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Pharmaceutics, Volume 13, Issue 12 (December 2021) – 218 articles

Cover Story (view full-size image): The use of mRNA as a therapeutic molecule faced some initial obstacles due to its inherent instability and requirements in large-scale production, purification, and safe delivery. In recent decades, these issues have been addressed, and innovative strategies have been explored to overcome some of these limitations. This year, the research on mRNA reached a significant milestone, as the mRNA vaccine against COVID-19 was developed with unprecedented speed as an effective weapon in the battle against COVID-19. Now, mRNA is recognized as a disruptive class of biomedicines with a variety of applications: vaccination, immunotherapy, regenerative medicine, protein replacement, and gene editing. Nevertheless, there are challenges that remain, and intensive research is currently being carried out in the field to develop new and effective solutions in delivery, stabilization, and manufacturing.View this paper
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17 pages, 1409 KiB  
Review
The TKI Era in Chronic Leukemias
by Danilo De Novellis, Fabiana Cacace, Valeria Caprioli, William G. Wierda, Kris M. Mahadeo and Francesco Paolo Tambaro
Pharmaceutics 2021, 13(12), 2201; https://doi.org/10.3390/pharmaceutics13122201 - 20 Dec 2021
Cited by 11 | Viewed by 4512
Abstract
Tyrosine kinases are proteins involved in physiological cell functions including proliferation, differentiation, and survival. However, the dysregulation of tyrosine kinase pathways occurs in malignancy, including hematological leukemias such as chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Particularly, the fusion oncoprotein BCR-ABL1 [...] Read more.
Tyrosine kinases are proteins involved in physiological cell functions including proliferation, differentiation, and survival. However, the dysregulation of tyrosine kinase pathways occurs in malignancy, including hematological leukemias such as chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Particularly, the fusion oncoprotein BCR-ABL1 in CML and the B-cell receptor (BCR) signaling pathway in CLL are critical for leukemogenesis. Therapeutic management of these two hematological conditions was fundamentally changed in recent years, making the role of conventional chemotherapy nearly obsolete. The first, second, and third generation inhibitors (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) of BCR-ABL1 and the allosteric inhibitor asciminib showed deep genetic and molecular remission rates in CML, leading to the evaluation of treatment discontinuation in prospective trials. The irreversible BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and spebrutinib) covalently bind to the C481 amino acid of BTK. The reversible BTK inhibitor pirtobrutinib has a different binding site, overcoming resistance associated with mutations at C481. The PI3K inhibitors (idelalisib and duvelisib) are also effective in CLL but are currently less used because of their toxicity profiles. These tyrosine kinase inhibitors are well-tolerated, do have some associated in-class side effects that are manageable, and have remarkably improved outcomes for patients with hematologic malignancies. Full article
(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)
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16 pages, 4923 KiB  
Article
The Role of Transmission Electron Microscopy in the Early Development of Mesoporous Materials for Tissue Regeneration and Drug Delivery Applications
by María Luisa Ruiz-González, Almudena Torres-Pardo and José M. González-Calbet
Pharmaceutics 2021, 13(12), 2200; https://doi.org/10.3390/pharmaceutics13122200 - 20 Dec 2021
Cited by 1 | Viewed by 2738
Abstract
For the last 20 years, silica-based mesoporous materials have provided a sound platform for the development of biomedical technology applied to tissue engineering and drug delivery. Their unique structural and textural characteristics, chiefly, the ordered distribution of homogeneous and tunable pores with high [...] Read more.
For the last 20 years, silica-based mesoporous materials have provided a sound platform for the development of biomedical technology applied to tissue engineering and drug delivery. Their unique structural and textural characteristics, chiefly, the ordered distribution of homogeneous and tunable pores with high surface areas and large pore volume, and their excellent biocompatibility provide an excellent starting point for bone tissue regeneration on the mesoporous surface, and also to load species of interest inside the pores. Adequate control of the synthesis conditions and functionalization of the mesoporous surface are critical factors in the design of new systems that are suitable for use in specific medical applications. Simultaneously, the use of appropriate characterization techniques in the several stages of design and manufacture of mesoporous particles allows us to ascertain the textural, structural and compositional modifications induced during the synthesis, functionalization and post-in vitro assays processes. In this scenario, the present paper shows, through several examples, the role of transmission electron microscopy and associated spectroscopic techniques in the search for useful information in the early design stages of mesoporous systems, with application in the fields of tissue regeneration and drug delivery systems. Full article
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19 pages, 2323 KiB  
Article
Sulfonated Amphiphilic Poly(α)glutamate Amine—A Potential siRNA Nanocarrier for the Treatment of Both Chemo-Sensitive and Chemo-Resistant Glioblastoma Tumors
by Adva Krivitsky, Sabina Pozzi, Eilam Yeini, Sahar Israeli Dangoor, Tal Zur, Sapir Golan, Vadim Krivitsky, Nitzan Albeck, Evgeny Pisarevsky, Paula Ofek, Asaf Madi and Ronit Satchi-Fainaro
Pharmaceutics 2021, 13(12), 2199; https://doi.org/10.3390/pharmaceutics13122199 - 20 Dec 2021
Cited by 2 | Viewed by 2853
Abstract
Development of chemo-resistance is a major challenge in glioblastoma (GB) treatment. This phenomenon is often driven by increased activation of genes associated with DNA repair, such as the alkyl-removing enzyme O6-methylguanine-DNA methyltransferase (MGMT) in combination with overexpression of canonical genes related [...] Read more.
Development of chemo-resistance is a major challenge in glioblastoma (GB) treatment. This phenomenon is often driven by increased activation of genes associated with DNA repair, such as the alkyl-removing enzyme O6-methylguanine-DNA methyltransferase (MGMT) in combination with overexpression of canonical genes related to cell proliferation and tumor progression, such as Polo-like kinase 1 (Plk1). Hereby, we attempt to sensitize resistant GB cells using our established amphiphilic poly(α)glutamate (APA): small interfering RNA (siRNA) polyplexes, targeting Plk1. Furthermore, we improved brain-targeting by decorating our nanocarrier with sulfonate groups. Our sulfonated nanocarrier showed superior selectivity towards P-selectin (SELP), a transmembrane glycoprotein overexpressed in GB and angiogenic brain endothelial cells. Self-assembled polyplexes of sulfonated APA and siPlk1 internalized into GB cells and into our unique 3-dimensional (3D) GB spheroids inducing specific gene silencing. Moreover, our RNAi nanotherapy efficiently reduced the cell viability of both chemo-sensitive and chemo-resistant GB cells. Our developed sulfonated amphiphilic poly(α)glutamate nanocarrier has the potential to target siRNA to GB brain tumors. Our findings may strengthen the therapeutic applications of siRNA for chemo-resistant GB tumors, or as a combination therapy for chemo-sensitive GB tumors. Full article
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18 pages, 7090 KiB  
Article
Silk Fibroin Microneedle Patches for the Treatment of Insomnia
by Zhenzhen Qi, Jiaxin Cao, Xiaosheng Tao, Xinyi Wu, Subhas C. Kundu and Shenzhou Lu
Pharmaceutics 2021, 13(12), 2198; https://doi.org/10.3390/pharmaceutics13122198 - 20 Dec 2021
Cited by 17 | Viewed by 4191
Abstract
As a patient-friendly technology, drug-loaded microneedles can deliver drugs through the skin into the body. This system has broad application prospects and is receiving wide attention. Based on the knowledge acquired in this work, we successfully developed a melatonin-loaded microneedle prepared from proline/melatonin/silk [...] Read more.
