Pharmaceutics

19 pages, 4322 KiB

Open AccessArticle

Hemostatic Alginate/Nano-Hydroxyapatite Composite Aerogel Loaded with Tranexamic Acid for the Potential Protection against Alveolar Osteitis

by Mai El Halawany, Randa Latif and Mohamed H. H. AbouGhaly

Pharmaceutics 2022, 14(10), 2255; https://doi.org/10.3390/pharmaceutics14102255 - 21 Oct 2022

Cited by 7 | Viewed by 2349

Abstract

Wound control in patients on anticoagulants is challenging and often leads to poor hemostasis. They have a higher tendency to develop alveolar osteitis after tooth extraction. The application of a hemostatic dressing that has a high absorbing capacity and is loaded with an [...] Read more.

Wound control in patients on anticoagulants is challenging and often leads to poor hemostasis. They have a higher tendency to develop alveolar osteitis after tooth extraction. The application of a hemostatic dressing that has a high absorbing capacity and is loaded with an antifibrinolytic drug could help in controlling the bleeding. Alginate/nano-hydroxyapatite (SA/Nano-HA) composite aerogels loaded with tranexamic acid (TXA) were prepared. Nano-HA served as a reinforcing material for the alginate matrix and a source of calcium ions that helps in blood clotting. It influenced the porosity and the water uptake capacity. TXA release from SA/Nano-HA aerogels showed a biphasic profile for up to 4 h. Blood coagulation studies were performed on human whole blood. The TXA-loaded aerogel significantly reduced the clotting time by 69% compared to the control (p < 0.0001). Recalcification time was significantly reduced by 80% (p < 0.0001). Scanning electron microscopy analysis revealed the porous nature of the aerogels and the ability of the optimum aerogel to activate and adhere platelets to its porous surface. The cell migration assay showed that there was a delay in wound healing caused by the TXA aerogel compared to the control sample after treating human fibroblasts. Results suggest that the developed aerogel is a promising dressing that will help in hemostasis after tooth extraction. Full article

(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)

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12 pages, 2954 KiB

Open AccessArticle

Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action

by Emilija Milović, Nenad Janković, Jelena Petronijević, Nenad Joksimović, Marijana Kosanić, Tatjana Stanojković, Ivana Matić, Nađa Grozdanić, Olivera Klisurić and Srđan Stefanović

Pharmaceutics 2022, 14(10), 2254; https://doi.org/10.3390/pharmaceutics14102254 - 21 Oct 2022

Cited by 10 | Viewed by 2293

Abstract

In this paper, the synthesis, characterization, and biological evaluation of the novel tetrahydropyrimidines—THPMs are described. THPMs are well-known for wide pharmacological activities such as antimicrobial, anticancer, antiviral, etc. This research includes obtained results of in vitro antimicrobial, anticancer, and α-glucosidase inhibitory activities of [...] Read more.

In this paper, the synthesis, characterization, and biological evaluation of the novel tetrahydropyrimidines—THPMs are described. THPMs are well-known for wide pharmacological activities such as antimicrobial, anticancer, antiviral, etc. This research includes obtained results of in vitro antimicrobial, anticancer, and α-glucosidase inhibitory activities of the eleven novel THPMs. An antibiotic assessment was done against five bacteria (two Gram-positive and three Gram-negative) and five fungi by determining the minimal inhibitory concentration (MIC), using the broth tube dilution method. The most active antibacterial compounds were 4a, 4b, and 4d, while the best antifungal activity was shown by 4e, 4f, and 4k. The lowest MIC value (0.20 mg/mL) was measured for 4e, 4f, and 4k against the Trichophyton mentagrophytes. Moreover, examining the α-glucosidase inhibitory activity revealed the compound 4g as the one with the best activity. The cytotoxic activity was performed on the tumor cell lines (HeLa, K562, and MDA-MB-231) and normal cells (MRC-5). The best antitumor activity was shown by compounds 4b and 4k against HeLa cell lines. The influence on cell cycle and mechanism of action of the most active compounds were examined too. Compound 4b had good antibacterial and anticancer activities, while 4k showed promising antifungal and anticancer activities. Full article

(This article belongs to the Special Issue Natural and Synthesized Anticancer Bioactive Compounds in Drug Discovery, Formulations and Delivery)

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20 pages, 3845 KiB

Open AccessArticle

Activation of Somatostatin-Expressing Neurons in the Lateral Septum Improves Stress-Induced Depressive-like Behaviors in Mice

by Huanhuan Li, Hyun Hailey Sung and Chunyue Geoffrey Lau

Pharmaceutics 2022, 14(10), 2253; https://doi.org/10.3390/pharmaceutics14102253 - 21 Oct 2022

Cited by 12 | Viewed by 4621

Abstract

Depression is a debilitating mood disorder with highly heterogeneous pathogenesis. The limbic system is well-linked to depression. As an important node in the limbic system, the lateral septum (LS) can modulate multiple affective and motivational behaviors. However, the role of LS in depression [...] Read more.

Depression is a debilitating mood disorder with highly heterogeneous pathogenesis. The limbic system is well-linked to depression. As an important node in the limbic system, the lateral septum (LS) can modulate multiple affective and motivational behaviors. However, the role of LS in depression remains unclear. By using c-Fos expression mapping, we first screened and showed activation of the LS in various depression-related behavioral tests, including the forced swim test (FST), tail suspension test (TST), and sucrose preference test. In the LS, more than 10% of the activated neurons were somatostatin-expressing (SST) neurons. We next developed a microendoscopic calcium imaging method in freely moving mice and revealed that LS^SST neural activity increased during mobility in the TST but not open field test. We hypothesize that LS^SST neuronal activity is linked to stress and depression. In two mouse models of depression, repeated lipopolysaccharide (LPS) injection and chronic restraint stress (CRS), we showed that LS neuronal activation was suppressed. To examine whether the re-activation of LS^SST neurons can be therapeutically beneficial, we optogenetically activated LS^SST neurons and produced antidepressant-like effects in LPS-injected mice by increasing TST motility. Moreover, chemogenetic activation of LS^SST neurons increased FST struggling in the CRS-exposed mice. Together, these results provide the first evidence of a role for LS^SST neurons in regulating depressive-like behaviors in mice and identify them as a potential therapeutic target for neuromodulation-based intervention in depression. Full article

(This article belongs to the Special Issue Drug Targeting for CNS Disease)

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22 pages, 2133 KiB

Open AccessReview

Exosomes as CNS Drug Delivery Tools and Their Applications

by Ke Sun, Xue Zheng, Hongzhen Jin, Fan Yu and Wei Zhao

Pharmaceutics 2022, 14(10), 2252; https://doi.org/10.3390/pharmaceutics14102252 - 21 Oct 2022

Cited by 28 | Viewed by 4057

Abstract

Central nervous system (CNS) diseases threaten the health of people all over the world. However, due to the structural and functional particularities of the brain and spinal cord, CNS-targeted drug development is rather challenging. Exosomes are small cellular vesicles with lipid bilayers that [...] Read more.

