Pharmaceutics

22 pages, 5814 KiB

Open AccessEditor’s ChoiceArticle

Electrospun Scaffolds as Cell Culture Substrates for the Cultivation of an In Vitro Blood–Brain Barrier Model Using Human Induced Pluripotent Stem Cells

by Felix Rohde, Karin Danz, Nathalie Jung, Sylvia Wagner and Maike Windbergs

Pharmaceutics 2022, 14(6), 1308; https://doi.org/10.3390/pharmaceutics14061308 - 20 Jun 2022

Cited by 8 | Viewed by 2948

Abstract

The human blood–brain barrier (BBB) represents the interface of microvasculature and the central nervous system, regulating the transport of nutrients and protecting the brain from external threats. To gain a deeper understanding of (patho)physiological processes affecting the BBB, sophisticated models mimicking the in [...] Read more.

The human blood–brain barrier (BBB) represents the interface of microvasculature and the central nervous system, regulating the transport of nutrients and protecting the brain from external threats. To gain a deeper understanding of (patho)physiological processes affecting the BBB, sophisticated models mimicking the in vivo situation are required. Currently, most in vitro models are cultivated on stiff, semipermeable, and non-biodegradable Transwell^® membrane inserts, not adequately mimicking the complexity of the extracellular environment of the native human BBB. To overcome these disadvantages, we developed three-dimensional electrospun scaffolds resembling the natural structure of the human extracellular matrix. The polymer fibers of the scaffold imitate collagen fibrils of the human basement membrane, exhibiting excellent wettability and biomechanical properties, thus facilitating cell adhesion, proliferation, and migration. Cultivation of human induced pluripotent stem cells (hiPSCs) on these scaffolds enabled the development of a physiological BBB phenotype monitored via the formation of tight junctions and validated by the paracellular permeability of sodium fluorescein, further accentuating the non-linearity of TEER and barrier permeability. The novel in vitro model of the BBB forms a tight endothelial barrier, offering a platform to study barrier functions in a (patho)physiologically relevant context. Full article

(This article belongs to the Special Issue Tissue Engineering and Organ-on-Chip of Biological Barriers for Drug Absorption and Delivery Testing)

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26 pages, 4092 KiB

Open AccessReview

Chitosans and Nanochitosans: Recent Advances in Skin Protection, Regeneration, and Repair

by Patricia Garcia Ferreira, Vitor Francisco Ferreira, Fernando de Carvalho da Silva, Cyntia Silva Freitas, Patricia Ribeiro Pereira and Vania Margaret Flosi Paschoalin

Pharmaceutics 2022, 14(6), 1307; https://doi.org/10.3390/pharmaceutics14061307 - 20 Jun 2022

Cited by 21 | Viewed by 3033

Abstract

Chitosan displays a dual function, acting as both an active ingredient and/or carrier for pharmaceutical bioactive molecules and metal ions. Its hydroxyl- and amino-reactive groups and acetylation degree can be used to adjust this biopolymer’s physicochemical and pharmacological properties in different forms, including [...] Read more.

Chitosan displays a dual function, acting as both an active ingredient and/or carrier for pharmaceutical bioactive molecules and metal ions. Its hydroxyl- and amino-reactive groups and acetylation degree can be used to adjust this biopolymer’s physicochemical and pharmacological properties in different forms, including scaffolds, nanoparticles, fibers, sponges, films, and hydrogels, among others. In terms of pharmacological purposes, chitosan association with different polymers and the immobilization or entrapment of bioactive agents are effective strategies to achieve desired biological responses. Chitosan biocompatibility, water entrapment within nanofibrils, antioxidant character, and antimicrobial and anti-inflammatory properties, whether enhanced by other active components or not, ensure skin moisturization, as well as protection against bacteria colonization and oxidative imbalance. Chitosan-based nanomaterials can maintain or reconstruct skin architecture through topical or systemic delivery of hydrophilic or hydrophobic pharmaceuticals at controlled rates to treat skin affections, such as acne, inflammatory manifestations, wounds, or even tumorigenesis, by coating chemotherapy drugs. Herein, chitosan obtention, physicochemical characteristics, chemical modifications, and interactions with bioactive agents are presented and discussed. Molecular mechanisms involved in chitosan skin protection and recovery are highlighted by overlapping the events orchestrated by the signaling molecules secreted by different cell types to reconstitute healthy skin tissue structures and components. Full article

(This article belongs to the Special Issue Chitosan Nanoparticles in Drug Delivery 2022)

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15 pages, 3859 KiB

Open AccessArticle

Turning a Targeting β-Catenin/Bcl9 Peptide Inhibitor into a GdOF@Au Core/Shell Nanoflower for Enhancing Immune Response to Cancer Therapy in Combination with Immune Checkpoint Inhibitors

by Weiming You, Fang Ma, Zhang Zhang and Jin Yan

Pharmaceutics 2022, 14(6), 1306; https://doi.org/10.3390/pharmaceutics14061306 - 20 Jun 2022

Cited by 1 | Viewed by 2313

Abstract

Combination administration is becoming a popular strategy in current cancer immunotherapy to enhance tumor response to ICIs. Recently, a peptide drug, a protein–protein interaction inhibitor (PPI), that disrupts the β-catenin/Bcl9 interaction in the tumoral Wnt/β-catenin pathway has become a promising candidate drug for [...] Read more.

Combination administration is becoming a popular strategy in current cancer immunotherapy to enhance tumor response to ICIs. Recently, a peptide drug, a protein–protein interaction inhibitor (PPI), that disrupts the β-catenin/Bcl9 interaction in the tumoral Wnt/β-catenin pathway has become a promising candidate drug for immune enhancement and tumor growth inhibition. However, the peptide usually suffers from poor cell membrane permeability and proteolytic degradation, limiting its adequate accumulation in tumors and ultimately leading to side effects. Herein, a gadolinium–gold-based core/shell nanostructure drug delivery system was established, where Bcl9 was incorporated into a gadolinium–gold core–shell nanostructure and formed GdOFBAu via mercaptogenic self-assembly. After construction, GdOFBAu, when combined with anti-PD1 antibodies, could effectively inhibit tumor growth and enhance the response to immune therapy in MC38 tumor-bearing mice; it not only induced the apoptosis of cancer cells, but also promoted the tumor infiltration of Teff cells (CD8⁺) and decreased Treg cells (CD25⁺). More importantly, GdOFBAu maintained good biosafety and biocompatibility during treatment. Taken together, this study may offer a promising opportunity for sensitizing cancer immunotherapy via metal–peptide self-assembling nanostructured material with high effectiveness and safety. Full article

(This article belongs to the Special Issue Drug Repurposing and Delivery Systems for Immunotherapy)

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19 pages, 1671 KiB

Open AccessArticle

4-Aminoquinoline-Based Adamantanes as Potential Anticholinesterase Agents in Symptomatic Treatment of Alzheimer’s Disease

by Katarina Komatović, Ana Matošević, Nataša Terzić-Jovanović, Suzana Žunec, Sandra Šegan, Mario Zlatović, Nikola Maraković, Anita Bosak and Dejan M. Opsenica

Pharmaceutics 2022, 14(6), 1305; https://doi.org/10.3390/pharmaceutics14061305 - 20 Jun 2022

Cited by 7 | Viewed by 1957

Abstract

Considering that acetylcholinesterase (AChE) inhibition is the most important mode of action expected of a potential drug used for the treatment of symptoms of Alzheimer’s disease (AD), our previous pilot study of 4-aminoquinolines as potential human cholinesterase inhibitors was extended to twenty-two new [...] Read more.

