounds in the solution during dissolution (as is commonly done), we monitor the decrease in the buoyant mass of the solid controlled-release pellet as it dissolves. We weigh single controlled-release pellets in fluid using a vibrating tube sensor, a piece of glass tubing bent into a tuning-fork shape and filled with any desired fluid. An electronic circuit keeps the glass tube vibrating at its resonance frequency, which is inversely proportional to the mass of the tube and its contents. When a pellet flows through the tube, the resonance frequency briefly changes by an amount that is inversely proportional to the buoyant mass of the pellet. By passing the pellet back-and-forth through the vibrating tube sensor, we can monitor its mass as it degrades or dissolves, with high temporal resolution (measurements every few seconds) and mass resolution (700 nanogram resolution). As a proof-of-concept, we used this technique to measure the single-pellet dissolution profiles of several commercial controlled-release proton pump inhibitors in simulated stomach and intestinal contents, as well as comparing name-brand and generic formulations of the same drug. In each case, vibrating tube sensor data revealed significantly different dissolution profiles for the different drugs, and in some cases our method also revealed differences between different pellets from the same drug product. By measuring any controlled-release pellets, particles, beads, or granules in any physiologically-relevant environment in a fully-automated fashion, this method can augment and potentially replace current dissolution tests and support product development and quality assurance in the pharmaceutical industry.

Escherichia coli, Thiazoles, Delayed-Action Preparations, Drug Carriers, Anti-Bacterial Agents, Microbial Sensitivity Tests, Drug Compounding, Microspheres, Diffusion, Nanostructures, and Drug Liberation

Hollow multishelled structures (HoMSs), with relatively isolated cavities and hierarchal pores in the shells, are structurally similar to cells. Functionally inspired by the different transmission forms in living cells, we studied the mass transport process in HoMSs in detail. In the present work, after introducing the antibacterial agent methylisothiazolinone (MIT) as model molecules into HoMSs, we discover three sequential release stages, i.e., burst release, sustained release and stimulus-responsive release, in one system. The triple-shelled structure can provide a long sterility period in a bacteria-rich environment that is nearly 8 times longer than that of the pure antimicrobial agent under the same conditions. More importantly, the HoMS system provides a smart responsive release mechanism that can be triggered by environmental changes. All these advantages could be attributed to chemical diffusion- and physical barrier-driven temporally-spatially ordered drug release, providing a route for the design of intelligent nanomaterials.

Leukocytes, Mononuclear, Cells, Cultured, Cytoplasm, Humans, HIV-1, HIV Infections, Ribonucleoproteins, Anti-Retroviral Agents, Drug Delivery Systems, Nanoparticles, Drug Liberation, Nanotechnology, HIV/AIDS, Infectious Diseases, Biotechnology, Bioengineering, 5.1 Pharmaceuticals, Infection, Organic Chemistry, Medicinal and Biomolecular Chemistry, and Biochemistry and Cell Biology

"Vaults" are ubiquitously expressed endogenous ribonucleoprotein nanoparticles with potential utility for targeted drug delivery. Here, we show that recombinant human vault nanoparticles are readily engulfed by certain key human peripheral blood mononuclear cells (PBMC), predominately dendritic cells, monocytes/macrophages, and activated T cells. As these cell types are the primary targets for human immunodeficiency virus type 1 (HIV-1) infection, we examined the utility of recombinant human vaults for targeted delivery of antiretroviral drugs. We chemically modified three different antiretroviral drugs, zidovudine, tenofovir, and elvitegravir, for direct conjugation to vaults. Tested in infection assays, drug-conjugated vaults inhibited HIV-1 infection of PBMC with equivalent activity to free drugs, indicating vault delivery and drug release in the cytoplasm of HIV-1-susceptible cells. The ability to deliver functional drugs via vault nanoparticle conjugates suggests their potential utility for targeted drug delivery against HIV-1.