Central nervous system (CNS) diseases threaten the health of people all over the world. However, due to the structural and functional particularities of the brain and spinal cord, CNS-targeted drug development is rather challenging. Exosomes are small cellular vesicles with lipid bilayers that can be secreted by almost all cells and play important roles in intercellular communication. The advantages of low immunogenicity, the ability to cross the blood-brain barrier, and the flexibility of drug encapsulation make them stand out among CNS drug delivery tools. Herein, we reviewed the research on exosomes in CNS drug delivery over the past decade and outlined the impact of the drug loading mode, administration route, and engineered modification on CNS targeting. Finally, we highlighted the problems and prospects of exosomes as CNS drug delivery tools. Full article

(This article belongs to the Special Issue Advances of Membrane Vesicles in Drug Delivery Systems)

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25 pages, 9722 KiB

Open AccessArticle

Therapeutic Intervention for Various Hospital Setting Strains of Biofilm Forming Candida auris with Multiple Drug Resistance Mutations Using Nanomaterial Ag-Silicalite-1 Zeolite

by Hanan A. Aldossary, Suriya Rehman, B. Rabindran Jermy, Reem AlJindan, Afra Aldayel, Sayed AbdulAzeez, Sultan Akhtar, Firdos Alam Khan, J. Francis Borgio and Ebtesam Abdullah Al-Suhaimi

Pharmaceutics 2022, 14(10), 2251; https://doi.org/10.3390/pharmaceutics14102251 - 21 Oct 2022

Cited by 8 | Viewed by 2583

Abstract

Candida auris (C. auris), an emerging multidrug-resistant microorganism, with limited therapeutical options, is one of the leading causes of nosocomial infections. The current study includes 19 C. auris strains collected from King Fahd Hospital of the University and King Fahad Specialist [...] Read more.

Candida auris (C. auris), an emerging multidrug-resistant microorganism, with limited therapeutical options, is one of the leading causes of nosocomial infections. The current study includes 19 C. auris strains collected from King Fahd Hospital of the University and King Fahad Specialist Hospital in Dammam, identified by 18S rRNA gene and ITS region sequencing. Drug-resistance-associated mutations in ERG11, TAC1B and FUR1 genes were screened to gain insight into the pattern of drug resistance. Molecular identification was successfully achieved using 18S rRNA gene and ITS region and 5 drug-resistance-associated missense variants identified in the ERG11 (F132Y and K143R) and TAC1B (H608Y, P611S and A640V) genes of C. auris strains, grouped into 3 clades. The prophylactic and therapeutic application of hydrothermally synthesized Ag-silicalite-1 (Si/Ag ratio 25) nanomaterial was tested against the 3 clades of clinical C. auris strains. 4wt%Ag/TiZSM-5 prepared using conventional impregnation technique was used for comparative study, and nano formulations were characterized using different techniques. The antibiofilm activity of nanomaterials was tested by cell kill assay, scanning electron microscopy (SEM) and light microscopy. Across all the clades of C. auris strains, 4 wt%Ag/TiZSM-5 and Ag-silicalite-1 demonstrated a significant (p = 1.1102 × 10⁻¹⁶) inhibitory effect on the biofilm’s survival rate: the lowest inhibition value was (10%) with Ag-silicalite-1 at 24 and 48 h incubation. A profound change in morphogenesis in addition to the reduction in the number of C.auris cells was shown by SEM and light microscopy. The presence of a high surface area and the uniform dispersion of nanosized Ag species displays enhanced anti-Candida activity, and therefore it has great potential against the emerging multidrug-resistant C. auris. Full article

(This article belongs to the Special Issue Nanotechnology Applied in Prevention, Diagnosis and Treatment of Infectious Diseases)

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23 pages, 2024 KiB

Open AccessReview

Nano-Based Drug Delivery Systems for Periodontal Tissue Regeneration

by Huanhuan Chen, Yunfan Zhang, Tingting Yu, Guangying Song, Tianmin Xu, Tianyi Xin, Yifan Lin and Bing Han

Pharmaceutics 2022, 14(10), 2250; https://doi.org/10.3390/pharmaceutics14102250 - 21 Oct 2022

Cited by 18 | Viewed by 3092

Abstract

Periodontitis is a dysbiotic biofilm-induced and host-mediated inflammatory disease of tooth supporting tissues that leads to progressive destruction of periodontal ligament and alveolar bone, thereby resulting in gingival recession, deep periodontal pockets, tooth mobility and exfoliation, and aesthetically and functionally compromised dentition. Due [...] Read more.

Periodontitis is a dysbiotic biofilm-induced and host-mediated inflammatory disease of tooth supporting tissues that leads to progressive destruction of periodontal ligament and alveolar bone, thereby resulting in gingival recession, deep periodontal pockets, tooth mobility and exfoliation, and aesthetically and functionally compromised dentition. Due to the improved biopharmaceutical and pharmacokinetic properties and targeted and controlled drug release, nano-based drug delivery systems have emerged as a promising strategy for the treatment of periodontal defects, allowing for increased efficacy and safety in controlling local inflammation, establishing a regenerative microenvironment, and regaining bone and attachments. This review provides an overview of nano-based drug delivery systems and illustrates their practical applications, future prospects, and limitations in the field of periodontal tissue regeneration. Full article

(This article belongs to the Special Issue Hydrogels in Drug Delivery: Progress and Challenges)

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18 pages, 4615 KiB

Open AccessArticle

Orange-Peel-Derived Nanobiochar for Targeted Cancer Therapy

by Daniela Iannazzo, Consuelo Celesti, Claudia Espro, Angelo Ferlazzo, Salvatore V. Giofrè, Mario Scuderi, Silvia Scalese, Bartolo Gabriele, Raffaella Mancuso, Ida Ziccarelli, Giuseppa Visalli and Angela Di Pietro

Pharmaceutics 2022, 14(10), 2249; https://doi.org/10.3390/pharmaceutics14102249 - 21 Oct 2022

Cited by 16 | Viewed by 2602

Abstract

Cancer-targeted drug delivery systems (DDS) based on carbon nanostructures have shown great promise in cancer therapy due to their ability to selectively recognize specific receptors overexpressed in cancer cells. In this paper, we have explored a green route to synthesize nanobiochar (NBC) endowed [...] Read more.

Cancer-targeted drug delivery systems (DDS) based on carbon nanostructures have shown great promise in cancer therapy due to their ability to selectively recognize specific receptors overexpressed in cancer cells. In this paper, we have explored a green route to synthesize nanobiochar (NBC) endowed with graphene structure from the hydrothermal carbonization (HTC) of orange peels and evaluated the suitability of this nanomaterial as a nanoplatform for cancer therapy. In order to compare the cancer-targeting ability of different widely used targeting ligands (TL), we have conjugated NBC with biotin, riboflavin, folic acid and hyaluronic acid and have tested, in vitro, their biocompatibility and uptake ability towards a human alveolar cancer cell line (A549 cells). The nanosystems which showed the best biological performances—namely, the biotin- and riboflavin- conjugated systems—have been loaded with the poorly water-soluble drug DHF (5,5-dimethyl-6a-phenyl-3-(trimethylsilyl)-6,6a-dihydrofuro[3,2-b]furan-2(5H)-one) and tested for their anticancer activity. The in vitro biological tests demonstrated the ability of both systems to internalize the drug in A549 cells. In particular, the biotin-functionalized NBC caused cell death percentages to more than double with respect to the drug alone. The reported results also highlight the positive effect of the presence of oxygen-containing functional groups, present on the NBC surface, to improve the water dispersion stability of the DDS and thus make the approach of using this nanomaterial as nanocarrier for poorly water-soluble drugs effective. Full article

(This article belongs to the Special Issue Carbon-Based Nanomaterials as Multifunctional Nanoplatforms for Cancer Diagnosis and Treatment)

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21 pages, 5234 KiB

Open AccessArticle

Intrinsic Aqueous Solubility: Mechanistically Transparent Data-Driven Modeling of Drug Substances

by Mare Oja, Sulev Sild, Geven Piir and Uko Maran

Pharmaceutics 2022, 14(10), 2248; https://doi.org/10.3390/pharmaceutics14102248 - 21 Oct 2022

Cited by 10 | Viewed by 2278

Abstract

Intrinsic aqueous solubility is a foundational property for understanding the chemical, technological, pharmaceutical, and environmental behavior of drug substances. Despite years of solubility research, molecular structure-based prediction of the intrinsic aqueous solubility of drug substances is still under active investigation. This paper describes [...] Read more.

