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Search Results (110)

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Keywords = nanoparticulate delivery systems

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27 pages, 11207 KiB  
Article
Future-Oriented Nanosystems Composed of Polyamidoamine Dendrimer and Biodegradable Polymers as an Anticancer Drug Carrier for Potential Targeted Treatment
by Katarzyna Strzelecka, Adam Kasiński, Tadeusz Biela, Anita Bocho-Janiszewska, Anna Laskowska, Łukasz Szeleszczuk, Maciej Gawlak, Marcin Sobczak and Ewa Oledzka
Pharmaceutics 2024, 16(11), 1482; https://doi.org/10.3390/pharmaceutics16111482 - 20 Nov 2024
Viewed by 584
Abstract
Background/Objectives: Camptothecin (CPT) is a well-known chemical compound recognized for its significant anticancer properties. However, its clinical application remains limited due to challenges related to CPT’s high hydrophobicity and the instability of its active form. To address these difficulties, our research focused [...] Read more.
Background/Objectives: Camptothecin (CPT) is a well-known chemical compound recognized for its significant anticancer properties. However, its clinical application remains limited due to challenges related to CPT’s high hydrophobicity and the instability of its active form. To address these difficulties, our research focused on the development of four novel nanoparticulate systems intended for either oral or intravenous administration. Methods: These nanosystems were based on a poly(amidoamine) (PAMAM) dendrimer/CPT complex, which had been coated with biodegradable homo- and copolymers, designed with appropriate physicochemical properties and chain microstructures. Results: The resulting nanomaterials, with diameters ranging from 110 to 406 nm and dispersity values between 0.10 and 0.67, exhibited a positive surface charge and were synthesized using biodegradable poly(L-lactide) (PLLA), poly(L-lactide-co-ε-caprolactone) (PLACL), and poly(glycolide-co-ε-caprolactone) (PGACL). Biological assessments, including cell viability and hemolysis tests, indicated that all polymers demonstrated less than 5% hemolysis, confirming their hemocompatibility for potential intravenous use. Furthermore, fibroblasts exposed to these matrices showed concentration-dependent viability. The entrapment efficiency (EE) of CPT reached up to 27%, with drug loading (DL) values as high as 17%. The in vitro drug release studies lasted over 400 h with the use of phosphate buffer solutions at two different pH levels, demonstrating that time-dependent processes allowed for a gradual and controlled release of CPT from the developed nanosystems. The release kinetics of the active compound at pH 7.4 ± 0.05 and 6.5 ± 0.05 followed near-first-order or first-order models, with diffusion and Fickian/non-Fickian transport mechanisms. Importantly, the nanoparticulate systems enabled the stabilization of the pharmacologically active form of CPT, while providing protection against hydrolysis, even in physiological environments. Conclusions: In our opinion, these results underscore the promising future of biodegradable nanosystems as effective drug delivery systems (DDSs) for targeted cancer treatment, offering stability and efficacy over short, medium, and long-term applications. Full article
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<p>Expansion of the domain of interest in <sup>13</sup>C NMR spectrum of carbonyl region for PLACL copolymer (M2).</p>
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<p>Expansion of the domain of interest in <sup>1</sup>H NMR spectrum of PGACL copolymer (M3 and M4).</p>
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<p>Hemolytic activity of the synthesized biodegradable polymers: M1, M2, M3, and M4 after 1 h of incubation. The graph depicts the level of hemolysis of RBC treated with increasing concentrations of the complex after 1 h of treatment. Two-way ANOVA followed by the Bonferroni post-test was used for statistical analysis. The results were considered statistically significant: * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01; *** <span class="html-italic">p</span> &lt; 0.005.</p>
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<p>The viability of normal fibroblasts treated for 72 h with the synthesized biodegradable polymers at pH 7.4 ± 0.05 (<b>a</b>) and pH 6.5 ± 0.05 (<b>b</b>). The graphs depict differences in the susceptibility of cells to the complex. The MTS assay was used to determine the relative cell number. The results are given as mean ± SEM. Two-way ANOVA was used for statistical analysis, followed by Bonferroni post-tests. When the following conditions were met, the results were considered statistically significant: * <span class="html-italic">p</span> &lt; 0.05.</p>
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<p>TEM image of: (<b>a</b>) NP1 sample, (<b>b</b>) NP2 sample, (<b>c</b>) NP3 sample, (<b>d</b>) NP4 sample.</p>
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<p>Confocal fluorescence imaging of: (<b>a</b>) CPT, (<b>b</b>) NP1 sample, (<b>c</b>) NP2 sample, (<b>d</b>) NP3 sample, (<b>e</b>) NP4 sample.</p>
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<p>CPT release profiles from the developed nanosystems at pH 6.50 ± 0.05.</p>
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<p>CPT release profiles from the developed nanosystems at pH 7.40 ± 0.05.</p>
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<p>Correlation between cumulative CPT release and percentage of the lactone form of CPT at 7.40 ± 0.05.</p>
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<p>Correlation between cumulative CPT release and percentage of the lactone form of CPT at 6.50 ± 0.05.</p>
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<p>The structure of MODEL 1—PAMAM dendrimer generation 4.0 loaded with three molecules of CPT and surrounded by PLLA matrix. Atom coloring: Hydrogen—light blue, Nitrogen—dark blue, Carbon—grey, Oxygen—red. Rendering: the atoms and bonds of PLLA are rendered as sticks, the atoms of PAMAM dendrimer generation 4.0 are rendered as solid cylinders, CPT atoms are rendered as spheres with radii that are related to the van der Waals radii of its atoms.</p>
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<p>The structure of MODEL 2—PAMAM dendrimer generation 4.0 loaded with three molecules of CPT and surrounded by PLACL matrix. Atom coloring: Hydrogen—light blue, Nitrogen—dark blue, Carbon—grey, Oxygen—red. Rendering: the atoms and bonds of PLLA are rendered as sticks, the atoms of PAMAM dendrimer generation 4.0 are rendered as solid cylinders, CPT atoms are rendered as spheres with radii that are related to the van der Waals radii of its atoms.</p>
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<p>The structure of MODEL 3—PAMAM dendrimer generation 4.0 loaded with three molecules of CPT and surrounded by PGACL 85:15 (<span class="html-italic">ε</span>-CL:GL) matrix. Atom coloring: Hydrogen—light blue, Nitrogen—dark blue, Carbon—grey, Oxygen—red. Rendering: the atoms and bonds of PLLA are rendered as sticks, the atoms of PAMAM dendrimer generation 4.0 are rendered as solid cylinders, CPT atoms are rendered as spheres with radii that are related to the van der Waals radii of its atoms.</p>
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<p>The structure of MODEL 4—PAMAM dendrimer generation 4.0 loaded with three molecules of CPT and surrounded by PGACL 90:10 (<span class="html-italic">ε</span>-CL:GL) matrix. Atom coloring: Hydrogen—light blue, Nitrogen—dark blue, Carbon—grey, Oxygen—red. Rendering: the atoms and bonds of PLLA are rendered as sticks, the atoms of PAMAM dendrimer generation 4.0 are rendered as solid cylinders, CPT atoms are rendered as spheres with radii that are related to the van der Waals radii of its atoms.</p>
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<p>The RDFs between PAMAM and CPT molecules.</p>
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<p>RMSD plots obtained for CPT in MODELS 1–4 during 100 ns MD simulation.</p>
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24 pages, 2222 KiB  
Review
Liposomes and Their Therapeutic Applications in Enhancing Psoriasis and Breast Cancer Treatments
by Amal Ali Elkordy, David Hill, Mohamed Attia and Cheng Shu Chaw
Nanomaterials 2024, 14(21), 1760; https://doi.org/10.3390/nano14211760 - 1 Nov 2024
Viewed by 963
Abstract
Psoriasis and breast cancer are two examples of diseases where associated inflammatory pathways within the body’s immune system are implicated. Psoriasis is a complex, chronic and incurable inflammatory skin disorder that is primarily recognized by thick, scaly plaques on the skin. The most [...] Read more.