Considering that acetylcholinesterase (AChE) inhibition is the most important mode of action expected of a potential drug used for the treatment of symptoms of Alzheimer’s disease (AD), our previous pilot study of 4-aminoquinolines as potential human cholinesterase inhibitors was extended to twenty-two new structurally distinct 4-aminoquinolines bearing an adamantane moiety. Inhibition studies revealed that all of the compounds were very potent inhibitors of AChE and butyrylcholinesterase (BChE), with inhibition constants (K_i) ranging between 0.075 and 25 µM. The tested compounds exhibited a modest selectivity between the two cholinesterases; the most selective for BChE was compound 14, which displayed a 10 times higher preference, while compound 19 was a 5.8 times more potent inhibitor of AChE. Most of the compounds were estimated to be able to cross the blood–brain barrier (BBB) by passive transport. Evaluation of druglikeness singled out fourteen compounds with possible oral route of administration. The tested compounds displayed modest but generally higher antioxidant activity than the structurally similar AD drug tacrine. Compound 19 showed the highest reducing power, comparable to those of standard antioxidants. Considering their simple structure, high inhibition of AChE and BChE, and ability to cross the BBB, 4-aminoquinoline-based adamantanes show promise as structural scaffolds for further design of novel central nervous system drugs. Among them, two compounds stand out: compound 5 as the most potent inhibitor of both cholinesterases with a K_i constant in low nano molar range and the potential to cross the BBB, and compound 8, which met all our requirements, including high cholinesterase inhibition, good oral bioavailability, and antioxidative effect. The QSAR model revealed that AChE and BChE inhibition was mainly influenced by the ring and topological descriptors MCD, Nnum, RP, and RSIpw3, which defined the shape, conformational flexibility, and surface properties of the molecules. Full article

(This article belongs to the Section Drug Targeting and Design)

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14 pages, 1099 KiB

Open AccessArticle

Therapeutic Drug Monitoring of Mycophenolic Acid as a Precision Medicine Tool for Heart Transplant Patients: Results of an Observational Pharmacokinetic Pilot Study

by Francesco Lo Re, Jacopo Angelini, Sandro Sponga, Chiara Nalli, Antonella Zucchetto, Jessica Biasizzo, Ugolino Livi and Massimo Baraldo

Pharmaceutics 2022, 14(6), 1304; https://doi.org/10.3390/pharmaceutics14061304 - 20 Jun 2022

Cited by 1 | Viewed by 1899

Abstract

In the clinical practice management of heart transplant (HTx), the impact of calcineurin inhibitors co-administration on pharmacokinetics (PKs) of mycophenolic acid (MPA), mycophenolate mofetil (MMF) active drug, is not adequately considered. This retrospective study investigated full MPA-PK profiles by therapeutic drug monitoring (TDM) [...] Read more.

In the clinical practice management of heart transplant (HTx), the impact of calcineurin inhibitors co-administration on pharmacokinetics (PKs) of mycophenolic acid (MPA), mycophenolate mofetil (MMF) active drug, is not adequately considered. This retrospective study investigated full MPA-PK profiles by therapeutic drug monitoring (TDM) in 21 HTx recipients treated with MMF combined with cyclosporine (CsA) or tacrolimus (TAC) at a median time of 2.6 months post-transplant. The two treatment groups were compared. We described the main MPA-PK parameters in patients developing acute cellular rejection (ACR) and those who did not. Median dose-adjusted MPA-trough levels and MPA-AUC_0–12h were higher in patients co-treated with TAC than with CsA (p = 0.0001 and p = 0.006, respectively). MPA-C_max and T_max were similar between the two groups, whereas the enterohepatic recirculation biomarker of MPA (MPA-AUC_4–12h) was higher in the MMF and TAC group (p = 0.004). Consistently, MPA clearance was higher in the MMF and CsA group (p = 0.006). In total, 87.5% of ACR patients were treated with MMF and CsA, presenting a lower MPA-AUC_0–12h (p = 0.02). This real-world study suggested the CsA interference on MPA-PK in HTx, evidencing the pivotal role of MPA TDM as a precision medicine tool in the early phase after HTx. A prospective study is mandatory to investigate this approach to HTx clinical outcomes. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy)

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28 pages, 2622 KiB

Open AccessReview

Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches

by Carla Navarro, Ángel Ortega, Raquel Santeliz, Bermary Garrido, Maricarmen Chacín, Néstor Galban, Ivana Vera, Juan Bautista De Sanctis and Valmore Bermúdez

Pharmaceutics 2022, 14(6), 1303; https://doi.org/10.3390/pharmaceutics14061303 - 19 Jun 2022

Cited by 22 | Viewed by 5591

Abstract

The constant changes in cancer cell bioenergetics are widely known as metabolic reprogramming. Reprogramming is a process mediated by multiple factors, including oncogenes, growth factors, hypoxia-induced factors, and the loss of suppressor gene function, which support malignant transformation and tumor development in addition [...] Read more.

The constant changes in cancer cell bioenergetics are widely known as metabolic reprogramming. Reprogramming is a process mediated by multiple factors, including oncogenes, growth factors, hypoxia-induced factors, and the loss of suppressor gene function, which support malignant transformation and tumor development in addition to cell heterogeneity. Consequently, this hallmark promotes resistance to conventional anti-tumor therapies by adapting to the drastic changes in the nutrient microenvironment that these therapies entail. Therefore, it represents a revolutionary landscape during cancer progression that could be useful for developing new and improved therapeutic strategies targeting alterations in cancer cell metabolism, such as the deregulated mTOR and PI3K pathways. Understanding the complex interactions of the underlying mechanisms of metabolic reprogramming during cancer initiation and progression is an active study field. Recently, novel approaches are being used to effectively battle and eliminate malignant cells. These include biguanides, mTOR inhibitors, glutaminase inhibition, and ion channels as drug targets. This review aims to provide a general overview of metabolic reprogramming, summarise recent progress in this field, and emphasize its use as an effective therapeutic target against cancer. Full article

(This article belongs to the Special Issue Drug Repurposing and Delivery Systems for Immunotherapy)

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17 pages, 28078 KiB

Open AccessArticle

Formulation and Optimal Design of Dioscorea bulbifera and Honey-Loaded Gantrez^®/Xyloglucan Hydrogel as Wound Healing Patches

by Pattaranut Eakwaropas, Tanasait Ngawhirunpat, Theerasak Rojanarata, Prasopchai Patrojanasophon, Praneet Opanasopit and Nopparat Nuntharatanapong

Pharmaceutics 2022, 14(6), 1302; https://doi.org/10.3390/pharmaceutics14061302 - 19 Jun 2022

Cited by 8 | Viewed by 2142

Abstract

Hydrogel patches are some of the most effective dressings for wound healing. In this study, the Gantrez^® S-97 (Gan)/xyloglucan (XG) hydrogel patches were formulated by using a full central composite design (CCD). The optimized hydrogel patches consisted of 17.78% w/w [...] Read more.