Humans, Drug Liberation, Folic Acid chemistry, Drug Delivery Systems, Hydrogen-Ion Concentration, Cell Line, Tumor, Paclitaxel chemistry, and Nanoparticles chemistry

Targeted chemotherapy is a prominent cancer treatment research trend that intends to boost the efficacy of drug delivery to cancer cells. The present work aimed to design, a folate-decorated biologically inspired alginate-polydopamine capped zinc doped copper oxide nanoparticles (Zn-CuO) loaded with paclitaxel (Zn-CuO@PTX/AlgPDA-FA) as a simple, efficient, and versatile nanoplatform. Interestingly, Zn species doped in CuO frameworks significantly improved paclitaxel (PTX) molecule loading efficiency without requiring any additional functionalization and fostered the increased antitumor efficacy by precisely delivering them in tumor's acidic microenvironment by obliterating the formed coordination connections between the host as well as guest species. According to DLS, average size of nanocomplex was 196 ± 5.01 nm with ȥ-potential -31.4 ± 1.54 mV. PTX encapsulation and loading efficiencies were 75.2 ± 1.54 % and 18.54 ± 2.31 %, respectively. Furthermore, nanocomplex demonstrates high stability and biocompatibility in vitro. Under an acidic environment (pH 5.0), there was greater PTX release compared to normal physiological conditions. Moreover, Zn-CuO@PTX/AlgPDA-FA NPs showed remarkable internalization efficiency in MCF-7 cells and demonstrated strong cytotoxicity with IC 50 (150 ± 2.58 μg/mL) along with improved ROS generation and changed mitochondrial membrane potential level. Therefore, our approach could suggest excellent potential for tumor targeting in cancer therapy with reduced off-target toxicity, and desirable therapeutic effects.
Competing Interests: Declaration of competing interest The author declares that the contents of this article are devoid of any conflicts of interest.
(Copyright © 2023 Elsevier B.V. All rights reserved.)

Mice, Animals, Drug Liberation, Wound Healing, Polysaccharides, Moxifloxacin, Chitosan, and Nanoparticles

Wound healing is a largely unmet medical issue in trauma, burn, and diabetes. In this study, a pullulan-based and nanoparticle-loaded smart microneedle patch is designed to release drugs differentially based on the needs of wound healing. Chitosan and fucoidan are first used to prepare moxifloxacin (MOX)-loaded nanoparticles (MOXNPs) with a diameter of 258.0 ± 10.86 nm, PDI 0.19 ± 0.06, and surface charge 45.1 ± 3.9 mV. MOXNPs, lidocaine (LH), and thrombin (TH) are then incorporated to a 30 % (w/w) pullulan-based microneedle patch (TH + LH + MOXNPs@MN). TH + LH + MOXNPs@MN possesses uniform and cone-shaped microneedles with a length of 725 μm, demonstrating good biocompatibility, sufficient strength for skin penetration, fast skin dissolution within 55 ± 5 min, rapid release of TH and LH within 1 h, and sustained release of MOX for 24 h. TH + LH + MOXNPs@MN heals mice skin wounds completely within 7 days and restores collagen deposition with accelerated cell proliferation, granulation, and reduced pro-inflammatory cytokines. In conclusion, this study utilizes combined polysaccharides to develop a smart multifunctional microneedle platform that achieves rapid hemostasis/analgesia and sustained bactericidal action. The smart and combined therapy is a potential strategy for high-quality wound healing.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)

Animals, Mice, Doxorubicin, Hydrogen-Ion Concentration, Phototherapy, Drug Liberation, Tumor Microenvironment, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy, Hyperthermia, Induced, and Nanoparticles

Efficiently synergistic therapy of hepatocellular carcinoma (HCC) by chemotherapeutic drug and photothermal agent remains a considerable challenge. Here, we report a nanodrug that integrates specific hepatoma-targeted delivery, pH-triggered drug release, and cooperative photothermal-chemotherapy function. By grafting the easily self-assembled CuS@polydopamine (CuS@PDA) nanocapsulation with polyacrylic acid (PAA), an inorganic-organic-polymeric hybrid nanovehicle was developed as a dual photothermal agent and carrier for loading antitumor drug-doxorubicin (DOX) through electrostatic adsorption and chemical linking antibody against GPC3 commonly overexpressed in HCC, resulting in the nanodrug, CuS@PDA/PAA/DOX/GPC3. The multifunctional nanovehicle had excellent biocompatibility, stability, and high photothermal conversion efficiency, due to the rationally designed binary CuS@PDA photothermal agent. The 72-h accumulative drug release in pH 5.5 tumor microenvironment can reach up to 84%, far higher than 15% measured in pH 7.4 condition. Notably, in contrast to the merely 20% survival rate of H9c2 and HL-7702 cells exposed to free DOX, their viabilities in the nanodrug circumstance can maintain 54% and 66%, respectively, suggesting the abated toxicity to the normal cell lines. When exposed to the hepatoma-targeting nanodrug, the viability of HepG2 cells was found to be 36%, which further drastically declined to 10% plus 808-nm NIR irradiation. Moreover, the nanodrug is potent to cause tumor ablation in HCC-modeled mice, and the therapeutic efficacy can be greatly enhanced under NIR stimulus. Histology analyses reveal that the nanodrug can effectively alleviate the chemical damage to heart and liver, as compared to free DOX. This work thus offers a facile strategy for design of targeting anti-HCC nanodrug toward combined photothermal-chemotherapy.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)

