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Pharmaceutics, Volume 15, Issue 2 (February 2023) – 410 articles

Cover Story (view full-size image): Recent advances in EVs’ extensive nanomedical drug delivery applications are presented, with special attention on red-blood-cell-derived EVs (RBCEVs). Indeed, EVs can be exploited as drug carriers owing to their advantageous properties over synthetic vehicles or nanoparticles. First, the nature and features of EVs and commonly employed methodologies for their isolation and characterization are illustrated. Furthermore, the biogenesis and composition of RBCEVs are described as naturally produced both under physiological and pathological conditions. Moreover, current procedures to isolate and/or produce RBCEVs in the lab and load them with specific cargo are discussed for therapeutic exploitations. Finally, the most recent in vitro and preclinical applications of RBCEVs and their potential industrial exploitation are shown. View this paper
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15 pages, 2192 KiB  
Article
Development of 3D Printed Multi-Layered Orodispersible Films with Porous Structure Applicable as a Substrate for Inkjet Printing
by Jan Elbl, Martin Veselý, Dagmar Blaháčková, Jaroslav Ondruš, Pavel Kulich, Eliška Mašková, Josef Mašek and Jan Gajdziok
Pharmaceutics 2023, 15(2), 714; https://doi.org/10.3390/pharmaceutics15020714 - 20 Feb 2023
Cited by 4 | Viewed by 2088
Abstract
The direct tailoring of the size, composition, or number of layers belongs to the advantages of 3D printing employment in producing orodispersible films (ODFs) compared to the frequently utilized solvent casting method. This study aimed to produce porous ODFs as a substrate for [...] Read more.
The direct tailoring of the size, composition, or number of layers belongs to the advantages of 3D printing employment in producing orodispersible films (ODFs) compared to the frequently utilized solvent casting method. This study aimed to produce porous ODFs as a substrate for medicated ink deposited by a 2D printer. The innovative semi-solid extrusion 3D printing method was employed to produce multilayered ODFs, where the bottom layer assures the mechanical properties. In contrast, the top layer provides a porous structure for ink entrapment. Hydroxypropyl methylcellulose and polyvinyl alcohol were utilized as film-forming polymers, glycerol as a plasticizer, and sodium starch glycolate as a disintegrant in the bottom matrix. Several porogen agents (Aeroperl® 300, Fujisil®, Syloid® 244 FP, Syloid® XDP 3050, Neusilin® S2, Neusilin® US2, and Neusilin® UFL2) acted as porosity enhancers in the two types of top layer. ODFs with satisfactory disintegration time were prepared. The correlation between the porogen content and the mechanical properties was proved. A porous ODF structure was detected in most samples and linked to the porogen content. SSE 3D printing represents a promising preparation method for the production of porous ODFs as substrates for subsequent drug deposition by 2D printing, avoiding the difficulties arising in casting or printing medicated ODFs directly. Full article
(This article belongs to the Special Issue 3D Printing Technology for Pharmaceutical and Biomedical Application)
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15 pages, 4898 KiB  
Article
Exploration of the Safety and Solubilization, Dissolution, Analgesic Effects of Common Basic Excipients on the NSAID Drug Ketoprofen
by Heba A. Abou-Taleb, Mai E. Shoman, Tarek Saad Makram, Jelan A. Abdel-Aleem and Hamdy Abdelkader
Pharmaceutics 2023, 15(2), 713; https://doi.org/10.3390/pharmaceutics15020713 - 20 Feb 2023
Cited by 2 | Viewed by 2262
Abstract
Since its introduction to the market in the 1970s, ketoprofen has been widely used due to its high efficacy in moderate pain management. However, its poor solubility and ulcer side effects have diminished its popularity. This study prepared forms of ketoprofen modified with [...] Read more.
Since its introduction to the market in the 1970s, ketoprofen has been widely used due to its high efficacy in moderate pain management. However, its poor solubility and ulcer side effects have diminished its popularity. This study prepared forms of ketoprofen modified with three basic excipients: tris, L-lysine, and L-arginine, and investigated their ability to improve water solubility and reduce ulcerogenic potential. The complexation/salt formation of ketoprofen and the basic excipients was prepared using physical mixing and coprecipitation methods. The prepared mixtures were studied for solubility, docking, dissolution, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), in vivo evaluation for efficacy (the writhing test), and safety (ulcerogenic liability). Phase solubility diagrams were constructed, and a linear solubility (AL type) curve was obtained with tris. Docking studies suggested a possible salt formation with L-arginine using Hirshfeld surface analysis. The order of enhancement of solubility and dissolution rates was as follows: L-arginine > L-lysine > tris. In vivo analgesic evaluation indicated a significant enhancement of the onset of action of analgesic activities for the three basic excipients. However, safety and gastric protection indicated that both ketoprofen arginine and ketoprofen lysine salts were more favorable than ketoprofen tris. Full article
(This article belongs to the Special Issue Recent Advances in Long-Acting Drug Delivery and Formulations)
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20 pages, 1449 KiB  
Review
Apoptotic Mechanisms of Quercetin in Liver Cancer: Recent Trends and Advancements
by Gautam Sethi, Prangya Rath, Abhishek Chauhan, Anuj Ranjan, Renuka Choudhary, Seema Ramniwas, Katrin Sak, Diwakar Aggarwal, Isha Rani and Hardeep Singh Tuli
Pharmaceutics 2023, 15(2), 712; https://doi.org/10.3390/pharmaceutics15020712 - 20 Feb 2023
Cited by 22 | Viewed by 3778
Abstract
Due to rising incidence rates of liver cancer and worries about the toxicity of current chemotherapeutic medicines, the hunt for further alternative methods to treat this malignancy has escalated. Compared to chemotherapy, quercetin, a flavonoid, is relatively less harmful to normal cells and [...] Read more.
Due to rising incidence rates of liver cancer and worries about the toxicity of current chemotherapeutic medicines, the hunt for further alternative methods to treat this malignancy has escalated. Compared to chemotherapy, quercetin, a flavonoid, is relatively less harmful to normal cells and is regarded as an excellent free-radical scavenger. Apoptotic cell death of cancer cells caused by quercetin has been demonstrated by many prior studies. It is present in many fruits, vegetables, and herbs. Quercetin targets apoptosis, by upregulating Bax, caspase-3, and p21 while downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, and Bcl-2. Additionally, it has been reported to increase STAT3 protein degradation in liver cancer cells while decreasing STAT3 activation. Quercetin has a potential future in chemoprevention, based on substantial research on its anticancer effects. The current review discusses quercetin’s mechanisms of action, nanodelivery strategies, and other potential cellular effects in liver cancer. Full article
(This article belongs to the Special Issue Recent Advances in Natural Product Drugs)
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24 pages, 3299 KiB  
Review
Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases
by Luis Alberto Bravo-Vázquez, Erick Octavio Mora-Hernández, Alma L. Rodríguez, Padmavati Sahare, Anindya Bandyopadhyay, Asim K. Duttaroy and Sujay Paul
Pharmaceutics 2023, 15(2), 711; https://doi.org/10.3390/pharmaceutics15020711 - 20 Feb 2023
Cited by 2 | Viewed by 3782
Abstract
Neurodegenerative diseases (NDDs) are characterized by the progressive degeneration and/or loss of neurons belonging to the central nervous system, and represent one of the major global health issues. Therefore, a number of immunotherapeutic approaches targeting the non-functional or toxic proteins that induce neurodegeneration [...] Read more.