Hydrogel patches are some of the most effective dressings for wound healing. In this study, the Gantrez^® S-97 (Gan)/xyloglucan (XG) hydrogel patches were formulated by using a full central composite design (CCD). The optimized hydrogel patches consisted of 17.78% w/w of Gan and 0.1% w/w of XG. Honey and D. bulbifera extract were loaded in the Gan/XG hydrogel patches. The physical properties of the hydrogel patches, including water content, water absorption, rate of water vapor transmission, and mechanical properties, were examined. The D. bulbifera extract/honey-loaded patch exhibited a higher value of water absorption, tensile strength, and elongation than the honey-loaded patch and the unloaded patch, respectively. The biological activities of the patches were also investigated. All hydrogel patches protected wounds from external bacterial infection. The D. bulbifera extract/honey-loaded patch exhibited stronger antioxidant activity than the honey-loaded patch and the unloaded patch. Besides, all the hydrogel patches with concentrations of 0.5–2.5 mg/mL showed that they were nontoxic to fibroblast cells. The combination of D. bulbifera extract and honey in the patch affected fibroblast proliferation. In addition, all Gan/XG hydrogel patches significantly induced recovery of the scratch area. Therefore, the Gan/XG hydrogel patches could be candidates as wound dressings. Full article

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

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14 pages, 2446 KiB

Open AccessArticle

Freeze-Drying of a Capsid Virus-like Particle-Based Platform Allows Stable Storage of Vaccines at Ambient Temperature

by Kara-Lee Aves, Christoph M. Janitzek, Cyrielle E. Fougeroux, Thor G. Theander and Adam F. Sander

Pharmaceutics 2022, 14(6), 1301; https://doi.org/10.3390/pharmaceutics14061301 - 18 Jun 2022

Cited by 3 | Viewed by 2467

Abstract

The requirement of an undisrupted cold chain during vaccine distribution is a major economic and logistical challenge limiting global vaccine access. Modular, nanoparticle-based platforms are expected to play an increasingly important role in the development of the next-generation vaccines. However, as with most [...] Read more.

The requirement of an undisrupted cold chain during vaccine distribution is a major economic and logistical challenge limiting global vaccine access. Modular, nanoparticle-based platforms are expected to play an increasingly important role in the development of the next-generation vaccines. However, as with most vaccines, they are dependent on the cold chain in order to maintain stability and efficacy. Therefore, there is a pressing need to develop thermostable formulations that can be stored at ambient temperature for extended periods without the loss of vaccine efficacy. Here, we investigate the compatibility of the Tag/Catcher AP205 capsid virus-like particle (cVLP) vaccine platform with the freeze-drying process. Tag/Catcher cVLPs can be freeze-dried under diverse buffer and excipient conditions while maintaining their original biophysical properties. Additionally, we show that for two model cVLP vaccines, including a clinically tested SARS-CoV-2 vaccine, freeze-drying results in a product that once reconstituted retains the structural integrity and immunogenicity of the original material, even following storage under accelerated heat stress conditions. Furthermore, the freeze-dried SARS-CoV-2 cVLP vaccine is stable for up to 6 months at ambient temperature. Our study offers a potential solution to overcome the current limitations associated with the cold chain and may help minimize the need for low-temperature storage. Full article

(This article belongs to the Special Issue Nanovaccine Fight against Infectious Diseases)

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13 pages, 3834 KiB

Open AccessArticle

Nanocrytals-Mediated Oral Drug Delivery: Enhanced Bioavailability of Amiodarone

by Anum Munir Awan, Arshad Farid, Shefaat Ullah Shah, Dildar Khan, Fiza Ur Rehman, Muhammad Junaid Dar, Tayyaba Iftikhar, Shakira Ghazanfar, Charis M. Galanakis, Abdulhakeem S. Alamri, Syed Mohammed Basheeruddin Asdaq and Kifayat Ullah Shah

Pharmaceutics 2022, 14(6), 1300; https://doi.org/10.3390/pharmaceutics14061300 - 18 Jun 2022

Cited by 8 | Viewed by 2151

Abstract

The aim of this study was to improve the saturation solubility, dissolution profile and oral bioavailability of amiodarone hydrochloride (AMH), a highly lipophilic drug. Stabilizer (Pluronic F-127)-coated AMH nanocrystals (AMH-NCs) were developed by a combination of antisolvent precipitation and homogenization techniques. The optimized [...] Read more.

The aim of this study was to improve the saturation solubility, dissolution profile and oral bioavailability of amiodarone hydrochloride (AMH), a highly lipophilic drug. Stabilizer (Pluronic F-127)-coated AMH nanocrystals (AMH-NCs) were developed by a combination of antisolvent precipitation and homogenization techniques. The optimized formulation comprised pluronic F-127 and AMH at the concentration of 4% and 2% w/v, respectively. The particle size (PS), zeta potential (ZP) and polydispersity index (PDI) of the optimized formulation was found to be 221 ± 1.2 nm, 35.3 mV and 0.333, respectively. The optimized formulation exhibited a rough surface morphology with particles in colloidal dimensions and a significant reduction in crystallinity of the drug. AMH-NCs showed a marked increase in the saturation solubility as well as rapid dissolution rate when compared with the AMH and marketed product. The stability study displayed that the formulation was stable for 3 months, with no significant change in the PS, ZP and PDI. The in vivo pharmacokinetic study demonstrated the ability of AMH-NCs to significantly (p < 0.05) improve the oral bioavailability (2.1-fold) of AMH in comparison with AMH solution, indicating that the production of AMH-NCs using a combination of antisolvent precipitation and homogenization techniques could enhance the bioavailability of the drug. Full article

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

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30 pages, 9257 KiB

Open AccessReview

Review on Starter Pellets: Inert and Functional Cores

by Nikolett Kállai-Szabó, Miléna Lengyel, Dóra Farkas, Ádám Tibor Barna, Christian Fleck, Bálint Basa and István Antal

Pharmaceutics 2022, 14(6), 1299; https://doi.org/10.3390/pharmaceutics14061299 - 18 Jun 2022

Cited by 3 | Viewed by 6588

Abstract

A significant proportion of pharmaceuticals are now considered multiparticulate systems. Modified-release drug delivery formulations can be designed with engineering precision, and patient-centric dosing can be accomplished relatively easily using multi-unit systems. In many cases, Multiple-Unit Pellet Systems (MUPS) are formulated on the basis [...] Read more.

A significant proportion of pharmaceuticals are now considered multiparticulate systems. Modified-release drug delivery formulations can be designed with engineering precision, and patient-centric dosing can be accomplished relatively easily using multi-unit systems. In many cases, Multiple-Unit Pellet Systems (MUPS) are formulated on the basis of a neutral excipient core which may carry the layered drug surrounded also by functional coating. In the present summary, commonly used starter pellets are presented. The manuscript describes the main properties of the various nuclei related to their micro- and macrostructure. In the case of layered pellets formed based on different inert pellet cores, the drug release mechanism can be expected in detail. Finally, the authors would like to prove the industrial significance of inert cores by presenting some of the commercially available formulations. Full article

(This article belongs to the Collection Advanced Drug Delivery Systems and Technology in Hungary)

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18 pages, 2887 KiB

Open AccessEditor’s ChoiceArticle

Integration of a Physiologically Based Pharmacokinetic and Pharmacodynamic Model for Tegoprazan and Its Metabolite: Application for Predicting Food Effect and Intragastric pH Alterations

by Hyeon-Cheol Jeong, Min-Gul Kim, Zhuodu Wei, Kyeong-Ryoon Lee, Jaehyeok Lee, Im-Sook Song and Kwang-Hee Shin

Pharmaceutics 2022, 14(6), 1298; https://doi.org/10.3390/pharmaceutics14061298 - 18 Jun 2022

Cited by 4 | Viewed by 2519

Abstract

A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for tegoprazan and its major metabolite M1 was developed to predict PK and PD profiles under various scenarios. The PBPK model for tegoprazan and M1 was developed and predicted using the SimCYP^® simulator and verified using [...] Read more.