Rats, Animals, Pharmaceutical Preparations, Powders, Crystallization, Solubility, Drug Liberation, Brain, Drug Compounding methods, Chemistry, Pharmaceutical methods, and Water chemistry

Intranasal administration has attracted increasing attention as a drug delivery approach based on nose-to-brain drug delivery from the nasal cavity to brain tissue directly, bypassing the blood-brain barrier. However, application of the method to poorly water-soluble drugs is potentially limited due to low aqueous solubility and dissolution, which can hinder drug transfer to brain tissue. In the present study, we focused on an amorphous solid dispersion (ASD) technique to improve drug dissolution. A carbamazepine-loaded ASD model drug was prepared using the solvent evaporation method (ASD-1). After screening six water-soluble polymer carriers, polyvinyl alcohol (PVA)-based ASD-1 formulation exhibited the most rapid and highest drug dissolution under experimental conditions in the nasal cavity (pH 6.0). A carbamazepine suspension dispersed with a PVA-ASD-1 formulation exhibited enhanced drug delivery into plasma and brain tissue of rats in vivo. A spray-dried powder formulation of PVA-ASD (PVA-ASD-2) exhibited improved drug dissolution and in vivo drug transfer. Our key finding is that the spray-dried PVA-ASD-2 formulation exhibited higher brain/plasma ratios than the PVA-ASD-1 suspension formulation. Our physical characterization data and demonstration of improved drug transfer suggest that ASD-based intranasal formulations hold promise for drug delivery to the brain.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)

Humans, Female, Silicon Dioxide chemistry, Serum Albumin, Bovine chemistry, Doxorubicin chemistry, Folic Acid, Drug Delivery Systems methods, Porosity, Drug Liberation, Breast Neoplasms drug therapy, and Nanoparticles chemistry

Combination therapy is an effective way to alleviate the shortcoming of monotherapy and enhances therapeutic efficacy. Herein, a distinctive hollow mesoporous silica nanoparticle (HMSNs) encapsulated with folic acid-modified bovine serum albumin (BSA-FA), denoted as HBF, was engineered for tumor targeting and dual-responsive release of loaded-therapeutic agents MD (methylene blue (MB) and doxorubicin (DOX)). The BSA molecule as a ''gatekeeper'' prevents premature drug leakage and actively unloads the cargos through BSA detachment in response to intracellular glutathione (GSH). Folic acid (FA) promotes the specific intracellular delivery of the drug to folate receptor (FR)-expressing cancer cells to improve the efficacy of chemo-photodynamic therapy (PDT). In vitro drug release profiles showed that the drug carrier could achieve pH/redox-responsive drug release from MD@HBF owing to the cleavage of the imine bonds between HMSNs-CHO and BSA-FA and BSA intramolecular disulfide bond. Additionally, a series of biological evaluations, such as cell uptake experiments, toxicity experiments, and in vivo therapeutic assays indicated that MD@HBF possesses the features of accurately targeting FR-expressing 4T1 cells to induce cells apoptosis in vitro, exhibits outstanding tumor cell synergistic killing efficiency of chemo-photodynamic therapy (combination index CI = 0.325), and inhibits tumors growth. These results demonstrated that the strategy of combining HMSNs with stimuli-responsive biodegradable protein molecules could provide a new potential direction toward the ''on-demand'' drug release for precision chemo-photodynamic therapy in cancer treatment.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)

Humans, Child, Drug Liberation, Solubility, Tablets, Administration, Oral, and Ritonavir

Amorphous solid dispersions (ASD) have been a successful formulation strategy to overcome the poor aqueous solubility of many novel drugs, but the development of pediatric formulations presents a special challenge due to variable gastrointestinal conditions in children. It was the aim of this work to design and apply a staged biopharmaceutical test protocol for the in vitro assessment of ASD-based pediatric formulations. Ritonavir was used as a model drug with poor aqueous solubility. Based on the commercial ASD powder formulation, a mini-tablet and a conventional tablet formulation were prepared. Drug release from the three formulations was studied in different biorelevant in vitro assays (i.e. MicroDiss, two-stage, transfer model, tiny-TIM) to consider different aspects of human GI physiology. Data from the two-stage and transfer model tests indicated that by controlled disintegration and dissolution excessive primary precipitation can be prevented. However, this advantage of the mini-tablet and tablet formulation did not translate into better performance in tiny-TIM. Here, the in vitro bioaccessibility was comparable for all three formulations. In the future, the staged biopharmaceutical action plan established herein will support the development of ASD-based pediatric formulations by improving the mechanistic understanding so that formulations are developed for which drug release is robust against variable physiological conditions.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)