As a patient-friendly technology, drug-loaded microneedles can deliver drugs through the skin into the body. This system has broad application prospects and is receiving wide attention. Based on the knowledge acquired in this work, we successfully developed a melatonin-loaded microneedle prepared from proline/melatonin/silk fibroin. The engineered microneedles’ morphological, physical, and chemical properties were characterized to investigate their structural transformation mechanism and transdermal drug-delivery capabilities. The results indicated that the crystal structure of silk fibroin in drug-loaded microneedles was mainly Silk I crystal structure, with a low dissolution rate and suitable swelling property. Melatonin-loaded microneedles showed high mechanical properties, and the breaking strength of a single needle was 1.2 N, which could easily be penetrated the skin. The drug release results in vitro revealed that the effective drug concentration was obtained quickly during the early delivery. The successful drug concentration was maintained through continuous release at the later stage. For in vivo experimentation, the Sprague Dawley (SD) rat model of insomnia was constructed. The outcome exhibited that the melatonin-loaded microneedle released the drug into the body through the skin and maintained a high blood concentration (over 5 ng/mL) for 4–6 h. The maximum blood concentration was above 10 ng/mL, and the peak time was 0.31 h. This system indicates that it achieved the purpose of mimicking physiological release and treating insomnia. Full article
(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)
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20 pages, 4445 KiB  
Article
Immunomodulatory and Antioxidant Potential of Biogenic Functionalized Polymeric Nutmeg Oil/Polyurethane/ZnO Bionanocomposite
by Musarat Amina, Nawal M. Al Musayeib, Nawal A. Alarfaj, Maha F. El-Tohamy, Gadah A. Al-Hamoud and Hanan M. Al-yousef
Pharmaceutics 2021, 13(12), 2197; https://doi.org/10.3390/pharmaceutics13122197 - 19 Dec 2021
Cited by 1 | Viewed by 2104
Abstract
The current study is focused on the biosynthesis of nutmeg oil/ polyurethane/ZnONPs bionanocomposite film for immunomodulatory and antioxidant activities. The fabricated film was prepared by using naturally extracted nutmeg oil functionalized with ZnONPs in the presence of polyutherane (PU) medium. The bionanocomposite film [...] Read more.
The current study is focused on the biosynthesis of nutmeg oil/ polyurethane/ZnONPs bionanocomposite film for immunomodulatory and antioxidant activities. The fabricated film was prepared by using naturally extracted nutmeg oil functionalized with ZnONPs in the presence of polyutherane (PU) medium. The bionanocomposite film was obtained by incorporating dropwise 10 % (w/v) of nutmeg oil to the PU solution/ZnONPs blend. The active constituents of nutmeg oil were determined by gas chromatography coupled with mass spectrometry (GC-MS). The morphological characteristics of the resulting bionanocomposite film were confirmed using various microscopic and spectroscopic methods. Immunomodulatory potential of bionanocomposite was evaluated for RAW 264.7 macrophages. The results exhibited an excellent reduction in inflammatory cytokines (IL-6, IL-10, and TNFα) secretions after the treatment with bionanocomposite. The bionanocomposite exerted the highest inhibitory effects on certain cell signaling constituents that influence the initiation of expression of proinflammatory cytokines. The bionanocomposite was also tested for DPPH and ABTS free radicals scavenging assays and showed excellent antioxidant potential with IC50 values (0.28 ± 0.22 and 0.49 ± 0.36), respectively. The outcomes suggested promising immunomodulatory and antioxidant potentials for the biogenic synthesized nutmeg oil/PU/ZnONPs polymeric bionanocomposite. Full article
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35 pages, 2199 KiB  
Article
Combination of Hyaluronan and Lyophilized Progenitor Cell Derivatives: Stabilization of Functional Hydrogel Products for Therapeutic Management of Tendinous Tissue Disorders
by Alexis Laurent, Alexandre Porcello, Paula Gonzalez Fernandez, Annick Jeannerat, Cédric Peneveyre, Philippe Abdel-Sayed, Corinne Scaletta, Nathalie Hirt-Burri, Murielle Michetti, Anthony de Buys Roessingh, Wassim Raffoul, Eric Allémann, Olivier Jordan and Lee Ann Applegate
Pharmaceutics 2021, 13(12), 2196; https://doi.org/10.3390/pharmaceutics13122196 - 19 Dec 2021
Cited by 7 | Viewed by 2940
Abstract
Cultured progenitor cells and derivatives have been used in various homologous applications of cutaneous and musculoskeletal regenerative medicine. Active pharmaceutical ingredients (API) in the form of progenitor cell derivatives such as lysates and lyophilizates were shown to retain function in controlled cellular models [...] Read more.
Cultured progenitor cells and derivatives have been used in various homologous applications of cutaneous and musculoskeletal regenerative medicine. Active pharmaceutical ingredients (API) in the form of progenitor cell derivatives such as lysates and lyophilizates were shown to retain function in controlled cellular models of wound repair. On the other hand, hyaluronan-based hydrogels are widely used as functional vehicles in therapeutic products for tendon tissue disorders. The aim of this study was the experimental characterization of formulations containing progenitor tenocyte-derived APIs and hyaluronan, for the assessment of ingredient compatibility and stability in view of eventual therapeutic applications in tendinopathies. Lyophilized APIs were determined to contain relatively low quantities of proteins and growth factors, while being physicochemically stable and possessing significant intrinsic antioxidant properties. Physical and rheological quantifications of the combination formulas were performed after hydrogen peroxide challenge, outlining significantly improved evolutive viscoelasticity values in accelerated degradation settings. Thus, potent effects of physicochemical protection or stability enhancement of hyaluronan by the incorporated APIs were observed. Finally, combination formulas were found to be easily injectable into ex vivo tendon tissues, confirming their compatibility with further translational clinical approaches. Overall, this study provides the technical bases for the development of progenitor tenocyte derivative-based injectable therapeutic products or devices, to potentially be applied in tendinous tissue disorders. Full article
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15 pages, 5067 KiB  
Article
Combination of Two Kinds of Medicated Microparticles Based on Hyaluronic Acid or Chitosan for a Wound Healing Spray Patch
by Angela Fabiano, Chiara Migone, Luca Cerri, Anna Maria Piras, Andrea Mezzetta, Giuseppantonio Maisetta, Semih Esin, Giovanna Batoni, Rossella Di Stefano and Ylenia Zambito
Pharmaceutics 2021, 13(12), 2195; https://doi.org/10.3390/pharmaceutics13122195 - 18 Dec 2021
Cited by 9 | Viewed by 2777
Abstract
Olive leaves extract (OLE) has been extensively studied as antioxidant and antibiotic and these characteristics make it particularly interesting for use on wounds. For this reason, the aim of this study was to introduce OLE in microparticles (MP) of hyaluronic acid (MPHA-OLE) or [...] Read more.
Olive leaves extract (OLE) has been extensively studied as antioxidant and antibiotic and these characteristics make it particularly interesting for use on wounds. For this reason, the aim of this study was to introduce OLE in microparticles (MP) of hyaluronic acid (MPHA-OLE) or chitosan (MPCs-OLE) to obtain a spray patch for the treatment of wounds in anatomical areas that are difficult to protect with traditional patches. The MP were characterized for particle size and ability to protect OLE from degradation, to absorb water from wound exudate, to control OLE release from MP. The MPHA and MPCs medicated or not and mixtures of the two types in different proportions were studied in vitro on fibroblasts by the scratch wound healing assay. The MP size was always less than 5 µm, and therefore, suitable for a spray patch. The MPCs-OLE could slow down the release of OLE therefore only about 60% of the polyphenols contained in it were released after 4 h. Both MPHA and MPCs could accelerate wound healing. A 50% MPHA-OLE-50% MPCs-OLE blend was the most suitable for accelerating wound healing. The MPHA-OLE-MPCs-OLE blends studied in this work were shown to have the characteristics suitable for a spray patch, thus giving a second life to the waste products of olive growers. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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16 pages, 2866 KiB  
Article
Modeling of High-Density Compaction of Pharmaceutical Tablets Using Multi-Contact Discrete Element Method
by Kostas Giannis, Carsten Schilde, Jan Henrik Finke and Arno Kwade
Pharmaceutics 2021, 13(12), 2194; https://doi.org/10.3390/pharmaceutics13122194 - 18 Dec 2021
Cited by 12 | Viewed by 3999
Abstract
The purpose of this work is to simulate the powder compaction of pharmaceutical materials at the microscopic scale in order to better understand the interplay of mechanical forces between particles, and to predict their compression profiles by controlling the microstructure. For this task, [...] Read more.