A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for tegoprazan and its major metabolite M1 was developed to predict PK and PD profiles under various scenarios. The PBPK model for tegoprazan and M1 was developed and predicted using the SimCYP^® simulator and verified using clinical study data obtained after a single administration of tegoprazan. The established PBPK/PD model was used to predict PK profiles after repeated administrations of tegoprazan, postprandial PK profiles, and intragastric pH changes. The predicted tegoprazan and M1 concentration–time profiles fit the observed profiles well. The arithmetic mean ratios (95% confidence intervals) of the predicted to observed values for the area under the curve (AUC_{0–24 h}), maximum plasma drug concentration (C_max), and clearance (CL) for tegoprazan and M1 were within a 30% interval. Delayed time of maximum concentration (T_max) and decreased C_max were predicted in the postprandial PK profiles compared with the fasted state. This PBPK/PD model may be used to predict PK profiles after repeated tegoprazan administrations and to predict differences in physiological factors in the gastrointestinal tract or changes in gastric acid pH after tegoprazan administration. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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16 pages, 4534 KiB

Open AccessArticle

Comparison of Physicochemical Properties of LipoParticles as mRNA Carrier Prepared by Automated Microfluidic System and Bulk Method

by Camille Ayad, Altan Yavuz, Jean-Paul Salvi, Pierre Libeau, Jean-Yves Exposito, Valentine Ginet, Claire Monge, Bernard Verrier and Danielle Campiol Arruda

Pharmaceutics 2022, 14(6), 1297; https://doi.org/10.3390/pharmaceutics14061297 - 18 Jun 2022

Cited by 2 | Viewed by 2346

Abstract

Polymeric and/or lipid platforms are promising tools for nucleic acid delivery into cells. We previously reported a lipid–polymer nanocarrier, named LipoParticles, consisting of polylactic acid nanoparticles surrounded by cationic lipids, and allowing the addition of mRNA and cationic LAH4-1 peptide at their surface. [...] Read more.

Polymeric and/or lipid platforms are promising tools for nucleic acid delivery into cells. We previously reported a lipid–polymer nanocarrier, named LipoParticles, consisting of polylactic acid nanoparticles surrounded by cationic lipids, and allowing the addition of mRNA and cationic LAH4-1 peptide at their surface. Although this mRNA platform has shown promising results in vitro in terms of mRNA delivery and translation, the bulk method used to prepare LipoParticles relies on a multistep and time-consuming procedure. Here, we developed an automated process using a microfluidic system to prepare LipoParticles, and we compared it to the bulk method in terms of morphology, physicochemical properties, and ability to vectorize and deliver mRNA in vitro. LipoParticles prepared by microfluidic presented a smaller size and more regular spherical shape than bulk method ones. In addition, we showed that the total lipid content in LipoParticles was dependent on the method of preparation, influencing their ability to complex mRNA. LipoParticles decorated with two mRNA/LAHA-L1 ratios (1/20, 1/5) could efficiently transfect mouse DC2.4 cells except for the automated 1/5 assay. Moreover, the 1/5 mRNA/LAHA-L1 ratio drastically reduced cell toxicity observed in 1/20 ratio assays. Altogether, this study showed that homogeneous LipoParticles can be produced by microfluidics, which represents a promising platform to transport functional mRNA into cells. Full article

(This article belongs to the Special Issue Research Advances in RNA Therapeutics in France)

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20 pages, 5175 KiB

Open AccessArticle

Formulated Curcumin Prevents Paclitaxel-Induced Peripheral Neuropathy through Reduction in Neuroinflammation by Modulation of α7 Nicotinic Acetylcholine Receptors

by Martial Caillaud, Danielle Thompson, Wisam Toma, Alyssa White, Jared Mann, Jane L. Roberts, John W. Bigbee, David A. Gewirtz and M. Imad Damaj

Pharmaceutics 2022, 14(6), 1296; https://doi.org/10.3390/pharmaceutics14061296 - 17 Jun 2022

Cited by 6 | Viewed by 2471

Abstract

Paclitaxel is widely used in the treatment of various types of solid malignancies. Paclitaxel-induced peripheral neuropathy (PIPN) is often characterized by burning pain, cold, and mechanical allodynia in patients. Currently, specific pharmacological treatments against PIPN are lacking. Curcumin, a polyphenol of Curcuma longa, [...] Read more.

Paclitaxel is widely used in the treatment of various types of solid malignancies. Paclitaxel-induced peripheral neuropathy (PIPN) is often characterized by burning pain, cold, and mechanical allodynia in patients. Currently, specific pharmacological treatments against PIPN are lacking. Curcumin, a polyphenol of Curcuma longa, shows antioxidant, anti-inflammatory, and neuroprotective effects and has recently shown efficacy in the mitigation of various peripheral neuropathies. Here, we tested, for the first time, the therapeutic effect of 1.5% dietary curcumin and Meriva (a lecithin formulation of curcumin) in preventing the development of PIPN in C57BL/6J mice. Curcumin or Meriva treatment was initiated one week before injection of paclitaxel and continued throughout the study (21 days). Mechanical and cold sensitivity as well as locomotion/motivation were tested by the von Frey, acetone, and wheel-running tests, respectively. Additionally, sensory-nerve-action-potential (SNAP) amplitude by caudal-nerve electrical stimulation, electronic microscopy of the sciatic nerve, and inflammatory-protein quantification in DRG and the spinal cord were measured. Interestingly, a higher concentration of curcumin was observed in the spinal cord with the Meriva diet than the curcumin diet. Our results showed that paclitaxel-induced mechanical hypersensitivity was partially prevented by the curcumin diet but completely prevented by Meriva. Both the urcumin diet and the Meriva diet completely prevented cold hypersensitivity, the reduction in SNAP amplitude and reduced mitochondrial pathology in sciatic nerves observed in paclitaxel-treated mice. Paclitaxel-induced inflammation in the spinal cord was also prevented by the Meriva diet. In addition, an increase in α7 nAChRs mRNA, known for its anti-inflammatory effects, was also observed in the spinal cord with the Meriva diet in paclitaxel-treated mice. The use of the α7 nAChR antagonist and α7 nAChR KO mice showed, for the first time in vivo, that the anti-inflammatory effects of curcumin in peripheral neuropathy were mediated by these receptors. The results presented in this study represent an important advance in the understanding of the mechanism of action of curcumin in vivo. Taken together, our results show the therapeutic potential of curcumin in preventing the development of PIPN and further confirms the role of α7 nAChRs in the anti-inflammatory effects of curcumin. Full article

(This article belongs to the Special Issue Curcumin in Biomedical Applications)

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15 pages, 2632 KiB

Open AccessArticle

Toxicity Assessment of Resveratrol Liposomes-in-Hydrogel Delivery System by EpiVaginal^TM Tissue Model

by May Wenche Jøraholmen, Pauliina Damdimopoulou, Ganesh Acharya and Nataša Škalko-Basnet

Pharmaceutics 2022, 14(6), 1295; https://doi.org/10.3390/pharmaceutics14061295 - 17 Jun 2022

Cited by 3 | Viewed by 2228

Abstract

The natural polyphenol resveratrol (RES) has shown great potential as an antimicrobial, including against microbes associated with vaginal infections. To fully exploit the activities of RES, an all-natural ingredients formulation for RES delivery at vaginal site has been developed, namely liposomes loaded with [...] Read more.