Humans, Female, Drug Liberation, Caseins therapeutic use, Eugenol therapeutic use, Cell Line, Tumor, Paclitaxel pharmacology, Paclitaxel therapeutic use, Paclitaxel chemistry, Breast Neoplasms drug therapy, and Nanoparticles chemistry

Proteins are promising base materials for developing drug carriers with efficient blood circulation due to low possibilities of clearance by macrophages. However, such natural biopolymers have highly sophisticated molecular structures, preventing them from being assembled into nano-platforms with manipulable payload release profiles. Here, we report the self-assembly of two natural proteins (milk casein and rice protein) into protein nanoparticles (NPs, ∼150 nm) with tailorable release profiles. Diffusion of plant-derived paclitaxel (PTX)-containing eugenol into the hydrophobic cores of the NPs and subsequent dialysis to remove eugenol from the cores lead to the carving of the NP interiors. With the increase in the mass ratios of casein and rice protein, this process generates all-natural NPs with PTX loaded in their full cavities, semi-full cavities, or solid cores. These NPs can be efficiently uptaken by breast cancer cells and could kill the cancer cells efficiently. PTX in these NPs demonstrates increasingly sustained in vivo release profiles from full cavities, semi-full cavities, to solid cores, gradually extending its pharmacokinetic profiles in blood plasma to favor drug accumulation in breast tumor models. Consequently, the NPs with solid cores completely inhibit tumor growth in vivo, more effectively than those with full and semi-full cavities. Our work opens up a new avenue to the use of diffusion-mediated nanoscale carving in producing biomaterials with controllable interior topologies relevant to drug release profiles.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)

Carboxymethylcellulose Sodium chemistry, Porosity, Povidone, Aluminum Oxide pharmacology, Emulsions, Water, Hydrogen-Ion Concentration, Drug Carriers chemistry, Drug Liberation, Fluorouracil chemistry, and Antineoplastic Agents

5-Fluorouracil (5-FU) is a cytotoxic drug with a low half-life. These features can cause some problems such as burst drug release and numerous side effects. In the present study, a pH-sensitive nanocomposite of polyvinylpyrrolidone (PVP)/carboxymethyl cellulose (CMC)/γ-alumina developed by using water in oil in water (W/O/W) double emulsion method. The fabricated emulsion has been employed as the 5-FU carrier to investigate its effects on drug half-life, side effects, drug loading efficiency (DLE), and drug entrapment efficiency (DEE). Analyzing the FTIR and XRD indicated the successful loading of 5-FU into the nanocarrier and affirmed the synthesized nanocomposite's chemical bonding and crystalline features. Furthermore, by using DLS and Zeta potential assessment, size and undersize distribution, as well as the stability of the drug-loaded nanocomposite were determined, which demonstrated the monodisperse and stable nanoparticles. Moreover, the nanocomposites with spherical shapes and homogeneous surfaces were shown in FE-SEM, which indicated good compatibility for the constituents of the nanocomposites. Moreover, by employing BET analysis the porosity has been investigated. Drug release pattern was studied, which indicated a controlled drug release behavior with above 96 h drug retention. Besides, the loading and entrapment efficiencies were obtained 44 % and 86 %, respectively. Furthermore, the curve fitting technique has been employed and the predominant release mechanism has been determined to evaluate the best-fitted kinetic models. MTT assay and flow cytometry assessment has been carried out to investigate the cytotoxic effects of the fabricated drug-loaded nanocomposite on MCF-7 and normal cells. The results showed enhanced cytotoxicity and late apoptosis for the PVP/CMC/γ-alumina/5-FU. Based on the MTT assay outcomes on normal cell lines (L929), which indicated above 90 % cell viability, the biocompatibility and biosafety of the synthesized nanocarrier have been confirmed. Moreover, due to the porosity of the PVP/CMC/γ-alumina, this nanocarrier can exploit from high specific surface area and be more sensitive to environmental conditions such as pH. These outcomes propose that the novel pH-sensitive PVP/CMC/γ-alumina nanocomposite can be a potential candidate for drug delivery applications, especially for cancer therapy.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023. Published by Elsevier B.V.)