Neurodegenerative diseases (NDDs) are characterized by the progressive degeneration and/or loss of neurons belonging to the central nervous system, and represent one of the major global health issues. Therefore, a number of immunotherapeutic approaches targeting the non-functional or toxic proteins that induce neurodegeneration in NDDs have been designed in the last decades. In this context, due to unprecedented advances in genetic engineering techniques and molecular farming technology, pioneering plant-based immunogenic antigen expression systems have been developed aiming to offer reliable alternatives to deal with important NDDs, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Diverse reports have evidenced that plant-made vaccines trigger significant immune responses in model animals, supported by the production of antibodies against the aberrant proteins expressed in the aforementioned NDDs. Moreover, these immunogenic tools have various advantages that make them a viable alternative for preventing and treating NDDs, such as high scalability, no risk of contamination with human pathogens, cold chain free production, and lower production costs. Hence, this article presents an overview of the current progress on plant-manufactured vaccines for NDDs and discusses its future prospects. Full article
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16 pages, 4627 KiB  
Article
Targeting IKKβ Activity to Limit Sterile Inflammation in Acetaminophen-Induced Hepatotoxicity in Mice
by Song-Hee Kim, Da-Eun Jung, Jin Yong Song, Jihye Jung, Jae-Kyung Jung, Heesoon Lee, Eunmiri Roh, Jin Tae Hong, Sang-Bae Han and Youngsoo Kim
Pharmaceutics 2023, 15(2), 710; https://doi.org/10.3390/pharmaceutics15020710 - 20 Feb 2023
Viewed by 1547
Abstract
The kinase activity of inhibitory κB kinase β (IKKβ) acts as a signal transducer in the activating pathway of nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death in the development of numerous hepatocellular injuries. However, the importance of IKKβ activity [...] Read more.
The kinase activity of inhibitory κB kinase β (IKKβ) acts as a signal transducer in the activating pathway of nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death in the development of numerous hepatocellular injuries. However, the importance of IKKβ activity on acetaminophen (APAP)-induced hepatotoxicity remains to be defined. Here, a derivative of caffeic acid benzylamide (CABA) inhibited the kinase activity of IKKβ, as did IMD-0354 and sulfasalazine which show therapeutic efficacy against inflammatory diseases through a common mechanism: inhibiting IKKβ activity. To understand the importance of IKKβ activity in sterile inflammation during hepatotoxicity, C57BL/6 mice were treated with CABA, IMD-0354, or sulfasalazine after APAP overdose. These small-molecule inhibitors of IKKβ activity protected the APAP-challenged mice from necrotic injury around the centrilobular zone in the liver, and rescued the mice from hepatic damage-associated lethality. From a molecular perspective, IKKβ inhibitors directly interrupted sterile inflammation in the Kupffer cells of APAP-challenged mice, such as damage-associated molecular pattern (DAMP)-induced activation of NF-κB activity via IKKβ, and NF-κB-regulated expression of cytokines and chemokines. However, CABA did not affect the upstream pathogenic events, including oxidative stress with glutathione depletion in hepatocytes after APAP overdose. N-acetyl cysteine (NAC), the only FDA-approved antidote against APAP overdose, replenishes cellular levels of glutathione, but its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver. Taken together, we propose a novel hypothesis that chemical inhibition of IKKβ activity in sterile inflammation could mitigate APAP-induced hepatotoxicity in mice, and have the potential to complement NAC treatment in APAP overdoses. Full article
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26 pages, 4664 KiB  
Article
Optimization and In Vitro Characterization of Telmisartan Loaded Sodium Alginate Beads and Its In Vivo Efficacy Investigation in Hypertensive Induced Animal Model
by Ubaidulla Uthumansha, Kousalya Prabahar, Dilli Bhai Gajapathy, Mohamed El-Sherbiny, Nehal Elsherbiny and Mona Qushawy
Pharmaceutics 2023, 15(2), 709; https://doi.org/10.3390/pharmaceutics15020709 - 20 Feb 2023
Cited by 2 | Viewed by 2058
Abstract
Background: Antihypertensive drug telmisartan (TEL) belongs to BCS class II, which is characterized by low water solubility and, consequently, low oral bioavailability. Gastroretentive systems may overcome the problems associated with low solubility of TEL and incomplete absorption by localizing the drug release in [...] Read more.
Background: Antihypertensive drug telmisartan (TEL) belongs to BCS class II, which is characterized by low water solubility and, consequently, low oral bioavailability. Gastroretentive systems may overcome the problems associated with low solubility of TEL and incomplete absorption by localizing the drug release in the stomach. The purpose of this study was to prepare TEL-loaded, oil-entrapped, floating alginate beads with the intent of enhancing the oral bioavailability of TEL for the treatment of hypertension. Methods: For the formulation and optimization of seventeen formulations of TEL-loaded oil-entrapped floating alginate beads, a central composite design was utilized. The concentration of sodium alginate (X1), the concentration of cross-linker (X2), and the concentration of sesame oil (X3) served as independent variables, whereas the entrapment efficiency (Y1), in vitro buoyancy (Y2), and drug release Q6h (Y3) served as dependent variables. Using the emulsion gelation method and calcium chloride as the cross-linking agent, different formulations of TEL alginate beads were produced. All formulations were evaluated for their entrapment efficiency percentage, in vitro buoyancy, and in vitro drug release. The optimal formulation of TEL alginate beads was prepared with and without oil and evaluated for entrapment efficiency percentage, in vitro buoyancy, swelling ratio, average size, and in vitro drug release. Using scanning electron microscopes, the surface morphology was determined. Using IR spectroscopy, the compatibility between the ingredients was determined. In vivo evaluation of the optimized formulation in comparison to the free TEL was done in hypertension-induced rats, and the systolic blood pressure and all pharmacokinetic parameters were measured. Results: The prepared beads exhibited a high entrapment efficiency percentage, in vitro buoyancy, and prolonged drug release. TEL was compatible with other ingredients, as approved by IR spectroscopy. The prepared TEL beads were spherical, as shown by the SEM. The relative bioavailability of TEL-loaded oil-entrapped beads was 222.52%, which was higher than that of the pure TEL suspension. The prepared TEL beads formulation exhibited a higher antihypertensive effect for a prolonged time compared to pure TEL suspension. Conclusions: It can be concluded that this innovative delivery method of TEL-loaded oil-entrapped beads is a promising tool for enhancing drug solubility and, thus, oral bioavailability and therapeutic efficacy, resulting in enhanced patient compliance. Furthermore, the in vivo study confirmed the formulation’s extended anti-hypertensive activity in animal models. Full article
(This article belongs to the Special Issue Design of Dosage Forms with Improved Biopharmaceutical Properties)
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17 pages, 3689 KiB  
Article
Polyethylenimine-Conjugated Hydroxyethyl Cellulose for Doxorubicin/Bcl-2 siRNA Co-Delivery Systems
by Jiwon Park, Seoyoung Kim and Tae-il Kim
Pharmaceutics 2023, 15(2), 708; https://doi.org/10.3390/pharmaceutics15020708 - 20 Feb 2023
Cited by 1 | Viewed by 1872
Abstract
Hydroxyethyl cellulose (HEC), widely known for its biocompatibility and water solubility, is a polysaccharide with potential for pharmaceutical applications. Here, we synthesized polyethylenimine2k (PEI2k)-conjugated hydroxyethyl cellulose (HECP2k) for doxorubicin/Bcl-2 siRNA co-delivery systems. HECP2ks were synthesized by reductive amination of PEI2k with periodate-oxidized HEC. [...] Read more.
