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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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31 pages, 3423 KiB  
Review
Transferrin Receptor-Targeted Nanocarriers: Overcoming Barriers to Treat Glioblastoma
by Maria João Ramalho, Joana Angélica Loureiro, Manuel A. N. Coelho and Maria Carmo Pereira
Pharmaceutics 2022, 14(2), 279; https://doi.org/10.3390/pharmaceutics14020279 - 25 Jan 2022
Cited by 48 | Viewed by 5770
Abstract
Glioblastoma multiforme (GBM) is the most common and lethal type of brain tumor, and the clinically available approaches for its treatment are not curative. Despite the intensive research, biological barriers such as the blood–brain barrier (BBB) and tumor cell membranes are major obstacles [...] Read more.
Glioblastoma multiforme (GBM) is the most common and lethal type of brain tumor, and the clinically available approaches for its treatment are not curative. Despite the intensive research, biological barriers such as the blood–brain barrier (BBB) and tumor cell membranes are major obstacles to developing novel effective therapies. Nanoparticles (NPs) have been explored as drug delivery systems (DDS) to improve GBM therapeutic strategies. NPs can circumvent many of the biological barriers posed by this devastating disease, enhancing drug accumulation in the target site. This can be achieved by employing strategies to target the transferrin receptor (TfR), which is heavily distributed in BBB and GBM cells. These targeting strategies comprise the modification of NPs’ surface with various molecules, such as transferrin (Tf), antibodies, and targeting peptides. This review provides an overview and discussion on the recent advances concerning the strategies to target the TfR in the treatment of GBM, as their benefits and limitations. Full article
(This article belongs to the Special Issue Functional Nanoparticles for Enhanced Cancer Therapy)
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16 pages, 2745 KiB  
Article
Simultaneous Delivery of Econazole, Terbinafine and Amorolfine with Improved Cutaneous Bioavailability: A Novel Micelle-Based Antifungal “Tri-Therapy”
by Si Gou, Michel Monod, Denis Salomon and Yogeshvar N. Kalia
Pharmaceutics 2022, 14(2), 271; https://doi.org/10.3390/pharmaceutics14020271 - 24 Jan 2022
Cited by 4 | Viewed by 2887
Abstract
Lack of accurate diagnosis and the use of formulations designed to address the poor aqueous solubility of antifungal agents, but not optimized for delivery, contribute to unsatisfactory outcomes for topical treatment of cutaneous mycoses. The objective of this study was to develop a [...] Read more.
Lack of accurate diagnosis and the use of formulations designed to address the poor aqueous solubility of antifungal agents, but not optimized for delivery, contribute to unsatisfactory outcomes for topical treatment of cutaneous mycoses. The objective of this study was to develop a micelle-based antifungal formulation containing econazole (ECZ), terbinafine (TBF) and amorolfine (AMF) using D-α-tocopheryl polyethylene glycol succinate (TPGS) for simultaneous cutaneous delivery of three agents with complementary mechanisms of action. The antifungal “tri-therapy” micelle-based formulation containing 0.1% ECZ, 0.1% TBF and 0.025% AMF had a drug loading 10-fold lower than the “reference” marketed formulations (Pevaryl®, 1% ECZ; Lamisil®, 1% TBF; Loceryl®, 0.25% AMF). Finite dose application of the micelle-based formulation for 6 h resulted in a statistically equivalent deposition of ECZ (p > 0.05) and TBF (p > 0.05) from the 2 systems, and a 2-fold higher accumulation of AMF (p = 0.017). Antifungal concentrations above MIC80 against Trichophyton rubrum were achieved in each skin layer with the “tri-therapy”, which also exhibited a preferential deposition of each antifungal agent in pilosebaceous unit (PSU)-containing biopsies as compared with PSU-free biopsies (p < 0.05). A planned clinical study will test whether these promising results translate to improved therapeutic outcomes in vivo. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Switzerland)
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13 pages, 3037 KiB  
Article
Factors Influencing the Crystallization-Onset Time of Metastable ASDs
by Friederike Wolbert, Ineke-Katharina Fahrig, Tobias Gottschalk, Christian Luebbert, Markus Thommes and Gabriele Sadowski
Pharmaceutics 2022, 14(2), 269; https://doi.org/10.3390/pharmaceutics14020269 - 23 Jan 2022
Cited by 13 | Viewed by 3811
Abstract
In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that [...] Read more.
In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that the long-term stability of ASDs strongly depends on the storage conditions (relative humidity, temperature), the manufacturing methods, and the resulting particle sizes. In this work, ASDs composed of the model APIs Griseofulvin (GRI) or Itraconazole (ITR) and the polymers poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) or Soluplus® were manufactured via spray drying and hot-melt extrusion. Each API/polymer combination was manufactured using the two manufacturing methods with at least two different API loads and two particle-size distributions. It was a priori known that these ASDs were metastable and would crystallize over time, even in the dry stage. The amount of water absorbed by the ASD from humid air (40 °C/75% relative humidity), the solubility of the API in the ASD at humid conditions, and the resulting glass-transition temperature were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon–Taylor approach, respectively. The onset of crystallization was determined via periodic powder X-ray diffraction (PXRD) measurements. It was shown that simple heuristics such as “larger particles always crystallize later than smaller particles” are correct within one manufacturing method but cannot be transferred from one manufacturing method to another. Moreover, amorphous phase separation in the ASDs was shown to also influence their crystallization kinetics. Counterintuitively, phase separation accelerated the crystallization time, which could be explained by the glass-transition temperatures of the evolving phases. Full article
(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Guy Van den Mooter)
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24 pages, 1150 KiB  
Review
Oligonucleotide Therapeutics: From Discovery and Development to Patentability
by Lara Moumné, Anne-Céline Marie and Nicolas Crouvezier
Pharmaceutics 2022, 14(2), 260; https://doi.org/10.3390/pharmaceutics14020260 - 22 Jan 2022
Cited by 76 | Viewed by 11216
Abstract
Following the first proof of concept of using small nucleic acids to modulate gene expression, a long period of maturation led, at the end of the last century, to the first marketing authorization of an oligonucleotide-based therapy. Since then, 12 more compounds have [...] Read more.
Following the first proof of concept of using small nucleic acids to modulate gene expression, a long period of maturation led, at the end of the last century, to the first marketing authorization of an oligonucleotide-based therapy. Since then, 12 more compounds have hit the market and many more are in late clinical development. Many companies were founded to exploit their therapeutic potential and Big Pharma was quickly convinced that oligonucleotides could represent credible alternatives to protein-targeting products. Many technologies have been developed to improve oligonucleotide pharmacokinetics and pharmacodynamics. Initially targeting rare diseases and niche markets, oligonucleotides are now able to benefit large patient populations. However, there is still room for oligonucleotide improvement and further breakthroughs are likely to emerge in the coming years. In this review we provide an overview of therapeutic oligonucleotides. We present in particular the different types of oligonucleotides and their modes of action, the tissues they target and the routes by which they are administered to patients, and the therapeutic areas in which they are used. In addition, we present the different ways of patenting oligonucleotides. We finally discuss future challenges and opportunities for this drug-discovery platform. Full article
(This article belongs to the Special Issue Oligonucleotides and Nucleic-Acid-Based Strategies to Address Therapeutic Challenges: From the Bench to the Bedside)
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20 pages, 6930 KiB  
Article
Engineered Full Thickness Electrospun Scaffold for Esophageal Tissue Regeneration: From In Vitro to In Vivo Approach
by Silvia Pisani, Stefania Croce, Simone Mauramati, Marta Marmonti, Lorenzo Cobianchi, Irene Herman, Rossella Dorati, Maria Antonietta Avanzini, Ida Genta, Marco Benazzo and Bice Conti
Pharmaceutics 2022, 14(2), 252; https://doi.org/10.3390/pharmaceutics14020252 - 21 Jan 2022
Cited by 5 | Viewed by 2920
Abstract
Acquired congenital esophageal malformations, such as malignant esophageal cancer, require esophagectomy resulting in full thickness resection, which cannot be left untreated. The proposed approach is a polymeric full-thickness scaffold engineered with mesenchymal stem cells (MSCs) to promote and speed up the regeneration process, [...] Read more.