Intrinsic aqueous solubility is a foundational property for understanding the chemical, technological, pharmaceutical, and environmental behavior of drug substances. Despite years of solubility research, molecular structure-based prediction of the intrinsic aqueous solubility of drug substances is still under active investigation. This paper describes the authors’ systematic data-driven modelling in which two fit-for-purpose training data sets for intrinsic aqueous solubility were collected and curated, and three quantitative structure–property relationships were derived to make predictions for the most recent solubility challenge. All three models perform well individually, while being mechanistically transparent and easy to understand. Molecular descriptors involved in the models are related to the following key steps in the solubility process: dissociation of the molecule from the crystal, formation of a cavity in the solvent, and insertion of the molecule into the solvent. A consensus modeling approach with these models remarkably improved prediction capability and reduced the number of strong outliers by more than two times. The performance and outliers of the second solubility challenge predictions were analyzed retrospectively. All developed models have been published in the QsarDB.org repository according to FAIR principles and can be used without restrictions for exploring, downloading, and making predictions. Full article

(This article belongs to the Collection Advanced Pharmaceutical Science and Technology in Estonia)

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14 pages, 2718 KiB

Open AccessArticle

G-Quadruplex Linked DNA Guides Selective Transfection into Nucleolin-Overexpressing Cancer Cells

by Mengxi Xiang, Yongkui Li, Jia Liu, Jie Shi, Yizhi Ge, Chen Peng, Yawen Bin, Zheng Wang and Lin Wang

Pharmaceutics 2022, 14(10), 2247; https://doi.org/10.3390/pharmaceutics14102247 - 21 Oct 2022

Cited by 1 | Viewed by 1954

Abstract

Gene therapy is a promising approach for treating tumors. Conventional approaches of DNA delivery depending on non-viral or viral vectors are unsatisfactory due to the concerns of biosafety and cell-targeting efficiency. The question how to deliver DNA into tumor cells efficiently and selectively [...] Read more.

Gene therapy is a promising approach for treating tumors. Conventional approaches of DNA delivery depending on non-viral or viral vectors are unsatisfactory due to the concerns of biosafety and cell-targeting efficiency. The question how to deliver DNA into tumor cells efficiently and selectively is a major technological problem in tumor gene therapy. Here, we develop a vector-free gene transfer strategy to deliver genes effectively and selectively by taking advantage of targeting nucleolin. Nucleolin, a shuttle protein moving between cell membrane, cytoplasm and nuclei, is overexpressed in tumor cells. It has a natural ligand G-quadruplex (Gq). Gq-linked DNA (Gq-DNA) is likely to be internalized by ligand dependent uptake mechanisms independently of vectors after neutralizing negative charges of cell membrane by targeting nucleolin. This strategy is referred to as Gq-DNA transfection. Benefiting from its high affinity to nucleolin, Gq-DNA can be effectively delivered into nucleolin-positive tumor cells even nuclei. Gq-DNA transfection is characterized by low cytotoxicity, high efficiency, ease of synthesis, high stability in serum, direct access into nuclei, and specific nucleolin-positive tumor cell targeting. Full article

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1 pages, 512 KiB

Open AccessCorrection

Correction: Martinez et al. Cavitation Characterization of Size-Isolated Microbubbles in a Vessel Phantom Using Focused Ultrasound. Pharmaceutics 2022, 14, 1925

by Payton Martinez, Nick Bottenus and Mark Borden

Pharmaceutics 2022, 14(10), 2246; https://doi.org/10.3390/pharmaceutics14102246 - 21 Oct 2022

Viewed by 1091

Abstract

In the original publication [...] Full article

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16 pages, 4304 KiB

Open AccessArticle

Formulation and Evaluation of a Drug-in-Adhesive Patch for Transdermal Delivery of Colchicine

by Yaran Lei, Guobao Yang, Feng Du, Jiahe Yi, Liangzhu Quan, Hanhan Liu, Xun Zhou, Wei Gong, Jing Han, Yuli Wang and Chunsheng Gao

Pharmaceutics 2022, 14(10), 2245; https://doi.org/10.3390/pharmaceutics14102245 - 21 Oct 2022

Cited by 10 | Viewed by 3512

Abstract

Gout is one of the most prevalent rheumatic diseases, globally. Colchicine (COL) is the first-line drug used for the treatment of acute gout. However, the oral administration of COL is restricted, owing to serious adverse reactions. Therefore, this study aimed to develop a [...] Read more.

Gout is one of the most prevalent rheumatic diseases, globally. Colchicine (COL) is the first-line drug used for the treatment of acute gout. However, the oral administration of COL is restricted, owing to serious adverse reactions. Therefore, this study aimed to develop a drug-in-adhesive (DIA) patch to achieve transdermal delivery of COL. We investigated the solubility of COL in different pressure-sensitive adhesives (PSAs) using slide crystallization studies. The COL-DIA patches were optimized based on in vitro skin penetration studies and evaluated by in vivo pharmacokinetics and pharmacodynamics. The results showed that the optimized COL-DIA patch contained 10% COL, Duro-Tak 87-2516 as PSA, 5% oleic acid (OA) and 5% propylene glycol (PG) as permeation enhancer, exhibiting the highest in vitro cumulative penetration amount of COL (235.14 ± 14.47 μg∙cm⁻² over 48 h). Pharmacokinetic studies demonstrated that the maximum plasma drug concentration (C_max) was 2.65 ± 0.26 ng/L and the mean retention time (MRT) was 37.47 ± 7.64 h of the COL-DIA patch, effectively reducing the drug side effects and prolonging drug activity. In addition, pharmacodynamic studies showed the patch significantly decreased the expression levels of inflammatory factors of gouty rats and reduced pathological damage in the ankle joint of rats, making it an attractive alternative to the administration of COL for the treatment of gout. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)

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19 pages, 3793 KiB

Open AccessReview

Immunomodulating Hydrogels as Stealth Platform for Drug Delivery Applications

by Zahra Rezaei, Dilara Yilmaz-Aykut, Fatima Mumtaza Tourk, Nicole Bassous, Margot Barroso-Zuppa, Asif Iqbal Shawl, Syed Salman Ashraf, Huseyin Avci and Shabir Hassan

Pharmaceutics 2022, 14(10), 2244; https://doi.org/10.3390/pharmaceutics14102244 - 21 Oct 2022

Cited by 9 | Viewed by 2774

Abstract

Non-targeted persistent immune activation or suppression by different drug delivery platforms can cause adverse and chronic physiological effects including cancer and arthritis. Therefore, non-toxic materials that do not trigger an immunogenic response during delivery are crucial for safe and effective in vivo treatment. [...] Read more.