The natural polyphenol resveratrol (RES) has shown great potential as an antimicrobial, including against microbes associated with vaginal infections. To fully exploit the activities of RES, an all-natural ingredients formulation for RES delivery at vaginal site has been developed, namely liposomes loaded with RES, incorporated into a chitosan hydrogel as secondary vehicle. Although considered non-toxic and safe on their own, the compatibility of the final formulation must be evaluated for its biocompatibility and non-irritancy to the vaginal mucosa. As a preclinical safety assessment, the impact of RES formulation on the tissue viability, the effect on barrier function and cell monolayer integrity, and cytotoxicity were evaluated using the cell-based vaginal tissue model, the EpiVaginal™ tissue. RES liposomes-in-hydrogel formulations neither affected the mitochondrial activity, nor the integrity of the cell monolayer in RES concentration up to 60 µg/mL. Moreover, the barrier function was maintained to a greater extent by RES in formulation, emphasizing the benefits of the delivery system. Additionally, none of the tested formulations expressed an increase in lactate dehydrogenase activity compared to the non-treated tissues. The evaluation of the RES delivery system suggests that it is non-irritant and biocompatible with vaginal tissue in vitro in the RES concentrations considered as therapeutic. Full article

(This article belongs to the Special Issue Novel Vaginal Drug Delivery Systems)

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38 pages, 11193 KiB

Open AccessArticle

Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia

by Jeanluc Bertrand, Hana Dostálová, Vladimír Kryštof, Radek Jorda, Thalía Delgado, Alejandro Castro-Alvarez, Jaime Mella, David Cabezas, Mario Faúndez, Christian Espinosa-Bustos and Cristian O. Salas

Pharmaceutics 2022, 14(6), 1294; https://doi.org/10.3390/pharmaceutics14061294 - 17 Jun 2022

Cited by 4 | Viewed by 2117

Abstract

We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our [...] Read more.

We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our previously developed purine derivatives. The synthesis of these purines was simple and used a microwave reactor for the final step. Kinase assays showed three inhibitors with high selectivity for each protein that were identified: 4f (IC₅₀ = 70 nM for Bcr-Abl), 5j (IC₅₀ = 0.41 μM for BTK) and 5b (IC₅₀ = 0.38 μM for FLT-ITD). The 3D-QSAR analysis and molecular docking studies suggested that two fragments are potent and selective inhibitors of these three kinases: a substitution at the 6-phenylamino ring and the length and volume of the alkyl group at N-9. The N-7 and the N-methyl-piperazine moiety linked to the aminophenyl ring at C-2 are also requirements for obtaining the activity. Furthermore, most of these purine derivatives were shown to have a significant inhibitory effect in vitro on the proliferation of leukaemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos) at low concentrations. Finally, we show that the selected purines (4i, 5b and 5j) inhibit the downstream signalling of the respective kinases in cell models. Thus, this study provides new evidence regarding how certain chemical modifications of purine ring substituents provide novel inhibitors of target kinases as potential anti-leukaemia drugs. Full article

(This article belongs to the Special Issue Current and Future Cancer Chemoprevention Strategies)

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20 pages, 2428 KiB

Open AccessArticle

Ruthenium(II)–Cyclopentadienyl-Derived Complexes as New Emerging Anti-Colorectal Cancer Drugs

by Catarina Teixeira-Guedes, Ana Rita Brás, Ricardo G. Teixeira, Andreia Valente and Ana Preto

Pharmaceutics 2022, 14(6), 1293; https://doi.org/10.3390/pharmaceutics14061293 - 17 Jun 2022

Cited by 10 | Viewed by 2162

Abstract

Colorectal cancer (CRC) is one of the most common malignancies and one of the leading causes of cancer-related death worldwide, urging the need for new and more efficient therapeutic approaches. Ruthenium complexes have emerged as attractive alternatives to traditional platinum-based compounds in the [...] Read more.

Colorectal cancer (CRC) is one of the most common malignancies and one of the leading causes of cancer-related death worldwide, urging the need for new and more efficient therapeutic approaches. Ruthenium complexes have emerged as attractive alternatives to traditional platinum-based compounds in the treatment of CRC. This work aims to evaluate anti-CRC properties, as well as to identify the mechanisms of action of ruthenium complexes with the general formula [Ru(η⁵-C₅H₄R)(PPh₃)(4,4′-R′-2,2′-bipyridine)][CF₃SO₃], where R = CH₃, CHO or CH₂OH and R′ = H, CH₃, CH₂OH, or dibiotin ester. The complexes (Ru 1–7) displayed high bioactivity, as shown by low IC₅₀ concentrations against CRC cells, namely, RKO and SW480. Four of the most promising ruthenium complexes (Ru 2, 5–7) were phenotypically characterized and were shown to inhibit cell viability by decreasing cell proliferation, inducing cell cycle arrest, and increasing apoptosis. These findings were in accordance with the inhibition of MEK/ERK and PI3K/AKT signaling pathways. Ruthenium complexes also led to a decrease in cellular clonogenic ability and cell migration, which was associated with the disruption of F-actin cytoskeleton integrity. Here, we demonstrated that ruthenium complexes, especially Ru7, have a high anticancer effect against CRC cells and are promising drugs to be used as a new therapeutical strategy for CRC treatment. Full article

(This article belongs to the Special Issue Metallodrugs in Cancer Therapy: The Newest Candidates in the Field)

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37 pages, 1117 KiB

Open AccessReview

Safety Challenges and Application Strategies for the Use of Dendrimers in Medicine

by Xiang Li, Abid Naeem, Shanghua Xiao, Lei Hu, Jing Zhang and Qin Zheng

Pharmaceutics 2022, 14(6), 1292; https://doi.org/10.3390/pharmaceutics14061292 - 17 Jun 2022

Cited by 22 | Viewed by 3018

Abstract

Dendrimers are used for a variety of applications in medicine but, due to their host–guest and entrapment characteristics, are particularly used for the delivery of genes and drugs. However, dendrimers are intrinsically toxic, thus creating a major limitation for their use in biological [...] Read more.

Dendrimers are used for a variety of applications in medicine but, due to their host–guest and entrapment characteristics, are particularly used for the delivery of genes and drugs. However, dendrimers are intrinsically toxic, thus creating a major limitation for their use in biological systems. To reduce such toxicity, biocompatible dendrimers have been designed and synthesized, and surface engineering has been used to create advantageous changes at the periphery of dendrimers. Although dendrimers have been reviewed previously in the literature, there has yet to be a systematic and comprehensive review of the harmful effects of dendrimers. In this review, we describe the routes of dendrimer exposure and their distribution in vivo. Then, we discuss the toxicity of dendrimers at the organ, cellular, and sub-cellular levels. In this review, we also describe how technology can be used to reduce dendrimer toxicity, by changing their size and surface functionalization, how dendrimers can be combined with other materials to generate a composite formulation, and how dendrimers can be used for the diagnosis of disease. Finally, we discuss future challenges, developments, and research directions in developing biocompatible and safe dendrimers for medical purposes. Full article

(This article belongs to the Special Issue Recent Advances in Dendrimer Nanomedicine)

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4 pages, 176 KiB

Open AccessEditorial

Biomaterials in Skin Wound Healing and Tissue Regenerations—An Overview

by Marek Konop

Pharmaceutics 2022, 14(6), 1291; https://doi.org/10.3390/pharmaceutics14061291 - 17 Jun 2022

Cited by 2 | Viewed by 1706

Abstract

Wound healing is a complex biological process [...] Full article

(This article belongs to the Special Issue Biomaterials in Skin Wound Healing and Tissue Regenerations)

15 pages, 1800 KiB

Open AccessArticle

Crocus sativus L. Petal Extract Inhibits Inflammation and Osteoclastogenesis in RAW 264.7 Cell Model

by Ciriana Orabona, Elena Orecchini, Claudia Volpi, Federico Bacaloni, Eleonora Panfili, Cinzia Pagano, Luana Perioli and Maria Laura Belladonna

Pharmaceutics 2022, 14(6), 1290; https://doi.org/10.3390/pharmaceutics14061290 - 17 Jun 2022

Cited by 6 | Viewed by 1828

Abstract

The dried stigmas of Crocus sativus L. (Iridaceae) are traditionally processed to produce saffron, a spice widely used as a food coloring and flavoring agent, which is important in the pharmaceutical and textile dye-producing industries. The labor-intensive by-hand harvesting and the use of [...] Read more.