Acquired congenital esophageal malformations, such as malignant esophageal cancer, require esophagectomy resulting in full thickness resection, which cannot be left untreated. The proposed approach is a polymeric full-thickness scaffold engineered with mesenchymal stem cells (MSCs) to promote and speed up the regeneration process, ensuring adequate support and esophageal tissue reconstruction and avoiding the use of autologous conduits. Copolymers poly-L-lactide-co-poly-ε-caprolactone (PLA-PCL) 70:30 and 85:15 ratio were chosen to prepare electrospun tubular scaffolds. Electrospinning apparatus equipped with two different types of tubular mandrels: cylindrical (∅ 10 mm) and asymmetrical (∅ 10 mm and ∅ 8 mm) were used. Tubular scaffolds underwent morphological, mechanical (uniaxial tensile stress) and biological (MTT and Dapi staining) characterization. Asymmetric tubular geometry resulted in the best properties and was selected for in vivo surgical implantation. Anesthetized pigs underwent full thickness circumferential resection of the mid-lower thoracic esophagus, followed by implantation of the asymmetric scaffold. Preliminary in vivo results demonstrated that detached stitch suture achieved better results in terms of animal welfare and scaffold integration; thus, it is to be preferred to continuous suture. Full article
(This article belongs to the Special Issue Electrospun Materials for Biomedical Applications)
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29 pages, 2980 KiB  
Review
Encapsulation, Release, and Cytotoxicity of Doxorubicin Loaded in Liposomes, Micelles, and Metal-Organic Frameworks: A Review
by Mihad Ibrahim, Waad H. Abuwatfa, Nahid S. Awad, Rana Sabouni and Ghaleb A. Husseini
Pharmaceutics 2022, 14(2), 254; https://doi.org/10.3390/pharmaceutics14020254 - 21 Jan 2022
Cited by 67 | Viewed by 8242
Abstract
Doxorubicin (DOX) is one of the most widely used anthracycline anticancer drugs due to its high efficacy and evident antitumoral activity on several cancer types. However, its effective utilization is hindered by the adverse side effects associated with its administration, the detriment to [...] Read more.
Doxorubicin (DOX) is one of the most widely used anthracycline anticancer drugs due to its high efficacy and evident antitumoral activity on several cancer types. However, its effective utilization is hindered by the adverse side effects associated with its administration, the detriment to the patients’ quality of life, and general toxicity to healthy fast-dividing cells. Thus, delivering DOX to the tumor site encapsulated inside nanocarrier-based systems is an area of research that has garnered colossal interest in targeted medicine. Nanoparticles can be used as vehicles for the localized delivery and release of DOX, decreasing the effects on neighboring healthy cells and providing more control over the drug’s release and distribution. This review presents an overview of DOX-based nanocarrier delivery systems, covering loading methods, release rate, and the cytotoxicity of liposomal, micellar, and metal organic frameworks (MOFs) platforms. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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44 pages, 3529 KiB  
Review
EGFR-Targeted Photodynamic Therapy
by Luca Ulfo, Paolo Emidio Costantini, Matteo Di Giosia, Alberto Danielli and Matteo Calvaresi
Pharmaceutics 2022, 14(2), 241; https://doi.org/10.3390/pharmaceutics14020241 - 20 Jan 2022
Cited by 53 | Viewed by 5959
Abstract
The epidermal growth factor receptor (EGFR) plays a pivotal role in the proliferation and metastatization of cancer cells. Aberrancies in the expression and activation of EGFR are hallmarks of many human malignancies. As such, EGFR-targeted therapies hold significant potential for the cure of [...] Read more.
The epidermal growth factor receptor (EGFR) plays a pivotal role in the proliferation and metastatization of cancer cells. Aberrancies in the expression and activation of EGFR are hallmarks of many human malignancies. As such, EGFR-targeted therapies hold significant potential for the cure of cancers. In recent years, photodynamic therapy (PDT) has gained increased interest as a non-invasive cancer treatment. In PDT, a photosensitizer is excited by light to produce reactive oxygen species, resulting in local cytotoxicity. One of the critical aspects of PDT is to selectively transport enough photosensitizers to the tumors environment. Accordingly, an increasing number of strategies have been devised to foster EGFR-targeted PDT. Herein, we review the recent nanobiotechnological advancements that combine the promise of PDT with EGFR-targeted molecular cancer therapy. We recapitulate the chemistry of the sensitizers and their modes of action in PDT, and summarize the advantages and pitfalls of different targeting moieties, highlighting future perspectives for EGFR-targeted photodynamic treatment of cancer. Full article
(This article belongs to the Special Issue Drug Delivery in Photodynamic Therapy (PDT))
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30 pages, 9360 KiB  
Review
An Overview of Nanotechnologies for Drug Delivery to the Brain
by Ahsan Ayub and Shawn Wettig
Pharmaceutics 2022, 14(2), 224; https://doi.org/10.3390/pharmaceutics14020224 - 19 Jan 2022
Cited by 48 | Viewed by 8344
Abstract
Drug delivery to the brain has been one of the toughest challenges researchers have faced to develop effective treatments for brain diseases. Owing to the blood–brain barrier (BBB), only a small portion of administered drug can reach the brain. A consequence of that [...] Read more.
Drug delivery to the brain has been one of the toughest challenges researchers have faced to develop effective treatments for brain diseases. Owing to the blood–brain barrier (BBB), only a small portion of administered drug can reach the brain. A consequence of that is the need to administer a higher dose of the drug, which, expectedly, leads to a variety of unwanted side effects. Research in a variety of different fields has been underway for the past couple of decades to address this very serious and frequently lethal problem. One area of research that has produced optimistic results in recent years is nanomedicine. Nanomedicine is the science birthed by fusing the fields of nanotechnology, chemistry and medicine into one. Many different types of nanomedicine-based drug-delivery systems are currently being studied for the sole purpose of improved drug delivery to the brain. This review puts together and briefly summarizes some of the major breakthroughs in this crusade. Inorganic nanoparticle-based drug-delivery systems, such as gold nanoparticles and magnetic nanoparticles, are discussed, as well as some organic nanoparticulate systems. Amongst the organic drug-delivery nanosystems, polymeric micelles and dendrimers are discussed briefly and solid polymeric nanoparticles are explored in detail. Full article
(This article belongs to the Special Issue Advanced Nanomaterials for Drug Delivery)
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21 pages, 3852 KiB  
Article
Resveratrol Encapsulation and Release from Pristine and Functionalized Mesoporous Silica Carriers
by Simona Ioniţă, Daniel Lincu, Raul-Augustin Mitran, Laila Ziko, Nada K. Sedky, Mihaela Deaconu, Ana-Maria Brezoiu, Cristian Matei and Daniela Berger
Pharmaceutics 2022, 14(1), 203; https://doi.org/10.3390/pharmaceutics14010203 - 16 Jan 2022
Cited by 19 | Viewed by 3478
Abstract
Resveratrol, a naturally occurring polyphenol, has attracted significant attention due to its antioxidant, cardioprotective and anticancer potential. However, its low aqueous solubility limits resveratrol bioavailability and use. In this work, different mesoporous silica matrices were used to encapsulate the polyphenol and to increase [...] Read more.