Psoriasis and breast cancer are two examples of diseases where associated inflammatory pathways within the body’s immune system are implicated. Psoriasis is a complex, chronic and incurable inflammatory skin disorder that is primarily recognized by thick, scaly plaques on the skin. The most noticeable pathophysiological effect of psoriasis is the abnormal proliferation of keratinocytes. Breast cancer is currently the most diagnosed cancer and the leading cause of cancer-related death among women globally. While treatments targeting the primary tumor have significantly improved, preventing metastasis with systemic treatments is less effective. Nanocarriers such as liposomes and lipid nanoparticles have emerged as promising drug delivery systems for drug targeting and specificity. Advances in technologies and drug combinations have emerged to develop more efficient lipid nanocarriers to include more than one drug in combinational therapy to enhance treatment outcomes and/or relief symptoms for better patients’ quality of life. Although there are FDA-approved liposomes with anti-cancer drugs for breast cancer, there are still unmet clinical needs to reduce the side effects associated with those nanomedicines. Hence, combinational nano-therapy may eliminate some of the issues and challenges. Furthermore, there are no nanomedicines yet clinically available for psoriasis. Hence, this review will focus on liposomes encapsulated single and/or combinational therapy to augment treatment outcomes with an emphasis on the effectiveness of combinational therapy within liposomal-based nanoparticulate drug delivery systems to tackle psoriasis and breast cancer. This review will also include an overview of both diseases, challenges in delivering drug therapy and the roles of nanomedicines as well as psoriasis and breast cancer models used for testing therapeutic interventions to pave the way for effective in vivo testing prior to the clinical trials. Full article
(This article belongs to the Section Biology and Medicines)
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<p>Pathogenesis of psoriasis showing cross talk and interactions among cells of the immune system, keratinocytes and skin microbiome at the lesional site with the release of different cytokines or chemokines. The altered skin microbiota disrupts the skin barrier and acts on the innate immune system that activates the inflammatory cascades. Skin microbiota is considered a key trigger in the psoriatic inflammation loop. Figure adapted from [<a href="#B8-nanomaterials-14-01760" class="html-bibr">8</a>].</p>
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<p>Cell biology models for the study of psoriasis. (<b>A</b>) Keratinocyte monolayer culture is a technically simple and versatile model for most applications. (<b>B</b>) Keratinocyte co-culture models with other cell types, including fibroblasts, endothelial cells and immune cells, are also performed in 2D monolayers but are more complex, requiring media optimization for multicellular culture. (<b>C</b>) Organ-on-a-chip models use microfluidics to maintain a consistent homeostatic microenvironment for continuous skin culture. (<b>D</b>) Organoids are another versatile model that can self-assemble or be bio-printed with keratinocytes only or multiple cell types, with or without stromal matrix added. (<b>E</b>) Full-thickness organotypic skin models are the most physiologically relevant models but require the most time and expertise to perform. (<b>F</b>) Biopsy skin explants can provide patient-specific drug response data, but sample size is a limiting factor in their use.</p>
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<p>Psoriasis treatment ladder with representative drug classes updated from [<a href="#B25-nanomaterials-14-01760" class="html-bibr">25</a>].</p>
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<p>Schematic representation of endocytic pathways involved in the internalization of amphiphilic copolymers and the associated factors modulating their uptake pathways and intracellular fate. Figure adapted from [<a href="#B64-nanomaterials-14-01760" class="html-bibr">64</a>].</p>
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<p>Schematic representation of structure of liposomal drug delivery systems: (<b>A</b>) unilamellar liposome, (<b>B</b>) multilamellar liposome, (<b>C</b>) liposome loaded with a hydrophobic drug, (<b>D</b>) liposome loaded with a hydrophobic drug in the bilayer membrane and a hydrophilic drug in the aqueous core, (<b>E</b>) pegylated liposome with surface PEG polymer chains, (<b>F</b>) liposome loaded with mRNA, (<b>G</b>) liposome with a surface-conjugated drug, targeting ligands and PEG, hydrophilic and hydrophobic drugs, (<b>H</b>) liposome with a surface-conjugated drug, targeting ligands, PEG polymer chains, hydrophilic drugs, hydrophobic drugs, mRNA-loaded. Figure adapted from [<a href="#B67-nanomaterials-14-01760" class="html-bibr">67</a>].</p>
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19 pages, 4846 KiB  
Article
Development of Hybrid Implantable Local Release Systems Based on PLGA Nanoparticles with Applications in Bone Diseases
by Maria Viorica Ciocîlteu, Andreea Gabriela Mocanu, Andrei Biță, Costel Valentin Manda, Claudiu Nicolicescu, Gabriela Rău, Ionela Belu, Andreea Silvia Pîrvu, Maria Balasoiu, Valentin Nănescu and Oana Elena Nicolaescu
Polymers 2024, 16(21), 3064; https://doi.org/10.3390/polym16213064 - 31 Oct 2024
Viewed by 744
Abstract
The current strategy for treating osteomyelitis includes surgical procedures for complete debridement of the formed biofilm and necrotic tissues, systemic and oral antibiotic therapy, and the clinical use of cements and three-dimensional scaffolds as bone defect fillers and delivery systems for therapeutic agents. [...] Read more.
The current strategy for treating osteomyelitis includes surgical procedures for complete debridement of the formed biofilm and necrotic tissues, systemic and oral antibiotic therapy, and the clinical use of cements and three-dimensional scaffolds as bone defect fillers and delivery systems for therapeutic agents. The aim of our research was to formulate a low-cost hybrid nanoparticulate biomaterial using poly(lactic-co-glycolic acid) (PLGA), in which we incorporated the therapeutic agent (ciprofloxacin), and to deposit this material on titanium plates using the matrix-assisted pulsed laser evaporation (MAPLE) technique. The deposited material demonstrated antibacterial properties, with all analyzed samples inhibiting the growth of tested bacterial strains, confirming the release of active substances from the investigated biocomposite. The poly(lactic-co-glycolic acid)-ciprofloxacin (PLGA-CIP) nanoparticle scaffolds displayed a prolonged local sustained release profile over a period of 45 days, which shows great promise in bone infections. Furthermore, the burst release ensures a highly efficient concentration, followed by a constant sustained release which allows the drug to remain in the implant-adjacent area for an extended time period. Full article
(This article belongs to the Special Issue Polymer Materials for Drug Delivery and Tissue Engineering II)
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<p>Biomaterial evolution in bone repair and regeneration.</p>
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<p>Formulation of PLGA-CIP and PLGA-CIP implantable local release systems.</p>
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<p>FTIR spectra of (<b>A</b>) PLGA-CIP and PLGA–CIP films deposited by MAPLE on titanium supports; (<b>B</b>) CIP; (<b>C</b>) PLGA.</p>
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<p>Volume distribution of PLGA-CIP (500 rpm) (<b>A</b>); number distribution of PLGA-CIP (500 rpm) (<b>B</b>); volume distribution of PLGA-CIP (1500 rpm) (<b>C</b>); number distribution of PLGA-CIP (1500 rpm) (<b>D</b>).</p>
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<p>Volume distribution of PLGA-CIP (500 rpm) (<b>A</b>); number distribution of PLGA-CIP (500 rpm) (<b>B</b>); volume distribution of PLGA-CIP (1500 rpm) (<b>C</b>); number distribution of PLGA-CIP (1500 rpm) (<b>D</b>).</p>
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<p>Scanning electron microscopy images of (<b>A</b>) PLGA-CIP (1500 rpm) and (<b>B</b>) PLGA-CIP (500 rpm).</p>
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<p>CIP release from the control sample: mechanical mixture CIP:HA (<span class="html-italic">w</span>:<span class="html-italic">w</span>) (25:75).</p>
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<p>CIP release from PLGA-CIP scaffolds.</p>
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<p>Release profile of CIP from implantable PLGA-CIP LRS.</p>
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<p>Korsmeyer–Peppas model for the mechanism of drug release.</p>
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<p>Higuchi release model or the mechanism of drug release.</p>
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<p>Antibacterial activity of scaffolds over tested germs.</p>
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<p>The zone of inhibition obtained for (<b>A</b>) PLGA-CIP scaffolds on Staphylococcus aureus; (<b>B</b>) PLGA-CIP scaffolds (1500 rpm) on methicillin-resistant Staphylococcus aureus using the disk diffusion agar method.</p>
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<p>The zone of inhibition obtained for implantable PLGA-CIP LRS (1500 rpm) on <span class="html-italic">Staphylococcus aureus.</span></p>
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34 pages, 3009 KiB  
Review
Lipid-Based Nanoformulations for Drug Delivery: An Ongoing Perspective
by Mubashar Rehman, Nayab Tahir, Muhammad Farhan Sohail, Muhammad Usman Qadri, Sofia O. D. Duarte, Pedro Brandão, Teresa Esteves, Ibrahim Javed and Pedro Fonte
Pharmaceutics 2024, 16(11), 1376; https://doi.org/10.3390/pharmaceutics16111376 - 26 Oct 2024
Viewed by 2820
Abstract
Oils and lipids help make water-insoluble drugs soluble by dispersing them in an aqueous medium with the help of a surfactant and enabling their absorption across the gut barrier. The emergence of microemulsions (thermodynamically stable), nanoemulsions (kinetically stable), and self-emulsifying drug delivery systems [...] Read more.
Oils and lipids help make water-insoluble drugs soluble by dispersing them in an aqueous medium with the help of a surfactant and enabling their absorption across the gut barrier. The emergence of microemulsions (thermodynamically stable), nanoemulsions (kinetically stable), and self-emulsifying drug delivery systems added unique characteristics that make them suitable for prolonged storage and controlled release. In the 1990s, solid-phase lipids were introduced to reduce drug leakage from nanoparticles and prolong drug release. Manipulating the structure of emulsions and solid lipid nanoparticles has enabled multifunctional nanoparticles and the loading of therapeutic macromolecules such as proteins, nucleic acid, vaccines, etc. Phospholipids and surfactants with a well-defined polar head and carbon chain have been used to prepare bilayer vesicles known as liposomes and niosomes, respectively. The increasing knowledge of targeting ligands and external factors to gain control over pharmacokinetics and the ever-increasing number of synthetic lipids are expected to make lipid nanoparticles and vesicular systems a preferred choice for the encapsulation and targeted delivery of therapeutic agents. This review discusses different lipids and oil-based nanoparticulate systems for the delivery of water-insoluble drugs. The salient features of each system are highlighted, and special emphasis is given to studies that compare them. Full article
(This article belongs to the Special Issue Liposomes Applied in Drug Delivery Systems)
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<p>Comparison of nanoemulsions and microemulsions in terms of energy state (<b>A</b>); methods of preparation of microemulsions, including high-energy methods, such as piston-gap method (<b>a</b>), microfluidization (<b>b</b>), and ultrasonication (<b>c</b>), and low-energy methods (<b>B</b>); and preparation of a microemulsion by the titration method, aided by a pseudoternary phase diagram (<b>C</b>). Adapted with permission from [<a href="#B19-pharmaceutics-16-01376" class="html-bibr">19</a>]. Copyright 2013, Taylor &amp; Francis.</p>
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<p>Structure and distribution of drugs in solid-phase lipid nanoparticles: uniform distribution of a drug inside SLNs (<b>A</b>), drug-enriched core of SLNs (<b>B</b>), drug concentrated in the shell of the SLNs (<b>C</b>), lipid crystal formation in SLNs leading to a disc-shaped unstable state (<b>D</b>), NLC structure with homogenous lipid phase of oil and lipid (<b>E</b>), presence of oil globule inside NLCs due to a higher amount of drug oil (<b>F</b>), and multicompartment SLNs with aqueous cores (<b>G</b>). Reproduced with modifications (CC BY 4.0) from [<a href="#B97-pharmaceutics-16-01376" class="html-bibr">97</a>].</p>
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<p>Application of thermoresponsive lipid nanoparticles targeting cancer. Lipid nanoparticles melt under hyperthermia (<b>A</b>), abrupt release of 5-FU under hyperthermia (<b>B</b>), nanoparticles under hyperthermia can squeeze through the BBB (<b>C</b>), and higher cytotoxicity to cancer cells under hyperthermia (<b>D</b>). Reproduced with modifications (CC BY 4.0) from [<a href="#B125-pharmaceutics-16-01376" class="html-bibr">125</a>].</p>
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<p>Comparison of penetration of different lipid-based nanocarriers and resulting permeability enhancement across different layers of the skin. Reproduced with modifications (CC BY 4.0) from [<a href="#B186-pharmaceutics-16-01376" class="html-bibr">186</a>].</p>
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<p>Schematic presentation of cancer-targeting by mitochondria-specific liposomes. Liposomes are formed by self-assembly with indocyanine G (ICG) as a model therapeutic agent (<b>A</b>). Liposomes extravasate the blood vessels to reach the acidic tumor microenvironment, where they undergo acid cleavage (<b>B</b>). Liposomes enter the cells by micropinocytosis, undergo endosome escape, and enter mitochondria due to carrier-mediated transport (<b>C</b>). Irradiation of ICG-loaded liposomes by a laser of 808 nm leads to photodynamic therapy-mediated production of reactive oxygen species (ROS) (<b>D</b>) and photothermal therapy (<b>E</b>). The resulting mitochondrial damage leads to the induction of apoptosis of the cells (<b>F</b>). Reproduced with modifications (CC BY 4.0) from [<a href="#B198-pharmaceutics-16-01376" class="html-bibr">198</a>].</p>
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16 pages, 1793 KiB  
Article
A Polysaccharide-Based Oral-Vaccine Delivery System and Adjuvant for the Influenza Virus Vaccine
by Chaitanya K. Valiveti, Mrigendra Rajput, Neelu Thakur, Tooba Momin, Malabika Bhowmik and Hemachand Tummala
Vaccines 2024, 12(10), 1121; https://doi.org/10.3390/vaccines12101121 - 29 Sep 2024
Viewed by 1604
Abstract
Influenza virus enters the host body through the mucosal surface of the respiratory tract. An efficient immune response at the mucosal site can interfere with virus entry and prevent infection. However, formulating oral vaccines and eliciting an effective mucosal immune response including at [...] Read more.