The purpose of this work is to simulate the powder compaction of pharmaceutical materials at the microscopic scale in order to better understand the interplay of mechanical forces between particles, and to predict their compression profiles by controlling the microstructure. For this task, the new framework of multi-contact discrete element method (MC-DEM) was applied. In contrast to the conventional discrete element method (DEM), MC-DEM interactions between multiple contacts on the same particle are now explicitly taken into account. A new adhesive elastic-plastic multi-contact model invoking neighboring contact interaction was introduced and implemented. The uniaxial compaction of two microcrystalline cellulose grades (Avicel® PH 200 (FMC BioPolymer, Philadelphia, PA, USA) and Pharmacel® 102 (DFE Pharma, Nörten-Hardenberg, Germany) subjected to high confining conditions was studied. The objectives of these simulations were: (1) to investigate the micromechanical behavior; (2) to predict the macroscopic behavior; and (3) to develop a methodology for the calibration of the model parameters needed for the MC-DEM simulations. A two-stage calibration strategy was followed: first, the model parameters were directly measured at the micro-scale (particle level) and second, a meso-scale calibration was established between MC-DEM parameters and compression profiles of the pharmaceutical powders. The new MC-DEM framework could capture the main compressibility characteristics of pharmaceutical materials and could successfully provide predictions on compression profiles at high relative densities. Full article
(This article belongs to the Collection Feature Papers in Pharmaceutical Technology)
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14 pages, 1254 KiB  
Article
Investigating the Contribution of Drug-Metabolizing Enzymes in Drug-Drug Interactions of Dapivirine and Miconazole
by Guru Raghavendra Valicherla, Phillip Graebing, Junmei Zhang, Ruohui Zheng, Jeremy Nuttall, Peter Silvera and Lisa Cencia Rohan
Pharmaceutics 2021, 13(12), 2193; https://doi.org/10.3390/pharmaceutics13122193 - 18 Dec 2021
Cited by 1 | Viewed by 2385
Abstract
Dapivirine (DPV) is a potent NNRTI used to prevent the sexual transmission of HIV. In a phase 1 trial (IPM 028), the concomitant use of a DPV vaginal ring and an antifungal miconazole (MIC) vaginal capsule was found to increase the systemic exposure [...] Read more.
Dapivirine (DPV) is a potent NNRTI used to prevent the sexual transmission of HIV. In a phase 1 trial (IPM 028), the concomitant use of a DPV vaginal ring and an antifungal miconazole (MIC) vaginal capsule was found to increase the systemic exposure to DPV in women, suggesting a potential for drug-drug interactions. This study’s objective was to investigate the mechanism of DPV-MIC interactions using drug-metabolizing enzymes (DMEs; CYPs and UGTs) that are locally expressed in the female reproductive tract (FRT). In vitro studies were performed to evaluate the metabolism of DPV and its inhibition and induction potential with DMEs. In addition, the impact of MIC on DPV metabolism and the inhibitory potential of DPV with DMEs were studied. Our findings suggest that DPV is a substrate of CYP1A1 and CYP3A4 enzymes and that MIC significantly decreased the DPV metabolism by inhibiting these two enzymes. DPV demonstrated potent inhibition of CYP1A1 and moderate/weak inhibition of the six CYP and eight UGT enzymes evaluated. MIC showed potent/moderate inhibition of seven CYP enzymes and weak/no inhibition of eight UGT enzymes. The combination of DPV and MIC showed potent inhibition of seven CYP enzymes (1A1, 1A2, 1B1, 2B6, 2C8, 2C19, and 3A4) and four UGT enzymes (1A3, 1A6, 1A9, and 2B7). DPV was not an inducer of CYP1A2, CYP2B6, and CYP3A4 enzymes in primary human hepatocytes. Therefore, the increased systemic concentrations of DPV observed in IPM 028 were likely due to the reduced metabolism of DPV because of CYP1A1 and CYP3A4 enzymes inhibition by MIC in the FRT. Full article
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11 pages, 724 KiB  
Review
Giving Oncolytic Viruses a Free Ride: Carrier Cells for Oncolytic Virotherapy
by Alberto Reale, Arianna Calistri and Jennifer Altomonte
Pharmaceutics 2021, 13(12), 2192; https://doi.org/10.3390/pharmaceutics13122192 - 18 Dec 2021
Cited by 17 | Viewed by 3074
Abstract
Oncolytic viruses (OVs) are an emerging class of therapeutics which combine multiple mechanisms of action, including direct cancer cell-killing, immunotherapy and gene therapy. A growing number of clinical trials have indicated that OVs have an excellent safety profile and provide some degree of [...] Read more.
Oncolytic viruses (OVs) are an emerging class of therapeutics which combine multiple mechanisms of action, including direct cancer cell-killing, immunotherapy and gene therapy. A growing number of clinical trials have indicated that OVs have an excellent safety profile and provide some degree of efficacy, but to date only a single OV drug, HSV-1 talimogene laherparepvec (T-Vec), has achieved marketing approval in the US and Europe. An important issue to consider in order to accelerate the clinical advancement of OV agents is the development of an effective delivery system. Currently, the most commonly employed OV delivery route is intratumoral; however, to target metastatic diseases and tumors that cannot be directly accessed, it is of great interest to develop effective approaches for the systemic delivery of OVs, such as the use of carrier cells. In general, the ideal carrier cell should have a tropism towards the tumor microenvironment (TME), and it must be susceptible to OV infection but remain viable long enough to allow migration and finally release of the OV within the tumor bed. Mesenchymal stem cells (MSCs) have been heavily investigated as carrier cells due to their inherent tumor tropism, in spite of some disadvantages in biodistribution. This review focuses on the other promising candidate carrier cells under development and discusses their interaction with specific OVs and future research lines. Full article
(This article belongs to the Special Issue Oncolytic Viruses as Cancer Therapeutics)
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18 pages, 2095 KiB  
Article
Microdosimetric Investigation and a Novel Model of Radiosensitization in the Presence of Metallic Nanoparticles
by Huagang Yan, David J. Carlson, Ramin Abolfath and Wu Liu
Pharmaceutics 2021, 13(12), 2191; https://doi.org/10.3390/pharmaceutics13122191 - 18 Dec 2021
Cited by 4 | Viewed by 2330
Abstract
Auger cascades generated in high atomic number nanoparticles (NPs) following ionization were considered a potential mechanism for NP radiosensitization. In this work, we investigated the microdosimetric consequences of the Auger cascades using the theory of dual radiation action (TDRA), and we propose the [...] Read more.