Resveratrol, a naturally occurring polyphenol, has attracted significant attention due to its antioxidant, cardioprotective and anticancer potential. However, its low aqueous solubility limits resveratrol bioavailability and use. In this work, different mesoporous silica matrices were used to encapsulate the polyphenol and to increase its dissolution rate. Pristine MCM-41, MCM-48, SBA-15, SBA-16, FDU-12 and MCF silica were obtained. The influence of SBA-15 functionalized with aminopropyl, isocyanate, phenyl, mercaptopropyl, and propionic acid moieties on resveratrol loading and release profiles was also assessed. The cytotoxic effects were evaluated for mesoporous carriers and resveratrol-loaded samples against human lung cancer (A549), breast cancer (MDA-MB-231) and human skin fibroblast (HSF) cell lines. The effect on apoptosis and cell cycle were assayed for selected resveratrol-loaded carriers. The polyphenol molecules are encapsulated only inside the mesopores, mostly in amorphous state. All materials containing either pristine or functionalized silica carriers increased polyphenol dissolution rate. The influence of the physico-chemical properties of the mesoporous carriers and resveratrol–loaded supports on the kinetic parameters was identified. Resv@SBA-15-SH and Resv@SBA-15-NCO samples exhibited the highest anticancer effect against A549 cells (IC50 values were 26.06 and 36.5 µg/mL, respectively) and against MDA-MB-231 (IC50 values were 35.56 and 19.30 µg/mL, respectively), which highlights their potential use against cancer. Full article
(This article belongs to the Special Issue Recent Progress in Formulation Approaches for Improving the Solubility and Bioavailability of Poorly Soluble Drugs)
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16 pages, 2848 KiB  
Article
Skin Regenerative Potential of Cupuaçu Seed Extract (Theobroma grandiflorum), a Native Fruit from the Amazon: Development of a Topical Formulation Based on Chitosan-Coated Nanocapsules
by Geisa Nascimento Barbalho, Breno Noronha Matos, Gabriel Ferreira da Silva Brito, Thamires da Cunha Miranda, Thuany Alencar-Silva, Fernando Fabriz Sodré, Guilherme Martins Gelfuso, Marcilio Cunha-Filho, Juliana Lott Carvalho, Joyce Kelly do Rosário da Silva and Taís Gratieri
Pharmaceutics 2022, 14(1), 207; https://doi.org/10.3390/pharmaceutics14010207 - 16 Jan 2022
Cited by 12 | Viewed by 3381
Abstract
Scarless skin regeneration is a challenge in regenerative medicine. Herein, we explore the regenerative potential of a Cupuaçu seed extract (Theobroma grandiflorum) to develop an innovative skin regeneration formulation based on chitosan-coated nanocapsules. Cupuaçu seed extract significantly stimulated cell proliferation and [...] Read more.
Scarless skin regeneration is a challenge in regenerative medicine. Herein, we explore the regenerative potential of a Cupuaçu seed extract (Theobroma grandiflorum) to develop an innovative skin regeneration formulation based on chitosan-coated nanocapsules. Cupuaçu seed extract significantly stimulated cell proliferation and migration. A reparative gene expression profile could be verified following extract treatment, which included high levels of MKI67, a cellular proliferation marker, and extracellular matrix genes, such as ELN and HAS2, which code for elastin and hyaluronic acid synthase 2. Formulations with Cupuaçu seed extract successfully entrapped into nanocapsules (EE% > 94%) were developed. Uncoated or coated nanocapsules with low-molecular-weight chitosan presented unimodal size distribution with hydrodynamic diameters of 278.3 ± 5.0 nm (PDI = 0.18 ± 0.02) and 337.2 ± 2.1 nm (PDI = 0.27 ± 0.01), respectively. Both nanosystems were physically stable for at least 120 days and showed to be non-irritating to reconstructed human epidermis. Chitosan coating promoted active penetration into undamaged skin areas, which were still covered by the stratum corneum. In conclusion, the present study demonstrated for the first time the biotechnological potential of the frequently discarded Cupuaçu seed as a valuable pharmaceutical ingredient to be used in regenerative skin products. Full article
(This article belongs to the Special Issue Phytopharmaceutical Technology)
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25 pages, 6600 KiB  
Article
Tablet Disintegration and Dispersion under In Vivo-like Hydrodynamic Conditions
by Jan Lenz, Frederik Fuest, Jan Henrik Finke, Heike Bunjes, Arno Kwade and Michael Juhnke
Pharmaceutics 2022, 14(1), 208; https://doi.org/10.3390/pharmaceutics14010208 - 16 Jan 2022
Cited by 3 | Viewed by 4544
Abstract
Disintegration and dispersion are functional properties of tablets relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information on these complex processes. It is considered not to be comparable to the biorelevant conditions due [...] Read more.
Disintegration and dispersion are functional properties of tablets relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information on these complex processes. It is considered not to be comparable to the biorelevant conditions due to the frequent occurrence of high hydrodynamic forces, among other reasons. In this study, 3D tomographic laser-induced fluorescence imaging (3D Tomo-LIF) is applied to analyse tablet disintegration and dispersion. Disintegration time (DT) and time-resolved particle size distribution in close proximity to the tablet are determined in a continuously operated flow channel, adjustable to very low fluid velocities. A case study on tablets of different porosity, which are composed of pharmaceutical polymers labelled with a fluorescent dye, a filler, and disintegrants, is presented to demonstrate the functionality and precision of the novel method. DT results from 3D Tomo-LIF are compared with results from the SDT, confirming the analytical limitations of the pharmacopoeial disintegration test. Results from the 3D Tomo-LIF method proved a strong impact of fluid velocity on disintegration and dispersion. Generally, shorter DTs were determined when cross-linked sodium carboxymethly cellulose (NaCMCXL) was used as disintegrant compared to polyvinyl polypyrrolidone (PVPP). Tablets containing Kollidon VA64 were found to disintegrate by surface erosion. The novel method provides an in-depth understanding of the functional behaviour of the tablet material, composition and structural properties under in vivo-like hydrodynamic forces regarding disintegration and the temporal progress of dispersion. We consider the 3D Tomo-LIF in vitro method to be of improved biorelevance in terms of hydrodynamic conditions in the human stomach. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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19 pages, 19149 KiB  
Article
DELOS Nanovesicles-Based Hydrogels: An Advanced Formulation for Topical Use
by Lídia Ballell-Hosa, Elisabet González-Mira, Hector Santana, Judit Morla-Folch, Marc Moreno-Masip, Yaima Martínez-Prieto, Albert Revuelta, Primiano Pio Di Mauro, Jaume Veciana, Santi Sala, Lidia Ferrer-Tasies and Nora Ventosa
Pharmaceutics 2022, 14(1), 199; https://doi.org/10.3390/pharmaceutics14010199 - 15 Jan 2022
Cited by 4 | Viewed by 3149
Abstract
Topical delivery has received great attention due to its localized drug delivery, its patient compliance, and its low risk for side effects. Recent developments have focused on studying new drug delivery systems as a strategy for addressing the challenges of current topical treatments. [...] Read more.