The dried stigmas of Crocus sativus L. (Iridaceae) are traditionally processed to produce saffron, a spice widely used as a food coloring and flavoring agent, which is important in the pharmaceutical and textile dye-producing industries. The labor-intensive by-hand harvesting and the use of only a small amount of each flower cause saffron to be the most expensive spice in the world. Crocus sp. petals are by-products of saffron production and represent an interesting raw material for the preparation of extracts intended for health protection in the perspective of a circular economy. In the present study, ethanolic extract from Crocus sativus L. petals (Crocus sativus L. petal extract, CsPE) was tested on macrophages by in vitro models of inflammation and osteoclastogenesis. The extract was found to be endowed with anti-inflammatory activity, significantly reducing the nitric oxide production and IL-6 release by RAW 264.7 murine cells. Moreover, CsPE demonstrated an anti-osteoclastogenic effect, as revealed by a complete inhibition of tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation and a decreased expression of key osteoclast-related genes. This study, which focuses on the macrophage as the target cell of the bioactive extract from Crocus sativus L. petals, suggests that the petal by-product of saffron processing can usefully be part of a circular economy network aimed at producing an extract that potentially prevents bone disruption. Full article

(This article belongs to the Special Issue Herbal Extracts and Natural Compounds: Nutraceutical and Pharmaceutical Aspects Volume II)

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19 pages, 2529 KiB

Open AccessArticle

Pharmacogenetic Analysis of Voriconazole Treatment in Children

by Romy Tilen, Paolo Paioni, Aljoscha N. Goetschi, Roland Goers, Isabell Seibert, Daniel Müller, Julia A. Bielicki, Christoph Berger, Stefanie D. Krämer and Henriette E. Meyer zu Schwabedissen

Pharmaceutics 2022, 14(6), 1289; https://doi.org/10.3390/pharmaceutics14061289 - 17 Jun 2022

Cited by 5 | Viewed by 2108

Abstract

Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually [...] Read more.

Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure SwissPK^cdw, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections. Full article

(This article belongs to the Special Issue Pharmacokinetics of Pediatric Drugs)

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17 pages, 3700 KiB

Open AccessArticle

Antioxidative NAC-Loaded Silk Nanoparticles with Opening Mucosal Tight Junctions for Nasal Drug Delivery: An In Vitro and In Vivo Study

by Tze-Wen Chung, Ting-Ya Wu, Zheng-Yu Siah and Der-Zen Liu

Pharmaceutics 2022, 14(6), 1288; https://doi.org/10.3390/pharmaceutics14061288 - 17 Jun 2022

Cited by 3 | Viewed by 1956

Abstract

Using nasal routes to deliver drugs to the brain using multifunctional nanoparticles (NPs) to bypass the blood–brain barrier (BBB) might enhance the delivery efficacy. Anti-oxidative N-Acetyl-L-cysteine (NAC)-loaded silk fibroin (SF/NAC) NPs are produced, characterized and studied as a potential delivery vehicle for NAC [...] Read more.

Using nasal routes to deliver drugs to the brain using multifunctional nanoparticles (NPs) to bypass the blood–brain barrier (BBB) might enhance the delivery efficacy. Anti-oxidative N-Acetyl-L-cysteine (NAC)-loaded silk fibroin (SF/NAC) NPs are produced, characterized and studied as a potential delivery vehicle for NAC delivered to the brain via nasal for both in vitro and in vivo studies. The NPs are not cytotoxic to RPMI 2650 cells, mucosal model cells, at a concentration of 6000 μg/mL. The anti-oxidative activities of SF/NAC NPs are demonstrated by high H₂O₂ scavenge capacities of the NPs and shown by mitochondrial superoxide (MitoSOX) immunostaining of human mesenchymal stem cells. Tight junctions in RPMI 2650 cells are opened after 30 min of incubation with SF/NAC NPs, which are demonstrated by measuring the decrease in trans-epithelial electrical resistance (TEER) values and discreteness in ZO-1 stains. The cellular uptake of SF/NAC NPs by RPMI 2650 cells is significantly greater than that for SF NPs and increased with increasing incubation time. In an in vivo imaging study (IVIS) using rats shows that the amount of NAC that is delivered to the brain by SF/NAC NPs increased by 1.40–2.60 times and NAC is retained longer in the nasal cavity than NAC solutions in a 2-h study. Full article

(This article belongs to the Special Issue Multifunctional Nanoparticles for Drug Delivery and Tissue Engineering Applications)

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30 pages, 1748 KiB

Open AccessEditor’s ChoiceReview

Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective

by Alessia Di Donfrancesco, Giulia Massaro, Ivano Di Meo, Valeria Tiranti, Emanuela Bottani and Dario Brunetti

Pharmaceutics 2022, 14(6), 1287; https://doi.org/10.3390/pharmaceutics14061287 - 17 Jun 2022

Cited by 10 | Viewed by 5409

Abstract

Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved in the oxidative phosphorylation (OXPHOS) system. MDs have a wide range of symptoms, ranging from organ-specific to multisystemic dysfunctions, with different [...] Read more.

Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved in the oxidative phosphorylation (OXPHOS) system. MDs have a wide range of symptoms, ranging from organ-specific to multisystemic dysfunctions, with different clinical outcomes. The lack of natural history information, the limits of currently available preclinical models, and the wide range of phenotypic presentations seen in MD patients have all hampered the development of effective therapies. The growing number of pre-clinical and clinical trials over the last decade has shown that gene therapy is a viable precision medicine option for treating MD. However, several obstacles must be overcome, including vector design, targeted tissue tropism and efficient delivery, transgene expression, and immunotoxicity. This manuscript offers a comprehensive overview of the state of the art of gene therapy in MD, addressing the main challenges, the most feasible solutions, and the future perspectives of the field. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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27 pages, 10632 KiB

Open AccessArticle

Novel In Situ-Cross-Linked Electrospun Gelatin/Hydroxyapatite Nonwoven Scaffolds Prove Suitable for Periodontal Tissue Engineering

by Martin Philipp Dieterle, Thorsten Steinberg, Pascal Tomakidi, Jiri Nohava, Kirstin Vach, Simon Daniel Schulz, Elmar Hellwig and Susanne Proksch

Pharmaceutics 2022, 14(6), 1286; https://doi.org/10.3390/pharmaceutics14061286 - 16 Jun 2022

Cited by 7 | Viewed by 2540

Abstract

Periodontal diseases affect millions of people worldwide and can result in tooth loss. Regenerative treatment options for clinical use are thus needed. We aimed at developing new nonwoven-based scaffolds for periodontal tissue engineering. Nonwovens of 16% gelatin/5% hydroxyapatite were produced by electrospinning and [...] Read more.