Auger cascades generated in high atomic number nanoparticles (NPs) following ionization were considered a potential mechanism for NP radiosensitization. In this work, we investigated the microdosimetric consequences of the Auger cascades using the theory of dual radiation action (TDRA), and we propose the novel Bomb model as a general framework for describing NP-related radiosensitization. When triggered by an ionization event, the Bomb model considers the NPs that are close to a radiation sensitive cellular target, generates dense secondary electrons and kills the cells according to a probability distribution, acting like a “bomb.” TDRA plus a distance model were used as the theoretical basis for calculating the change in α of the linear-quadratic survival model and the relative biological effectiveness (RBE). We calculated these quantities for SQ20B and Hela human cancer cells under 250 kVp X-ray irradiation with the presence of gadolinium-based NPs (AGuIXTM), and 220 kVp X-ray irradiation with the presence of 50 nm gold NPs (AuNPs), respectively, and compared with existing experimental data. Geant4-based Monte Carlo (MC) simulations were used to (1) generate the electron spectrum and the phase space data of photons entering the NPs and (2) calculate the proximity functions and other related parameters for the TDRA and the Bomb model. The Auger cascade electrons had a greater proximity function than photoelectric and Compton electrons in water by up to 30%, but the resulting increases in α were smaller than those derived from experimental data. The calculated RBEs cannot explain the experimental findings. The relative increase in α predicted by TDRA was lower than the experimental result by a factor of at least 45 for SQ20B cells with AGuIX under 250 kVp X-ray irradiation, and at least four for Hela cells with AuNPs under 220 kVp X-ray irradiation. The application of the Bomb model to Hela cells with AuNPs under 220 kVp X-ray irradiation indicated that a single ionization event for NPs caused by higher energy photons has a higher probability of killing a cell. NPs that are closer to the cell nucleus are more effective for radiosensitization. Microdosimetric calculations of the RBE for cell death of the Auger electron cascade cannot explain the experimentally observed radiosensitization by AGuIX or AuNP, while the proposed Bomb model is a potential candidate for describing NP-related radiosensitization at low NP concentrations. Full article
(This article belongs to the Special Issue Nanocarriers for Cancer Therapy and Diagnosis)
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20 pages, 6273 KiB  
Article
Influence of Massage and Skin Hydration on Dermal Penetration Efficacy of Nile Red from Petroleum Jelly—An Unexpected Outcome
by Vasudha Kaushik, Yameera Ganashalingam, Robert Schesny, Christian Raab, Soma Sengupta and Cornelia M. Keck
Pharmaceutics 2021, 13(12), 2190; https://doi.org/10.3390/pharmaceutics13122190 - 18 Dec 2021
Cited by 14 | Viewed by 4286
Abstract
The study aimed at comparing the influence of direct and indirect skin hydration as well as massage on the dermal penetration efficacy of active compounds. Nile red was used as a lipophilic drug surrogate and was incorporated into Vaseline (petroleum jelly). The formulation [...] Read more.
The study aimed at comparing the influence of direct and indirect skin hydration as well as massage on the dermal penetration efficacy of active compounds. Nile red was used as a lipophilic drug surrogate and was incorporated into Vaseline (petroleum jelly). The formulation was applied with and without massage onto either dry skin or pre-hydrated, moist skin. It was expected that the occlusive properties of Vaseline in combination with massage and enhanced skin hydration would cause a superposition of penetration-enhancing effects, which should lead to a tremendous increase in the dermal penetration efficacy of the lipophilic drug surrogate. Results obtained were diametral to the expectations, and various reasons were identified for causing the effect observed. Firstly, it was found that Vaseline undergoes syneresis after topical application. The expulsed mineral oil forms a film on top of the skin, and parts of it penetrate into the skin. The lipophilic drug surrogate, which is dissolved in the mineral oil, enters the skin with the mineral oil, i.e., via a solvent drag mechanism. Secondly, it was found that massage squeezes the skin and causes the expulsion of water from deeper layers of the SC. The expulsed water can act as a water barrier that prevents the penetration of lipophilic compounds and promotes the penetration of hydrophilic compounds. Based on the data, it is concluded that dermal penetration is a complex process that cannot only be explained by Fick’s law. It is composed of at least three different mechanisms. The first mechanism is the penetration of active ingredients with their solvents into the skin (convection, solvent drag), the second mechanism is the penetration of the active ingredient via passive diffusion, and the third mechanism can involve local penetration phenomena, e.g., the formation of liquid menisci and particle-associated penetration enhancement, which occur upon the evaporation of water and/or other ingredients from the formulation on top of the skin. Full article
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26 pages, 2676 KiB  
Review
Review of the Current Landscape of the Potential of Nanotechnology for Future Malaria Diagnosis, Treatment, and Vaccination Strategies
by Arnau Guasch-Girbau and Xavier Fernàndez-Busquets
Pharmaceutics 2021, 13(12), 2189; https://doi.org/10.3390/pharmaceutics13122189 - 17 Dec 2021
Cited by 5 | Viewed by 5414
Abstract
Malaria eradication has for decades been on the global health agenda, but the causative agents of the disease, several species of the protist parasite Plasmodium, have evolved mechanisms to evade vaccine-induced immunity and to rapidly acquire resistance against all drugs entering clinical [...] Read more.
Malaria eradication has for decades been on the global health agenda, but the causative agents of the disease, several species of the protist parasite Plasmodium, have evolved mechanisms to evade vaccine-induced immunity and to rapidly acquire resistance against all drugs entering clinical use. Because classical antimalarial approaches have consistently failed, new strategies must be explored. One of these is nanomedicine, the application of manipulation and fabrication technology in the range of molecular dimensions between 1 and 100 nm, to the development of new medical solutions. Here we review the current state of the art in malaria diagnosis, prevention, and therapy and how nanotechnology is already having an incipient impact in improving them. In the second half of this review, the next generation of antimalarial drugs currently in the clinical pipeline is presented, with a definition of these drugs’ target product profiles and an assessment of the potential role of nanotechnology in their development. Opinions extracted from interviews with experts in the fields of nanomedicine, clinical malaria, and the economic landscape of the disease are included to offer a wider scope of the current requirements to win the fight against malaria and of how nanoscience can contribute to achieve them. Full article
(This article belongs to the Special Issue Development of Micro and Nano Systems for the Drug Delivery)
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23 pages, 7790 KiB  
Article
Advanced Microparticulate/Nanoparticulate Respirable Dry Powders of a Selective RhoA/Rho Kinase (Rock) Inhibitor for Targeted Pulmonary Inhalation Aerosol Delivery
by Priya Muralidharan, Don Hayes, Jr., Jeffrey R. Fineman, Stephen M. Black and Heidi M. Mansour
Pharmaceutics 2021, 13(12), 2188; https://doi.org/10.3390/pharmaceutics13122188 - 17 Dec 2021
Cited by 4 | Viewed by 3266
Abstract
Pulmonary hypertension (PH) is a progressive disease that eventually leads to heart failure and potentially death for some patients. There are many unique advantages to treating pulmonary diseases directly and non-invasively by inhalation aerosols and dry powder inhalers (DPIs) possess additional unique advantages. [...] Read more.
Pulmonary hypertension (PH) is a progressive disease that eventually leads to heart failure and potentially death for some patients. There are many unique advantages to treating pulmonary diseases directly and non-invasively by inhalation aerosols and dry powder inhalers (DPIs) possess additional unique advantages. There continues to be significant unmet medical needs in the effective treatment of PH that target the underlying mechanisms. To date, there is no FDA-approved DPI indicated for the treatment of PH. Fasudil is a novel RhoA/Rho kinase (ROCK) inhibitor that has shown great potential in effectively treating pulmonary hypertension. This systematic study is the first to report on the design and development of DPI formulations comprised of respirable nanoparticles/microparticles using particle engineering design by advanced spray drying. In addition, comprehensive physicochemical characterization, in vitro aerosol aerosol dispersion performance with different types of human DPI devices, in vitro cell-drug dose response cell viability of different human respiratory cells from distinct lung regions, and in vitro transepithelial electrical resistance (TEER) as air-interface culture (AIC) demonstrated that these innovative DPI fasudil formulations are safe on human lung cells and have high aerosol dispersion performance properties. Full article
(This article belongs to the Special Issue Medical Aerosol Drug Delivery)
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17 pages, 20404 KiB  
Article
Machine Learning and Machine Vision Accelerate 3D Printed Orodispersible Film Development
by Colm S. O’Reilly, Moe Elbadawi, Neel Desai, Simon Gaisford, Abdul W. Basit and Mine Orlu
Pharmaceutics 2021, 13(12), 2187; https://doi.org/10.3390/pharmaceutics13122187 - 17 Dec 2021
Cited by 20 | Viewed by 5116
Abstract
Orodispersible films (ODFs) are an attractive delivery system for a myriad of clinical applications and possess both large economical and clinical rewards. However, the manufacturing of ODFs does not adhere to contemporary paradigms of personalised, on-demand medicine, nor sustainable manufacturing. To address these [...] Read more.