Hydroxyethyl cellulose (HEC), widely known for its biocompatibility and water solubility, is a polysaccharide with potential for pharmaceutical applications. Here, we synthesized polyethylenimine2k (PEI2k)-conjugated hydroxyethyl cellulose (HECP2k) for doxorubicin/Bcl-2 siRNA co-delivery systems. HECP2ks were synthesized by reductive amination of PEI2k with periodate-oxidized HEC. The synthesis of the polymers was characterized using 1H NMR, 13C NMR, primary amine quantification, FT-IR, and GPC. Via agarose gel electrophoresis and Zeta-sizer measurement, it was found that HECP2ks condensed pDNA to positively charged and nano-sized complexes (100–300 nm, ~30 mV). The cytotoxicity of HECP2ks was low and HECP2k 10X exhibited higher transfection efficiency than PEI25k even in serum condition, showing its high serum stability from ethylene oxide side chains. Flow cytometry analysis and confocal laser microscopy observation verified the superior cellular uptake and efficient endosome escape of HECP2k 10X. HECP2k 10X also could load Dox and Bcl-2 siRNA, forming nano-particles (HECP2k 10X@Dox/siRNA). By median effect analysis and annexin V staining analysis, it was found that HECP2k 10X@Dox/siRNA complexes could cause synergistically enhanced anti-cancer effects to cancer cells via induction of apoptosis. Consequently, it was concluded that HECP2k possesses great potential as a promising Dox/Bcl-2 siRNA co-delivery carrier. Full article
(This article belongs to the Special Issue Carbohydrate-Based Carriers for Drug Delivery)
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17 pages, 2398 KiB  
Article
Immunomodulatory Effect of Novel Electrospun Nanofibers Loaded with Doxycycline as an Adjuvant Treatment in Periodontitis
by Vlad Andrei, Sanda Andrei, Adrian Florin Gal, Vasile Rus, Luciana-Mădălina Gherman, Bianca Adina Boșca, Mihaela Niculae, Reka Barabas, Oana Cadar, Elena Dinte, Dana-Maria Muntean, Cosmin Petru Peștean, Horațiu Rotar, Antonia Boca, Andreea Chiș, Manuela Tăut, Sebastian Candrea and Aranka Ilea
Pharmaceutics 2023, 15(2), 707; https://doi.org/10.3390/pharmaceutics15020707 - 20 Feb 2023
Cited by 6 | Viewed by 1943
Abstract
The immunomodulatory effect of a novel biomaterial obtained through electrospinning, based on polylactic acid (PLA) and nano-hydroxyapatite (nano-HAP), loaded with doxycycline (doxy) was evaluated in an animal model. The treatment capabilities as a local non-surgical treatment of periodontitis was investigated on the lower [...] Read more.
The immunomodulatory effect of a novel biomaterial obtained through electrospinning, based on polylactic acid (PLA) and nano-hydroxyapatite (nano-HAP), loaded with doxycycline (doxy) was evaluated in an animal model. The treatment capabilities as a local non-surgical treatment of periodontitis was investigated on the lower incisors of Wistar rats, after the induction of localized periodontitis using the ligature technique. Following the induction of the disease, the non-surgical treatment of scaling and root planing was applied, in conjunction with the application of the new material. The results of the treatment were evaluated clinically, using the tooth mobility and gingival index scores, as well as histologically. The salivary concentrations of matrix metalloproteinase 8 (MMP-8) and plasmatic concentrations of interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) were also monitored. Two weeks after the ligature application, the periodontal disease was successfully induced in rats. The application of the novel biomaterial obtained through electrospinning was proven to be more effective in improving the clinical parameters, while decreasing the salivary MMP-8 and plasmatic IL-1 and TNF-α concentrations, compared to the simple scaling and root planing. Thus, the novel electrospun biomaterial could be a strong candidate as an adjuvant to the non-surgical periodontal therapy. Full article
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21 pages, 3905 KiB  
Article
Tailoring the Lamellarity of Liposomes Prepared by Dual Centrifugation
by Jonas K. Koehler, Lars Gedda, Leonie Wurster, Johannes Schnur, Katarina Edwards, Heiko Heerklotz and Ulrich Massing
Pharmaceutics 2023, 15(2), 706; https://doi.org/10.3390/pharmaceutics15020706 - 20 Feb 2023
Cited by 4 | Viewed by 2489
Abstract
Dual centrifugation (DC) is a new and versatile technique for the preparation of liposomes by in-vial homogenization of lipid-water mixtures. Size, size distribution, and entrapping efficiencies are strongly dependent on the lipid concentration during DC-homogenization. In this study, we investigated the detailed structure [...] Read more.
Dual centrifugation (DC) is a new and versatile technique for the preparation of liposomes by in-vial homogenization of lipid-water mixtures. Size, size distribution, and entrapping efficiencies are strongly dependent on the lipid concentration during DC-homogenization. In this study, we investigated the detailed structure of DC-made liposomes. To do so, an assay to determine the ratio of inner to total membrane surfaces of liposomes (inaccessible surface) was developed based on either time-resolved or steady-state fluorescence spectroscopy. In addition, cryogenic electron microscopy (cryo-EM) was used to confirm the lamellarity results and learn more about liposome morphology. One striking result leads to the possibility of producing a novel type of liposome—small multilamellar vesicles (SMVs) with low PDI, sizes of the order of 100 nm, and almost completely filled with bilayers. A second particularly important finding is that VPGs can be prepared to contain open bilayer structures that will close spontaneously when, after storage, more aqueous phase is added and liposomes are formed. Through this process, a drug can effectively be entrapped immediately before application. In addition, dual centrifugation at lower lipid concentrations is found to produce predominantly unilamellar vesicles. Full article
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20 pages, 4813 KiB  
Article
Cell-Friendly Chitosan-Xanthan Gum Membranes Incorporating Hydroxyapatite Designed for Periodontal Tissue Regeneration
by Rafael Maza Barbosa, Daniel Navarro da Rocha, Renata Francielle Bombaldi de Souza, Jheison Lopes Santos, José Ricardo M. Ferreira and Ângela Maria Moraes
Pharmaceutics 2023, 15(2), 705; https://doi.org/10.3390/pharmaceutics15020705 - 20 Feb 2023
Cited by 6 | Viewed by 1511
Abstract
In this work, a simple method was proposed to produce dense composite polysaccharide-based membranes to be used for guided tissue and guided bone regeneration. The mucoadhesive polysaccharides chitosan (C) and xanthan gum (X) were used to produce polyelectrolyte-based complex membranes. Hydroxyapatite (HA) was [...] Read more.
In this work, a simple method was proposed to produce dense composite polysaccharide-based membranes to be used for guided tissue and guided bone regeneration. The mucoadhesive polysaccharides chitosan (C) and xanthan gum (X) were used to produce polyelectrolyte-based complex membranes. Hydroxyapatite (HA) was added to the formulation as a potential drug carrier, in C:X:HA mass proportions equal to 1:1:0.4, 1:1:2, and 1:1:10, and also to improve membranes bioactivity and biomimetic properties. FTIR analysis indicated successful incorporation of HA in the membranes and XRD analysis showed that no changes in the HA crystalline structure were observed after incorporation. The residual mass evaluated by TGA was higher for the formulation produced at the proportion 1:1:10. The membranes produced showed asymmetrical surfaces, with distinct roughness. Increasing the HA concentration increased the surface roughness. Greater in vitro proliferation of dental pulp mesenchymal stem cells was observed on the surface of the membrane with 1:1:10 C:X:HA proportion. However, the 1:1:2 formulation showed the most adequate balance of mechanical and biological properties. These results suggest that adding HA to the membranes can influence mechanical parameters as well as cell adhesion and proliferation, supporting the potential application of these materials in regenerative techniques and the treatment of periodontal lesions. Full article
(This article belongs to the Special Issue Mucoadhesive Drug Delivery Systems)
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18 pages, 3878 KiB  
Article
Decreased Levels of Chaperones in Mucopolysaccharidoses and Their Elevation as a Putative Auxiliary Therapeutic Approach
by Magdalena Żabińska, Lidia Gaffke, Patrycja Bielańska, Magdalena Podlacha, Estera Rintz, Zuzanna Cyske, Grzegorz Węgrzyn and Karolina Pierzynowska
Pharmaceutics 2023, 15(2), 704; https://doi.org/10.3390/pharmaceutics15020704 - 20 Feb 2023
Cited by 3 | Viewed by 1590
Abstract
Mucopolysaccharidoses (MPS) are rare genetic disorders belonging to the lysosomal storage diseases. They are caused by mutations in genes encoding lysosomal enzymes responsible for degrading glycosaminoglycans (GAGs). As a result, GAGs accumulate in lysosomes, leading to impairment of cells, organs and, consequently, the [...] Read more.