Non-targeted persistent immune activation or suppression by different drug delivery platforms can cause adverse and chronic physiological effects including cancer and arthritis. Therefore, non-toxic materials that do not trigger an immunogenic response during delivery are crucial for safe and effective in vivo treatment. Hydrogels are excellent candidates that can be engineered to control immune responses by modulating biomolecule release/adsorption, improving regeneration of lymphoid tissues, and enhancing function during antigen presentation. This review discusses the aspects of hydrogel-based systems used as drug delivery platforms for various diseases. A detailed investigation on different immunomodulation strategies for various delivery options and deliberate upon the outlook of such drug delivery platforms are conducted. Full article

(This article belongs to the Special Issue Rational Design and Characterization of Hydrogels to Improve Pharmaceutical and Biomedical Applicability)

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16 pages, 5622 KiB

Open AccessArticle

Injectable pH Thermo-Responsive Hydrogel Scaffold for Tumoricidal Neural Stem Cell Therapy for Glioblastoma Multiforme

by Jasmine L. King, Panita Maturavongsadit, Shawn D. Hingtgen and S. Rahima Benhabbour

Pharmaceutics 2022, 14(10), 2243; https://doi.org/10.3390/pharmaceutics14102243 - 20 Oct 2022

Cited by 14 | Viewed by 2520

Abstract

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults and despite recent advances in treatment modalities, GBM remains incurable. Injectable hydrogel scaffolds are a versatile delivery system that can improve delivery of drug and cell therapeutics for GBM. In this [...] Read more.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults and despite recent advances in treatment modalities, GBM remains incurable. Injectable hydrogel scaffolds are a versatile delivery system that can improve delivery of drug and cell therapeutics for GBM. In this report, we investigated an injectable nanocellulose/chitosan-based hydrogel scaffold for neural stem cell encapsulation and delivery. Hydrogels were prepared using thermogelling beta-glycerophosphate (BGP) and hydroxyethyl cellulose (HEC), chitosan (CS), and cellulose nanocrystals (CNCs). We evaluated the impact of neural stem cells on hydrogel gelation kinetics, microstructures, and degradation. Furthermore, we investigated the biomaterial effects on cell viability and functionality. We demonstrated that the incorporation of cells at densities of 1, 5 and 10 million does not significantly impact rheological and physical properties CS scaffolds. However, addition of CNCs significantly prolonged hydrogel degradation when cells were seeded at 5 and 10 million per 1 mL hydrogel. In vitro cell studies demonstrated high cell viability, release of TRAIL at therapeutic concentrations, and effective tumor cell killing within 72 h. The ability of these hydrogel scaffolds to support stem cell encapsulation and viability and maintain stem cell functionality makes them an attractive cell delivery system for local treatment of post-surgical cancers. Full article

(This article belongs to the Special Issue Brain-Targeted Drug Delivery Volume II)

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17 pages, 6630 KiB

Open AccessArticle

Methylene Blue-Loaded Mesoporous Silica-Coated Gold Nanorods on Graphene Oxide for Synergistic Photothermal and Photodynamic Therapy

by Sun-Hwa Seo, Ara Joe, Hyo-Won Han, Panchanathan Manivasagan and Eue-Soon Jang

Pharmaceutics 2022, 14(10), 2242; https://doi.org/10.3390/pharmaceutics14102242 - 20 Oct 2022

Cited by 17 | Viewed by 2679

Abstract

Photo-nanotheranostics integrates near-infrared (NIR) light-triggered diagnostics and therapeutics, which are combined into a novel all-in-one phototheranostic nanomaterial that holds great promise for the early detection and precise treatment of cancer. In this study, we developed methylene blue-loaded mesoporous silica-coated gold nanorods on graphene [...] Read more.

Photo-nanotheranostics integrates near-infrared (NIR) light-triggered diagnostics and therapeutics, which are combined into a novel all-in-one phototheranostic nanomaterial that holds great promise for the early detection and precise treatment of cancer. In this study, we developed methylene blue-loaded mesoporous silica-coated gold nanorods on graphene oxide (MB-GNR@mSiO₂-GO) as an all-in-one photo-nanotheranostic agent for intracellular surface-enhanced Raman scattering (SERS) imaging-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer. Amine functionalization of the MB-GNR@mSiO₂ surfaces was performed using 3-aminopropyltriethoxysilane (APTES), which was well anchored on the carboxyl groups of graphene oxide (GO) nanosheets uniformly, and showed a remarkably higher photothermal conversion efficiency (48.93%), resulting in outstanding PTT/PDT for cancer. The in vitro photothermal/photodynamic effect of MB-GNR@mSiO₂-GO with laser irradiation showed significantly reduced cell viability (6.32%), indicating that MB-GNR@mSiO₂-GO with laser irradiation induced significantly more cell deaths. Under laser irradiation, MB-GNR@mSiO₂-GO showed a strong SERS effect, which permits accurate cancer cell detection by SERS imaging. Subsequently, the same Raman laser can focus on highly detected MDA-MB-23l cells for a prolonged time to perform PTT/PDT. Therefore, MB-GNR@mSiO₂-GO has great potential for precise SERS imaging-guided synergistic PTT/PDT for cancer. Full article

(This article belongs to the Special Issue Metal Nanoparticles for Cancer Therapy)

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22 pages, 7556 KiB

Open AccessArticle

Using Copper-Doped Mesoporous Bioactive Glass Nanospheres to Impart Anti-Bacterial Properties to Dental Composites

by Arooj Munir, Danijela Marovic, Liebert Parreiras Nogueira, Roger Simm, Ali-Oddin Naemi, Sander Marius Landrø, Magnus Helgerud, Kai Zheng, Matej Par, Tobias T. Tauböck, Thomas Attin, Zrinka Tarle, Aldo R. Boccaccini and Håvard J. Haugen

Pharmaceutics 2022, 14(10), 2241; https://doi.org/10.3390/pharmaceutics14102241 - 20 Oct 2022

Cited by 8 | Viewed by 4377

Abstract

Experimental dental resin composites containing copper-doped mesoporous bioactive glass nanospheres (Cu-MBGN) were developed to impart anti-bacterial properties. Increasing amounts of Cu-MBGN (0, 1, 5 and 10 wt%) were added to the BisGMA/TEGDMA resin matrix containing micro- and nano-fillers of inert glass, keeping the [...] Read more.