Orodispersible films (ODFs) are an attractive delivery system for a myriad of clinical applications and possess both large economical and clinical rewards. However, the manufacturing of ODFs does not adhere to contemporary paradigms of personalised, on-demand medicine, nor sustainable manufacturing. To address these shortcomings, both three-dimensional (3D) printing and machine learning (ML) were employed to provide on-demand manufacturing and quality control checks of ODFs. Direct ink writing (DIW) was able to fabricate complex ODF shapes, with thicknesses of less than 100 µm. ML algorithms were explored to classify the ODFs according to their active ingredient, by using their near-infrared (NIR) spectrums. A supervised model of linear discriminant analysis was found to provide 100% accuracy in classifying ODFs. A subsequent partial least square algorithm was applied to verify the dose, where a coefficient of determination of 0.96, 0.99 and 0.98 was obtained for ODFs of paracetamol, caffeine, and theophylline, respectively. Therefore, it was concluded that the combination of 3D printing, NIR and ML can result in a rapid production and verification of ODFs. Additionally, a machine vision tool was used to automate the in vitro testing. These collective digital technologies demonstrate the potential to automate the ODF workflow. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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15 pages, 1768 KiB  
Article
Therapeutic Potential of Injectable Nano-Mupirocin Liposomes for Infections Involving Multidrug-Resistant Bacteria
by Ahuva Cern, Yaelle Bavli, Atara Hod, Daniel Zilbersheid, Shazad Mushtaq, Ayelet Michael-Gayego, Dinorah Barasch, Yael Feinstein Rotkopf, Allon E. Moses, David M. Livermore and Yechezkel Barenholz
Pharmaceutics 2021, 13(12), 2186; https://doi.org/10.3390/pharmaceutics13122186 - 17 Dec 2021
Cited by 5 | Viewed by 2948
Abstract
Antibiotic resistance is a global health threat. There are a few antibiotics under development, and even fewer with new modes of action and no cross-resistance to established antibiotics. Accordingly, reformulation of old antibiotics to overcome resistance is attractive. Nano-mupirocin is a PEGylated nano-liposomal [...] Read more.
Antibiotic resistance is a global health threat. There are a few antibiotics under development, and even fewer with new modes of action and no cross-resistance to established antibiotics. Accordingly, reformulation of old antibiotics to overcome resistance is attractive. Nano-mupirocin is a PEGylated nano-liposomal formulation of mupirocin, potentially enabling parenteral use in deep infections, as previously demonstrated in several animal models. Here, we describe extensive in vitro profiling of mupirocin and Nano-mupirocin and correlate the resulting MIC data with the pharmacokinetic profiles seen for Nano-mupirocin in a rat model. Nano-mupirocin showed no cross-resistance with other antibiotics and retained full activity against vancomycin-, daptomycin-, linezolid- and methicillin- resistant Staphylococcus aureus, against vancomycin-resistant Enterococcus faecium, and cephalosporin-resistant Neisseria gonorrhoeae. Following Nano-mupirocin injection to rats, plasma levels greatly exceeded relevant MICs for >24 h, and a biodistribution study in mice showed that mupirocin concentrations in vaginal secretions greatly exceeded the MIC90 for N. gonorrhoeae (0.03 µg/mL) for >24 h. In summary, Nano-mupirocin has excellent potential for treatment of several infection types involving multiresistant bacteria. It has the concomitant benefits from utilizing an established antibiotic and liposomes of the same size and lipid composition as Doxil®, an anticancer drug product now used for the treatment of over 700,000 patients globally. Full article
(This article belongs to the Special Issue Pegylation in Drug Delivery Applications)
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22 pages, 785 KiB  
Review
Can Plant Materials Be Valuable in the Treatment of Periodontal Diseases? Practical Review
by Anna Gościniak, Magdalena Paczkowska-Walendowska, Agnieszka Skotnicka, Marek A. Ruchała and Judyta Cielecka-Piontek
Pharmaceutics 2021, 13(12), 2185; https://doi.org/10.3390/pharmaceutics13122185 - 17 Dec 2021
Cited by 16 | Viewed by 4612
Abstract
Periodontal diseases are one of the most significant challenges in dental health. It is estimated that only a few percent of the worldwide population have entirely healthy teeth, and according to WHO, oral diseases may affect up to 3.5 billion people worldwide. One [...] Read more.
Periodontal diseases are one of the most significant challenges in dental health. It is estimated that only a few percent of the worldwide population have entirely healthy teeth, and according to WHO, oral diseases may affect up to 3.5 billion people worldwide. One of the most serious oral diseases is periodontitis, an inflammatory disease affecting periodontal tissues, caused by pathogenic bacteria and environmental factors such as the ageing population, abuse of tobacco products, and lack of adequate oral hygiene due low public awareness. Plant materials are widely and successfully used in the management of many conditions, including periodontitis. Plant materials for periodontitis exhibit antibacterial, anti-inflammatory, antioxidant activities and affect the periodontium structure. Numerous studies demonstrate the advantages of phytotherapy for periodontitis relief and indicate the usefulness of Baikal skullcap root, Pomegranate fruit peel and root cortex, Tea leaves, Chamomile flowers, Magnolia bark, Blackberry leaves and fruits, Cranberry fruits and Lippia sidoides essential oil. This review aims to analyze the use and applicability of selected plant materials in periodontitis management since it is of paramount importance to evaluate the evidence of the traditionally used plant materials in light of continuously growing interest in phytotherapy and its adjuvant role in the treatment of periodontitis. Full article
(This article belongs to the Special Issue Pharmaceutical Formulations with Antimicrobial Properties)
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16 pages, 4310 KiB  
Article
The Potential of Optimized Liposomes in Enhancement of Cytotoxicity and Apoptosis of Encapsulated Egyptian Propolis on Hep-2 Cell Line
by Enas Alaa El-din Abd El-aziz, Sherif Farouk Elgayar, Fatma M. Mady, Mohammed A. S. Abourehab, Omiya Ali Hasan, Lamis M. Reda and Eman Alaaeldin
Pharmaceutics 2021, 13(12), 2184; https://doi.org/10.3390/pharmaceutics13122184 - 17 Dec 2021
Cited by 19 | Viewed by 2631
Abstract
Purpose: Development of pharmaceutical dosage forms of natural products has gained great interest recently. Propolis is a natural product with various active compounds and multiple pharmacological activities. Its resinous nature and low bioavailability were obstacles in the optimum use of this magnificent natural [...] Read more.