Mucopolysaccharidoses (MPS) are rare genetic disorders belonging to the lysosomal storage diseases. They are caused by mutations in genes encoding lysosomal enzymes responsible for degrading glycosaminoglycans (GAGs). As a result, GAGs accumulate in lysosomes, leading to impairment of cells, organs and, consequently, the entire body. Many of the therapies proposed thus far require the participation of chaperone proteins, regardless of whether they are therapies in common use (enzyme replacement therapy) or remain in the experimental phase (gene therapy, STOP-codon-readthrough therapy). Chaperones, which include heat shock proteins, are responsible for the correct folding of other proteins to the most energetically favorable conformation. Without their appropriate levels and activities, the correct folding of the lysosomal enzyme, whether supplied from outside or synthesized in the cell, would be impossible. However, the baseline level of nonspecific chaperone proteins in MPS has never been studied. Therefore, the purpose of this work was to determine the basal levels of nonspecific chaperone proteins of the Hsp family in MPS cells and to study the effect of normalizing GAG concentrations on these levels. Results of experiments with fibroblasts taken from patients with MPS types I, II, IIIA, IIIB, IIIC, IID, IVA, IVB, VI, VII, and IX, as well as from the brains of MPS I mice (Idua−/−), indicated significantly reduced levels of the two chaperones, Hsp70 and Hsp40. Interestingly, the reduction in GAG levels in the aforementioned cells did not lead to normalization of the levels of these chaperones but caused only a slight increase in the levels of Hsp40. An additional transcriptomic analysis of MPS cells indicated that the expression of other genes involved in protein folding processes and the cell response to endoplasmic reticulum stress, resulting from the appearance of abnormally folded proteins, was also modulated. To summarize, reduced levels of chaperones may be an additional cause of the low activity or inactivity of lysosomal enzymes in MPS. Moreover, this may point to causes of treatment failure where the correct structure of the enzyme supplied or synthesized in the cell is crucial to lower GAG levels. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Rare Genetic Diseases)
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19 pages, 10383 KiB  
Article
Prediction of Unwanted Crystallization of Freeze-Dried Protein Formulations Using α-Relaxation Measurements
by Sebastian Groël, Tim Menzen and Gerhard Winter
Pharmaceutics 2023, 15(2), 703; https://doi.org/10.3390/pharmaceutics15020703 - 20 Feb 2023
Cited by 2 | Viewed by 1410
Abstract
There is a lack of methods to predict the isothermal crystallization behavior of amorphous freeze-dried formulations stored below the glass transition temperature. This study applies isothermal microcalorimetry to predict long-term crystallization during product storage time. The relaxation curve of a fresh sample recorded [...] Read more.
There is a lack of methods to predict the isothermal crystallization behavior of amorphous freeze-dried formulations stored below the glass transition temperature. This study applies isothermal microcalorimetry to predict long-term crystallization during product storage time. The relaxation curve of a fresh sample recorded within 12 h after lyophilization is correlated with the long-term crystallization time at the same temperature. Storage conditions of 25 °C and 40 °C are examined and five model formulations containing either sucrose or trehalose with different concentrations of an IgG1 antibody are investigated. The amorphous formulations were created by different freeze-drying processes only differing in their freezing step (random nucleation; additional annealing step of 1.5 h and 3 h, controlled nucleation; quench cooling). Samples that crystallized during the study time of 12 months showed a promising correlation between their relaxation time and crystallization behavior upon storage. Furthermore, the study shows that polysorbate 20 strongly accelerates crystallization of sucrose and that the freezing step itself has a strong impact on the relaxation phenomena that is not levelled out by primary and secondary drying. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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18 pages, 1098 KiB  
Review
Role and Recent Advancements of Ionic Liquids in Drug Delivery Systems
by Monu Kumar Shukla, Harshita Tiwari, Rachna Verma, Wen-Liang Dong, Shavkatjon Azizov, Brajesh Kumar, Sadanand Pandey and Deepak Kumar
Pharmaceutics 2023, 15(2), 702; https://doi.org/10.3390/pharmaceutics15020702 - 20 Feb 2023
Cited by 16 | Viewed by 3146
Abstract
Advancements in the fields of ionic liquids (ILs) broaden its applications not only in traditional use but also in different pharmaceutical and biomedical fields. Ionic liquids “Solutions for Your Success” have received a lot of interest from scientists due to a myriad of [...] Read more.
Advancements in the fields of ionic liquids (ILs) broaden its applications not only in traditional use but also in different pharmaceutical and biomedical fields. Ionic liquids “Solutions for Your Success” have received a lot of interest from scientists due to a myriad of applications in the pharmaceutical industry for drug delivery systems as well as targeting different diseases. Solubility is a critical physicochemical property that determines the drug’s fate at the target site. Many promising drug candidates fail in various phases of drug research due to poor solubility. In this context, ionic liquids are regarded as effective drug delivery systems for poorly soluble medicines. ILs are also able to combine different anions/cations with other cations/anions to produce salts that satisfy the concept behind the ILs. The important characteristics of ionic liquids are the modularity of their physicochemical properties depending on the application. The review highlights the recent advancement and further applications of ionic liquids to deliver drugs in the pharmaceutical and biomedical fields. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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12 pages, 1665 KiB  
Article
Acceptability, Swallowability, Palatability, and Safety of Multiple Film-Coated Mini-Tablets in Children Aged ≥2–<7 Years: Results of an Open-Label Randomised Study
by Juliane Münch, Carolin Kloft, Madhi Farhan, Vladislav Fishman, Sining Leng, Hans Martin Bosse and Viviane Klingmann
Pharmaceutics 2023, 15(2), 701; https://doi.org/10.3390/pharmaceutics15020701 - 20 Feb 2023
Cited by 1 | Viewed by 1794
Abstract
This single-centre, open-label, randomised, parallel-group study assessed the acceptability, swallowability, palatability, and safety of film-coated, 3 mm diameter mini-tablets in children aged ≥2–<7 years. In total, 300 participants were randomised (2:2:1:1) to receive a single oral administration of 16 (group A) or 32 [...] Read more.