Influenza virus enters the host body through the mucosal surface of the respiratory tract. An efficient immune response at the mucosal site can interfere with virus entry and prevent infection. However, formulating oral vaccines and eliciting an effective mucosal immune response including at respiratory mucosa presents numerous challenges including the potential degradation of antigens by acidic gastric fluids and the risk of antigen dilution and dispersion over a large surface area of the gut, resulting in minimal antigen uptake by the immune cells. Additionally, oral mucosal vaccines have to overcome immune tolerance in the gut. To address the above challenges, in the current study, we evaluated inulin acetate (InAc) nanoparticles (NPs) as a vaccine adjuvant and antigen delivery system for oral influenza vaccines. InAc was developed as the first polysaccharide polymer-based TLR4 agonist; when tailored as a nanoparticulate vaccine delivery system, it enhanced antigen delivery to dendritic cells and induced a strong cellular and humoral immune response. This study compared the efficacy of InAc-NPs as a delivery system for oral vaccines with Poly (lactic-co-glycolic acid) (PLGA) NPs, utilizing influenza A nucleoprotein (Inf-A) as an antigen. InAc-NPs effectively protected the encapsulated antigen in both simulated gastric (pH 1.1) and intestinal fluids (pH 6.8). Moreover, InAc-NPs facilitated enhanced antigen delivery to macrophages, compared to PLGA-NPs. Oral vaccination studies in Balb/c mice revealed that InAc-Inf-A NPs significantly boosted the levels of Influenza virus-specific IgG and IgA in serum, as well as total and virus-specific IgA in the intestines and lungs. Furthermore, mice vaccinated with InAc-Inf-A-NPs exhibited notably higher hemagglutination inhibition (HI) titers at mucosal sites compared to those receiving the antigen alone. Overall, our study underscores the efficacy of InAc-NPs in safeguarding vaccine antigens post-oral administration, enhancing antigen delivery to antigen-presenting cells, and eliciting higher virus-neutralizing antibodies at mucosal sites following vaccination. Full article
(This article belongs to the Special Issue The Recent Development of Influenza Vaccine: 2nd Edition)
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<p>Characterization of InAc-Inf-A-NPs: (<b>A</b>) the mean particle size distribution was measured using DLS; (<b>B</b>) Zeta potential shows the surface charge of InAc-Inf-A-NPs a slightly negative or neutral (−0.9 ± 0.2 mV); (<b>C</b>) the morphology of InAc-Inf-A-NPs were spherical particles with a diameter of ~500 nm as shown by scanning electron microscopy (SEM).</p>
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<p>Efficacy of InAc-NPs in preventing premature release of the encapsulated antigen. InAc-NPs containing Fluoresceine Sodium dye as the encapsulated antigen were dispersed in DI Water, Simulated Gastric Fluid (SGF), or Simulated Intestinal Fluid (SIF). Suspension was incubated in an orbital shaker at a speed of 100 rpm at 37 °C for 24 h. Fluorescein concentration in the supernatant solution at different time points was measured by fluorimeter and % cumulated release was calculated by comparing its fluorescent intensity with 100% release of Fluoresceine Sodium from NPs dissolved in 100% acetone or DMF.</p>
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<p>InAc-FITC-Ova-NPs uptake by murine macrophages. The InAc-FITC-Ova-NPs or PLGA-FITC-Ova-NPs each with 25 µg equivalent to FITC-Ova were incubated with wild-type macrophages. After 1 h incubation, the cells were analyzed by flow cytometry for the number of cells having the antigen (FITC-Ova, green fluorescence) and the relative amount of antigen per cell by mean fluorescent intensity (MFI).</p>
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<p>Fold change in Inf-A specific IgG (panel (<b>A</b>)) and IgA (panel (<b>B</b>)) in the serum following oral vaccination. BALB/c mice were vaccinated by oral administration of saline, Influenza A peptide alone in saline, or Influenza A peptide encapsulated in InAc-NPs (InAc-Inf-A-NPs). Two doses were given at one-week intervals. Blood was collected on day 0, day 7, and day 35 post-first vaccination. Panel (<b>A</b>) shows fold change in Inf-A-specific IgG tier at day 0, day 7-, and 35 days post-first vaccination while Panel (<b>B</b>) shows fold change in Inf-A-specific IgA tiers in serum at 35 days post-first vaccination. * Shows a significant difference at a 95% level of significance (<span class="html-italic">p</span> &lt; 0.05).</p>
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<p>The concentration of total IgA (panel (<b>A</b>)) and Inf-A specific IgA (panel (<b>B</b>)) in the tissues following oral vaccination. BALB/c mice were orally vaccinated with two doses of saline, Influenza A peptide alone in saline, or InAc-Inf-A-NPs one week apart. Following five weeks of the first vaccination, the mice were sacrificed, and the tissues such as ileum (small intestine), lungs, and spleen were collected. Collected tissue samples were homogenized in protease inhibitor and normalized for equal protein concentration followed by measuring the concentration of total IgA (panel (<b>A</b>)) and influenza virus A specific IgA (panel (<b>B</b>)) by sandwich ELISA. * shows a significant difference at a 95% level of significance (<span class="html-italic">p</span> &lt; 0.05).</p>
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<p>Hemagglutination inhibition (HI) titer following oral vaccination. BALB/c mice were orally vaccinated with two doses of saline, Influenza A peptide alone in saline, or InAc-Inf-A-NPs one week apart. After five weeks of the first vaccination, mice were sacrificed, and tissues were collected. The tissue samples were homogenized in protease inhibitor and supernatants of these homogenates were analyzed for the functionality of Influenza A virus-specific antibodies using HI assays. * shows a significant difference at a 95% level of significance (<span class="html-italic">p</span> &lt; 0.05 in HI titer in tissue homogenates.</p>
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18 pages, 1650 KiB  
Article
Evaluating Nanoparticulate Vaccine Formulations for Effective Antigen Presentation and T-Cell Proliferation Using an In Vitro Overlay Assay
by Dedeepya Pasupuleti, Priyal Bagwe, Amarae Ferguson, Mohammad N. Uddin, Martin J. D’Souza and Susu M. Zughaier
Vaccines 2024, 12(9), 1049; https://doi.org/10.3390/vaccines12091049 - 13 Sep 2024
Viewed by 1153
Abstract
Inducing T lymphocyte (T-cell) activation and proliferation with specificity against a pathogen is crucial in vaccine formulation. Assessing vaccine candidates’ ability to induce T-cell proliferation helps optimize formulation for its safety, immunogenicity, and efficacy. Our in-house vaccine candidates use microparticles (MPs) and nanoparticles [...] Read more.