Purpose: Development of pharmaceutical dosage forms of natural products has gained great interest recently. Propolis is a natural product with various active compounds and multiple pharmacological activities. Its resinous nature and low bioavailability were obstacles in the optimum use of this magnificent natural product. Aim: This study evaluates the effect of using liposomes as a drug delivery system on the enhancement of the cytotoxic effect of propolis on squamous cell carcinoma cell lines (Hep-2) of head and neck. Methods: An optimized liposomal formulation of propolis was prepared using the conventional thin film hydration method 1, 2. The prepared (Hep-2) cell line was treated with different concentrations of propolis and optimized propolis liposomes for 24 h. The effect of both propolis and propolis liposomes on cell line was investigated using MTT assay, cytological examination, and nuclear morphometric analysis. The effect of the drugs on the cell apoptosis was evaluated using Annexin V. Results: The findings revealed that both propolis and propolis liposomes have a cytotoxic effect on Hep-2 cell line through induction of apoptosis. The effect was dose dependent. However, a statistically significant enhancement in propolis-mediated apoptosis on Hep-2 cells was elucidated due to encapsulation within the prepared liposomes. Conclusion: Liposome is a powerful tool for enhancing the cytotoxicity of propolis against Hep-2 cell line. Full article
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9 pages, 2266 KiB  
Article
Two Laser Treatments Can Improve Tumor Ablation Efficiency of Chemophototherapy
by Sanjana Ghosh and Jonathan F. Lovell
Pharmaceutics 2021, 13(12), 2183; https://doi.org/10.3390/pharmaceutics13122183 - 17 Dec 2021
Cited by 3 | Viewed by 2153
Abstract
Chemophototherapy is an emerging tumor ablation modality that can improve local delivery of chemotherapeutic agents. Long circulating doxorubicin (Dox) in porphyrin-phospholipid (PoP) liposomes (LC-Dox-PoP) has previously been developed as an effective chemophototherapy agent. In the present study, we observed that in mice, LC-Dox-PoP [...] Read more.
Chemophototherapy is an emerging tumor ablation modality that can improve local delivery of chemotherapeutic agents. Long circulating doxorubicin (Dox) in porphyrin-phospholipid (PoP) liposomes (LC-Dox-PoP) has previously been developed as an effective chemophototherapy agent. In the present study, we observed that in mice, LC-Dox-PoP showed enhanced accumulation in human pancreatic tumor xenografts even with suboptimal light doses, as assessed by fluorometric analysis of tissue homogenates and microscopic imaging of Dox and PoP in tumor slices. A second laser treatment, at a time point in which tumors had greater drug accumulation as a result of the first laser treatment, induced potent tumor ablation. Efficacy studies were carried out in two human pancreatic cancer subcutaneous mouse tumor models; MIA PaCa-2 or low-passage patient derived pancreatic cancer xenografts. A single treatment of 3 mg/kg LC-Dox-PoP and an initial 150 J/cm2 laser treatment 1 h after drug administration, followed by second laser treatment of 50 J/cm2 8 h after drug administration, was more effective than a single laser treatment of 200 J/cm2 at either of those time points. Thus, this study presents proof-of-principle and rationale for using two discrete laser treatments to enhance the efficacy of chemophototherapy. Full article
(This article belongs to the Special Issue Nanoparticle Delivery to Tumors: Challenges and Advances)
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18 pages, 5849 KiB  
Article
Non-Cationic RGD-Containing Protein Nanocarrier for Tumor-Targeted siRNA Delivery
by Xiaolin Yu, Lu Xue, Jing Zhao, Shuhua Zhao, Daqing Wu and Hong Yan Liu
Pharmaceutics 2021, 13(12), 2182; https://doi.org/10.3390/pharmaceutics13122182 - 17 Dec 2021
Cited by 5 | Viewed by 2585
Abstract
Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effects, poor clearance, [...] Read more.
Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effects, poor clearance, low serum stability, and high toxicity. In this study, we genetically engineered a non-cationic non-viral tumor-targeted universal siRNA nanocarrier (MW 26 KDa). This protein nanocarrier consists of three function domains: a dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidine for endosome escape, and two RGD peptides at the N- and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specifically targets integrin αvβ3 expressing cells in vitro, and homes siRNA to tumors in vivo. The delivered siRNA leads to target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional and biomimetic siRNA carrier is biodegradable, has low toxicity, is suitable for mass production by fermentation, and is serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery. Full article
(This article belongs to the Special Issue Cancer Gene Therapy With Non-Viral Nanocarriers)
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12 pages, 2492 KiB  
Article
PEGylated Liposomes Remotely Loaded with the Combination of Doxorubicin, Quinine, and Indocyanine Green Enable Successful Treatment of Multidrug-Resistant Tumors
by Emma Grabarnick (Portnoy), Alexander V. Andriyanov, Hadas Han, Sara Eyal and Yechezkel Barenholz
Pharmaceutics 2021, 13(12), 2181; https://doi.org/10.3390/pharmaceutics13122181 - 17 Dec 2021
Cited by 13 | Viewed by 2391
Abstract
Multidrug resistance (MDR) of cancer cells remains a major obstacle to favorable outcomes of treatment with many drugs, including doxorubicin. Most of the clinical trials failed to demonstrate the benefit of the drug efflux transporter P-glycoprotein (P-gp) inhibitors to circumvent P-gp-mediated drug resistance [...] Read more.
Multidrug resistance (MDR) of cancer cells remains a major obstacle to favorable outcomes of treatment with many drugs, including doxorubicin. Most of the clinical trials failed to demonstrate the benefit of the drug efflux transporter P-glycoprotein (P-gp) inhibitors to circumvent P-gp-mediated drug resistance in vivo. The present study explored the therapeutic potential of combined treatment with liposomal doxorubicin, P-gp inhibitor quinine, and the photodynamic therapy (PDT) using indocyanine green (ICG) in the adenocarcinoma drug-resistant tumor model. Liposomes were actively co-remotely loaded with doxorubicin and quinine, and ICG was passively adsorbed. The liposomes were characterized by differential scanning calorimetry (DSC) and cryogenic transmission microscopy (Cryo-TEM). We found that quinine impaired the crystalline structure of doxorubicin. In vitro, treatment with single agents themselves was insufficient to inhibit the growth of HT-29 MDR1 cells. However, pegylated liposomal doxorubicin and quinine (PLDQ) significantly diminished HT-29 MDR1 cell survival. Furthermore, survival inhibition intensified by the addition of ICG to the PLDQ (ICG + PLDQ). In vivo, ICG + PLDQ significantly decreased tumor growth when combined with tumor irradiation with NIR light (** p < 0.01). ICG + PLDQ + irradiation was superior to single treatments or combinational treatments without irradiation. These findings suggest that ICG + PLDQ can overcome P-gp-mediated MDR in cancer cells. Full article
(This article belongs to the Special Issue Pegylation in Drug Delivery Applications)
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17 pages, 3702 KiB  
Article
Unveiling the Membrane and Cell Wall Action of Antimicrobial Cyclic Lipopeptides: Modulation of the Spectrum of Activity
by Roser Segovia, Judith Solé, Ana Maria Marqués, Yolanda Cajal and Francesc Rabanal
Pharmaceutics 2021, 13(12), 2180; https://doi.org/10.3390/pharmaceutics13122180 - 17 Dec 2021
Cited by 10 | Viewed by 2902
Abstract
Antibiotic resistance is a major public health challenge, and Gram-negative multidrug-resistant bacteria are particularly dangerous. The threat of running out of active molecules is accelerated by the extensive use of antibiotics in the context of the COVID-19 pandemic, and new antibiotics are urgently [...] Read more.
Antibiotic resistance is a major public health challenge, and Gram-negative multidrug-resistant bacteria are particularly dangerous. The threat of running out of active molecules is accelerated by the extensive use of antibiotics in the context of the COVID-19 pandemic, and new antibiotics are urgently needed. Colistin and polymyxin B are natural antibiotics considered as last resort drugs for multi-resistant infections, but their use is limited because of neuro- and nephrotoxicity. We previously reported a series of synthetic analogues inspired in natural polymyxins with a flexible scaffold that allows multiple modifications to improve activity and reduce toxicity. In this work, we focus on modifications in the hydrophobic domains, describing analogues that broaden or narrow the spectrum of activity including both Gram-positive and Gram-negative bacteria, with MICs in the low µM range and low hemolytic activity. Using biophysical methods, we explore the interaction of the new molecules with model membranes that mimic the bacterial inner and outer membranes, finding a selective effect on anionic membranes and a mechanism of action based on the alteration of membrane function. Transmission electron microscopy observation confirms that polymyxin analogues kill microbial cells primarily by damaging membrane integrity. Redistribution of the hydrophobicity within the polymyxin molecule seems a plausible approach for the design and development of safer and more selective antibiotics. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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17 pages, 2823 KiB  
Review
Chronology of Global Success: 20 Years of Prof Vallet-Regí Solving Questions
by Miguel Manzano
Pharmaceutics 2021, 13(12), 2179; https://doi.org/10.3390/pharmaceutics13122179 - 17 Dec 2021
Cited by 2 | Viewed by 2127
Abstract
Twenty years ago, a group of bold scientists led by Prof Vallet-Regí suggested for the first time the use of mesoporous materials as potential drug delivery systems. Without knowing it; these pioneers unleashed the beast of creativity around the world because that original [...] Read more.