This single-centre, open-label, randomised, parallel-group study assessed the acceptability, swallowability, palatability, and safety of film-coated, 3 mm diameter mini-tablets in children aged ≥2–<7 years. In total, 300 participants were randomised (2:2:1:1) to receive a single oral administration of 16 (group A) or 32 (group B) mini-tablets with soft food or 16 (group C) or 32 (group D) mini-tablets with water. Children in each group were stratified by age group (2–<3 years; 3–<4 years; 4–<5 years; 5–<6 years; and 6–<7 years). Groups C and D were pooled for statistical analyses. The rates of acceptability (swallowed ≥80% of the mini-tablets with or without chewing), swallowability (swallowed all mini-tablets without chewing or any leftover), and palatability (positive/neutral responses) were ≥80.0%, ≥42.0%, and ≥82.0%, respectively, across the study groups. No marked differences were observed between groups or across age groups. No adverse events or issues of clinical relevance with deglutition were reported. Mini-tablets taken with soft food or water provide a suitable method for administering medicines to children aged ≥2–<7 years. This study was registered in the German Clinical Trial Register (No. DRKS00024617). Full article
(This article belongs to the Special Issue Advances in Age Related Drug Delivery)
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19 pages, 4137 KiB  
Article
Evaluation of Antimicrobial Properties and Potential Applications of Pseudomonas gessardii M15 Rhamnolipids towards Multiresistant Staphylococcus aureus
by Carmine Buonocore, Rosa Giugliano, Gerardo Della Sala, Fortunato Palma Esposito, Pietro Tedesco, Veronica Folliero, Massimiliano Galdiero, Gianluigi Franci and Donatella de Pascale
Pharmaceutics 2023, 15(2), 700; https://doi.org/10.3390/pharmaceutics15020700 - 19 Feb 2023
Cited by 3 | Viewed by 1835
Abstract
Staphylococcus aureus is a Gram-positive opportunistic human pathogen responsible for severe infections and thousands of deaths annually, mostly due to its multidrug-resistant (MDR) variants. The cell membrane has emerged as a promising new therapeutic target, and lipophilic molecules, such as biosurfactants, are currently [...] Read more.
Staphylococcus aureus is a Gram-positive opportunistic human pathogen responsible for severe infections and thousands of deaths annually, mostly due to its multidrug-resistant (MDR) variants. The cell membrane has emerged as a promising new therapeutic target, and lipophilic molecules, such as biosurfactants, are currently being utilized. Herein, we evaluated the antimicrobial activity of a rhamnolipids mixture produced by the Antarctic marine bacterium Pseudomonas gessardii M15. We demonstrated that our mixture has bactericidal activity in the range of 12.5–50 µg/mL against a panel of clinical MDR isolates of S. aureus, and that the mixture eradicated the bacterial population in 30 min at MIC value, and in 5 min after doubling the concentration. We also tested abilities of RLs to interfere with biofilm at different stages and determined that RLs can penetrate biofilm and kill the bacteria at sub-MICs values. The mixture was then used to functionalize a cotton swab to evaluate the prevention of S. aureus proliferation. We showed that by using 8 µg of rhamnolipids per swab, the entire bacterial load is eradicated, and just 0.5 µg is sufficient to reduce the growth by 99.99%. Our results strongly indicate the possibility of using this mixture as an additive for wound dressings for chronic wounds. Full article
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31 pages, 4505 KiB  
Review
Modulating Inflammation-Mediated Diseases via Natural Phenolic Compounds Loaded in Nanocarrier Systems
by Tojofaniry Fabien Rakotondrabe, Min-Xia Fan, Felix Wambua Muema and Ming-Quan Guo
Pharmaceutics 2023, 15(2), 699; https://doi.org/10.3390/pharmaceutics15020699 - 19 Feb 2023
Cited by 6 | Viewed by 1991
Abstract
The global increase and prevalence of inflammatory-mediated diseases have been a great menace to human welfare. Several works have demonstrated the anti-inflammatory potentials of natural polyphenolic compounds, including flavonoid derivatives (EGCG, rutin, apigenin, naringenin) and phenolic acids (GA, CA, etc.), among others (resveratrol, [...] Read more.
The global increase and prevalence of inflammatory-mediated diseases have been a great menace to human welfare. Several works have demonstrated the anti-inflammatory potentials of natural polyphenolic compounds, including flavonoid derivatives (EGCG, rutin, apigenin, naringenin) and phenolic acids (GA, CA, etc.), among others (resveratrol, curcumin, etc.). In order to improve the stability and bioavailability of these natural polyphenolic compounds, their recent loading applications in both organic (liposomes, micelles, dendrimers, etc.) and inorganic (mesoporous silica, heavy metals, etc.) nanocarrier technologies are being employed. A great number of studies have highlighted that, apart from improving their stability and bioavailability, nanocarrier systems also enhance their target delivery, while reducing drug toxicity and adverse effects. This review article, therefore, covers the recent advances in the drug delivery of anti-inflammatory agents loaded with natural polyphenolics by the application of both organic and inorganic nanocarriers. Even though nanocarrier technology offers a variety of possible anti-inflammatory advantages to naturally occurring polyphenols, the complexes’ inherent properties and mechanisms of action have not yet been fully investigated. Thus, expanding the quest on novel natural polyphenolic-loaded delivery systems, together with the optimization of complexes’ activity toward inflammation, will be a new direction of future efforts. Full article
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15 pages, 4195 KiB  
Review
Microbubble Delivery Platform for Ultrasound-Mediated Therapy in Brain Cancers
by Kibeom Kim, Jungmin Lee and Myoung-Hwan Park
Pharmaceutics 2023, 15(2), 698; https://doi.org/10.3390/pharmaceutics15020698 - 19 Feb 2023
Cited by 3 | Viewed by 2371
Abstract
The blood-brain barrier (BBB) is one of the most selective endothelial barriers that protect the brain and maintains homeostasis in neural microenvironments. This barrier restricts the passage of molecules into the brain, except for gaseous or extremely small hydrophobic molecules. Thus, the BBB [...] Read more.
The blood-brain barrier (BBB) is one of the most selective endothelial barriers that protect the brain and maintains homeostasis in neural microenvironments. This barrier restricts the passage of molecules into the brain, except for gaseous or extremely small hydrophobic molecules. Thus, the BBB hinders the delivery of drugs with large molecular weights for the treatment of brain cancers. Various methods have been used to deliver drugs to the brain by circumventing the BBB; however, they have limitations such as drug diversity and low delivery efficiency. To overcome this challenge, microbubbles (MBs)-based drug delivery systems have garnered a lot of interest in recent years. MBs are widely used as contrast agents and are recently being researched as a vehicle for delivering drugs, proteins, and gene complexes. The MBs are 1–10 μm in size and consist of a gas core and an organic shell, which cause physical changes, such as bubble expansion, contraction, vibration, and collapse, in response to ultrasound. The physical changes in the MBs and the resulting energy lead to biological changes in the BBB and cause the drug to penetrate it, thus enhancing the therapeutic effect. Particularly, this review describes a state-of-the-art strategy for fabricating MB-based delivery platforms and their use with ultrasound in brain cancer therapy. Full article
(This article belongs to the Special Issue Research Progress of Nanomedicine and Its Pharmacokinetics)
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12 pages, 1703 KiB  
Article
Structure Determination of Felodipine Photoproducts in UV-Irradiated Medicines Using ESI-LC/MS/MS
by Kohei Kawabata, Miya Kohashi, Shiori Akimoto and Hiroyuki Nishi
Pharmaceutics 2023, 15(2), 697; https://doi.org/10.3390/pharmaceutics15020697 - 19 Feb 2023
Cited by 4 | Viewed by 1502
Abstract
Dihydropyridine drugs are well known as photodegradable pharmaceuticals. Herein, we evaluate the photostability of felodipine (FL) medicine (Splendil® (SPL) tablets) and its altered forms (powders and suspensions). FL is a type of dihydropyridine drug, but its photochemical behavior is unknown. FL contents [...] Read more.