Experimental dental resin composites containing copper-doped mesoporous bioactive glass nanospheres (Cu-MBGN) were developed to impart anti-bacterial properties. Increasing amounts of Cu-MBGN (0, 1, 5 and 10 wt%) were added to the BisGMA/TEGDMA resin matrix containing micro- and nano-fillers of inert glass, keeping the resin/filler ratio constant. Surface micromorphology and elemental analysis were performed to evaluate the homogeneous distribution of filler particles. The study investigated the effects of Cu-MBGN on the degree of conversion, polymerization shrinkage, porosity, ion release and anti-bacterial activity on S. mutans and A. naeslundii. Experimental materials containing Cu-MBGN showed a dose-dependent Cu release with an initial burst and a further increase after 28 days. The composite containing 10% Cu-MBGN had the best anti-bacterial effect on S. mutans, as evidenced by the lowest adherence of free-floating bacteria and biofilm formation. In contrast, the 45S5-containing materials had the highest S. mutans adherence. Ca release was highest in the bioactive control containing 15% 45S5, which correlated with the highest number of open porosities on the surface. Polymerization shrinkage was similar for all tested materials, ranging from 3.8 to 4.2%, while the degree of conversion was lower for Cu-MBGN materials. Cu-MBGN composites showed better anti-bacterial properties than composites with 45S5 BG. Full article

(This article belongs to the Special Issue Organic-Inorganic Nanocomposites as Delivery Systems of Therapeutic Agents for Regenerative Medicine)

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17 pages, 678 KiB

Open AccessReview

Interpreting the Benefit and Risk Data in Between-Drug Comparisons: Illustration of the Challenges Using the Example of Mefenamic Acid versus Ibuprofen

by André Farkouh, Margit Hemetsberger, Christian R. Noe and Christoph Baumgärtel

Pharmaceutics 2022, 14(10), 2240; https://doi.org/10.3390/pharmaceutics14102240 - 20 Oct 2022

Cited by 5 | Viewed by 9810

Abstract

Evidence-based pain therapy should rely on precisely defined and personalized criteria. This includes balancing the benefits and risks not only of single drugs but often requires complex between-drug comparisons. Non-steroidal anti-inflammatory drugs (NSAIDs) have been available for several decades and their use is [...] Read more.

Evidence-based pain therapy should rely on precisely defined and personalized criteria. This includes balancing the benefits and risks not only of single drugs but often requires complex between-drug comparisons. Non-steroidal anti-inflammatory drugs (NSAIDs) have been available for several decades and their use is described in an abundance of guidelines. Most of these guidelines recommend that ‘the selection of a particular NSAID should be based on the benefit-risk balance for each patient’. However, head-to-head studies are often lacking or of poor quality, reflecting the lower standards for clinical research and regulatory approval at the time. The inconsistency of approved indications between countries due to national applications adds to the complexity. Finally, a fading research interest once drugs become generic points to a general deficit in the post-marketing evaluation of medicines. Far from claiming completeness, this narrative review aimed to illustrate the challenges that physicians encounter when trying to balance benefits and risks in a situation of incomplete and inconsistent data on longstanding treatment concepts. Ibuprofen and mefenamic acid, the most frequently sold NSAIDs in Austria, serve as examples. The illustrated principles are, however, not specific to these drugs and are generalizable to any comparison of older drugs in daily clinical practice. Full article

(This article belongs to the Special Issue Personalisation the Management of Inflammatory Diseases)

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25 pages, 10993 KiB

Open AccessReview

Modulation of Macrophages Using Nanoformulations with Curcumin to Treat Inflammatory Diseases: A Concise Review

by Huxiao Sun, Mengsi Zhan, Serge Mignani, Dzmitry Shcharbin, Jean-Pierre Majoral, João Rodrigues, Xiangyang Shi and Mingwu Shen

Pharmaceutics 2022, 14(10), 2239; https://doi.org/10.3390/pharmaceutics14102239 - 20 Oct 2022

Cited by 13 | Viewed by 2770

Abstract

Curcumin (Cur), a traditional Chinese medicine extracted from natural plant rhizomes, has become a candidate drug for the treatment of diseases due to its anti-inflammatory, anticancer, antioxidant, and antibacterial activities. However, the poor water solubility and low bioavailability of Cur limit its therapeutic [...] Read more.

Curcumin (Cur), a traditional Chinese medicine extracted from natural plant rhizomes, has become a candidate drug for the treatment of diseases due to its anti-inflammatory, anticancer, antioxidant, and antibacterial activities. However, the poor water solubility and low bioavailability of Cur limit its therapeutic effects for clinical applications. A variety of nanocarriers have been successfully developed to improve the water solubility, in vivo distribution, and pharmacokinetics of Cur, as well as to enhance the ability of Cur to polarize macrophages and relieve macrophage oxidative stress or anti-apoptosis, thus accelerating the therapeutic effects of Cur on inflammatory diseases. Herein, we review the design and development of diverse Cur nanoformulations in recent years and introduce the biomedical applications and potential therapeutic mechanisms of Cur nanoformulations in common inflammatory diseases, such as arthritis, neurodegenerative diseases, respiratory diseases, and ulcerative colitis, by regulating macrophage behaviors. Finally, the perspectives of the design and preparation of future nanocarriers aimed at efficiently exerting the biological activity of Cur are briefly discussed. Full article

(This article belongs to the Special Issue Nanoparticles for Targeting and Treating Macrophages)

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13 pages, 2426 KiB

Open AccessArticle

A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells

by Amineh Ghaderi, Wen Zhong, Mohammad Ali Okhovat, Johanna Aschan, Ann Svensson, Birgitta Sander, Johan Schultz, Thomas Olin, Anders Österborg, Mohammad Hojjat-Farsangi and Håkan Mellstedt

Pharmaceutics 2022, 14(10), 2238; https://doi.org/10.3390/pharmaceutics14102238 - 20 Oct 2022

Cited by 7 | Viewed by 2781

Abstract

The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small [...] Read more.

The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3Kδ inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB). Cytotoxicity was analyzed by MTT and apoptosis by Annexin V/PI staining as well as signaling and apoptotic proteins (WB). ROR1 was expressed both in patient-derived MCL cells and human MCL cell lines. KAN0441571C alone induced significant time- and dose-dependent apoptosis of MCL cells. Apoptosis was accompanied by decreased expression of MCL-1 and BCL-2 and cleavage of PARP and caspase 3. ROR1 was dephosphorylated as well as ROR1-associated signaling pathway molecules, including the non-canonical WNT signaling pathway (PI3Kδ/AKT/mTOR). The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL. Full article

(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)

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17 pages, 2694 KiB

Open AccessEditor’s ChoiceReview

Blood–Brain Barrier Transport of Transferrin Receptor-Targeted Nanoparticles

by Maj Schneider Thomsen, Kasper Bendix Johnsen, Krzysztof Kucharz, Martin Lauritzen and Torben Moos

Pharmaceutics 2022, 14(10), 2237; https://doi.org/10.3390/pharmaceutics14102237 - 19 Oct 2022

Cited by 34 | Viewed by 4938

Abstract

The blood–brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes [...] Read more.

The blood–brain barrier (BBB), built by brain endothelial cells (BECs), is impermeable to biologics. Liposomes and other nanoparticles are good candidates for the delivery of biologics across the BECs, as they can encapsulate numerous molecules of interest in an omnipotent manner. The liposomes need attachment of a targeting molecule, as BECs unfortunately are virtually incapable of uptake of non-targeted liposomes from the circulation. Experiments of independent research groups have qualified antibodies targeting the transferrin receptor as superior for targeted delivery of nanoparticles to BECs. Functionalization of nanoparticles via conjugation with anti-transferrin receptor antibodies leads to nanoparticle uptake by endothelial cells of both brain capillaries and post-capillary venules. Reducing the density of transferrin receptor-targeted antibodies conjugated to liposomes limits uptake in BECs. Opposing the transport of nanoparticles conjugated to high-affine anti-transferrin receptor antibodies, lowering the affinity of the targeting antibodies or implementing monovalent antibodies increase uptake by BECs and allows for further transport across the BBB. The novel demonstration of transport of targeted liposomes in post-capillary venules from blood to the brain is interesting and clearly warrants further mechanistic pursuit. The recent evidence for passing targeted nanoparticles through the BBB shows great promise for future drug delivery of biologics to the brain. Full article

(This article belongs to the Special Issue Advanced Blood-Brain Barrier Drug Delivery)

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25 pages, 1724 KiB

Open AccessReview

Extracellular Vesicles as Delivery Vehicles for Therapeutic Nucleic Acids in Cancer Gene Therapy: Progress and Challenges

by Rong Du, Chen Wang, Ling Zhu and Yanlian Yang

Pharmaceutics 2022, 14(10), 2236; https://doi.org/10.3390/pharmaceutics14102236 - 19 Oct 2022

Cited by 18 | Viewed by 4699

Abstract

Extracellular vesicles (EVs) are nanoscale vesicles secreted by most types of cells as natural vehicles to transfer molecular information between cells. Due to their low toxicity and high biocompatibility, EVs have attracted increasing attention as drug delivery systems. Many studies have demonstrated that [...] Read more.