Topical delivery has received great attention due to its localized drug delivery, its patient compliance, and its low risk for side effects. Recent developments have focused on studying new drug delivery systems as a strategy for addressing the challenges of current topical treatments. Here we describe the advances on an innovative drug delivery platform called DELOS nanovesicles for topical drug delivery. Previously, the production of DELOS nanovesicles demonstrated potentiality for the topical treatment of complex wounds, achieving well-tolerated liquid dispersions by this route. Here, research efforts have been focused on designing these nanocarriers with the best skin tolerability to be applied even to damaged skin, and on exploring the feasibility of adapting the colloidal dispersions to a more suitable dosage form for topical application. Accordingly, these drug delivery systems have been efficiently evolved to a hydrogel using MethocelTM K4M, presenting proper stability and rheological properties. Further, the integrity of these nanocarriers when being gellified has been confirmed by cryo-transmission electron microscopy and by Förster resonance energy transfer analysis with fluorescent-labeled DELOS nanovesicles, which is a crucial characterization not widely reported in the literature. Additionally, in vitro experiments have shown that recombinant human Epidermal Growth Factor (rhEGF) protein integrated into gellified DELOS nanovesicles exhibits an enhanced bioactivity compared to the liquid form. Therefore, these studies suggest that such a drug delivery system is maintained unaltered when hydrogellified, becoming the DELOS nanovesicles-based hydrogels, an advanced formulation for topical use. Full article
(This article belongs to the Special Issue Skin Performance of Drug Delivery Systems: Scope, Challenges and Future Research and Regulatory Prospects)
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18 pages, 1608 KiB  
Review
Mesoporous Bioglasses Enriched with Bioactive Agents for Bone Repair, with a Special Highlight of María Vallet-Regí’s Contribution
by Antonio J. Salinas and Pedro Esbrit
Pharmaceutics 2022, 14(1), 202; https://doi.org/10.3390/pharmaceutics14010202 - 15 Jan 2022
Cited by 14 | Viewed by 3297
Abstract
Throughout her impressive scientific career, Prof. María Vallet-Regí opened various research lines aimed at designing new bioceramics, including mesoporous bioactive glasses for bone tissue engineering applications. These bioactive glasses can be considered a spin-off of silica mesoporous materials because they are designed with [...] Read more.
Throughout her impressive scientific career, Prof. María Vallet-Regí opened various research lines aimed at designing new bioceramics, including mesoporous bioactive glasses for bone tissue engineering applications. These bioactive glasses can be considered a spin-off of silica mesoporous materials because they are designed with a similar technical approach. Mesoporous glasses in addition to SiO2 contain significant amounts of other oxides, particularly CaO and P2O5 and therefore, they exhibit quite different properties and clinical applications than mesoporous silica compounds. Both materials exhibit ordered mesoporous structures with a very narrow pore size distribution that are achieved by using surfactants during their synthesis. The characteristics of mesoporous glasses made them suitable to be enriched with various osteogenic agents, namely inorganic ions and biopeptides as well as mesenchymal cells. In the present review, we summarize the evolution of mesoporous bioactive glasses research for bone repair, with a special highlight on the impact of Prof. María Vallet-Regí´s contribution to the field. Full article
(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Maria Vallet Regí: 20 Years of Silica-Based Mesoporous Materials)
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14 pages, 3539 KiB  
Article
Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials
by Naroa Serna, Aïda Falgàs, Annabel García-León, Ugutz Unzueta, Yáiza Núñez, Alejandro Sánchez-Chardi, Carlos Martínez-Torró, Ramón Mangues, Esther Vazquez, Isolda Casanova and Antonio Villaverde
Pharmaceutics 2022, 14(1), 192; https://doi.org/10.3390/pharmaceutics14010192 - 14 Jan 2022
Cited by 10 | Viewed by 2536
Abstract
The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically hybrid depots [...] Read more.
The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically hybrid depots and sustain a prolonged secretion of the therapeutic agent. For this, we covalently attached hydrophobic molecules (including the antitumoral drug Monomethyl Auristatin E) to a protein targeting a tumoral cell surface marker abundant in several human neoplasias, namely the cytokine receptor CXCR4. By this, a controlled aggregation of the complex is achieved, resulting in mechanically stable protein–drug microparticles. These materials, which are mimetics of bacterial inclusion bodies and of mammalian secretory granules, allow the slow leakage of fully functional conjugates at the nanoscale, both in vitro and in vivo. Upon subcutaneous administration in a mouse model of human CXCR4+ lymphoma, the protein–drug depots release nanoconjugates for at least 10 days, which accumulate in the tumor with a potent antitumoral effect. The modification of scaffold cell-targeted proteins by hydrophobic drug conjugation is then shown as a novel transversal platform for the design of slow releasing protein–drug depots, with potential application in a broad spectrum of clinical settings. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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18 pages, 2532 KiB  
Article
Evaluation of the Mucoadhesive Properties of Chitosan-Based Microstructured Lipid Carrier (CH-MLC)
by Marta Guerini, Giorgia Condrò and Paola Perugini
Pharmaceutics 2022, 14(1), 170; https://doi.org/10.3390/pharmaceutics14010170 - 12 Jan 2022
Cited by 14 | Viewed by 3604
Abstract
Different mucoadhesive systems have been studied in recent years to increase the residence time of the delivery systems and to prolong the release of the drug. The aim of this work was to evaluate the mucoadhesive properties of chitosan-based Microstructured Lipid Carrier (CH-MLC) [...] Read more.
Different mucoadhesive systems have been studied in recent years to increase the residence time of the delivery systems and to prolong the release of the drug. The aim of this work was to evaluate the mucoadhesive properties of chitosan-based Microstructured Lipid Carrier (CH-MLC) with a new approach which requires chitosan and mucin to be compacted into a tablet and mucoadhesion to be assessed on a non-mucoadhesive substrate. This type of test showed that chitosan maintains a close bond with mucin even in the presence of a fluid and even encapsulated in microparticles. After this, using a bioreactor, the release of N-acetylcysteine (NAC) from the microparticles (NA-CH-MLC) through a layer of mucus mimicking the pathological conditions of a patient with cystic fibrosis was tested. The release of the active from NAC-CH-MLC demonstrated how the chitosan inside the microparticles acts as a penetration enhancer and how the microparticles can impart a prolonged release over time. Full article
(This article belongs to the Topic Cystic Fibrosis)
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43 pages, 7542 KiB  
Article
Insights from a Box–Behnken Optimization Study of Microemulsions with Salicylic Acid for Acne Therapy
by Maria-Cristina Anicescu, Cristina-Elena Dinu-Pîrvu, Marina-Theodora Talianu, Mihaela Violeta Ghica, Valentina Anuța, Răzvan-Mihai Prisada, Anca Cecilia Nicoară and Lăcrămioara Popa
Pharmaceutics 2022, 14(1), 174; https://doi.org/10.3390/pharmaceutics14010174 - 12 Jan 2022
Cited by 8 | Viewed by 3355
Abstract
The present study brings to attention a method to develop salicylic acid-based oil in water (O/W) microemulsions using a tensioactive system based on Tween 80, lecithin, and propylene glycol (PG), enriched with a vegetable oat oil phase and hyaluronic acid. The systems were [...] Read more.