Periodontal diseases affect millions of people worldwide and can result in tooth loss. Regenerative treatment options for clinical use are thus needed. We aimed at developing new nonwoven-based scaffolds for periodontal tissue engineering. Nonwovens of 16% gelatin/5% hydroxyapatite were produced by electrospinning and in situ glyoxal cross-linking. In a subset of scaffolds, additional porosity was incorporated via extractable polyethylene glycol fibers. Cell colonization and penetration by human mesenchymal stem cells (hMSCs), periodontal ligament fibroblasts (PDLFs), or cocultures of both were visualized by scanning electron microscopy and 4′,6-diamidin-2-phenylindole (DAPI) staining. Metabolic activity was assessed via Alamar Blue^® staining. Cell type and differentiation were analyzed by immunocytochemical staining of Oct4, osteopontin, and periostin. The electrospun nonwovens were efficiently populated by both hMSCs and PDLFs, while scaffolds with additional porosity harbored significantly more cells. The metabolic activity was higher for cocultures of hMSCs and PDLFs, or for PDLF-seeded scaffolds. Periostin and osteopontin expression was more pronounced in cocultures of hMSCs and PDLFs, whereas Oct4 staining was limited to hMSCs. These novel in situ-cross-linked electrospun nonwoven scaffolds allow for efficient adhesion and survival of hMSCs and PDLFs. Coordinated expression of differentiation markers was observed, which rendered this platform an interesting candidate for periodontal tissue engineering. Full article

(This article belongs to the Special Issue Electrospun Materials for Biomedical Applications)

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13 pages, 3693 KiB

Open AccessCommunication

Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue

by Laura Else, Sujan D. Penchala, Azure-Dee Pillay, Thabiso B. Seiphetlo, Limakatso Lebina, Christian Callebaut, Suks Minhas, Roland Morley, Tina Rashid, Neil Martinson, Julie Fox, Saye Khoo and Carolina Herrera

Pharmaceutics 2022, 14(6), 1285; https://doi.org/10.3390/pharmaceutics14061285 - 16 Jun 2022

Cited by 3 | Viewed by 2060

Abstract

Background: HIV-1 pre-exposure prophylaxis (PrEP) has focused predominantly on protective efficacy in receptive sex, with limited research on the dosing requirements for insertive sex. We pre-clinically assessed the ex vivo pharmacokinetic–pharmacodynamic (PK–PD) profile of tenofovir (TFV) and tenofovir alafenamide (TAF) in foreskin tissue. [...] Read more.

Background: HIV-1 pre-exposure prophylaxis (PrEP) has focused predominantly on protective efficacy in receptive sex, with limited research on the dosing requirements for insertive sex. We pre-clinically assessed the ex vivo pharmacokinetic–pharmacodynamic (PK–PD) profile of tenofovir (TFV) and tenofovir alafenamide (TAF) in foreskin tissue. Methods: Inner and outer foreskin explants were exposed to serial dilutions of TFV or TAF prior to addition of HIV-1_BaL at a high (HVT) or a low viral titer (LVT). Infection was assessed by measurement of p24 in foreskin culture supernatants. TFV, TAF and TFV–diphosphate (TFV–DP) concentrations were measured in tissues, culture supernatants and dosing and washing solutions. Results: Dose–response curves were obtained for both drugs, with greater potency observed against LVT. Inhibitory equivalency mimicking oral dosing was defined between 1 mg/mL of TFV and 15 µg/mL of TAF against HVT challenge. Concentrations of TFV–DP in foreskin explants were approximately six-fold higher after ex vivo dosing with TAF than with TFV. Statistically significant negative linear correlations were observed between explant levels of TFV or TFV–DP and p24 concentrations following HVT. Conclusions: Pre-clinical evaluation of TAF in foreskin explants revealed greater potency than TFV against penile HIV transmission. Clinical evaluation is underway to support this finding. Full article

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

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16 pages, 4246 KiB

Open AccessArticle

Combination of [¹⁷⁷Lu]Lu-DOTA-TATE Targeted Radionuclide Therapy and Photothermal Therapy as a Promising Approach for Cancer Treatment: In Vivo Studies in a Human Xenograft Mouse Model

by Marina Simón, Jesper Tranekjær Jørgensen, Harshvardhan A. Khare, Camilla Christensen, Carsten Haagen Nielsen and Andreas Kjaer

Pharmaceutics 2022, 14(6), 1284; https://doi.org/10.3390/pharmaceutics14061284 - 16 Jun 2022

Cited by 3 | Viewed by 2517

Abstract

Peptide receptor radionuclide therapy (PRRT) relies on α- and β-emitting radionuclides bound to a peptide that commonly targets somatostatin receptors (SSTRs) for the localized killing of tumors through ionizing radiation. A Lutetium-177 (¹⁷⁷Lu)-based probe linked to the somatostatin analog octreotate ([ [...] Read more.

Peptide receptor radionuclide therapy (PRRT) relies on α- and β-emitting radionuclides bound to a peptide that commonly targets somatostatin receptors (SSTRs) for the localized killing of tumors through ionizing radiation. A Lutetium-177 (¹⁷⁷Lu)-based probe linked to the somatostatin analog octreotate ([¹⁷⁷Lu]Lu-DOTA-TATE) is approved for the treatment of certain SSTR-expressing tumors and has been shown to improve survival. However, a limiting factor of PRRT is the potential toxicity derived from the high doses needed to kill the tumor. This could be circumvented by combining PRRT with other treatments for an enhanced anti-tumor effect. Photothermal therapy (PTT) relies on nanoparticle-induced hyperthermia for cancer treatment and could be a useful add-on to PRRT. Here, we investigate a strategy combining [¹⁷⁷Lu]Lu-DOTA-TATE PRRT and nanoshell (NS)-based PTT for the treatment of SSTR-expressing small-cell lung tumors in mice. Our results showed that the combination treatment improved survival compared to PRRT alone, but only when PTT was performed one day after [¹⁷⁷Lu]Lu-DOTA-TATE injection (one of the timepoints examined), showcasing the effect of treatment timing in relation to outcome. Furthermore, the combination treatment was well-tolerated in the mice. This indicates that strategies involving NS-based PTT as an add-on to PRRT could be promising and should be investigated further. Full article

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

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178 pages, 12752 KiB

Open AccessEditor’s ChoiceReview

A Historical Review of Brain Drug Delivery

by William M. Pardridge

Pharmaceutics 2022, 14(6), 1283; https://doi.org/10.3390/pharmaceutics14061283 - 16 Jun 2022

Cited by 63 | Viewed by 12557

Abstract

The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood–brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved [...] Read more.

The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood–brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Drugs that do not cross the BBB can be re-engineered for transport on endogenous BBB carrier-mediated transport and receptor-mediated transport systems, which were identified during the 1970s–1980s. By the 1990s, a multitude of brain drug delivery technologies emerged, including trans-cranial delivery, CSF delivery, BBB disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, and biologics. The advantages and limitations of each of these brain drug delivery technologies are critically reviewed. Full article

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

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28 pages, 19793 KiB

Open AccessReview

Ultrasound and Nanomedicine for Cancer-Targeted Drug Delivery: Screening, Cellular Mechanisms and Therapeutic Opportunities

by Chien-Hsiu Li, Yu-Chan Chang, Michael Hsiao and Ming-Hsien Chan

Pharmaceutics 2022, 14(6), 1282; https://doi.org/10.3390/pharmaceutics14061282 - 16 Jun 2022

Cited by 2 | Viewed by 3429

Abstract

Cancer is a disease characterized by abnormal cell growth. According to a report published by the World Health Organization (WHO), cancer is the second leading cause of death globally, responsible for an estimated 9.6 million deaths in 2018. It should be noted that [...] Read more.