Extracellular vesicles (EVs) are nanoscale vesicles secreted by most types of cells as natural vehicles to transfer molecular information between cells. Due to their low toxicity and high biocompatibility, EVs have attracted increasing attention as drug delivery systems. Many studies have demonstrated that EV-loaded nucleic acids, including RNA-based nucleic acid drugs and CRISPR/Cas gene-editing systems, can alter gene expressions and functions of recipient cells for cancer gene therapy. Here in this review, we discuss the advantages and challenges of EV-based nucleic acid delivery systems in cancer therapy. We summarize the techniques and methods to increase EV yield, enhance nucleic acid loading efficiency, extend circulation time, and improve targeted delivery, as well as their applications in gene therapy and combination with other cancer therapies. Finally, we discuss the current status, challenges, and prospects of EVs as a therapeutic tool for the clinical application of nucleic acid drugs. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges)

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26 pages, 5060 KiB

Open AccessReview

Recent Progress on Hyaluronan-Based Products for Wound Healing Applications

by Kuncham Sudhakar, Seong min Ji, Madhusudhana Rao Kummara and Sung Soo Han

Pharmaceutics 2022, 14(10), 2235; https://doi.org/10.3390/pharmaceutics14102235 - 19 Oct 2022

Cited by 12 | Viewed by 3318

Abstract

Hyaluronic acid (HA) based nanocomposites are considered excellent for improving wound healing. HA is biocompatible, biodegradable, non-toxic, biologically active, has hemostatic ability, and resists bacterial adhesion. HA-based nanocomposites promote wound healing in four different sequential phases hemostasis, inflammation, proliferation, and maturation. The unique [...] Read more.

Hyaluronic acid (HA) based nanocomposites are considered excellent for improving wound healing. HA is biocompatible, biodegradable, non-toxic, biologically active, has hemostatic ability, and resists bacterial adhesion. HA-based nanocomposites promote wound healing in four different sequential phases hemostasis, inflammation, proliferation, and maturation. The unique biological characteristics of HA enable it to serve as a drug, an antibacterial agent, and a growth factor, which combine to accelerate the healing process. In this review, we focus on the use of HA-based nanocomposites for wound healing applications and we describe the importance of HA for the wound healing process in each sequential phase, such as hemostasis, inflammation, proliferation, and maturation. Metal nanoparticles (MNPs) or metal oxide nanoparticles (MO-NPs) loaded with HA nanocomposite are used for wound healing applications. Insights into important antibacterial mechanisms are described in HA nanocomposites. Furthermore, we explain antibiotics loaded with HA nanocomposite and its combination with the MNPs/MO-NPs used for wound healing applications. In addition, HA derivatives are discussed and used in combination with the other polymers of the composite for the wound healing process, as is the role of the polymer in wound healing applications. Finally, HA-based nanocomposites used for clinical trials in animal models are presented for wound healing applications. Full article

(This article belongs to the Special Issue Nanotechnology Applied in Prevention, Diagnosis and Treatment of Infectious Diseases)

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20 pages, 3320 KiB

Open AccessArticle

Cationic Polyethyleneimine (PEI)–Gold Nanocomposites Modulate Macrophage Activation and Reprogram Mouse Breast Triple-Negative MET-1 Tumor Immunological Microenvironment

by Vladimir Mulens-Arias, Alba Nicolás-Boluda, Florent Carn and Florence Gazeau

Pharmaceutics 2022, 14(10), 2234; https://doi.org/10.3390/pharmaceutics14102234 - 19 Oct 2022

Cited by 4 | Viewed by 2783

Abstract

Nanomedicines based on inorganic nanoparticles have grown in the last decades due to the nanosystems’ versatility in the coating, tuneability, and physical and chemical properties. Nonetheless, concerns have been raised regarding the immunotropic profile of nanoparticles and how metallic nanoparticles affect the immune [...] Read more.

Nanomedicines based on inorganic nanoparticles have grown in the last decades due to the nanosystems’ versatility in the coating, tuneability, and physical and chemical properties. Nonetheless, concerns have been raised regarding the immunotropic profile of nanoparticles and how metallic nanoparticles affect the immune system. Cationic polymer nanoparticles are widely used for cell transfection and proved to exert an adjuvant immunomodulatory effect that improves the efficiency of conventional vaccines against infection or cancer. Likewise, gold nanoparticles (AuNPs) also exhibit diverse effects on immune response depending on size or coatings. Photothermal or photodynamic therapy, radiosensitization, and drug or gene delivery systems take advantage of the unique properties of AuNPs to deeply modify the tumoral ecosystem. However, the collective effects that AuNPs combined with cationic polymers might exert on their own in the tumor immunological microenvironment remain elusive. The purpose of this study was to analyze the triple-negative breast tumor immunological microenvironment upon intratumoral injection of polyethyleneimine (PEI)–AuNP nanocomposites (named AuPEI) and elucidate how it might affect future immunotherapeutic approaches based on this nanosystem. AuPEI nanocomposites were synthesized through a one-pot synthesis method with PEI as both a reducing and capping agent, resulting in fractal assemblies of about 10 nm AuNPs. AuPEI induced an inflammatory profile in vitro in the mouse macrophage-like cells RAW264.7 as determined by the secretion of TNF-α and CCL5 while the immunosuppressor IL-10 was not increased. However, in vivo in the mouse breast MET-1 tumor model, AuPEI nanocomposites shifted the immunological tumor microenvironment toward an M2 phenotype with an immunosuppressive profile as determined by the infiltration of PD-1-positive lymphocytes. This dichotomy in AuPEI nanocomposites in vitro and in vivo might be attributed to the highly complex tumor microenvironment and highlights the importance of testing the immunogenicity of nanomaterials in vitro and more importantly in vivo in relevant immunocompetent mouse tumor models to better elucidate any adverse or unexpected effect. Full article

(This article belongs to the Special Issue Gold Nanoparticles for Biomedical Application)

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20 pages, 32534 KiB

Open AccessArticle

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

by Michael E. Stokes, Matthew D. Surman, Veronica Calvo, David Surguladze, An-Hu Li, Jennifer Gasparek, Matthew Betzenhauser, Guangyu Zhu, Hongwen Du, Alan C. Rigby and Mark J. Mulvihill

Pharmaceutics 2022, 14(10), 2233; https://doi.org/10.3390/pharmaceutics14102233 - 19 Oct 2022

Cited by 6 | Viewed by 2765

Abstract

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as [...] Read more.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice. Full article

(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)

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20 pages, 3415 KiB

Open AccessArticle

Microemulsions Enhance the In Vitro Antioxidant Activity of Oleanolic Acid in RAW 264.7 Cells

by Chiara De Stefani, Marzia Vasarri, Maria Cristina Salvatici, Lucia Grifoni, Jose Carlos Quintela, Anna Rita Bilia, Donatella Degl’Innocenti and Maria Camilla Bergonzi

Pharmaceutics 2022, 14(10), 2232; https://doi.org/10.3390/pharmaceutics14102232 - 19 Oct 2022

Cited by 10 | Viewed by 2251

Abstract

Oleanolic acid (OA) is the main triterpenic acid of olive leaves known for numerous pharmacological properties, including antioxidant activity. However, it is poorly soluble in water and consequently with low bioavailability, which limits its pharmacological application. Microemulsions (MEs) are dispersed systems consisting of [...] Read more.