The present study brings to attention a method to develop salicylic acid-based oil in water (O/W) microemulsions using a tensioactive system based on Tween 80, lecithin, and propylene glycol (PG), enriched with a vegetable oat oil phase and hyaluronic acid. The systems were physically characterized and the Quality by design approach was applied to optimize the attributes of microemulsions using Box–Behnken modeling, combined with response surface methodology. For this purpose, a 33 fractional factorial design was selected. The effect of independent variables namely X1: Tween 80/PG (%), X2: Lecithin (%), X3: Oil phase (%) was analyzed considering their impact upon the internal structure and evaluated parameters chosen as dependent factors: viscosity, mean droplet size, and work of adhesion. A high viscosity, a low droplet size, an adequate wettability—with a reduced mechanical work—and clarity were considered as desirable for the optimal systems. It was found that the optimal microemulsion which complied with the established conditions was based on: Tween 80/PG 40%, lecithin 0.3%, oat oil 2%, salicylic acid 0.5%, hyaluronic acid 1%, and water 56.2%. The response surface methodology was considered an appropriate tool to explain the impact of formulation factors on the physical properties of microemulsions, offering a complex pattern in the assessment of stability and quality attributes for the optimized formulation. Full article
(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)
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17 pages, 1797 KiB  
Review
Disrupting GPCR Complexes with Smart Drug-like Peptides
by Maria Gallo, Sira Defaus and David Andreu
Pharmaceutics 2022, 14(1), 161; https://doi.org/10.3390/pharmaceutics14010161 - 11 Jan 2022
Cited by 11 | Viewed by 3340
Abstract
G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure [...] Read more.
G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action. However, despite such potential, TM-derived, GPCR-disrupting peptides often suffer from inadequate pharmacokinetic properties, such as low bioavailability, a short half-life or rapid clearance, which put into question their therapeutic relevance and promise. In this review, we provide a comprehensive overview of GPCR complexes, with an emphasis on current studies using GPCR-disrupting peptides mimicking TM domains involved in multimerization, and we also highlight recent strategies used to achieve drug-like versions of such TM peptide candidates for therapeutic application. Full article
(This article belongs to the Special Issue Chemically Enhanced Peptide and Protein Therapeutics)
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20 pages, 4495 KiB  
Article
Superparamagnetic Iron Oxide Nanoparticles Decorated Mesoporous Silica Nanosystem for Combined Antibiofilm Therapy
by Elena Álvarez, Manuel Estévez, Alvaro Gallo-Cordova, Blanca González, Rafael R. Castillo, María del Puerto Morales, Montserrat Colilla, Isabel Izquierdo-Barba and María Vallet-Regí
Pharmaceutics 2022, 14(1), 163; https://doi.org/10.3390/pharmaceutics14010163 - 11 Jan 2022
Cited by 22 | Viewed by 3436
Abstract
A crucial challenge to face in the treatment of biofilm-associated infection is the ability of bacteria to develop resistance to traditional antimicrobial therapies based on the administration of antibiotics alone. This study aims to apply magnetic hyperthermia together with controlled antibiotic delivery from [...] Read more.
A crucial challenge to face in the treatment of biofilm-associated infection is the ability of bacteria to develop resistance to traditional antimicrobial therapies based on the administration of antibiotics alone. This study aims to apply magnetic hyperthermia together with controlled antibiotic delivery from a unique magnetic-responsive nanocarrier for a combination therapy against biofilm. The design of the nanosystem is based on antibiotic-loaded mesoporous silica nanoparticles (MSNs) externally functionalized with a thermo-responsive polymer capping layer, and decorated in the outermost surface with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are able to generate heat upon application of an alternating magnetic field (AMF), reaching the temperature needed to induce a change in the polymer conformation from linear to globular, therefore triggering pore uncapping and the antibiotic cargo release. The microbiological assays indicated that exposure of E. coli biofilms to 200 µg/mL of the nanosystem and the application of an AMF (202 kHz, 30 mT) decreased the number of viable bacteria by 4 log10 units compared with the control. The results of the present study show that combined hyperthermia and antibiotic treatment is a promising approach for the effective management of biofilm-associated infections. Full article
(This article belongs to the Topic Emerging Material-Based Approaches to Chronic and Infectious Diseases)
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31 pages, 2178 KiB  
Review
Tunable Spun Fiber Constructs in Biomedicine: Influence of Processing Parameters in the Fibers’ Architecture
by Catarina S. Miranda, Ana Francisca G. Silva, Sílvia M. M. A. Pereira-Lima, Susana P. G. Costa, Natália C. Homem and Helena P. Felgueiras
Pharmaceutics 2022, 14(1), 164; https://doi.org/10.3390/pharmaceutics14010164 - 11 Jan 2022
Cited by 32 | Viewed by 3919
Abstract
Electrospinning and wet-spinning have been recognized as two of the most efficient and promising techniques for producing polymeric fibrous constructs for a wide range of applications, including optics, electronics, food industry and biomedical applications. They have gained considerable attention in the past few [...] Read more.
Electrospinning and wet-spinning have been recognized as two of the most efficient and promising techniques for producing polymeric fibrous constructs for a wide range of applications, including optics, electronics, food industry and biomedical applications. They have gained considerable attention in the past few decades because of their unique features and tunable architectures that can mimic desirable biological features, responding more effectively to local demands. In this review, various fiber architectures and configurations, varying from monolayer and core-shell fibers to tri-axial, porous, multilayer, side-by-side and helical fibers, are discussed, highlighting the influence of processing parameters in the final constructs. Additionally, the envisaged biomedical purposes for the examined fiber architectures, mainly focused on drug delivery and tissue engineering applications, are explored at great length. Full article
(This article belongs to the Special Issue Electrospun Materials for Biomedical Applications)
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22 pages, 4598 KiB  
Article
Novel Nanoparticles Based on N,O-Carboxymethyl Chitosan-Dopamine Amide Conjugate for Nose-to-Brain Delivery
by Adriana Trapani, Stefania Cometa, Elvira De Giglio, Filomena Corbo, Roberta Cassano, Maria Luisa Di Gioia, Sonia Trombino, Md Niamat Hossain, Sante Di Gioia, Giuseppe Trapani and Massimo Conese
Pharmaceutics 2022, 14(1), 147; https://doi.org/10.3390/pharmaceutics14010147 - 8 Jan 2022
Cited by 18 | Viewed by 3054
Abstract
A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson’s disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying [...] Read more.