Inducing T lymphocyte (T-cell) activation and proliferation with specificity against a pathogen is crucial in vaccine formulation. Assessing vaccine candidates’ ability to induce T-cell proliferation helps optimize formulation for its safety, immunogenicity, and efficacy. Our in-house vaccine candidates use microparticles (MPs) and nanoparticles (NPs) to enhance antigen stability and target delivery to antigen-presenting cells (APCs), providing improved immunogenicity. Typically, vaccine formulations are screened for safety and immunostimulatory effects using in vitro methods, but extensive animal testing is often required to assess immunogenic responses. We identified the need for a rapid, intermediate screening process to select promising candidates before advancing to expensive and time-consuming in vivo evaluations. In this study, an in vitro overlay assay system was demonstrated as an effective high-throughput preclinical testing method to evaluate the immunogenic properties of early-stage vaccine formulations. The overlay assay’s effectiveness in testing particulate vaccine candidates for immunogenic responses has been evaluated by optimizing the carboxyfluorescein succinimidyl ester (CFSE) T-cell proliferation assay. DCs were overlaid with T-cells, allowing vaccine-stimulated DCs to present antigens to CFSE-stained T-cells. T-cell proliferation was quantified using flow cytometry on days 0, 1, 2, 4, and 6 upon successful antigen presentation. The assay was tested with nanoparticulate vaccine formulations targeting Neisseria gonorrhoeae (CDC F62, FA19, FA1090), measles, H1N1 flu prototype, canine coronavirus, and Zika, with adjuvants including Alhydrogel® (Alum) and AddaVax™. The assay revealed robust T-cell proliferation in the vaccine treatment groups, with variations between bacterial and viral vaccine candidates. A dose-dependent study indicated immune stimulation varied with antigen dose. These findings highlight the assay’s potential to differentiate and quantify effective antigen presentation, providing valuable insights for developing and optimizing vaccine formulations. Full article
(This article belongs to the Special Issue Advances in the Use of Nanoparticles for Vaccine Platform Development)
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<p>Live cell imaging of DAPI-stained naïve T-cells interacting with activated dendritic cells. (<b>A</b>): Overview of the culture showing DAPI-stained T-cells (blue) interacting with activated dendritic cells that are stimulated with ICG-coated BSA MPs (green) across the field. Scale bar: 100 µm. (<b>B</b>): Close-up view highlighting a DAPI-stained T-cell engaging with a dendritic cell, indicated by the black arrow. Scale bar: 100 µm. (<b>C</b>): Magnified image displaying multiple T-cells in the process of interacting with dendritic cells. Black arrows indicate T-cells undergoing division. Scale bar: 100 µm. (<b>D</b>): Detailed image of T-cells post-division, as indicated by black arrows, continuing their interaction with dendritic cells. Scale bar: 100 µm.</p>
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<p>Representative flow cytometry data of T-lymphocyte profiling. (<b>A</b>). Gating strategy for separating T lymphocytes from the forward scattering vs. side scattering plot. T-cells were gated, capturing 16.5% of the total population of the scatter plot. (<b>B</b>). Singlets are shown on the forward scattering a vs. forward scattering height plot from the T lymphocyte gating. (<b>C</b>). Histograms gated 1, 2, 3, and 4 according to daughter T-cell proliferation over time intervals: 0–1, 1–2, 2–4, and 4–6 days, respectively. Gates were established in accordance with the proliferation pattern of bacterial and viral-based vaccine candidates. Gates were left unchanged for the corresponding blank MP/NP groups.</p>
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<p>Quantitative comparisons of CFSE (FITC-A filter) expressions due to T-cells proliferated as days passed. CFSE is expressed by the proliferating T-cells in response to antigen presentation by the DCs upon stimulation by various treatment groups. (<b>A</b>). Comparison of all blank groups involved in the experiment, including blank CFSE-stained T-cells only, blank BSA MPs, and blank PLGA NPs. (<b>B</b>). comparison of all viral antigen-based vaccine candidates. (<b>C</b>). comparison of all bacterial antigen-based vaccine candidates. All treatments are at 200 µg per well dose. Data are expressed as mean ± SEM, ordinary one-way ANOVA test, post-hoc Tukey’s multiple comparison test. ns, non-significant, * <span class="html-italic">p</span> ≤ 0.05, ** <span class="html-italic">p</span> ≤ 0.01, *** <span class="html-italic">p</span> ≤ 0.001, **** <span class="html-italic">p</span> ≤ 0.0001.</p>
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<p>Dose-dependent study results quantifying T-cell proliferation against various concentrations of vaccine candidates. (<b>A</b>). T-cell proliferation analysis measured on days 1, 2, 4, and 6 when treated with vaccine candidate against <span class="html-italic">N. gonorrhoeae</span> strain FA1090 at concentrations of 200 µg, 160 µg, 120 µg, 80 µg, and 40 µg vaccine MPs per well. (<b>B</b>). T-cell proliferation analysis was measured on days 1, 2, 4, and 6 when treated with a vaccine candidate against the measles virus at concentrations of 200 µg, 160 µg, 120 µg, 80 µg, and 40 µg vaccine NPs per well. (<b>C</b>,<b>D</b>). T-cell proliferation trends quantified in response to H1N1 virus particle vaccine candidate and <span class="html-italic">N. gonorrhoeae</span> strain CDC F62 bacterial particle vaccine candidates on day 6. Both were tested at concentrations of 200 µg, 160 µg, 120 µg, 80 µg, and 40 µg per well on day 6. Data are expressed as mean ± SEM, one-way ANOVA, post hoc Tukey’s multiple comparisons test; ns, non-significant, * <span class="html-italic">p</span> ≤ 0.05, ** <span class="html-italic">p</span> ≤ 0.01, *** <span class="html-italic">p</span> ≤ 0.001, **** <span class="html-italic">p</span> ≤ 0.0001.</p>
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37 pages, 5693 KiB  
Review
Alzheimer’s Disease Pathology and Assistive Nanotheranostic Approaches for Its Therapeutic Interventions
by Anuvab Dey, Subhrojyoti Ghosh, Ramya Lakshmi Rajendran, Tiyasa Bhuniya, Purbasha Das, Bidyabati Bhattacharjee, Sagnik Das, Atharva Anand Mahajan, Anushka Samant, Anand Krishnan, Byeong-Cheol Ahn and Prakash Gangadaran
Int. J. Mol. Sci. 2024, 25(17), 9690; https://doi.org/10.3390/ijms25179690 - 7 Sep 2024
Viewed by 1296
Abstract
Alzheimer’s disease (AD) still prevails and continues to increase indiscriminately throughout the 21st century, and is thus responsible for the depreciating quality of health and associated sectors. AD is a progressive neurodegenerative disorder marked by a significant amassment of beta-amyloid plaques and neurofibrillary [...] Read more.
Alzheimer’s disease (AD) still prevails and continues to increase indiscriminately throughout the 21st century, and is thus responsible for the depreciating quality of health and associated sectors. AD is a progressive neurodegenerative disorder marked by a significant amassment of beta-amyloid plaques and neurofibrillary tangles near the hippocampus, leading to the consequent loss of cognitive abilities. Conventionally, amyloid and tau hypotheses have been established as the most prominent in providing detailed insight into the disease pathogenesis and revealing the associative biomarkers intricately involved in AD progression. Nanotheranostic deliberates rational thought toward designing efficacious nanosystems and strategic endeavors for AD diagnosis and therapeutic implications. The exceeding advancements in this field enable the scientific community to envisage and conceptualize pharmacokinetic monitoring of the drug, sustained and targeted drug delivery responses, fabrication of anti-amyloid therapeutics, and enhanced accumulation of the targeted drug across the blood–brain barrier (BBB), thus giving an optimistic approach towards personalized and precision medicine. Current methods idealized on the design and bioengineering of an array of nanoparticulate systems offer higher affinity towards neurocapillary endothelial cells and the BBB. They have recently attracted intriguing attention to the early diagnostic and therapeutic measures taken to manage the progression of the disease. In this article, we tend to furnish a comprehensive outlook, the detailed mechanism of conventional AD pathogenesis, and new findings. We also summarize the shortcomings in diagnostic, prognostic, and therapeutic approaches undertaken to alleviate AD, thus providing a unique window towards nanotheranostic advancements without disregarding potential drawbacks, side effects, and safety concerns. Full article
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<p>In a healthy brain (<b>A</b>), insulin binding to its receptor activates IRS-1 and PI3K, supporting neuronal health, growth, and cognitive functions. This process also balances blood vessel dilation and constriction to meet metabolic needs. In AD (<b>B</b>), Aβ oligomers disrupt this system by increasing TNF-α and activating stress kinases like JNK, which negatively affects IRS-1 (1). These oligomers also displace insulin receptors (IRs) from the cell surface by the actions of CK2 and CaMKII, relocating them away from areas where they are needed (2). This leads to insulin resistance, decreasing Aβ-degrading enzyme (IDE) levels (3), thus reducing Aβ clearance. The impaired insulin signaling escalates GSK-3β activity (4), promoting abnormal tau phosphorylation and damaging neuronal functions and cognitive abilities (5). Furthermore, this dysfunction disrupts vascular regulation (6), reducing nitric oxide (NO) production, decreasing cerebral blood flow, and increasing inflammation and oxidative stress (reprinted with permission from ref [<a href="#B17-ijms-25-09690" class="html-bibr">17</a>] with CC BY license Copyright© 2015 Bedse, Di Domenico, Serviddio and Cassano). CaMKII—Calcium/calmodulin-dependent protein kinase II; CK2—Casein kinase 2; eNOS—Endothelial nitric oxide synthase; ET—Endothelin; GSK-3β—Glycogen synthase kinase-3 beta; IDE—Insulin-degrading enzyme; IRS-1—Insulin receptor substrate 1; JNK—c-Jun N-terminal kinase; NO—Nitric oxide; PI3K—Phosphoinositide 3-kinase; TNF-α—Tumor necrosis factor-alpha; and TNFR—Tumor necrosis factor receptor.</p>
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<p>Pathways leading to AD because of oxidative stress and protein misfolding. This diagram illustrates the cascade of events starting with oxidative stress, characterized by the overproduction of ROS. This triggers neuroinflammation and activates microglia, leading to mitochondrial dysfunction (as indicated by decreased ATP levels). The process involves the increased activity of GSK-3β and decreased activity of PP2A, contributing to the hyperphosphorylation of tau proteins. Consequently, there is an accumulation of NFTs and Aβ plaques, which are hallmarks of AD. This sequence of events leads to proteasomal malfunction, further exacerbating protein misfolding and ultimately causing neuronal apoptosis. These interconnected pathways culminate in the development and progression of AD (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>).</p>
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<p>Diagram illustrating the routes for autophagy and mitophagy. (<b>A</b>) In response to nutrient or energy stress, AMPK is activated, and mTORC1 is suppressed, which increases ULK1 complex activity and stimulates the creation of the VPS34 and ATG5-12-16L complexes, which, in turn, stimulates the production of phagophores and autophagosomes. (<b>B</b>) Depolarization of the mitochondria stabilizes PINK1 and stimulates PINK/Parkin signaling, which increases OMM’s phospho-ubiquitin conjugation. Mitophagy receptors like OPTN and NDP52 identify the polyubiquitin chain, which promotes mitophagosome formation (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>).</p>
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<p>Diagram illustrating how antibodies specific to tau and Aβ work near each other; along with streptavidin-coated gold nanoparticles (S-AuNP) and biotin-coated Aβ-antibody interaction, we can diagnose AD (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>).</p>
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<p>The role of nanoparticles in overcoming the BBB for efficient delivery of therapeutic moieties to treat AD. (<b>A</b>) Image of human brain. (<b>B</b>) Components of the BBB. (<b>C</b>) Functionalized nanoparticles (NPs) for imaging and targeted drug delivery to the AD brain. (<b>D</b>) Different pathways of transport (a–e) across the BBB utilized by functionalized NPs. (a) Transport of NPs through cellular transport proteins; (b) transport of NPs through tight junctions; (c) transport of NPs via receptor-mediated transcytosis; (d) transport of NPs via transcellular pathway following diffusion, specifically adopted by gold NPs; (e) transport of cationic NPs and liposomes via adsorption-mediated transcytosis. (<b>E</b>) Effect of functionalized NPs in treating AD via the degradation of tau aggregates and efflux of Aβ fibrils after becoming solubilized by the NPs (reprinted with permission from ref [<a href="#B129-ijms-25-09690" class="html-bibr">129</a>] with CC BY 4.0 license Copyright© 2021 Khan, Mir, Ngowi, Zafar, Khakwani, Khattak, Zhai, Jiang, Zheng, Duan, Wei, Wu, and Ji).</p>
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<p>Schematic representation of a biosensor device for detecting biomarkers in a sample. The device consists of a bioreceptor component where specific biomarkers from the sample bind to the surface. Various nanomaterials such as carbon nanotubes, quantum dots, graphene oxide, metallic nanoparticles, and magnetic nanoparticles are used to enhance the specificity and sensitivity of the bioreceptor. In contact with the bioreceptor, the transducer element converts the biochemical signal into an electrical signal through either optical or electrochemical means. This signal is then relayed to the electronics component, which processes the signal for subsequent detection and quantification of the analyte (created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>).</p>
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58 pages, 1391 KiB  
Review
Advancements in Plant-Based Therapeutics for Hepatic Fibrosis: Molecular Mechanisms and Nanoparticulate Drug Delivery Systems
by Alina Ciceu, Ferenc Fenyvesi, Anca Hermenean, Simona Ardelean, Simona Dumitra and Monica Puticiu
Int. J. Mol. Sci. 2024, 25(17), 9346; https://doi.org/10.3390/ijms25179346 - 28 Aug 2024
Viewed by 1135
Abstract
Chronic liver injuries often lead to hepatic fibrosis, a condition characterized by excessive extracellular matrix accumulation and abnormal connective tissue hyperplasia. Without effective treatment, hepatic fibrosis can progress to cirrhosis or hepatocellular carcinoma. Current treatments, including liver transplantation, are limited by donor shortages [...] Read more.