Oleanolic acid (OA) is the main triterpenic acid of olive leaves known for numerous pharmacological properties, including antioxidant activity. However, it is poorly soluble in water and consequently with low bioavailability, which limits its pharmacological application. Microemulsions (MEs) are dispersed systems consisting of two immiscible phases that promote rapid solubilization and absorption in the gastrointestinal tract. To improve both solubility and intestinal permeability of this molecule, OA has been formulated in two different microemulsions (ME-1 and ME-2). A solubility screening was carried out to select the ME components, and pseudoternary phase diagrams were constructed to evaluate the region of existence and select the appropriate amount of the constituents. ME-1 was prepared using Capmul PG-8/NF as the oily phase, and Transcutol and Tween 20 (7:3) as surfactants, while ME-2 contained Nigella oil and Isopropil myristate as the oily phase, and Transcutol HP and Cremophor EL (2:1) as surfactants. The OA solubility was increased by 1000-fold and 3000-fold in ME-1-OA and ME-2-OA, respectively. The MEs’ droplet size and the PdI were evaluated, and the stability was assessed for 8 weeks by monitoring chemical and physical parameters. The parallel artificial membrane permeability assay (PAMPA) also demonstrated an enhanced intestinal permeability of both OA formulations compared with free OA. The potential ability of both MEs to enhance the bioactivity of OA against LPS-induced oxidative stress in RAW 264.7 murine macrophages was also investigated. Overall, this study suggests that both MEs promote a bio-enhancement of the protective action of OA against the LPS-induced pro-oxidant stress in macrophages. Overall, this study suggests that MEs could be an interesting formulation to improve OA oral bioavailability with potential clinical applications. Full article

(This article belongs to the Special Issue Potential of Nano/Microemulsions for Drugs and Phytochemicals Delivery)

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32 pages, 2853 KiB

Open AccessReview

Harnessing Ultrasound for Targeting Drug Delivery to the Brain and Breaching the Blood–Brain Tumour Barrier

by Anita Barzegar-Fallah, Kushan Gandhi, Shakila B. Rizwan, Tania L. Slatter and John N. J. Reynolds

Pharmaceutics 2022, 14(10), 2231; https://doi.org/10.3390/pharmaceutics14102231 - 19 Oct 2022

Cited by 16 | Viewed by 3292

Abstract

Despite significant advances in developing drugs to treat brain tumours, achieving therapeutic concentrations of the drug at the tumour site remains a major challenge due to the presence of the blood–brain barrier (BBB). Several strategies have evolved to enhance brain delivery of chemotherapeutic [...] Read more.

Despite significant advances in developing drugs to treat brain tumours, achieving therapeutic concentrations of the drug at the tumour site remains a major challenge due to the presence of the blood–brain barrier (BBB). Several strategies have evolved to enhance brain delivery of chemotherapeutic agents to treat tumours; however, most approaches have several limitations which hinder their clinical utility. Promising studies indicate that ultrasound can penetrate the skull to target specific brain regions and transiently open the BBB, safely and reversibly, with a high degree of spatial and temporal specificity. In this review, we initially describe the basics of therapeutic ultrasound, then detail ultrasound-based drug delivery strategies to the brain and the mechanisms by which ultrasound can improve brain tumour therapy. We review pre-clinical and clinical findings from ultrasound-mediated BBB opening and drug delivery studies and outline current therapeutic ultrasound devices and technologies designed for this purpose. Full article

(This article belongs to the Special Issue Brain-Targeted Drug Delivery Volume II)

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10 pages, 1942 KiB

Open AccessArticle

Therapeutic Drug Monitoring of Quinidine in Pediatric Patients with KCNT1 Genetic Variants

by Alessandro Ferretti, Raffaele Simeoli, Sara Cairoli, Nicola Pietrafusa, Marina Trivisano, Carlo Dionisi Vici, Nicola Specchio and Bianca Maria Goffredo

Pharmaceutics 2022, 14(10), 2230; https://doi.org/10.3390/pharmaceutics14102230 - 19 Oct 2022

Cited by 3 | Viewed by 1971

Abstract

Quinidine (QND) is an old antimalarial drug that was used in the early 20th century as an antiarrhythmic agent. Currently, QND is receiving attention for its use in epilepsy of infancy with migrating focal seizures (EIMFS) due to potassium sodium-activated channel subfamily T [...] Read more.

Quinidine (QND) is an old antimalarial drug that was used in the early 20th century as an antiarrhythmic agent. Currently, QND is receiving attention for its use in epilepsy of infancy with migrating focal seizures (EIMFS) due to potassium sodium-activated channel subfamily T member 1 (KCNT1) genetic variants. Here, we report the application of Therapeutic Drug Monitoring (TDM) in pediatric patients carrying KCNT1 genetic variants and orally treated with QND for developmental and epileptic encephalopathies (DEE). We measured plasma levels of QND and its metabolite hydroquinidine (H-QND) by using a validated method based on liquid chromatography coupled with mass spectrometry (LC-MS/MS). Three pediatric patients (median age 4.125 years, IQR 2.375–4.125) received increasing doses of QND. Cardiac toxicity was monitored at every dose change. Reduction in seizure frequency ranged from 50 to 90%. Our results show that QND is a promising drug for pediatric patients with DEE due to KCNT1 genetic variants. Although QND blood levels were significantly lower than the therapeutic range as an anti-arrhythmic drug, patients showed a significant improvement in seizure burden. These data underlie the utility of TDM for QND not only to monitor its toxic effects but also to evaluate possible drug–drug interactions. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring as a Useful Tool in Therapy Improvement, 2nd Edition)

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21 pages, 900 KiB

Open AccessReview

Therapies Based on Adipose-Derived Stem Cells for Lower Urinary Tract Dysfunction: A Narrative Review

by Meng Liu, Jiasheng Chen, Nailong Cao, Weixin Zhao, Guo Gao, Ying Wang and Qiang Fu

Pharmaceutics 2022, 14(10), 2229; https://doi.org/10.3390/pharmaceutics14102229 - 19 Oct 2022

Cited by 2 | Viewed by 1972

Abstract

Lower urinary tract dysfunction often requires tissue repair or replacement to restore physiological functions. Current clinical treatments involving autologous tissues or synthetic materials inevitably bring in situ complications and immune rejection. Advances in therapies using stem cells offer new insights into treating lower [...] Read more.