Twenty years ago, a group of bold scientists led by Prof Vallet-Regí suggested for the first time the use of mesoporous materials as potential drug delivery systems. Without knowing it; these pioneers unleashed the beast of creativity around the world because that original idea has been the inspiration of hundreds of scientific groups for the design of many versatile delivery systems based on mesoporous materials. Because the dream is not the destination, it is the journey, the present review aims to summarise the chain of events that catapulted a small and young research team from the grassroots of academia to the elite of the Biomedical Engineering field. Full article
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17 pages, 1202 KiB  
Review
Medical Device Development for Children and Young People—Reviewing the Challenges and Opportunities
by Paul Dimitri, Valeria Pignataro, Mariangela Lupo, Donato Bonifazi, Maria Henke, Umberto M. Musazzi, Floris Ernst, Paola Minghetti, Davide F. Redaelli, Sophia G. Antimisiaris, Giovanni Migliaccio, Fedele Bonifazi, Luca Marciani, Aaron J. Courtenay, Nunzio Denora and Angela Lopedota
Pharmaceutics 2021, 13(12), 2178; https://doi.org/10.3390/pharmaceutics13122178 - 17 Dec 2021
Cited by 10 | Viewed by 4840
Abstract
Development of specific medical devices (MDs) is required to meet the healthcare needs of children and young people (CYP). In this context, MD development should address changes in growth and psychosocial maturation, physiology, and pathophysiology, and avoid inappropriate repurposing of adult technologies. Underpinning [...] Read more.
Development of specific medical devices (MDs) is required to meet the healthcare needs of children and young people (CYP). In this context, MD development should address changes in growth and psychosocial maturation, physiology, and pathophysiology, and avoid inappropriate repurposing of adult technologies. Underpinning the development of MD for CYP is the need to ensure MD safety and effectiveness through pediatric MD-specific regulations. Contrary to current perceptions of limited market potential, the global pediatric healthcare market is expected to generate around USD 15,984 million by 2025. There are 1.8 billion young people in the world today; 40% of the global population is under 24, creating significant future healthcare market opportunities. This review highlights a number of technology areas that have led to successful pediatric MD, including 3D printing, advanced materials, drug delivery, and diagnostic imaging. To ensure the targeted development of MD for CYP, collaboration across multiple professional disciplines is required, facilitated by a platform to foster collaboration and drive innovation. The European Pediatric Translational Research Infrastructure (EPTRI) will be established as the European platform to support collaboration, including the life sciences industrial sector, to identify unmet needs in child health and support the development, adoption, and commercialization of pediatric MDs. Full article
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24 pages, 6229 KiB  
Article
Optimization and Transfollicular Delivery of Finasteride-Loaded Proniosomes for Hair Growth Stimulation in C57BL/6Mlac Mice
by Wandee Rungseevijitprapa, Panikchar Wichayapreechar, Bhagavathi Sundaram Sivamaruthi, Damrongsak Jinarat and Chaiyavat Chaiyasut
Pharmaceutics 2021, 13(12), 2177; https://doi.org/10.3390/pharmaceutics13122177 - 17 Dec 2021
Cited by 4 | Viewed by 3015
Abstract
The study aimed to develop the finasteride-loaded proniosome (FLP) to enhance the transfollicular delivery of finasteride (FN). The response surface methodology (RSM) combined with central composite design (CCD) with three independent variables (FN concentrations, total lipid content, and cholesterol content) was used to [...] Read more.
The study aimed to develop the finasteride-loaded proniosome (FLP) to enhance the transfollicular delivery of finasteride (FN). The response surface methodology (RSM) combined with central composite design (CCD) with three independent variables (FN concentrations, total lipid content, and cholesterol content) was used to optimize the FLP preparation. The particles size, zeta potential, entrapment efficiency, and drug loading capacity of the FLP were analyzed. The transfollicular delivery of the optimum formulation was investigated in vitro. In vivo hair growth stimulation study was performed on C57BL/6Mlac mice dorsal areas. The Draize primary skin irritation test for erythema and edema was performed in the New Zealand white rabbit skin. The optimum FLP consists of 5.0 mM of FN, 10.1 mM of total lipid content, and 50.0% of the cholesterol in the total lipid. The prepared proniosome delivered the FN significantly (p < 0.05), compared to the naked finasteride solution in a dose- and time-dependent manner. The FLP treatment significantly increases the number and size of hair follicles in a dose-dependent manner. The efficiency of 1% FLP was comparable to the 2% minoxidil solution. The FLP exhibited no skin irritation after 72 h. Therefore, the results demonstrated that the FLP could stimulate hair growth via a transfollicular delivery system. Full article
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20 pages, 6068 KiB  
Article
Inhibitory Effects of Cinnamaldehyde Derivatives on Biofilm Formation and Virulence Factors in Vibrio Species
by Olajide Sunday Faleye, Ezhaveni Sathiyamoorthi, Jin-Hyung Lee and Jintae Lee
Pharmaceutics 2021, 13(12), 2176; https://doi.org/10.3390/pharmaceutics13122176 - 17 Dec 2021
Cited by 18 | Viewed by 3216
Abstract
Vibrio parahaemolyticus is considered one of the most relevant pathogenic marine bacteria with a range of virulence factors to establish food-related gastrointestinal infections in humans. Cinnamaldehyde (CNMA) and some of its derivatives have antimicrobial and antivirulence activities against several bacterial pathogens. This study [...] Read more.
Vibrio parahaemolyticus is considered one of the most relevant pathogenic marine bacteria with a range of virulence factors to establish food-related gastrointestinal infections in humans. Cinnamaldehyde (CNMA) and some of its derivatives have antimicrobial and antivirulence activities against several bacterial pathogens. This study examined the inhibitory effects of CNMA and its derivatives on biofilm formation and the virulence factors in Vibrio species, particularly V. parahaemolyticus. CNMA and ten of its derivatives were initially screened against V. parahaemolyticus biofilm formation, and their effects on the production of virulence factors and gene expression were studied. Among the CNMA derivatives tested, 4-nitrocinnamaldehyde, 4-chlorocinnamaldehyde, and 4-bromocinnamaldehyde displayed antibacterial and antivirulence activities, while the backbone CNMA had weak effects. The derivatives could prevent the adhesion of V. parahaemolyticus to surfaces by the dose-dependent inhibition of cell surface hydrophobicity, fimbriae production, and flagella-mediated swimming and swarming phenotypes. They also decreased the protease secretion required for virulence and indole production, which could act as an important signal molecule. The expression of QS and biofilm-related genes (aphA, cpsA, luxS, and opaR), virulence genes (fliA, tdh, and vopS), and membrane integrity genes (fadL, and nusA) were downregulated in V. parahaemolyticus by these three CNMA analogs. Interestingly, they eliminated V. parahaemolyticus and reduced the background flora from the squid surface. In addition, they exhibited similar antimicrobial and antibiofilm activities against Vibrio harveyi. This study identified CNMA derivatives as potential broad-spectrum antimicrobial agents to treat biofilm-mediated Vibrio infections and for surface disinfection in food processing facilities. Full article
(This article belongs to the Special Issue Biofilm Busting Strategies for Eradicating Infections)
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18 pages, 3295 KiB  
Article
New Intracellular Peptide Derived from Hemoglobin Alpha Chain Induces Glucose Uptake and Reduces Blood Glycemia
by Renée N. O. Silva, Ricardo P. Llanos, Rosangela A. S. Eichler, Thiago B. Oliveira, Fábio C. Gozzo, William T. Festuccia and Emer S. Ferro
Pharmaceutics 2021, 13(12), 2175; https://doi.org/10.3390/pharmaceutics13122175 - 16 Dec 2021
Cited by 3 | Viewed by 2727
Abstract
Intracellular peptides were shown to derive from proteasomal degradation of proteins from mammalian and yeast cells, being suggested to play distinctive roles both inside and outside these cells. Here, the role of intracellular peptides previously identified from skeletal muscle and adipose tissues of [...] Read more.