Dihydropyridine drugs are well known as photodegradable pharmaceuticals. Herein, we evaluate the photostability of felodipine (FL) medicine (Splendil® (SPL) tablets) and its altered forms (powders and suspensions). FL is a type of dihydropyridine drug, but its photochemical behavior is unknown. FL contents after ultraviolet light (UV) irradiation for 24 h were monitored using high-performance liquid chromatography (HPLC). Values of the residual amounts of FL in UV-irradiated SPL powders and suspensions were 32.76 ± 4.88% and 0.79 ± 0.74%, respectively, with the generation of two photoproducts (FL photoproduct 1 and 2). To identify the chemical structures of these photoproducts, electrospray ionization liquid chromatography mass spectrometry (ESI-LC/MS/MS) analysis was performed. Based on their mass-to-charge ratio values and fragment patterns, it was proposed that FL photoproduct 1 was a pyridine derivative and FL photoproduct 2 was an FL dimer. Interestingly, generation rates of FL photoproduct 1 and 2 were dependent on the presence of the aqueous media. The photodimerization of FL was induced in UV-irradiated SPL suspensions. This is the first report evaluating the photostability of SPL tablets and its altered forms and estimating FL photoproducts induced by UV irradiation in the formulation of SPL. Full article
(This article belongs to the Special Issue Formulation of Photosensitive Drugs)
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14 pages, 2314 KiB  
Article
Cytotoxic Effects of New Palladium(II) Complexes with Thiazine or Thiazoline Derivative Ligands in Tumor Cell Lines
by Elena Fernández-Delgado, Samuel Estirado, Ana B. Rodríguez, Francisco Luna-Giles, Emilio Viñuelas-Zahínos, Javier Espino and José Antonio Pariente
Pharmaceutics 2023, 15(2), 696; https://doi.org/10.3390/pharmaceutics15020696 - 18 Feb 2023
Cited by 2 | Viewed by 1470
Abstract
The synthesis of analogs of cisplatin, which is a widely used chemotherapeutic agent, using other metal centers could be an alternative for cancer treatment. Pd(II) could be a substitute for Pt(II) due to its coordination chemistry similarity. For that reason, six squared-planar Pd(II) [...] Read more.
The synthesis of analogs of cisplatin, which is a widely used chemotherapeutic agent, using other metal centers could be an alternative for cancer treatment. Pd(II) could be a substitute for Pt(II) due to its coordination chemistry similarity. For that reason, six squared-planar Pd(II) complexes with thiazine and thiazoline ligands and formula [PdCl2(L)] were synthesized and characterized in this work. The potential anticarcinogenic ability of the compounds was studied via cytotoxicity assay in three different human tumor cell lines, i.e., epithelial cervix carcinoma (HeLa), promyelocytic leukemia (HL-60), and histiocytic lymphoma (U-937). Data obtained showed that complexes with methyl substitutions did not modify cell viability, while no-methyl substituted compounds had a moderate cytotoxic effect on all three cell lines. The complexes with phenyl substitutions displayed the lowest IC50 values, which ranged between 46.39 ± 3.99 μM and 62.74 ± 6.45 μM. Moreover, Pd accumulation inside the cell was observed after incubation with any of the four complexes mentioned, and the two complexes with phenyl rings were found to induce an increase in the percentage of apoptotic cells. These results suggested that the presence of bulky substitutions on the ligands such as phenyl groups may influence the cytotoxicity of the chemotherapeutic agents synthesized. Full article
(This article belongs to the Special Issue Metallodrugs in Cancer Therapy: The Newest Candidates in the Field)
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23 pages, 710 KiB  
Review
Drug Delivery Systems in Regenerative Medicine: An Updated Review
by Alaa Mansour, Maya Romani, Anirudh Balakrishna Acharya, Betul Rahman, Elise Verron and Zahi Badran
Pharmaceutics 2023, 15(2), 695; https://doi.org/10.3390/pharmaceutics15020695 - 18 Feb 2023
Cited by 24 | Viewed by 3460
Abstract
Modern drug discovery methods led to evolving new agents with significant therapeutic potential. However, their properties, such as solubility and administration-related challenges, may hinder their benefits. Moreover, advances in biotechnology resulted in the development of a new generation of molecules with a short [...] Read more.
Modern drug discovery methods led to evolving new agents with significant therapeutic potential. However, their properties, such as solubility and administration-related challenges, may hinder their benefits. Moreover, advances in biotechnology resulted in the development of a new generation of molecules with a short half-life that necessitates frequent administration. In this context, controlled release systems are required to enhance treatment efficacy and improve patient compliance. Innovative drug delivery systems are promising tools that protect therapeutic proteins and peptides against proteolytic degradation where controlled delivery is achievable. The present review provides an overview of different approaches used for drug delivery. Full article
(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine)
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21 pages, 2842 KiB  
Article
N-Benzylethanolammonium Ionic Liquids and Molten Salts in the Synthesis of 68Ga- and Al18F-Labeled Radiopharmaceuticals
by Yulia A. Kondratenko, Julia S. Shilova, Vladislav A. Gavrilov, Andrey A. Zolotarev, Michail A. Nadporojskii, Tatyana A. Kochina and Dmitrii O. Antuganov
Pharmaceutics 2023, 15(2), 694; https://doi.org/10.3390/pharmaceutics15020694 - 18 Feb 2023
Cited by 2 | Viewed by 1221
Abstract
Ionic liquids (ILs), due to their structural features, have unique physical and chemical properties and are environmentally friendly. Every year, the number of studies devoted to the use of ILs in medicine and pharmaceutics is growing. In nuclear medicine, the use of ILs [...] Read more.
Ionic liquids (ILs), due to their structural features, have unique physical and chemical properties and are environmentally friendly. Every year, the number of studies devoted to the use of ILs in medicine and pharmaceutics is growing. In nuclear medicine, the use of ILs with self-buffering capacity in the synthesis of radiopharmaceuticals is extremely important. This research is devoted to obtaining new ionic buffer agents containing N-benzylethanolammonium (BEA) cations and anions of carboxylic acids. A series of new BEA salts was synthesized and identified by NMR (1H, 13C), IR spectroscopy and elemental and thermal analysis. The crystal structures of BEA hydrogen succinate, hydrogen oxalate and oxalate were determined by x-ray diffraction. Newly synthesized compounds were tested as buffer solutions in 68Ga- and Al18F-radiolabeling reactions with a series of bifunctional chelating agents and clinically relevant peptides used for visualization of malignancies by positron emission tomography. The results obtained confirm the promise of using new buffers in the synthesis of 68Ga- and Al18F-labeled radiopharmaceuticals. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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26 pages, 1691 KiB  
Review
Therapeutic Potential of Dopamine and Related Drugs as Anti-Inflammatories and Antioxidants in Neuronal and Non-Neuronal Pathologies
by Cindy Bandala, Noemi Cárdenas-Rodríguez, Julieta Griselda Mendoza-Torreblanca, Itzel Jatziri Contreras-García, Valentín Martínez-López, Teresita Rocio Cruz-Hernández, Jazmín Carro-Rodríguez, Marco Antonio Vargas-Hernández, Iván Ignacio-Mejía, Alfonso Alfaro-Rodriguez and Eleazar Lara-Padilla
Pharmaceutics 2023, 15(2), 693; https://doi.org/10.3390/pharmaceutics15020693 - 18 Feb 2023
Cited by 5 | Viewed by 2978
Abstract
Dopamine (DA), its derivatives, and dopaminergic drugs are compounds widely used in the management of diseases related to the nervous system. However, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis [...] Read more.