Chronic liver injuries often lead to hepatic fibrosis, a condition characterized by excessive extracellular matrix accumulation and abnormal connective tissue hyperplasia. Without effective treatment, hepatic fibrosis can progress to cirrhosis or hepatocellular carcinoma. Current treatments, including liver transplantation, are limited by donor shortages and high costs. As such, there is an urgent need for effective therapeutic strategies. This review focuses on the potential of plant-based therapeutics, particularly polyphenols, phenolic acids, and flavonoids, in treating hepatic fibrosis. These compounds have demonstrated anti-fibrotic activities through various signaling pathways, including TGF-β/Smad, AMPK/mTOR, Wnt/β-catenin, NF-κB, PI3K/AKT/mTOR, and hedgehog pathways. Additionally, this review highlights the advancements in nanoparticulate drug delivery systems that enhance the pharmacokinetics, bioavailability, and therapeutic efficacy of these bioactive compounds. Methodologically, this review synthesizes findings from recent studies, providing a comprehensive analysis of the mechanisms and benefits of these plant-based treatments. The integration of novel drug delivery systems with plant-based therapeutics holds significant promise for developing effective treatments for hepatic fibrosis. Full article
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<p>A diagram of signaling pathways modulated by polyphenols and their drug delivery systems in hepatic fibrosis. This figure was created with BioRender.com.</p>
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<p>A diagram illustrating the role of immune cells and immune responses mediated by polyphenols in the resolution of liver fibrosis. This figure was created with BioRender.com.</p>
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47 pages, 3150 KiB  
Review
Progress in Topical and Transdermal Drug Delivery Research—Focus on Nanoformulations
by Dominique Lunter, Victoria Klang, Adina Eichner, Sanela M. Savic, Snezana Savic, Guoping Lian and Franciska Erdő
Pharmaceutics 2024, 16(6), 817; https://doi.org/10.3390/pharmaceutics16060817 - 16 Jun 2024
Cited by 2 | Viewed by 3530
Abstract
Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The [...] Read more.
Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The skin is involved in body temperature regulation by the storage of fat and water. It is an interesting tissue in regard to the local and transdermal application of active ingredients for prevention or treatment of pathological conditions. Topical and transdermal delivery is an emerging route of drug and cosmetic administration. It is beneficial for avoiding side effects and rapid metabolism. Many pharmaceutical, technological and cosmetic innovations have been described and patented recently in the field. In this review, the main features of skin morphology and physiology are presented and are being followed by the description of classical and novel nanoparticulate dermal and transdermal drug formulations. The biophysical aspects of the penetration of drugs and cosmetics into or across the dermal barrier and their investigation in diffusion chambers, skin-on-a-chip devices, high-throughput measuring systems or with advanced analytical techniques are also shown. The current knowledge about mathematical modeling of skin penetration and the future perspectives are briefly discussed in the end, all also involving nanoparticulated systems. Full article
(This article belongs to the Special Issue Nanoparticles for Local Drug Delivery)
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<p>Main cellular elements of the human skin.</p>
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<p>Example of nanoparticle (NP)-based carriers used as topical, dermal and transdermal drug delivery systems.</p>
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<p><b>Top row</b>: Laser light interacts with matter, Stokes scattering provides Raman spectrum, divided into fingerprint and high wavenumber region; <b>Bottom row</b>: laser light focused into different depths of the skin generates one spectrum per skin depth from which the penetration profile is calculated.</p>
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<p>Microscopic PBPK modeling of 4-cyanophenol disposition in SC lipids (<b>a</b>) and corneocytes (<b>b</b>) domains under in vivo exposure to healthy volunteers at 1 min(-------) (•), 5 min (- - -) (<b>×</b>) and 15 min (………) (■). Predicted overall disposition (<b>c</b>) by combining both lipids and corneocytes domains showed good agreement with tape striping data. Figure modified from [<a href="#B183-pharmaceutics-16-00817" class="html-bibr">183</a>] with permission of John Wiley and sons at the License Number 5810360623095.</p>
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<p>Microscopic PBPK modeling of caffeine deposition in SC lipids and corneocytes domains after 20 min application to the chest of health volunteers (above). The predicted effect of hair follicle open (<b>a</b>) and blocked (<b>b</b>) on systemic bioavailability agreed well with experimental data. Figure adopted from [<a href="#B163-pharmaceutics-16-00817" class="html-bibr">163</a>] open access.</p>
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25 pages, 2058 KiB  
Article
Evaluation of Efficacy of Surface Coated versus Encapsulated Influenza Antigens in Mannose–Chitosan Nanoparticle-Based Intranasal Vaccine in Swine
by Dina Bugybayeva, Ekachai Dumkliang, Veerupaxagouda Patil, Ganesh Yadagiri, Raksha Suresh, Mithilesh Singh, Jennifer Schrock, Sara Dolatyabi, Olaitan C. Shekoni, Hadi M. Yassine, Praneet Opanasopit, Harm HogenEsch and Gourapura J. Renukaradhya
Vaccines 2024, 12(6), 647; https://doi.org/10.3390/vaccines12060647 - 11 Jun 2024
Viewed by 1512
Abstract
This study focuses on the development and characterization of an intranasal vaccine platform using adjuvanted nanoparticulate delivery of swine influenza A virus (SwIAV). The vaccine employed whole inactivated H1N2 SwIAV as an antigen and STING-agonist ADU-S100 as an adjuvant, with both surface adsorbed [...] Read more.
This study focuses on the development and characterization of an intranasal vaccine platform using adjuvanted nanoparticulate delivery of swine influenza A virus (SwIAV). The vaccine employed whole inactivated H1N2 SwIAV as an antigen and STING-agonist ADU-S100 as an adjuvant, with both surface adsorbed or encapsulated in mannose–chitosan nanoparticles (mChit-NPs). Optimization of mChit-NPs included evaluating size, zeta potential, and cytotoxicity, with a 1:9 mass ratio of antigen to NP demonstrating high loading efficacy and non-cytotoxic properties suitable for intranasal vaccination. In a heterologous H1N1 pig challenge trial, the mChit-NP intranasal vaccine induced cross-reactive sIgA antibodies in the respiratory tract, surpassing those of a commercial SwIAV vaccine. The encapsulated mChit-NP vaccine induced high virus-specific neutralizing antibody and robust cellular immune responses, while the adsorbed vaccine elicited specific high IgG and hemagglutinin inhibition antibodies. Importantly, both the mChit-NP vaccines reduced challenge heterologous viral replication in the nasal cavity higher than commercial swine influenza vaccine. In summary, a novel intranasal mChit-NP vaccine platform activated both the arms of the immune system and is a significant advancement in swine influenza vaccine design, demonstrating its potential effectiveness for pig immunization. Full article
(This article belongs to the Special Issue Porcine Virus and Vaccines)
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<p>Evaluation of cytotoxicity of mChit-NPs on pig PBMCs. Different concentrations of mChit-NPs (µg/mL) encapsulated with BSA were assessed for toxicity on PBMCs using the MTS assay. The results are presented as follows: (<b>A</b>) linear bar graph; the dotted line represents 75% cell viability at a concentration of 500 µg/mL mChit-NPs. (<b>B</b>) Exponential curve: utilizing non-linear regression analysis on PBMCs viability data enabled the extrapolation of the 50% inhibitory concentration (IC) 50 value at 2200 µg/mL. Mean ± SEM obtained from a single experiment (<span class="html-italic">n</span> = 4).</p>
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<p>Heatmap illustrating percentage nucleotide identity of HA gene of different vaccine SwIAVs compared to 2009 pandemic CA09-H1N1 challenge virus. Multiple sequence alignments of influenza A virus HA gene sequences were conducted using the BLAST server. The main comparisons related to our study include analysis of intranasal vaccine antigen strain OH10-H1N2 with challenge virus CA09-H1N1 and the commercial vaccine virus strains NC05-H1N1, OK08-H1N2, MN05-H3N2, and MX10-H1N1, with challenge virus CA09-H1N1.</p>