Intracellular peptides were shown to derive from proteasomal degradation of proteins from mammalian and yeast cells, being suggested to play distinctive roles both inside and outside these cells. Here, the role of intracellular peptides previously identified from skeletal muscle and adipose tissues of C57BL6/N wild type (WT) and neurolysin knockout mice were investigated. In differentiated C2C12 mouse skeletal muscle cells, some of these intracellular peptides like insulin activated the expression of several genes related to muscle contraction and gluconeogenesis. One of these peptides, LASVSTVLTSKYR (Ric4; 600 µg/kg), administrated either intraperitoneally or orally in WT mice, decreased glycemia. Neither insulin (10 nM) nor Ric4 (100 µM) induced glucose uptake in adipose tissue explants obtained from conditional knockout mice depleted of insulin receptor. Ric4 (100 µM) similarly to insulin (100 nM) induced Glut4 translocation to the plasma membrane of C2C12 differentiated cells, and increased GLUT4 mRNA levels in epididymal adipose tissue of WT mice. Ric4 (100 µM) increased both Erk and Akt phosphorylation in C2C12, as well as in epididymal adipose tissue from WT mice; Erk, but not Akt phosphorylation was activated by Ric4 in tibial skeletal muscle from WT mice. Ric4 is rapidly degraded in vitro by WT liver and kidney crude extracts, such a response that is largely reduced by structural modifications such as N-terminal acetylation, C-terminal amidation, and substitution of Leu8 for DLeu8 (Ac-LASVSTV[DLeu]TSKYR-NH2; Ric4-16). Ric4-16, among several Ric4 derivatives, efficiently induced glucose uptake in differentiated C2C12 cells. Among six Ric4-derivatives evaluated in vivo, Ac-LASVSTVLTSKYR-NH2 (Ric4-2; 600 µg/kg) and Ac-LASVSTV[DLeu]TSKYR (Ric4-15; 600 µg/kg) administrated orally efficiently reduced glycemia in a glucose tolerance test in WT mice. The potential clinical application of Ric4 and Ric4-derivatives deserves further attention. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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18 pages, 7662 KiB  
Article
Nanoformulation Composed of Ellagic Acid and Functionalized Zinc Oxide Nanoparticles Inactivates DNA and RNA Viruses
by Khaled AbouAitah, Abdou K. Allayh, Jacek Wojnarowicz, Yasser M. Shaker, Anna Swiderska-Sroda and Witold Lojkowski
Pharmaceutics 2021, 13(12), 2174; https://doi.org/10.3390/pharmaceutics13122174 - 16 Dec 2021
Cited by 22 | Viewed by 3093
Abstract
The COVID-19 pandemic has strongly impacted daily life across the globe and caused millions of infections and deaths. No drug therapy has yet been approved for the clinic. In the current study, we provide a novel nanoformulation against DNA and RNA viruses that [...] Read more.
The COVID-19 pandemic has strongly impacted daily life across the globe and caused millions of infections and deaths. No drug therapy has yet been approved for the clinic. In the current study, we provide a novel nanoformulation against DNA and RNA viruses that also has a potential for implementation against COVID-19. The inorganic–organic hybrid nanoformulation is composed of zinc oxide nanoparticles (ZnO NPs) functionalized with triptycene organic molecules (TRP) via EDC/NHS coupling chemistry and impregnated with a natural agent, ellagic acid (ELG), via non-covalent interactions. The physicochemical properties of prepared materials were identified with several techniques. The hybrid nanoformulation contained 9.5 wt.% TRP and was loaded with up to 33.3 wt.% ELG. ELG alone exhibited higher cytotoxicity than both the ZnO NPs and nanoformulation against host cells. The nanoformulation efficiently inhibited viruses, compared to ZnO NPs or ELG alone. For H1N1 and HCoV-229E (RNA viruses), the nanoformulation had a therapeutic index of 77.3 and 75.7, respectively. For HSV-2 and Ad-7 (DNA viruses), the nanoformulation had a therapeutic index of 57.5 and 51.7, respectively. In addition, the nanoformulation showed direct inactivation of HCoV-229E via a virucidal mechanism. The inhibition by this mechanism was > 60%. Thus, the nanoformulation is a potentially safe and low-cost hybrid agent that can be explored as a new alternative therapeutic strategy for COVID-19. Full article
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18 pages, 21491 KiB  
Article
Pro-Apoptotic Potential of Pseudevernia furfuracea (L.) Zopf Extract and Isolated Physodic Acid in Acute Lymphoblastic Leukemia Model In Vitro
by Martin Kello, Tomas Kuruc, Klaudia Petrova, Michal Goga, Zuzana Michalova, Matus Coma, Dajana Rucova and Jan Mojzis
Pharmaceutics 2021, 13(12), 2173; https://doi.org/10.3390/pharmaceutics13122173 - 16 Dec 2021
Cited by 7 | Viewed by 2404
Abstract
Acute lymphoblastic leukemia (ALL) is the most frequently diagnosed type of leukemia among children. Although chemotherapy is a common treatment for cancer, it has a wide range of serious side effects, including myelo- and immunosuppression, hepatotoxicity and neurotoxicity. Combination therapies using natural substances [...] Read more.
Acute lymphoblastic leukemia (ALL) is the most frequently diagnosed type of leukemia among children. Although chemotherapy is a common treatment for cancer, it has a wide range of serious side effects, including myelo- and immunosuppression, hepatotoxicity and neurotoxicity. Combination therapies using natural substances are widely recommended to attenuate the adverse effects of chemotherapy. The aim of the present study was to investigate the anti-leukemic potential of extract from the lichen Pseudevernia furfuracea (L.) Zopf (PSE) and isolated physodic acid (Phy) in an in vitro ALL model. A screening assay, flow cytometry and Western blotting were used to analyze apoptosis occurrence, oxidative stress, DNA damage and stress/survival/apoptotic pathway modulation induced by the tested substances in Jurkat cells. We demonstrate for the first time that PSE and Phy treatment-induced intrinsic caspase-dependent cell death was associated with increased oxidative stress, DNA damage and cell cycle arrest with the activation of cell cycle checkpoint proteins p53, p21 and p27 and stress/survival kinases p38 MAPK, JNK and PI3K/Akt. Moreover, using peripheral T lymphocytes, we confirmed that PSE and Phy treatment caused minimal cytotoxicity in normal cells, and therefore, these naturally occurring lichen secondary metabolites could be promising substances for ALL therapy. Full article
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13 pages, 1060 KiB  
Article
Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats
by Agnieszka Karbownik, Danuta Szkutnik-Fiedler, Tomasz Grabowski, Anna Wolc, Joanna Stanisławiak-Rudowicz, Radosław Jaźwiec, Edmund Grześkowiak and Edyta Szałek
Pharmaceutics 2021, 13(12), 2172; https://doi.org/10.3390/pharmaceutics13122172 - 16 Dec 2021
Cited by 7 | Viewed by 2659
Abstract
A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety [...] Read more.
A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t, and AUC0–∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0–t of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0–t, and AUC0–∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects. Full article
(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)
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