Dopamine (DA), its derivatives, and dopaminergic drugs are compounds widely used in the management of diseases related to the nervous system. However, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis or septic shock, blood pressure, renal failure, diabetes, and obesity, among others. In addition, DA and dopaminergic drugs have shown anti-inflammatory and antioxidant properties in different kinds of cells. Aim: To compile the mechanism of action of DA and the main dopaminergic drugs and show the findings that support the therapeutic potential of these molecules for the treatment of neurological and non-neurological diseases considering their antioxidant and anti-inflammatory actions. Method: We performed a review article. An exhaustive search for information was carried out in specialized databases such as PubMed, PubChem, ProQuest, EBSCO, Scopus, Science Direct, Web of Science, Bookshelf, DrugBank, Livertox, and Clinical Trials. Results: We showed that DA and dopaminergic drugs have emerged for the management of neuronal and nonneuronal diseases with important therapeutic potential as anti-inflammatories and antioxidants. Conclusions: DA and DA derivatives can be an attractive treatment strategy and a promising approach to slowing the progression of disorders through repositioning. Full article
(This article belongs to the Section Clinical Pharmaceutics)
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20 pages, 2842 KiB  
Article
Prenatal Exposure to Δ9-Tetrahydrocannabinol Affects Hippocampus-Related Cognitive Functions in the Adolescent Rat Offspring: Focus on Specific Markers of Neuroplasticity
by Valentina Castelli, Gianluca Lavanco, Salvatore Feo, Cesare D’Amico, Vincenzo Micale, Martin Kuchar, Fulvio Plescia, Anna Brancato and Carla Cannizzaro
Pharmaceutics 2023, 15(2), 692; https://doi.org/10.3390/pharmaceutics15020692 - 17 Feb 2023
Cited by 7 | Viewed by 1731
Abstract
Previous evidence suggests that prenatal exposure to THC (pTHC) derails the neurodevelopmental trajectories towards a vulnerable phenotype for impaired emotional regulation and limbic memory. Here we aimed to investigate pTHC effect on hippocampus-related cognitive functions and markers of neuroplasticity in adolescent male offspring. [...] Read more.
Previous evidence suggests that prenatal exposure to THC (pTHC) derails the neurodevelopmental trajectories towards a vulnerable phenotype for impaired emotional regulation and limbic memory. Here we aimed to investigate pTHC effect on hippocampus-related cognitive functions and markers of neuroplasticity in adolescent male offspring. Wistar rats were exposed to THC (2 mg/kg) from gestational day 5 to 20 and tested for spatial memory, object recognition memory and reversal learning in the reinforce-motivated Can test and in the aversion-driven Barnes maze test; locomotor activity and exploration, anxiety-like behaviour, and response to natural reward were assessed in the open field, elevated plus maze, and sucrose preference tests, respectively. The gene expression levels of NMDA NR1-2A subunits, mGluR5, and their respective scaffold proteins PSD95 and Homer1, as well as CB1R and the neuromodulatory protein HINT1, were measured in the hippocampus. pTHC offspring exhibited deficits in spatial and object recognition memory and reversal learning, increased locomotor activity, increased NR1-, decreased NR2A- and PSD95-, increased mGluR5- and Homer1-, and augmented CB1R- and HINT1-hippocampal mRNA levels. Our data shows that pTHC is associated with specific impairment in spatial cognitive processing and effectors of hippocampal neuroplasticity and suggests novel targets for future pharmacological challenges. Full article
(This article belongs to the Special Issue Drugs in Pregnancy and Lactation)
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14 pages, 1014 KiB  
Article
In Vivo Evaluation of Thiamine Hydrochloride with Gastro-Retentive Drug Delivery in Healthy Human Volunteers Using Gamma Scintigraphy
by Li-Ying Kam, Jia-Woei Wong and Kah-Hay Yuen
Pharmaceutics 2023, 15(2), 691; https://doi.org/10.3390/pharmaceutics15020691 - 17 Feb 2023
Cited by 2 | Viewed by 1503
Abstract
A floating tablet system containing thiamine hydrochloride, a model drug with a narrow absorption window, was evaluated. The tablet was found to have a floating lag time of less than 30 s with a sustained drug release over 12 h during in vitro [...] Read more.
A floating tablet system containing thiamine hydrochloride, a model drug with a narrow absorption window, was evaluated. The tablet was found to have a floating lag time of less than 30 s with a sustained drug release over 12 h during in vitro dissolution studies. The gastro-retentive property of the tablet in relation to the bioavailability of thiamine was determined in healthy human volunteers using gamma scintigraphy under fasted and fed conditions. The gastro-retentive time of the floating tablet could be prolonged up to 10 h under the fed state, compared to about 1.8 h in the fasted state. The prolonged gastric retention under the fed state resulted in a 2.8-fold increase in oral bioavailability of thiamine compared to that of the fasted state. There was also a 1.4-fold increase in thiamine absorption compared to that of a conventional immediate release tablet in the fed state. In the fasted state, the extent of thiamine absorption from the floating tablet was only about 70% of that absorbed from the immediate release tablet. Thus, to achieve a better performance, such floating tablet systems should be administered under a fed condition, to prolong the gastric retention time. Full article
(This article belongs to the Special Issue New Technology for Prolonged Drug Release)
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15 pages, 2927 KiB  
Article
Rationalizing the Binding Modes of PET Radiotracers Targeting the Norepinephrine Transporter
by Anna Tutov, Xinyu Chen, Rudolf A. Werner, Saskia Mühlig, Thomas Zimmermann, Naoko Nose, Kazuhiro Koshino, Constantin Lapa, Michael Decker and Takahiro Higuchi
Pharmaceutics 2023, 15(2), 690; https://doi.org/10.3390/pharmaceutics15020690 - 17 Feb 2023
Viewed by 2015
Abstract
Purpose: A new PET radiotracer 18F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations [...] Read more.
Purpose: A new PET radiotracer 18F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure–activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Methods: Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of 18F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Results: Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer–NET interaction, whereby a T-shaped π–π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. Conclusion: The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors. Full article
(This article belongs to the Special Issue Radiopharmaceuticals: From Design to Applications)
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21 pages, 2296 KiB  
Article
Biological Effects in Cancer Cells of Mono- and Bidentate Conjugation of Cisplatin on PAMAM Dendrimers: A Comparative Study
by Cláudia Camacho, Dina Maciel, Helena Tomás and João Rodrigues
Pharmaceutics 2023, 15(2), 689; https://doi.org/10.3390/pharmaceutics15020689 - 17 Feb 2023
Cited by 1 | Viewed by 1675
Abstract
Cisplatin (cis-diamminedichloroplatinum(II)) is a potent chemotherapeutic agent commonly used to treat cancer. However, its use also leads to serious side effects, such as nephrotoxicity, ototoxicity, and cardiotoxicity, which limit the dose that can be safely administered to patients. To minimize these [...] Read more.
Cisplatin (cis-diamminedichloroplatinum(II)) is a potent chemotherapeutic agent commonly used to treat cancer. However, its use also leads to serious side effects, such as nephrotoxicity, ototoxicity, and cardiotoxicity, which limit the dose that can be safely administered to patients. To minimize these problems, dendrimers may be used as carriers for cisplatin through the coordination of their terminal functional groups to platinum. Here, cisplatin was conjugated to half-generation anionic PAMAM dendrimers in mono- and bidentate forms, and their biological effects were assessed in vitro. After preparation and characterization of the metallodendrimers, their cytotoxicity was evaluated against several cancer cell lines (A2780, A2780cisR, MCF-7, and CACO-2 cells) and a non-cancer cell line (BJ cells). The results showed that all the metallodendrimers were cytotoxic and that the cytotoxicity level depended on the cell line and the type of coordination mode (mono- or bidentate). Although, in this study, a correlation between dendrimer generation (number of carried metallic fragments) and cytotoxicity could not be completely established, the monodentate coordination form of cisplatin resulted in lower IC50 values, thus revealing a more accessible cisplatin release from the dendritic scaffold. Moreover, most of the metallodendrimers were more potent than the cisplatin, especially for the A2780 and A2780cisR cell lines, which showed higher selectivity than for non-cancer cells (BJ cells). The monodentate G0.5COO(Pt(NH3)2Cl)8 and G2.5COO(Pt(NH3)2Cl)32 metallodendrimers, as well as the bidentate G2.5COO(Pt(NH3)2)16 metallodendrimer, were even more active towards the cisplatin-resistant cell line (A2780cisR cells) than the correspondent cisplatin-sensitive one (A2780 cells). Finally, the effect of the metallodendrimers on the hemolysis of human erythrocytes was neglectable, and metallodendrimers’ interaction with calf thymus DNA seemed to be stronger than that of free cisplatin. Full article
(This article belongs to the Special Issue Applications of Dendrimers in Biomedicine)
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17 pages, 2597 KiB  
Review
Glycomimetic Peptides as Therapeutic Tools
by J. Kenneth Hoober and Laura L. Eggink
Pharmaceutics 2023, 15(2), 688; https://doi.org/10.3390/pharmaceutics15020688 - 17 Feb 2023
Viewed by 1770
Abstract
The entry of peptides into glycobiology has led to the development of a unique class of therapeutic tools. Although numerous and well-known peptides are active as endocrine regulatory factors that bind to specific receptors, and peptides have been used extensively as epitopes for [...] Read more.