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<p>Efficacy of both the mChit-SwAIV + S100-NP vaccines against viral replication in the upper respiratory tract. Nasal swab specimen collected at DPIs-2, -4 and -6 were subjected to influenza A virus titration by estimating the 50% tissue culture infectious dose (TCID<sub>50</sub>). Data are presented as TCID<sub>50</sub> log<sub>10</sub> viral loads, individual symbols indicate single pig value, and each bar is the mean ± SEM of six pigs in each group. A line drawn above the titer value ‘0’ indicates the limit of virus detection. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) were determined by one-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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<p>Hemagglutination inhibition (HAI) and virus neutralization (VN) antibody titers in pigs immunized with mChit-SwAIV + S100-NP vaccines and challenged with a heterologous influenza A virus. Pigs were prime-boost vaccinated intranasally with either encapsulated or surface adsorbed mannose–chitosan NPs vaccine or intramuscularly with a commercial vaccine. (<b>A</b>) BAL fluid, (<b>B</b>) serum antibody HAI endpoint titers, and (<b>C</b>) VN titers in serum collected at DPI-6 were assessed against the challenge CA09-H1N1 virus. Each marking represents the titer of an individual pig in a group (<span class="html-italic">n</span> = 6). HAI titers were transformed to log<sub>2</sub> values and error bars indicate means ± SEM. VN titer is the reciprocal endpoint titer transformed to log<sub>10</sub> value and plotted as a geometric mean titer with SD (GMT) from triplicate wells. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) were determined by one-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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<p>Influenza A virus specific IgG antibody responses in the serum of mChit-SwAIV + S100-NP vaccinated pigs challenged with a heterologous virus. Pigs were prime-boost vaccinated with either encapsulated or surface adsorbed mChit-SwAIV + S100-NPs vaccine intranasally, or intramuscularly with a commercial vaccine. Serum samples collected at (<b>A</b>) DPI-0 and (<b>B</b>) DPI-6 were assessed for specific IgG antibody responses against CA09-H1N1, OH10-H1N2, and OH4-H3N2 strains of viruses by ELISA. Each data point on the horizontal lines is the mean ± SEM values of 5–6 pigs. Alphabets above markings indicate significant difference between vaccine groups at a specific dilution such as: a—mock + challenge vs. mChit-SwAIV + S100-eNPs; b—mock + challenge vs. mChit-SwAIV + S100-sNPs; c—mock + challenge vs. commercial vaccine; d—mChit-SwAIV + S100-eNPs vs. mChit-SwAIV + S100-sNPs; e—SwAIV + S100-eNPs vs. commercial vaccine; f—mChit-SwAIV + S100-sNPs vs. commercial vaccine. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) were determined by two-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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<p>Influenza A virus specific IgG antibody responses in the lungs of mChit-SwAIV + S100-NP vaccinated pigs challenged with a heterologous virus. Pigs were prime-boost vaccinated with either encapsulated or surface adsorbed mChit-SwAIV + S100-NPs vaccine intranasally, or intramuscularly with a commercial vaccine. (<b>A</b>) Lung lysate and (<b>B</b>) BAL fluid specimenscollected at DPI-6 were assessed for specific IgG antibody responses against CA09-H1N1, OH10-H1N2 and OH4-H3N2 strain of viruses by ELISA. Each point on horizontal lines is the mean ± SEM values of 5–6 pigs. Alphabets above markings indicate significant difference between vaccine groups at a specific dilution such as: a—mock + challenge vs. mChit-SwAIV + S100-eNPs; b—mock + challenge vs. mChit-SwAIV + S100-sNPs; c—mock + challenge vs. commercial vaccine; d—mChit-SwAIV + S100-eNPs vs. mChit-SwAIV + S100-sNPs; e—SwAIV + S100-eNPs vs. commercial vaccine; f—mChit-SwAIV + S100-sNPs vs. commercial vaccine. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) were determined by two-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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<p>Influenza A virus specific sIgA antibody responses in the respiratory tract of mChit-SwAIV + S100-NPs vaccinated pigs challenged with a heterologous virus. Pigs were prime-boost vaccinated with either encapsulated or surface adsorbed mChit-SwAIV + S100-NPs vaccine intranasally, or intramuscularly with a commercial vaccine. (<b>A</b>) Lung lysate, (<b>B</b>) BAL fluid, and (<b>C</b>) Nasal swab specimenscollected at DPI-6 were assessed for specific sIgA antibody responses against CA09-H1N1, OH10-H1N2, and OH4-H3N2 strain of viruses by ELISA. Each point on horizontal lines is the mean ± SEM values of 5–6 pigs. Alphabets above markings indicate significant difference between vaccine groups at a specific dilution such as: a—mock + challenge vs. mChit-SwAIV + S100-eNPs; b—mock + challenge vs. mChit-SwAIV + S100-sNPs; d—mChit-SwAIV + S100-eNPs vs. mChit-SwAIV + S100-sNPs; f—mChit-SwAIV + S100-sNPs vs. commercial vaccine. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) were determined by two-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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<p>Avidity of cross-reactive influenza A virus specific IgG and sIgA antibody at various ammonium thiocyanate (NH<sub>4</sub>SCN) concentrations in the mChit-SwAIV + S100-NP vaccinated pigs challenged with a heterologous virus. Relative binding avidity of (<b>A</b>) IgG and (<b>B</b>) IgA to CA09-H1N1 antigen was assessed using a single test dilution of serum (IgG only), lung lysate, BAL fluid, and nasal swabs (sIgA only) in the absence or presence of NH<sub>4</sub>SCN at different concentrations. Each data point is the mean titer ± SEM from duplicate wells. Alphabets above markings indicate significant differences between vaccine groups at a specific dilution such as: a—mock + challenge vs. mChit-SwAIV + S100-eNPs; b—mock + challenge vs. mChit-SwAIV + S100-sNPs; c—mock + challenge vs. commercial vaccine; d—mChit-SwAIV + S100-eNPs vs. mChit-SwAIV + S100-sNPs; e—SwAIV + S100-eNPs vs. commercial vaccine; f—mChit-SwAIV + S100-sNPs vs. commercial vaccine. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) were determined by two-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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<p>Avidity index of cross-reactive influenza A virus specific IgG antibody in mChit-SwAIV + S100-NPs vaccinated pigs challenged with a heterologous virus. The IgG avidity index in (<b>A</b>) serum and (<b>B</b>) BAL fluid was calculated using OD values obtained upon treatment, with single NH<sub>4</sub>SCN concentration at 1.25 M compared to untreated control samples. Box-and-whisker plot indicates interquartile ranges, horizontal lines show group median. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) determined by one-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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<p>A representative gating strategy of pig TBLN MNCs by flow cytometry. (<b>A</b>) Top: Isotype control for myeloid cells; Bottom: specific antibody staining for myeloid cells; (<b>B</b>) IFNγ<sup>+</sup> T-helper/memory cells and IFNγ<sup>+</sup> cytotoxic T lymphocytes; (<b>C</b>) IL-17A<sup>+</sup> T-helper/memory and IL-17A<sup>+</sup> cytotoxic T lymphocytes. The flow cytometry results were analyzed using FlowJo Software.</p>
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<p>A representative gating strategy of pig TBLN MNCs by flow cytometry. (<b>A</b>) Top: Isotype control for myeloid cells; Bottom: specific antibody staining for myeloid cells; (<b>B</b>) IFNγ<sup>+</sup> T-helper/memory cells and IFNγ<sup>+</sup> cytotoxic T lymphocytes; (<b>C</b>) IL-17A<sup>+</sup> T-helper/memory and IL-17A<sup>+</sup> cytotoxic T lymphocytes. The flow cytometry results were analyzed using FlowJo Software.</p>
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<p>A representative gating strategy of pig TBLN MNCs by flow cytometry. (<b>A</b>) Top: Isotype control for myeloid cells; Bottom: specific antibody staining for myeloid cells; (<b>B</b>) IFNγ<sup>+</sup> T-helper/memory cells and IFNγ<sup>+</sup> cytotoxic T lymphocytes; (<b>C</b>) IL-17A<sup>+</sup> T-helper/memory and IL-17A<sup>+</sup> cytotoxic T lymphocytes. The flow cytometry results were analyzed using FlowJo Software.</p>
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<p>Frequencies of myeloid cells in PBMCs and TBLN MNCs of mChit-SwAIV + S100-NP vaccinated pigs challenged with a heterologous virus. (<b>A</b>,<b>B</b>) PBMCs and (<b>C</b>,<b>D</b>) TBLN MNCs of pigs stimulated in vitro with CA09-H1N1 virus. Cell frequency was determined by flow cytometry. Error bars indicate means ± SEMs of 5–6 pigs. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) were determined by two-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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<p>Lymphocyte stimulation index in mChit-SwAIV + S100-NP vaccinated pigs challenged with a heterologous virus. (<b>A</b>) PBMCs and (<b>B</b>) TBLN MNCs isolated at DPI-6 were stimulated with 0.1 MOI of CA09-H1N1 virus in the presence of recombinant porcine IL-2 for 48 h and analyzed for cell proliferation index. Error bars indicate means ± SEMs of 5–6 pigs. The statistical significance <span class="html-italic">p</span> &lt; 0.05 was obtained by analysis of variance (ANOVA) with Tukey’s pair-wise comparison.</p>
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<p>Analysis of T-helper/memory cell frequency in mChit-SwAIV + S100-NP vaccinated pigs challenged with a heterologous virus. (<b>A</b>) TBLN MNCs and (<b>B</b>) PBMCs isolated at DPI-6 were stimulated with CA09-H1N1 virus and analyzed for the frequency of T-helper/memory cells by flow cytometry. Error bars indicate means ± SEMs of 5–6 pigs. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) were determined by two-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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<p>Analysis of IFNγ and IL-17A positive CTLs frequency in mChit-SwAIV + S100-NP vaccinated pigs challenged with a heterologous virus. (<b>A</b>,<b>C</b>) PBMCs and (<b>B</b>) TBLN MNCs isolated at DPI-6 were stimulated with CA09-H1N1 virus and analyzed for the frequency of (<b>A</b>) IFNγ<sup>+</sup> CTLs in PBMC, (<b>B</b>) IFNγ<sup>+</sup> CTLs in TBLN MNCs, and (<b>C</b>) IL-17A<sup>+</sup> CTLs in PBMCs by flow cytometry. The central line in each pig group indicates the mean ± SEM of 5–6 pigs. The <span class="html-italic">p</span> values between groups (<span class="html-italic">p</span> &lt; 0.05) were determined by two-way ANOVA with Tukey’s multiple comparisons post-hoc test.</p>
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34 pages, 498 KiB  
Review
Leading Paediatric Infectious Diseases—Current Trends, Gaps, and Future Prospects in Oral Pharmacotherapeutic Interventions
by Penelope N. Rampedi, Modupe O. Ogunrombi and Oluwatoyin A. Adeleke
Pharmaceutics 2024, 16(6), 712; https://doi.org/10.3390/pharmaceutics16060712 - 26 May 2024
Viewed by 1505
Abstract
Paediatric infectious diseases contribute significantly to global health challenges. Conventional therapeutic interventions are not always suitable for children, as they are regularly accompanied with long-standing disadvantages that negatively impact efficacy, thus necessitating the need for effective and child-friendly pharmacotherapeutic interventions. Recent advancements in [...] Read more.