A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson’s disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying therapy. Although several bio-nanomaterials have been evaluated for encapsulation of neurotransmitter dopamine (DA) or dopaminergic drugs in order to restore the DA content in parkinsonian patients, the premature leakage of the therapeutic agent limits this approach. To tackle this drawback, we undertook a study where the active was linked to the polymeric backbone by a covalent bond. Thus, novel nanoparticles (NPs) based on N,O-Carboxymethylchitosan-DA amide conjugate (N,O-CMCS-DA) were prepared by the nanoprecipitation method and characterized from a technological view point, cytotoxicity and uptake by Olfactory Ensheating Cells (OECs). Thermogravimetric analysis showed high chemical stability of N,O-CMCS-DA NPs and X-ray photoelectron spectroscopy evidenced the presence of amide linkages on the NPs surface. MTT test indicated their cytocompatibility with OECs, while cytofluorimetry and fluorescent microscopy revealed the internalization of labelled N,O-CMCS-DA NPs by OECs, that was increased by the presence of mucin. Altogether, these findings seem promising for further development of N,O-CMCS-DA NPs for nose-to-brain delivery application in PD. Full article
(This article belongs to the Special Issue Intranasal Administration: Potential Route as Diverse Targeting Systems)
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31 pages, 4598 KiB  
Review
Advanced Microfluidic Technologies for Lipid Nano-Microsystems from Synthesis to Biological Application
by Bruna G. Carvalho, Bruno T. Ceccato, Mariano Michelon, Sang W. Han and Lucimara G. de la Torre
Pharmaceutics 2022, 14(1), 141; https://doi.org/10.3390/pharmaceutics14010141 - 7 Jan 2022
Cited by 42 | Viewed by 9887
Abstract
Microfluidics is an emerging technology that can be employed as a powerful tool for designing lipid nano-microsized structures for biological applications. Those lipid structures can be used as carrying vehicles for a wide range of drugs and genetic materials. Microfluidic technology also allows [...] Read more.
Microfluidics is an emerging technology that can be employed as a powerful tool for designing lipid nano-microsized structures for biological applications. Those lipid structures can be used as carrying vehicles for a wide range of drugs and genetic materials. Microfluidic technology also allows the design of sustainable processes with less financial demand, while it can be scaled up using parallelization to increase production. From this perspective, this article reviews the recent advances in the synthesis of lipid-based nanostructures through microfluidics (liposomes, lipoplexes, lipid nanoparticles, core-shell nanoparticles, and biomimetic nanovesicles). Besides that, this review describes the recent microfluidic approaches to produce lipid micro-sized structures as giant unilamellar vesicles. New strategies are also described for the controlled release of the lipid payloads using microgels and droplet-based microfluidics. To address the importance of microfluidics for lipid-nanoparticle screening, an overview of how microfluidic systems can be used to mimic the cellular environment is also presented. Future trends and perspectives in designing novel nano and micro scales are also discussed herein. Full article
(This article belongs to the Special Issue Recent Trends on Liposome Technology: From Emerging Synthesis Strategies to Advanced Lipid Nanosystems for Drug Delivery)
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20 pages, 32370 KiB  
Article
Enzyme-Responsive Amphiphilic Peptide Nanoparticles for Biocompatible and Efficient Drug Delivery
by Su Jeong Song and Joon Sig Choi
Pharmaceutics 2022, 14(1), 143; https://doi.org/10.3390/pharmaceutics14010143 - 7 Jan 2022
Cited by 15 | Viewed by 3109
Abstract
Self-assembled peptide nanostructures recently have gained much attention as drug delivery systems. As biomolecules, peptides have enhanced biocompatibility and biodegradability compared to polymer-based carriers. We introduce a peptide nanoparticle system containing arginine, histidine, and an enzyme-responsive core of repeating GLFG oligopeptides. GLFG oligopeptides [...] Read more.
Self-assembled peptide nanostructures recently have gained much attention as drug delivery systems. As biomolecules, peptides have enhanced biocompatibility and biodegradability compared to polymer-based carriers. We introduce a peptide nanoparticle system containing arginine, histidine, and an enzyme-responsive core of repeating GLFG oligopeptides. GLFG oligopeptides exhibit specific sensitivity towards the enzyme cathepsin B that helps effective controlled release of cargo molecules in the cytoplasm. Arginine can induce cell penetration, and histidine facilitates lysosomal escape by its buffering capacity. Herein, we propose an enzyme-responsive amphiphilic peptide delivery system (Arg-His-(Gly-Phe-Lue-Gly)3, RH-(GFLG)3). The self-assembled RH-(GFLG)3 globular nanoparticle structure exhibited a positive charge and formulation stability for 35 days. Nile Red-tagged RH-(GFLG)3 nanoparticles showed good cellular uptake compared to the non-enzyme-responsive control groups with d-form peptides (LD (LRH-D(GFLG)3), DL (DRH-L(GFLG)3), and DD (DRH-D(GFLG)3). The RH-(GFLG)3 nanoparticles showed negligible cytotoxicity in HeLa cells and human RBCs. To determine the drug delivery efficacy, we introduced the anticancer drug doxorubicin (Dox) in the RH-(GFLG)3 nanoparticle system. LL-Dox exhibited formulation stability, maintaining the physical properties of the nanostructure, as well as a robust anticancer effect in HeLa cells compared to DD-Dox. These results indicate that the enzyme-sensitive RH-(GFLG)3 peptide nanoparticles are promising candidates as drug delivery carriers for biomedical applications. Full article
(This article belongs to the Special Issue Biodegradable, Biocompatible Carriers for Drug and Gene Delivery)
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32 pages, 7831 KiB  
Review
Polysaccharide 3D Printing for Drug Delivery Applications
by Alexandra Zamboulis, Georgia Michailidou, Ioanna Koumentakou and Dimitrios N. Bikiaris
Pharmaceutics 2022, 14(1), 145; https://doi.org/10.3390/pharmaceutics14010145 - 7 Jan 2022
Cited by 57 | Viewed by 6704
Abstract
3D printing, or additive manufacturing, has gained considerable interest due to its versatility regarding design as well as in the large choice of materials. It is a powerful tool in the field of personalized pharmaceutical treatment, particularly crucial for pediatric and geriatric patients. [...] Read more.
3D printing, or additive manufacturing, has gained considerable interest due to its versatility regarding design as well as in the large choice of materials. It is a powerful tool in the field of personalized pharmaceutical treatment, particularly crucial for pediatric and geriatric patients. Polysaccharides are abundant and inexpensive natural polymers, that are already widely used in the food industry and as excipients in pharmaceutical and cosmetic formulations. Due to their intrinsic properties, such as biocompatibility, biodegradability, non-immunogenicity, etc., polysaccharides are largely investigated as matrices for drug delivery. Although an increasing number of interesting reviews on additive manufacturing and drug delivery are being published, there is a gap concerning the printing of polysaccharides. In this article, we will review recent advances in the 3D printing of polysaccharides focused on drug delivery applications. Among the large family of polysaccharides, the present review will particularly focus on cellulose and cellulose derivatives, chitosan and sodium alginate, printed by fused deposition modeling and extrusion-based printing. Full article
(This article belongs to the Special Issue Functional Polymeric Materials for Drug Delivery and Sustained Drug Release)
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16 pages, 3643 KiB  
Review
Gene Therapy Using Nanocarriers for Pancreatic Ductal Adenocarcinoma: Applications and Challenges in Cancer Therapeutics
by Eun-Jeong Won, Hyeji Park, Tae-Jong Yoon and Young-Seok Cho
Pharmaceutics 2022, 14(1), 137; https://doi.org/10.3390/pharmaceutics14010137 - 6 Jan 2022
Cited by 6 | Viewed by 3243
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and its incidence is increasing. PDAC often shows resistance to several therapeutic modalities and a higher recurrence rate after surgical treatment in the early localized stage. Combination chemotherapy in advanced pancreatic [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and its incidence is increasing. PDAC often shows resistance to several therapeutic modalities and a higher recurrence rate after surgical treatment in the early localized stage. Combination chemotherapy in advanced pancreatic cancer has minimal impact on overall survival. RNA interference (RNAi) is a promising tool for regulating target genes to achieve sequence-specific gene silencing. Here, we summarize RNAi-based therapeutics using nanomedicine-based delivery systems that are currently being tested in clinical trials and are being developed for the treatment of PDAC. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing has been widely used for the development of cancer models as a genetic screening tool for the identification and validation of therapeutic targets, as well as for potential cancer therapeutics. This review discusses current advances in CRISPR/Cas9 technology and its application to PDAC research. Continued progress in understanding the PDAC tumor microenvironment and nanomedicine-based gene therapy will improve the clinical outcomes of patients with PDAC. Full article
(This article belongs to the Special Issue Cancer Gene Therapy With Non-Viral Nanocarriers)
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23 pages, 8259 KiB  
Article
Tailoring of Novel Azithromycin-Loaded Zinc Oxide Nanoparticles for Wound Healing
by Mohammed S. Saddik, Mahmoud M. A. Elsayed, Mohamed A. El-Mokhtar, Haitham Sedky, Jelan A. Abdel-Aleem, Ahmed M. Abu-Dief, Mostafa F. Al-Hakkani, Hazem L. Hussein, Samah A. Al-Shelkamy, Fatma Y. Meligy, Ali Khames and Heba A. Abou-Taleb
Pharmaceutics 2022, 14(1), 111; https://doi.org/10.3390/pharmaceutics14010111 - 5 Jan 2022
Cited by 85 | Viewed by 6075
Abstract
Skin is the largest mechanical barrier against invading pathogens. Following skin injury, the healing process immediately starts to regenerate the damaged tissues and to avoid complications that usually include colonization by pathogenic bacteria, leading to fever and sepsis, which further impairs and complicates [...] Read more.