The entry of peptides into glycobiology has led to the development of a unique class of therapeutic tools. Although numerous and well-known peptides are active as endocrine regulatory factors that bind to specific receptors, and peptides have been used extensively as epitopes for vaccine production, the use of peptides that mimic sugars as ligands of lectin-type receptors has opened a unique approach to modulate activity of immune cells. Ground-breaking work that initiated the use of peptides as tools for therapy identified sugar mimetics by screening phage display libraries. The peptides that have been discovered show significant potential as high-avidity, therapeutic tools when synthesized as multivalent structures. Advantages of peptides over sugars as drugs for immune modulation will be illustrated in this review. Full article
(This article belongs to the Special Issue Peptides and Peptide Mimetics: Potential Tools for Therapy)
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22 pages, 13118 KiB  
Article
Glioblastoma Multiforme: Probing Solutions to Systemic Toxicity towards High-Dose Chemotherapy and Inflammatory Influence in Resistance against Temozolomide
by Sadia Nasir, Sadia Nazir, Rumeza Hanif and Aneela Javed
Pharmaceutics 2023, 15(2), 687; https://doi.org/10.3390/pharmaceutics15020687 - 17 Feb 2023
Cited by 5 | Viewed by 1961
Abstract
Temozolomide (TMZ), the first-line chemotherapeutic drug against glioblastoma multiforme (GBM), often fails to provide the desired clinical outcomes due to inflammation-induced resistance amid inefficient drug delivery across the blood-brain barrier (BBB). The current study utilized solid lipid nanoparticles (SLNPs) for targeted delivery of [...] Read more.
Temozolomide (TMZ), the first-line chemotherapeutic drug against glioblastoma multiforme (GBM), often fails to provide the desired clinical outcomes due to inflammation-induced resistance amid inefficient drug delivery across the blood-brain barrier (BBB). The current study utilized solid lipid nanoparticles (SLNPs) for targeted delivery of TMZ against GBM. After successful formulation and characterization of SLNPs and conjugation with TMZ (SLNP-TMZ), their in-vitro anti-cancer efficacy and effect on the migratory potential of cancer cells were evaluated using temozolomide-sensitive (U87-S) as well as TMZ-resistant (U87-R) glioma cell lines. Elevated cytotoxicity and reduction in cell migration in both cell lines were observed with SLNP-TMZ as compared to the free drug (p < 0.05). Similar results were obtained in-vivo using an orthotopic xenograft mouse model (XM-S and XM-R), where a reduction in tumor size was observed with SLNP-TMZ treatment compared to TMZ. Concomitantly, higher concentrations of the drug were found in brain tissue resections of mice treated with SLNP-TMZ as compared to other vital organs than mice treated with free TMZ. Expression of inflammatory markers (Interleukin-1β, Interleukin-6 and Tumor Necrosis factor-α) in a resistant cell line (U87-R) and its respective mouse model (XM-R) were also found to be significantly elevated as compared to the sensitive U87-S cell line and its respective mouse model (XM-S). Thus, the in-vitro and in-vivo results of the study strongly support the potential application of SLNP-TMZ for TMZ-sensitive and resistant GBM therapy, indicatively through inflammatory mechanisms, and thus merit further detailed insights Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies for Glioblastoma)
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34 pages, 4709 KiB  
Review
Bioimaging Probes Based on Magneto-Fluorescent Nanoparticles
by Sayan Ganguly and Shlomo Margel
Pharmaceutics 2023, 15(2), 686; https://doi.org/10.3390/pharmaceutics15020686 - 17 Feb 2023
Cited by 10 | Viewed by 2916
Abstract
Novel nanomaterials are of interest in biology, medicine, and imaging applications. Multimodal fluorescent-magnetic nanoparticles demand special attention because they have the potential to be employed as diagnostic and medication-delivery tools, which, in turn, might make it easier to diagnose and treat cancer, as [...] Read more.
Novel nanomaterials are of interest in biology, medicine, and imaging applications. Multimodal fluorescent-magnetic nanoparticles demand special attention because they have the potential to be employed as diagnostic and medication-delivery tools, which, in turn, might make it easier to diagnose and treat cancer, as well as a wide variety of other disorders. The most recent advancements in the development of magneto-fluorescent nanocomposites and their applications in the biomedical field are the primary focus of this review. We describe the most current developments in synthetic methodologies and methods for the fabrication of magneto-fluorescent nanocomposites. The primary applications of multimodal magneto-fluorescent nanoparticles in biomedicine, including biological imaging, cancer treatment, and drug administration, are covered in this article, and an overview of the future possibilities for these technologies is provided. Full article
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32 pages, 2469 KiB  
Review
Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development
by Kevin Y. Wu, Merve Kulbay, Dana Toameh, An Qi Xu, Ananda Kalevar and Simon D. Tran
Pharmaceutics 2023, 15(2), 685; https://doi.org/10.3390/pharmaceutics15020685 - 17 Feb 2023
Cited by 18 | Viewed by 7577
Abstract
Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors leading to progressive visual decline. It is the most common type of inherited retinal dystrophy and has a high burden on both patients and society. This [...] Read more.
Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors leading to progressive visual decline. It is the most common type of inherited retinal dystrophy and has a high burden on both patients and society. This condition causes gradual loss of vision, with its typical manifestations including nyctalopia, concentric visual field loss, and ultimately bilateral central vision loss. It is one of the leading causes of visual disability and blindness in people under 60 years old and affects over 1.5 million people worldwide. There is currently no curative treatment for people with RP, and only a small group of patients with confirmed RPE65 mutations are eligible to receive the only gene therapy on the market: voretigene neparvovec. The current therapeutic armamentarium is limited to retinoids, vitamin A supplements, protection from sunlight, visual aids, and medical and surgical interventions to treat ophthalmic comorbidities, which only aim to slow down the progression of the disease. Considering such a limited therapeutic landscape, there is an urgent need for developing new and individualized therapeutic modalities targeting retinal degeneration. Although the heterogeneity of gene mutations involved in RP makes its target treatment development difficult, recent fundamental studies showed promising progress in elucidation of the photoreceptor degeneration mechanism. The discovery of novel molecule therapeutics that can selectively target specific receptors or specific pathways will serve as a solid foundation for advanced drug development. This article is a review of recent progress in novel treatment of RP focusing on preclinical stage fundamental research on molecular targets, which will serve as a starting point for advanced drug development. We will review the alterations in the molecular pathways involved in the development of RP, mainly those regarding endoplasmic reticulum (ER) stress and apoptotic pathways, maintenance of the redox balance, and genomic stability. We will then discuss the therapeutic approaches under development, such as gene and cell therapy, as well as the recent literature identifying novel potential drug targets for RP. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Development in Retinal Diseases)
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