Paediatric infectious diseases contribute significantly to global health challenges. Conventional therapeutic interventions are not always suitable for children, as they are regularly accompanied with long-standing disadvantages that negatively impact efficacy, thus necessitating the need for effective and child-friendly pharmacotherapeutic interventions. Recent advancements in drug delivery technologies, particularly oral formulations, have shown tremendous progress in enhancing the effectiveness of paediatric medicines. Generally, these delivery methods target, and address challenges associated with palatability, dosing accuracy, stability, bioavailability, patient compliance, and caregiver convenience, which are important factors that can influence successful treatment outcomes in children. Some of the emerging trends include moving away from creating liquid delivery systems to developing oral solid formulations, with the most explored being orodispersible tablets, multiparticulate dosage forms using film-coating technologies, and chewable drug products. Other ongoing innovations include gastro-retentive, 3D-printed, nipple-shield, milk-based, and nanoparticulate (e.g., lipid-, polymeric-based templates) drug delivery systems, possessing the potential to improve therapeutic effectiveness, age appropriateness, pharmacokinetics, and safety profiles as they relate to the paediatric population. This manuscript therefore highlights the evolving landscape of oral pharmacotherapeutic interventions for leading paediatric infectious diseases, crediting the role of innovative drug delivery technologies. By focusing on the current trends, pointing out gaps, and identifying future possibilities, this review aims to contribute towards ongoing efforts directed at improving paediatric health outcomes associated with the management of these infectious ailments through accessible and efficacious drug treatments. Full article
36 pages, 5832 KiB  
Review
Drug Delivery Systems of Betulin and Its Derivatives: An Overview
by Bartosz Jaroszewski, Katarzyna Jelonek and Janusz Kasperczyk
Biomedicines 2024, 12(6), 1168; https://doi.org/10.3390/biomedicines12061168 - 24 May 2024
Cited by 2 | Viewed by 1782
Abstract
Natural origin products are regarded as promising for the development of new therapeutic therapies with improved effectiveness, biocompatibility, reduced side effects, and low cost of production. Betulin (BE) is very promising due to its wide range of pharmacological activities, including its anticancer, antioxidant, [...] Read more.
Natural origin products are regarded as promising for the development of new therapeutic therapies with improved effectiveness, biocompatibility, reduced side effects, and low cost of production. Betulin (BE) is very promising due to its wide range of pharmacological activities, including its anticancer, antioxidant, and antimicrobial properties. However, despite advancements in the use of triterpenes for clinical purposes, there are still some obstacles that hinder their full potential, such as their hydrophobicity, low solubility, and poor bioavailability. To address these concerns, new BE derivatives have been synthesized. Moreover, drug delivery systems have emerged as a promising solution to overcome the barriers faced in the clinical application of natural products. The aim of this manuscript is to summarize the recent achievements in the field of delivery systems of BE and its derivatives. This review also presents the BE derivatives mostly considered for medical applications. The electronic databases of scientific publications were searched for the most interesting achievements in the last ten years. Thus far, it is mostly nanoparticles (NPs) that have been considered for the delivery of betulin and its derivatives, including organic NPs (e.g., micelles, conjugates, liposomes, cyclodextrins, protein NPs), inorganic NPs (carbon nanotubes, gold NPs, silver), and complex/hybrid and miscellaneous nanoparticulate systems. However, there are also examples of microparticles, gel-based systems, suspensions, emulsions, and scaffolds, which seem promising for the delivery of BE and its derivatives. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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Figure 1

Figure 1
<p>A schematic presentation of the biological effects of betulin and its chemical structure. The C-3, C-28, and C-30 groups considered for chemical modification are marked.</p>
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<p>Chemical structure of betulinic acid (<b>A</b>), 28-O-propynoylbetulin (<b>B</b>), 28-O-propynoylbetulone (<b>C</b>), 3β,28-diacetoxy-30-diethoxyphosphoryl-lup-20(29)-ene (<b>D</b>), and 29-diethoxyphosphoryl-28-propynoyloxy-lup-20E(29)-en-3-ol (<b>E</b>).</p>
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<p>Chemical structure of 3-diethoxyphosphoryl-28-propynoylbetulin (<b>A</b>), 3-dihydroxyphosphoryl-28-propynoylbetulin (<b>B</b>), 30-diethoxyphosphoryloxy-28-O-propynoylbetulin (<b>C</b>), and 28-(2-Butynoyl)-30-diethoxyphosphoryloxybetulin (<b>D</b>).</p>
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<p>Chemical structure of 3,28-O,O′-di(propynoyl)betulin (<b>A</b>), 3,28-O,O′-di[1-(4-fluorobenzyl-1H-1,2,3-triazol-4-yl) carbonyl]betulin (<b>B</b>), 28-O-[1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl]carbonylbetulin (<b>C</b>), 3,28-O,O′-di[1-(3-hydroxypropyl-1H-1,2,3-triazol-4-yl)carbonyl]betulin (<b>D</b>), and 28-O-[1-(3′-deoxythymidine-5′-yl)-1H-1,2,3-triazol-4-yl]carbonylbetulin (<b>E</b>).</p>
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<p>Chemical structure of 3β-O-Acetyl-30-(1H-1,2,4-triazole-3-ylsulfanyl)-betulinic acid.</p>
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<p>Chemical structure of 3β-O-acetyl-30-[5-(4-methoxyphenyl)-1H-1,2,4-triazol-3-yl)-sulfanyl]-betulinic acid (<b>A</b>) and 3β-O-acetyl-30-{5-[4-(dimethylamino)phenyl]-1H-1,2,4-triazol-3-yl)sulfanyl}-betulinic acid (<b>B</b>).</p>
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<p>Chemical structure of 6-chloro-7-(28-propynoyl-3-betulinyloxy)-5,8-quinolinedione (<b>A</b>), 7-(28-acetyl-3-betulinyloxy)-6-chloro-2-methyl-5,8-quinolinedione (<b>B</b>), and 3-(28-acetyl-3-betulinyloxy)-2-chloro-1,4-naphthoquinolinedione (<b>C</b>).</p>
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<p>Chemical structure of 3β-Hydroxylup-20(29)-en-28-yl 3-bromopropanoate (<b>A</b>), 3β-Hydroxylup-20(29)-en-28-yl 4-bromobutanoate (<b>B</b>), and 3β-Hydroxylup-20(29)-en-28-yl 5-bromopentanoate (<b>C</b>).</p>
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<p>Chemical structure of 3β,28-di-O-propionyl-lup-20(29)-lupene (<b>A</b>), 3-(2-butynoyl)botulin (<b>B</b>), betulin-dab-NH<sub>2</sub> (<b>C</b>).</p>
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<p>Chemical structure of (1R)-3a-(acetoxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl 3-methyl-4-oxo-4-(2-sulfamoylethylamino)butanoate (<b>A</b>) and (((1R)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl 3-methyl-4-oxo-4-(2-sulfamoylethylamino)butanoate) (<b>B</b>).</p>
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<p>Different types of delivery systems designed for BE and its derivatives.</p>
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<p>Chemical structure of 1-isopropenyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,5a,6,7,7a,8,11,11a,11b, 12,13,13b-octadecahydro cyclopenta[a]chrysene-3a-carboxylic acid (<b>A</b>), BA analogue (<b>B</b>).</p>
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<p>Schematic diagram of NA1-A-BAM NP synthesis [<a href="#B71-biomedicines-12-01168" class="html-bibr">71</a>].</p>
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<p>Schematic illustration of self-assembled Soluplus–BA micelles [<a href="#B75-biomedicines-12-01168" class="html-bibr">75</a>].</p>
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<p>Schematic illustration of the synthetic route to the PEGylated BA liposome and cancer therapy [<a href="#B79-biomedicines-12-01168" class="html-bibr">79</a>].</p>
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<p>Scheme of preparation BA-C<sub>60</sub>(OH)<sub>n</sub>-GBP-TPGS NPs [<a href="#B94-biomedicines-12-01168" class="html-bibr">94</a>].</p>
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<p>Schematic illustration of the synthesis route for the multifunctional Au NPs and the NIR laser irradiation-induced chemo-photothermal therapy in tumor-bearing mice [<a href="#B95-biomedicines-12-01168" class="html-bibr">95</a>].</p>
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15 pages, 2928 KiB  
Article
Cryo-Milled β-Glucan Nanoparticles for Oral Drug Delivery
by Guanyu Chen, Yi Liu, Darren Svirskis, Hongyu Li, Man Ying, Weiyue Lu and Jingyuan Wen
Pharmaceutics 2024, 16(4), 546; https://doi.org/10.3390/pharmaceutics16040546 - 16 Apr 2024
Viewed by 1651
Abstract
Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a [...] Read more.
Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a novel nanoparticulate drug delivery system for the oral delivery of gemcitabine to improve its oral bioavailability. In this study, gemcitabine-loaded β-glucan NPs were fabricated using a film-casting method followed by a freezer-milling technique. As a result, the NPs showed a small particle size of 447.6 ± 14.2 nm, and a high drug entrapment efficiency of 64.3 ± 2.1%. By encapsulating gemcitabine into β-glucan NPs, a sustained drug release profile was obtained, and the anomalous diffusion release mechanism was analyzed, indicating that the drug release was governed by diffusion through the NP matrix as well as matrix erosion. The drug-loaded NPs had a greater ex vivo drug permeation through the porcine intestinal epithelial membrane compared to the plain drug solution. Cytotoxicity studies showed a safety profile of the β-glucan polymers, and the IC50s of drug solution and drug-loaded β-glucan NPs were calculated as 228.8 ± 31.2 ng·mL−1 and 306.1 ± 46.3 ng·mL−1, respectively. Additionally, the LD50 of BALB/c nude mice was determined as 204.17 mg/kg in the acute toxicity studies. Notably, pharmacokinetic studies showed that drug-loaded β-glucan NPs could achieve a 7.4-fold longer T1/2 and a 5.1-fold increase in oral bioavailability compared with plain drug solution. Finally, in vivo pharmacodynamic studies showed the promising capability of gemcitabine-loaded β-glucan NPs to inhibit the 4T1 breast tumor growth, with a 3.04- and 1.74-fold reduction compared to the untreated control and drug solution groups, respectively. In conclusion, the presented freezer-milled β-glucan NP system is a suitable drug delivery method for the oral delivery of gemcitabine and demonstrates a promising potential platform for oral chemotherapy. Full article
(This article belongs to the Special Issue Advances in Oral Administration)
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<p>SEM images (50,000× magnification) of the optimal formulation of β-glucan NPs prepared via freezer milling.</p>
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<p>In vitro drug release of gemcitabine solution and gemcitabine loaded β-glucan NPs (mean ± SD, n = 3).</p>
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<p>Ex vivo permeation studies of gemcitabine loaded β-glucan NPs and gemcitabine solution through the porcine intestinal epithelial membrane (mean <span class="html-italic">±</span> SD, n = 3).</p>
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<p>Cytotoxicity of gemcitabine solution and drug-loaded β-glucan NPs on 4T1 breast cancer cells at the tested concentrations (mean ± SD, n = 3).</p>
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<p>Plasma concentrations of the drug in SD rats following the oral administration of drug solution, drug-loaded β-glucan NPs, and <span class="html-italic">i.v</span>. injection of drug solution (mean ± SD, n = 6). The oral administration group results were significantly different from the results obtained with the <span class="html-italic">i.v</span>. administration of gemcitabine (<span class="html-italic">p</span> &lt; 0.001) and the oral administration of gemcitabine solution; (*), <span class="html-italic">p</span> &lt; 0.01.</p>
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<p>(<b>A</b>) Changes in the body weight of BALB/c nude mice after the oral administration of various dosages over 10 days (mean ± SD, n = 10); (<b>B</b>) percentage inhibition versus logarithm of dosages to determine LD<sub>50</sub> of gemcitabine in BALB/c nude mice.</p>
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<p>(<b>A</b>) The time course of tumor size in BALB/c nude mice recorded during the period of treatment with drug solution and drug-loaded β-glucan NPs, as well as in those without treatment (saline group) over 12 days (mean ± SD, n = 6, <span class="html-italic">p</span> &lt; 0.01 at day 12); (<b>B</b>) the body weight change in BALB/c nude mice during the period of treatment over 12 days (mean ± SD, n = 6, <span class="html-italic">p</span> &lt; 0.01 at day 12); (<b>C</b>) photography of the solid tumors with saline, 3 doses of 30 mg/kg drug solution, and an equivalent dose of drug-loaded β-glucan NPs, given on days 0, 2, and 4, and harvested on day 12 (n = 6).</p>
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46 pages, 4899 KiB  
Review
Lipid Nanocarriers-Enabled Delivery of Antibiotics and Antimicrobial Adjuvants to Overcome Bacterial Biofilms
by Anam Ahsan, Nicky Thomas, Timothy J. Barnes, Santhni Subramaniam, Thou Chen Loh, Paul Joyce and Clive A. Prestidge
Pharmaceutics 2024, 16(3), 396; https://doi.org/10.3390/pharmaceutics16030396 - 14 Mar 2024
Cited by 4 | Viewed by 3235
Abstract
The opportunistic bacteria growing in biofilms play a decisive role in the pathogenesis of chronic infectious diseases. Biofilm-dwelling bacteria behave differently than planktonic bacteria and are likely to increase resistance and tolerance to antimicrobial therapeutics. Antimicrobial adjuvants have emerged as a promising strategy [...] Read more.
The opportunistic bacteria growing in biofilms play a decisive role in the pathogenesis of chronic infectious diseases. Biofilm-dwelling bacteria behave differently than planktonic bacteria and are likely to increase resistance and tolerance to antimicrobial therapeutics. Antimicrobial adjuvants have emerged as a promising strategy to combat antimicrobial resistance (AMR) and restore the efficacy of existing antibiotics. A combination of antibiotics and potential antimicrobial adjuvants, (e.g., extracellular polymeric substance (EPS)-degrading enzymes and quorum sensing inhibitors (QSI) can improve the effects of antibiotics and potentially reduce bacterial resistance). In addition, encapsulation of antimicrobials within nanoparticulate systems can improve their stability and their delivery into biofilms. Lipid nanocarriers (LNCs) have been established as having the potential to improve the efficacy of existing antibiotics in combination with antimicrobial adjuvants. Among them, liquid crystal nanoparticles (LCNPs), liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) are promising due to their superior properties compared to traditional formulations, including their greater biocompatibility, higher drug loading capacity, drug protection from chemical or enzymatic degradation, controlled drug release, targeted delivery, ease of preparation, and scale-up feasibility. This article reviews the recent advances in developing various LNCs to co-deliver some well-studied antimicrobial adjuvants combined with antibiotics from different classes. The efficacy of various combination treatments is compared against bacterial biofilms, and synergistic therapeutics that deserve further investigation are also highlighted. This review identifies promising LNCs for the delivery of combination therapies that are in recent development. It discusses how LNC-enabled co-delivery of antibiotics and adjuvants can advance current clinical antimicrobial treatments, leading to innovative products, enabling the reuse of antibiotics, and providing opportunities for saving millions of lives from bacterial infections. Full article
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Graphical abstract
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<p>The biofilm formation cycle consists of five main stages: I, attachment; II, colonization; III, development; IV, maturation; V, active dispersal. This figure was created with BioRender.com.</p>
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<p>An illustration of the different mechanisms of biofilm-mediated resistance to antimicrobials. The figure was created with BioRender.com.</p>
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<p>(<b>A</b>). an illustration of the various antibiofilm agents that target the different compounds that are responsible for biofilm formation. (<b>B</b>). an illustration of the various therapeutic techniques involved in directly targeting the biofilm formation process. This figure was created with Biorender.com.</p>
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<p>Synergy of antibiofilm peptide 1018 with conventional antibiotics in eradicating preformed biofilms. Biofilms were grown in a flow cell. Treatments (antibiotics, peptide, or combinations) were added after 2 days of biofilm growth and continued for 24 h. After 3 days, before confocal imaging, the bacteria were stained green with the all-bacteria stain Syto-9 and red with the dead-bacteria stain propidium iodide (merged images shown as color change from yellow to red). Each panel shows reconstructions from the top of the large panel and the sides of the right and bottom panels (x-y, y-z, and x-z dimensions, respectively). This figure was reproduced from Reffuveille et al. [<a href="#B63-pharmaceutics-16-00396" class="html-bibr">63</a>]. Copyright 2014, with permission from the American Society for Microbiology.</p>
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<p>The structures of quorum sensing signaling molecules: (<b>A</b>) acyl-homoserine lactone (AHL), (<b>B</b>) autoinducer-2 (AI-2), and (<b>C</b>) IDR-1018 anti-biofilm peptide.</p>
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<p>Various lipid nanocarriers for the co-delivery of antibiotics and antimicrobial adjuvants i.e., biofilm dispersing enzymes, and/or quorum sensing inhibitors to combat different bacterial biofilms. This figure was created with Biorender.com.</p>
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<p>A schematic illustration of lyotropic liquid crystalline phases (<b>a</b>) Lamellar, (<b>b</b>) reverse hexagonal, (<b>c</b>) inverse micellar cubic (Fd3m), (<b>d</b>) inverse bicontinuous cubic phase (lm3m), (<b>e</b>), inverse bicontinuous cubic phase (Pn3m), and (<b>f</b>) inverse bicontinuous cubic phase (la3d). This figure is reproduced from Huang et al. [<a href="#B213-pharmaceutics-16-00396" class="html-bibr">213</a>] Copyright 2018, with permission from the Royal Society of Chemistry.</p>
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<p>L4 stage <span class="html-italic">C. elegans</span> infected with PAO1 for 6 h following treatment with tobramycin (3 μg/mL) alone or in combination with PslG (20 nM)-as unformulated solution or encapsulated in MO-LCNPs (0.05 mg/mL MO) or PHY-LCNPs (0.05 mg/mL PHY). Nematode survival and bacterial burden (CFU) 24 h after infection was established (<b>A</b>,<b>B</b>), and Nematode survival and bacterial burden (CFU) 48 h after infection was established (<b>C</b>,<b>D</b>). Data are expressed as mean ± SD, n = 6, two-way ANOVA followed by Tukey’s multiple comparisons test, ** <span class="html-italic">p</span> &lt; 0.01 and * <span class="html-italic">p</span> &lt; 0.05. It is reproduced from Thorn et al. [<a href="#B13-pharmaceutics-16-00396" class="html-bibr">13</a>] Copyright 2021, with permission from the American Chemical Society.</p>
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31 pages, 1516 KiB  
Review
State-of-the-Art Review on Inhalable Lipid and Polymer Nanocarriers: Design and Development Perspectives
by Gabriella Costabile, Gemma Conte, Susy Brusco, Pouria Savadi, Agnese Miro, Fabiana Quaglia, Ivana d’Angelo and Francesca Ungaro
Pharmaceutics 2024, 16(3), 347; https://doi.org/10.3390/pharmaceutics16030347 - 1 Mar 2024
Cited by 4 | Viewed by 2154
Abstract
Nowadays, the interest in research towards the local administration of drugs via the inhalation route is growing as it enables the direct targeting of the lung tissue, at the same time reducing systemic side effects. This is of great significance in the era [...] Read more.
Nowadays, the interest in research towards the local administration of drugs via the inhalation route is growing as it enables the direct targeting of the lung tissue, at the same time reducing systemic side effects. This is of great significance in the era of nucleic acid therapeutics and personalized medicine for the local treatment of severe lung diseases. However, the success of any inhalation therapy is driven by a delicate interplay of factors, such as the physiochemical profile of the payload, formulation, inhalation device, aerodynamic properties, and interaction with the lung fluids. The development of drug delivery systems tailored to the needs of this administration route is central to its success and to revolutionize the treatment of respiratory diseases. With this review, we aim to provide an up-to-date overview of advances in the development of nanoparticulate carriers for drug delivery to the lung tissue, with special regard concerning lipid and polymer-based nanocarriers (NCs). Starting from the biological barriers that the anatomical structure of the lung imposes, and that need to be overcome, the current strategies to achieve efficient lung delivery and the best support for the success of NCs for inhalation are highlighted. Full article
(This article belongs to the Special Issue Application of Polymeric Nanoparticles in Pulmonary Drug Delivery)
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<p>Schematic diagram showing the barriers imposed by the lung to inhaled drugs and drug-loaded NCs.</p>
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<p>Schematic representation of different architectures of lipid-based NCs.</p>
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<p>Schematic representation of different architectures of polymer-based NCs.</p>
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