Skin is the largest mechanical barrier against invading pathogens. Following skin injury, the healing process immediately starts to regenerate the damaged tissues and to avoid complications that usually include colonization by pathogenic bacteria, leading to fever and sepsis, which further impairs and complicates the healing process. So, there is an urgent need to develop a novel pharmaceutical material that promotes the healing of infected wounds. The present work aimed to prepare and evaluate the efficacy of novel azithromycin-loaded zinc oxide nanoparticles (AZM-ZnONPs) in the treatment of infected wounds. The Box–Behnken design and response surface methodology were used to evaluate loading efficiency and release characteristics of the prepared NPs. The minimum inhibitory concentration (MIC) of the formulations was determined against Staphylococcus aureus and Escherichia coli. Moreover, the anti-bacterial and wound-healing activities of the AZM-loaded ZnONPs impregnated into hydroxyl propyl methylcellulose (HPMC) gel were evaluated in an excisional wound model in rats. The prepared ZnONPs were loaded with AZM by adsorption. The prepared ZnONPs were fully characterized by XRD, EDAX, SEM, TEM, and FT-IR analysis. Particle size distribution for the prepared ZnO and AZM-ZnONPs were determined and found to be 34 and 39 nm, respectively. The mechanism by which AZM adsorbed on the surface of ZnONPs was the best fit by the Freundlich model with a maximum load capacity of 160.4 mg/g. Anti-microbial studies showed that AZM-ZnONPs were more effective than other controls. Using an experimental infection model in rats, AZM-ZnONPs impregnated into HPMC gel enhanced bacterial clearance and epidermal regeneration, and stimulated tissue formation. In conclusion, AZM -loaded ZnONPs are a promising platform for effective and rapid healing of infected wounds. Full article
(This article belongs to the Special Issue Biopolymer Materials for Wound Healing)
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30 pages, 1320 KiB  
Review
A Narrative Review of Cell-Based Approaches for Cranial Bone Regeneration
by Maria I. Falguera Uceda, Silvia Sánchez-Casanova, Clara Escudero-Duch and Nuria Vilaboa
Pharmaceutics 2022, 14(1), 132; https://doi.org/10.3390/pharmaceutics14010132 - 5 Jan 2022
Cited by 10 | Viewed by 3652
Abstract
Current cranial repair techniques combine the use of autologous bone grafts and biomaterials. In addition to their association with harvesting morbidity, autografts are often limited by insufficient quantity of bone stock. Biomaterials lead to better outcomes, but their effectiveness is often compromised by [...] Read more.
Current cranial repair techniques combine the use of autologous bone grafts and biomaterials. In addition to their association with harvesting morbidity, autografts are often limited by insufficient quantity of bone stock. Biomaterials lead to better outcomes, but their effectiveness is often compromised by the unpredictable lack of integration and structural failure. Bone tissue engineering offers the promising alternative of generating constructs composed of instructive biomaterials including cells or cell-secreted products, which could enhance the outcome of reconstructive treatments. This review focuses on cell-based approaches with potential to regenerate calvarial bone defects, including human studies and preclinical research. Further, we discuss strategies to deliver extracellular matrix, conditioned media and extracellular vesicles derived from cell cultures. Recent advances in 3D printing and bioprinting techniques that appear to be promising for cranial reconstruction are also discussed. Finally, we review cell-based gene therapy approaches, covering both unregulated and regulated gene switches that can create spatiotemporal patterns of transgenic therapeutic molecules. In summary, this review provides an overview of the current developments in cell-based strategies with potential to enhance the surgical armamentarium for regenerating cranial vault defects. Full article
(This article belongs to the Special Issue Application of Nano- and Bio-materials in Cell-Based Therapy)
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25 pages, 4060 KiB  
Review
Silica-Based Stimuli-Responsive Systems for Antitumor Drug Delivery and Controlled Release
by Avelino Corma, Pablo Botella and Eva Rivero-Buceta
Pharmaceutics 2022, 14(1), 110; https://doi.org/10.3390/pharmaceutics14010110 - 4 Jan 2022
Cited by 28 | Viewed by 3769
Abstract
The administration of cytotoxic drugs in classical chemotherapy is frequently limited by water solubility, low plasmatic stability, and a myriad of secondary effects associated with their diffusion to healthy tissue. In this sense, novel pharmaceutical forms able to deliver selectively these drugs to [...] Read more.
The administration of cytotoxic drugs in classical chemotherapy is frequently limited by water solubility, low plasmatic stability, and a myriad of secondary effects associated with their diffusion to healthy tissue. In this sense, novel pharmaceutical forms able to deliver selectively these drugs to the malign cells, and imposing a space-time precise control of their discharge, are needed. In the last two decades, silica nanoparticles have been proposed as safe vehicles for antitumor molecules due to their stability in physiological medium, high surface area and easy functionalization, and good biocompatibility. In this review, we focus on silica-based nanomedicines provided with specific mechanisms for intracellular drug release. According to silica nature (amorphous, mesostructured, and hybrids) nanocarriers responding to a variety of stimuli endogenously (e.g., pH, redox potential, and enzyme activity) or exogenously (e.g., magnetic field, light, temperature, and ultrasound) are proposed. Furthermore, the incorporation of targeting molecules (e.g., monoclonal antibodies) that interact with specific cell membrane receptors allows a selective delivery to cancer cells to be carried out. Eventually, we present some remarks on the most important formulations in the pipeline for clinical approval, and we discuss the most difficult tasks to tackle in the near future, in order to extend the use of these nanomedicines to real patients. Full article
(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Maria Vallet Regí: 20 Years of Silica-Based Mesoporous Materials)
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11 pages, 1099 KiB  
Article
Implementation and Comparison of Two Pharmacometric Tools for Model-Based Therapeutic Drug Monitoring and Precision Dosing of Daptomycin
by Justine Heitzmann, Yann Thoma, Romain Bricca, Marie-Claude Gagnieu, Vincent Leclerc, Sandrine Roux, Anne Conrad, Tristan Ferry and Sylvain Goutelle
Pharmaceutics 2022, 14(1), 114; https://doi.org/10.3390/pharmaceutics14010114 - 4 Jan 2022
Cited by 10 | Viewed by 2243
Abstract
Daptomycin is a candidate for therapeutic drug monitoring (TDM). The objectives of this work were to implement and compare two pharmacometric tools for daptomycin TDM and precision dosing. A nonparametric population PK model developed from patients with bone and joint infection was implemented [...] Read more.