Lower urinary tract dysfunction often requires tissue repair or replacement to restore physiological functions. Current clinical treatments involving autologous tissues or synthetic materials inevitably bring in situ complications and immune rejection. Advances in therapies using stem cells offer new insights into treating lower urinary tract dysfunction. One of the most frequently used stem cell sources is adipose tissue because of its easy access, abundant source, low risk of severe complications, and lack of ethical issues. The regenerative capabilities of adipose-derived stem cells (ASCs) in vivo are primarily orchestrated by their paracrine activities, strong regenerative potential, multi-differentiation potential, and cell–matrix interactions. Moreover, biomaterial scaffolds conjugated with ASCs result in an extremely effective tissue engineering modality for replacing or repairing diseased or damaged tissues. Thus, ASC-based therapy holds promise as having a tremendous impact on reconstructive urology of the lower urinary tract. Full article

(This article belongs to the Special Issue Bio-Organic Materials for Tissue Engineering and Regenerative Medicine)

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11 pages, 1570 KiB

Open AccessArticle

Revisiting the Dissolution of Praziquantel in Biorelevant Media and the Impact of Digestion of Milk on Drug Dissolution

by Thomas Eason, Gisela Ramirez, Andrew J. Clulow, Malinda Salim and Ben J. Boyd

Pharmaceutics 2022, 14(10), 2228; https://doi.org/10.3390/pharmaceutics14102228 - 19 Oct 2022

Cited by 5 | Viewed by 2644

Abstract

Praziquantel is a poorly water-soluble drug used to treat parasitic infections. Previous studies have suggested that its rate and extent of dissolution in milk and biorelevant media are slow and limited compared to dissolution in the pharmacopoeial-recommended medium, despite being reported as displaying [...] Read more.

Praziquantel is a poorly water-soluble drug used to treat parasitic infections. Previous studies have suggested that its rate and extent of dissolution in milk and biorelevant media are slow and limited compared to dissolution in the pharmacopoeial-recommended medium, despite being reported as displaying a positive food effect upon administration. This study aimed to revisit the dissolution of praziquantel in biorelevant media and milk to better understand this apparent dichotomy. The context of digestion was introduced to better understand drug solubilisation under more relevant gastrointestinal conditions. The amount of praziquantel solubilised in the various media during digestion was quantified using high performance liquid chromatography (HPLC) and the kinetics of dissolution were confirmed by tracking the disappearance of solid crystalline drug using in situ small angle X-ray scattering (SAXS). For the dissolution media, where sodium lauryl sulfate (SLS) is typically included as a wetting agent, a prominent effect of SLS on drug dissolution was also apparent where >2.5 fold more drug was solubilised in SLS-containing dissolution medium compared to that without (0.1 M HCl only). In milk, significant dissolution of praziquantel was observed only during digestion and not during dispersion, hence suggesting that (1) milk can be potentially administered with praziquantel to improve oral bioavailability and (2) incorporating a digestion step into existing in vitro dissolution testing can better reflect the potential for a positive food effect when lipids are present. Full article

(This article belongs to the Collection Advanced Pharmaceutical Science and Technology)

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16 pages, 3629 KiB

Open AccessArticle

Molecular Imaging of Ultrasound-Mediated Blood-Brain Barrier Disruption in a Mouse Orthotopic Glioblastoma Model

by Chiara Bastiancich, Samantha Fernandez, Florian Correard, Anthony Novell, Benoit Larrat, Benjamin Guillet and Marie-Anne Estève

Pharmaceutics 2022, 14(10), 2227; https://doi.org/10.3390/pharmaceutics14102227 - 19 Oct 2022

Cited by 3 | Viewed by 2992

Abstract

Glioblastoma (GBM) is an aggressive and malignant primary brain tumor. The blood-brain barrier (BBB) limits the therapeutic options available to tackle this incurable tumor. Transient disruption of the BBB by focused ultrasound (FUS) is a promising and safe approach to increase the brain [...] Read more.

Glioblastoma (GBM) is an aggressive and malignant primary brain tumor. The blood-brain barrier (BBB) limits the therapeutic options available to tackle this incurable tumor. Transient disruption of the BBB by focused ultrasound (FUS) is a promising and safe approach to increase the brain and tumor concentration of drugs administered systemically. Non-invasive, sensitive, and reliable imaging approaches are required to better understand the impact of FUS on the BBB and brain microenvironment. In this study, nuclear imaging (SPECT/CT and PET/CT) was used to quantify neuroinflammation 48 h post-FUS and estimate the influence of FUS on BBB opening and tumor growth in vivo. BBB disruptions were performed on healthy and GBM-bearing mice (U-87 MG xenograft orthotopic model). The BBB recovery kinetics were followed and quantified by [99mTc]Tc-DTPA SPECT/CT imaging at 0.5 h, 3 h and 24 h post-FUS. The absence of neuroinflammation was confirmed by [18F]FDG PET/CT imaging 48 h post-FUS. The presence of the tumor and its growth were evaluated by [68Ga]Ga-RGD₂ PET/CT imaging and post-mortem histological analysis, showing that tumor growth was not influenced by FUS. In conclusion, molecular imaging can be used to evaluate the time frame for systemic treatment combined with transient BBB opening and to test its efficacy over time. Full article

(This article belongs to the Special Issue Non-invasive Device-Mediated Brain Drug Delivery across the Blood-Brain Barrier)

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15 pages, 3551 KiB

Open AccessArticle

Population Pharmacokinetic/Pharmacodynamic Modelling of Daptomycin for Schedule Optimization in Patients with Renal Impairment

by Teresa García-Martínez, María Dolores Bellés-Medall, Maria García-Cremades, Raúl Ferrando-Piqueres, Victor Mangas-Sanjuán and Matilde Merino-Sanjuan

Pharmaceutics 2022, 14(10), 2226; https://doi.org/10.3390/pharmaceutics14102226 - 18 Oct 2022

Cited by 4 | Viewed by 2083

Abstract

The aims of this study are (i) to develop a population pharmacokinetic/pharmacodynamic model of daptomycin in patients with normal and impaired renal function, and (ii) to establish the optimal dose recommendation of daptomycin in clinical practice. Several structural PK models including linear and [...] Read more.

The aims of this study are (i) to develop a population pharmacokinetic/pharmacodynamic model of daptomycin in patients with normal and impaired renal function, and (ii) to establish the optimal dose recommendation of daptomycin in clinical practice. Several structural PK models including linear and non-linear binding kinetics were evaluated. Monte Carlo simulations were conducted with a fixed combination of creatinine clearance (30–90 mL/min/1.73 m²) and body weight (50–100 kg). The final dataset included 46 patients and 157 daptomycin observations. A two-compartment model with first-order peripheral distribution and elimination kinetics assuming non-linear protein-binding kinetics was selected. The bactericidal effect for Gram+ strains with MIC ≤ 0.5 mg/L could be achieved with 5–12 mg/kg daily daptomycin based on body weight and renal function. The administration of 10–17 mg/kg q48 h daptomycin allows to achieve bactericidal effect for Gram+ strains with MIC ≤ 1 mg/L. Four PK samples were selected as the optimal sampling strategy for an accurate AUC estimation. A quantitative framework has served to characterize the non-linear binding kinetics of daptomycin in patients with normal and impaired renal function. The impact of different dosing regimens on the efficacy and safety outcomes of daptomycin treatment based on the unbound exposure of daptomycin and individual patient characteristics has been evaluated. Full article

(This article belongs to the Special Issue The Role of Pharmacometrics in Drug Discovery and Development Process (Volume II))

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