Cancer is a disease characterized by abnormal cell growth. According to a report published by the World Health Organization (WHO), cancer is the second leading cause of death globally, responsible for an estimated 9.6 million deaths in 2018. It should be noted that ultrasound is already widely used as a diagnostic procedure for detecting tumorigenesis. In addition, ultrasound energy can also be utilized effectively for treating cancer. By filling the interior of lipospheres with gas molecules, these particles can serve both as contrast agents for ultrasonic imaging and as delivery systems for drugs such as microbubbles and nanobubbles. Therefore, this review aims to describe the nanoparticle-assisted drug delivery system and how it can enhance image analysis and biomedicine. The formation characteristics of nanoparticles indicate that they will accumulate at the tumor site upon ultrasonic imaging, in accordance with their modification characteristics. As a result of changing the accumulation of materials, it is possible to examine the results by comparing images of other tumor cell lines. It is also possible to investigate ultrasound images for evidence of cellular effects. In combination with a precision ultrasound imaging system, drug-carrying lipospheres can precisely track tumor tissue and deliver drugs to tumor cells to enhance the ability of this nanocomposite to treat cancer. Full article

(This article belongs to the Special Issue Ultrasound-Assisted Drug Delivery System)

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10 pages, 1591 KiB

Open AccessArticle

Effects of Wall Material on Medium-Chain Triglyceride (MCT) Oil Microcapsules Prepared by Spray Drying

by Su Mon San, Montree Jaturanpinyo and Waree Limwikrant

Pharmaceutics 2022, 14(6), 1281; https://doi.org/10.3390/pharmaceutics14061281 - 16 Jun 2022

Cited by 5 | Viewed by 2134

Abstract

A medium-chain triglyceride (MCT) oil microcapsule was prepared by spray drying. The effects of the wall-material parameters of wall-to-oil ratio (1:1 to 3:1) and type of wall material (gum arabic (GA), whey protein isolate (WPI), and octenyl succinic anhydride (OSA) starch) on the [...] Read more.

A medium-chain triglyceride (MCT) oil microcapsule was prepared by spray drying. The effects of the wall-material parameters of wall-to-oil ratio (1:1 to 3:1) and type of wall material (gum arabic (GA), whey protein isolate (WPI), and octenyl succinic anhydride (OSA) starch) on the microcapsules were evaluated. The droplet size, size distribution, viscosity, zeta potential, and stability of the emulsions were measured. The spray-dried powder was characterized by its morphology, yield, encapsulation efficiency, and moisture content. The wall material influenced the characteristics of the emulsions and microcapsules. The formulation with a 2:1 wall-to-oil ratio and OSA starch/maltodextrin as the wall material resulted in a small droplet size (0.177 ± 0.002 µm) with high encapsulation efficiency (98.38 ± 0.01%). This formulation had good physical stability over three months under accelerated conditions. Thus, OSA starch/maltodextrin is an appropriate wall material for encapsulating MCT oil. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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19 pages, 3887 KiB

Open AccessArticle

Stereomicroscope with Imaging Analysis: A Versatile Tool for Wetting, Gel Formation and Erosion Rate Determinations of Eutectic Effervescent Tablet

by Pornsit Chaiya, Siriporn Okonogi and Thawatchai Phaechamud

Pharmaceutics 2022, 14(6), 1280; https://doi.org/10.3390/pharmaceutics14061280 - 16 Jun 2022

Cited by 2 | Viewed by 1935

Abstract

Wettability, gel formation and erosion behaviors could influence the drug release pattern of solid dosage forms. Typically, these parameters are evaluated using a variety of techniques. Nonetheless, there has been no previous research on versatile tool development for evaluating several tablet characteristics with [...] Read more.

Wettability, gel formation and erosion behaviors could influence the drug release pattern of solid dosage forms. Typically, these parameters are evaluated using a variety of techniques. Nonetheless, there has been no previous research on versatile tool development for evaluating several tablet characteristics with a single tool. The aim of this study was to develop the versatile tool for measuring various physical properties of eutectic effervescent tablets and also investigate the relationship between these parameters with parameters from drug dissolution. Ibuprofen (IBU)-poloxamer 407 (P407) eutectic effervescent tablets were fabricated with a direct compression method. Their wetting properties, gel formation and erosion behaviors were investigated using a stereomicroscope with imaging analysis in terms of the liquid penetration distance, gel thickness and erosion boundary diameter, respectively. In addition, the dissolution rate (k) and disintegration time of eutectic effervescent tablets in 0.1 N HCl buffer pH 1.2 were also determined. Incorporation of P407 into the IBU tablet improved the tablet wetting properties with increasing liquid penetration distance under stereoscope. CO₂ liberation from effervescent agents promoted tablet surface roughness from matrix erosion. The relationship between observed physical properties and disintegration and dissolution parameters suggested that the combination of erosion by effervescent agents and gel formation by P407 had a potential influence on dissolution enhancement of the formulation. Therefore, a developed stereomicroscope with an imaging analysis technique was exhibited as an alternative versatile tool for determining the wetting properties, gel formation and erosion behaviors of pharmaceutical solid dosage forms. Full article

(This article belongs to the Special Issue Smart Drug Delivery Strategies Based on Porous Materials)

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20 pages, 3712 KiB

Open AccessArticle

Zein-Stabilized Nanospheres as Nanocarriers for Boosting the Aphrodisiac Activity of Icariin: Response Surface Optimization and In Vivo Assessment

by Hani Z. Asfour, Nabil A. Alhakamy, Usama A. Fahmy, Osama A. A. Ahmed, Waleed Y. Rizg, Raed I. Felimban, Ashraf B. Abdel-Naim, Mohammad A. S. Abourehab, Rasha A. Mansouri, Ulfat M. Omar and Shaimaa M. Badr-Eldin

Pharmaceutics 2022, 14(6), 1279; https://doi.org/10.3390/pharmaceutics14061279 - 16 Jun 2022

Cited by 1 | Viewed by 1849

Abstract

Icariin (ICA), a main active compound of the Epimedium genus, is used as an aphrodisiac in traditional Chinese herbal medicine. Despite its therapeutic efficacy, ICA displays reduced oral absorption, and therefore, low bioavailability hindered its clinical application. Implementing nanotechnology in the field of [...] Read more.

Icariin (ICA), a main active compound of the Epimedium genus, is used as an aphrodisiac in traditional Chinese herbal medicine. Despite its therapeutic efficacy, ICA displays reduced oral absorption, and therefore, low bioavailability hindered its clinical application. Implementing nanotechnology in the field of formulation has been a focus to improve the efficacy of ICA. In this regard, polymeric nanoparticles find a potential application as drug delivery systems. A nanosphere formula was designed, aiming to improve the drug’s efficacy. The proposed ICA nanosphere formula (tocozeinolate) was optimized using D-optimal response surface design. The concentrations of ICA (X₁), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS, X₂), zein (X₃), and sodium deoxycholate (SDC, X₄) expressed as percentages were investigated as quantitative independent variables. As per the experimental design, 23 formulations were developed, which were investigated for particle size (PS, nm), zeta potential (ZP, mV), and entrapment efficiency (EE, %) as response parameters. Numerical optimization and desirability approach were employed to predict the optimized variable levels that, upon combination, could result in minimized size and maximized zeta potential and ICA entrapment. The optimized ICA–tocozeinolate nanospheres showed a particle size of 224.45 nm, zeta potential of 0.961 mV, and drug entrapment of 65.29% that coincide well with the predicted values. The optimized ICA–tocozeinolate nanospheres were evaluated for sexual behavior in Wistar male rats compared to raw ICA at equivalent doses (20 mg/kg). In vivo assessment results showed significant sexual behavior enhancement by the optimized formulation, as evidenced by decreased average time of both mount latency (ML) and ejaculation latency (EL) to almost half those of raw ICA. Additionally, intromission latency (IL) time was reduced by 41% compared to the raw ICA. These results highlighted the potential of the proposed ICA–tocozeinolate nanospheres as a promising platform for improving the delivery and efficacy of therapeutic agents. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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