Daptomycin is a candidate for therapeutic drug monitoring (TDM). The objectives of this work were to implement and compare two pharmacometric tools for daptomycin TDM and precision dosing. A nonparametric population PK model developed from patients with bone and joint infection was implemented into the BestDose software. A published parametric model was imported into Tucuxi. We compared the performance of the two models in a validation dataset based on mean error (ME) and mean absolute percent error (MAPE) of individual predictions, estimated exposure and predicted doses necessary to achieve daptomycin efficacy and safety PK/PD targets. The BestDose model described the data very well in the learning dataset. In the validation dataset (94 patients, 264 concentrations), 21.3% of patients were underexposed (AUC24h < 666 mg.h/L) and 31.9% of patients were overexposed (Cmin > 24.3 mg/L) on the first TDM occasion. The BestDose model performed slightly better than the model in Tucuxi (ME = −0.13 ± 5.16 vs. −1.90 ± 6.99 mg/L, p < 0.001), but overall results were in agreement between the two models. A significant proportion of patients exhibited underexposure or overexposure to daptomycin after the initial dosage, which supports TDM. The two models may be useful for model-informed precision dosing. Full article
(This article belongs to the Special Issue Innovative Tools for Therapeutic Drug Monitoring)
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21 pages, 556 KiB  
Review
Development of Pharmaceutical Nanomedicines: From the Bench to the Market
by Abdulrahman A. Halwani
Pharmaceutics 2022, 14(1), 106; https://doi.org/10.3390/pharmaceutics14010106 - 3 Jan 2022
Cited by 143 | Viewed by 8217
Abstract
Nanotechnology plays a significant role in the field of medicine and in drug delivery, mainly due to the major limitations affecting the conventional pharmaceutical agents, and older formulations and delivery systems. The effect of nanotechnology on healthcare is already being felt, as various [...] Read more.
Nanotechnology plays a significant role in the field of medicine and in drug delivery, mainly due to the major limitations affecting the conventional pharmaceutical agents, and older formulations and delivery systems. The effect of nanotechnology on healthcare is already being felt, as various nanotechnology applications have been developed, and several nanotechnology-based medicines are now on the market. Across many parts of the world, nanotechnology draws increasing investment from public authorities and the private sector. Most conventional drug-delivery systems (CDDSs) have an immediate, high drug release after administration, leading to increased administration frequency. Thus, many studies have been carried out worldwide focusing on the development of pharmaceutical nanomedicines for translation into products manufactured by local pharmaceutical companies. Pharmaceutical nanomedicine products are projected to play a major role in the global pharmaceutical market and healthcare system. Our objectives were to examine the nanomedicines approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in the global market, to briefly cover the challenges faced during their development, and to look at future perspectives. Additionally, the importance of nanotechnology in developing pharmaceutical products, the ideal properties of nanocarriers, the reasons behind the failure of some nanomedicines, and the important considerations in the development of nanomedicines will be discussed in brief. Full article
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20 pages, 2457 KiB  
Article
Purification Process of a Recombinant Human Follicle Stimulating Hormone Biosimilar (Primapur®) to Yield a Pharmaceutical Product with High Batch-to-Batch Consistency
by Maria Sinegubova, Ivan Vorobiev, Anatoly Klishin, Dmitry Eremin, Nadezhda Orlova, Natalya Orlova and Mikhail Polzikov
Pharmaceutics 2022, 14(1), 96; https://doi.org/10.3390/pharmaceutics14010096 - 1 Jan 2022
Cited by 4 | Viewed by 4454
Abstract
Recombinant human follicle stimulating hormone (r-hFSH) is widely used for infertility treatment and is subject to the development of biosimilars. There are different purification strategies that can yield r-hFSH of pharmaceutical quality from Chinese hamster ovary cell culture broth. We developed a purification [...] Read more.
Recombinant human follicle stimulating hormone (r-hFSH) is widely used for infertility treatment and is subject to the development of biosimilars. There are different purification strategies that can yield r-hFSH of pharmaceutical quality from Chinese hamster ovary cell culture broth. We developed a purification process for r-hFSH centered on immunoaffinity chromatography with single-domain recombinant camelid antibodies. The resulting downstream process is simple and devoid of ultrafiltration operations. Studies on chromatography resin resource and ligand leakage showed that the immunoaffinity matrix employed was suitable for industrial use and stable for at least 40 full chromatography cycles, and the leaked single-domain antibody ligand was completely removed by subsequent purification steps. All chromatography resins employed withstood the same 40 cycles of use without significant changes in separation efficiency and product binding capacity. The resulting industrial purification process yielded batches of r-hFSH with consistent levels of purity and bioactivity. Full article
(This article belongs to the Special Issue Design, Development, and Characterization of Drug and Gene Delivery Systems in the Russian Federation)
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18 pages, 1591 KiB  
Review
Making Sense of Antisense Oligonucleotide Therapeutics Targeting Bcl-2
by Maria Gagliardi and Ana Tari Ashizawa
Pharmaceutics 2022, 14(1), 97; https://doi.org/10.3390/pharmaceutics14010097 - 1 Jan 2022
Cited by 15 | Viewed by 3249
Abstract
The B-cell lymphoma 2 (Bcl-2) family, comprised of pro- and anti-apoptotic proteins, regulates the delicate balance between programmed cell death and cell survival. The Bcl-2 family is essential in the maintenance of tissue homeostasis, but also a key culprit in tumorigenesis. Anti-apoptotic Bcl-2, [...] Read more.
The B-cell lymphoma 2 (Bcl-2) family, comprised of pro- and anti-apoptotic proteins, regulates the delicate balance between programmed cell death and cell survival. The Bcl-2 family is essential in the maintenance of tissue homeostasis, but also a key culprit in tumorigenesis. Anti-apoptotic Bcl-2, the founding member of this family, was discovered due to its dysregulated expression in non-Hodgkin’s lymphoma. Bcl-2 is a central protagonist in a wide range of human cancers, promoting cell survival, angiogenesis and chemotherapy resistance; this has prompted the development of Bcl-2-targeting drugs. Antisense oligonucleotides (ASO) are highly specific nucleic acid polymers used to modulate target gene expression. Over the past 25 years several Bcl-2 ASO have been developed in preclinical studies and explored in clinical trials. This review will describe the history and development of Bcl-2-targeted ASO; from initial attempts, optimizations, clinical trials undertaken and the promising candidates at hand. Full article
(This article belongs to the Special Issue Oligonucleotides and Nucleic-Acid-Based Strategies to Address Therapeutic Challenges: From the Bench to the Bedside)
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