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Pharmaceutics
Volume 12
Issue 7
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Pharmaceutics, Volume 12, Issue 7 (July 2020) – 94 articles

Cover Story (view full-size image): In this study, biodegradable polymeric multilayer microcapsules were assembled from dextran sulfate and poly-L-arginine, then loaded with a photosensitizer that efficiently eliminated cancer cells and microbial pathogens. The capsules were loaded with a water-soluble cationic photosensitizer, Cholosens, after removing the CaCO3 template. Possessing low toxicity in the original state, the encapsulated forms of Cholosens acquired significant cyto- and bacterial toxicity, which was triggered by 680 mn light and a result of the singlet oxygen generated by a photosensitizer. In this paper, we discovered the potential of Cholosens to be efficient as a PDT drug for both eukaryotic cells and bacteria at specified capsule-to-cell ratios. View this paper
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28 pages, 8042 KiB  
Article
Salt Cocrystal of Diclofenac Sodium-L-Proline: Structural, Pseudopolymorphism, and Pharmaceutics Performance Study
by Ilma Nugrahani, Rizka A. Kumalasari, Winni N. Auli, Ayano Horikawa and Hidehiro Uekusa
Pharmaceutics 2020, 12(7), 690; https://doi.org/10.3390/pharmaceutics12070690 - 21 Jul 2020
Cited by 25 | Viewed by 5777
Abstract
Previously, we have reported on a zwitterionic cocrystal of diclofenac acid and L-proline. However, the solubility of this multicomponent crystal was still lower than that of diclofenac sodium salt. Therefore, this study aimed to observe whether a multicomponent crystal could be produced from [...] Read more.
Previously, we have reported on a zwitterionic cocrystal of diclofenac acid and L-proline. However, the solubility of this multicomponent crystal was still lower than that of diclofenac sodium salt. Therefore, this study aimed to observe whether a multicomponent crystal could be produced from diclofenac sodium hydrate with the same coformer, L-proline, which was expected to improve the pharmaceutics performance. Methods involved screening, solid phase characterization, structure determination, stability, and in vitro pharmaceutical performance tests. First, a phase diagram screen was carried out to identify the molar ratio of the multicomponent crystal formation. Next, the single crystals were prepared by slow evaporation under two conditions, which yielded two forms: one was a rod-shape and the second was a flat-square form. The characterization by infrared spectroscopy, thermal analysis, and diffractometry confirmed the formation of the new phases. Finally, structural determination using single crystal X-ray diffraction analysis solved the new salt cocrystals as a stable diclofenac–sodium–proline–water (1:1:1:4) named NDPT (natrium diclofenac proline tetrahydrate), and unstable diclofenac–sodium–proline–water (1:1:1:1), named NDPM (natrium diclofenac proline monohydrate). The solubility and dissolution rate of these multicomponent crystals were superior to those of diclofenac sodium alone. The experimental results that this salt cocrystal is suitable for further development. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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18 pages, 3992 KiB  
Article
Combinatorial Inhibition of Cell Surface Receptors Using Dual Aptamer-Functionalized Nanoconstructs for Cancer Treatment
by Hyojin Lee, Tae Hee Kim, Daechan Park, Mihue Jang, Justin J. Chung, Soo Hyun Kim, Sang-Heon Kim, Kwan Hyi Lee, Youngmee Jung and Seung Ja Oh
Pharmaceutics 2020, 12(7), 689; https://doi.org/10.3390/pharmaceutics12070689 - 21 Jul 2020
Cited by 4 | Viewed by 2608
Abstract
Membrane receptors overexpressed in diseased states are considered novel therapeutic targets. However, the single targeting approach faces several fundamental issues, such as poor efficacy, resistance, and toxicity. Here, we report a dual-targeting strategy to enhance anti-cancer efficacy via synergistic proximity interactions between therapeutics [...] Read more.
Membrane receptors overexpressed in diseased states are considered novel therapeutic targets. However, the single targeting approach faces several fundamental issues, such as poor efficacy, resistance, and toxicity. Here, we report a dual-targeting strategy to enhance anti-cancer efficacy via synergistic proximity interactions between therapeutics and two receptor proteins. Importantly, we report the first finding of an interaction between c-Met and nucleolin and demonstrate the therapeutic value of targeting the interaction between them. Bispecific nanocarriers densely grafted with anti-c-Met and -nucleolin aptamer increased the local concentration of aptamers at the target sites, in addition to inducing target receptor clustering. It was also demonstrated that the simultaneous targeting of c-Met and nucleolin inhibited the cellular functions of the receptors and increased anti-cancer efficacy by altering the cell cycle. Our findings pave the way for the development of an effective combinatorial treatment based on nanoconstruct-mediated interaction between receptors. Full article
(This article belongs to the Special Issue Stimuli-Responsive Nanomedicine for the Effective and Controlled Delivery of Drug Molecules to the Tumor Microenvironment)
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35 pages, 1903 KiB  
Review
Surface Active Agents and Their Health-Promoting Properties: Molecules of Multifunctional Significance
by Ioannis Anestopoulos, Despoina Eugenia Kiousi, Ariel Klavaris, Alex Galanis, Karina Salek, Stephen R. Euston, Aglaia Pappa and Mihalis I. Panayiotidis
Pharmaceutics 2020, 12(7), 688; https://doi.org/10.3390/pharmaceutics12070688 - 21 Jul 2020
Cited by 42 | Viewed by 5325
Abstract
Surface active agents (SAAs) are molecules with the capacity to adsorb to solid surfaces and/or fluid interfaces, a property that allows them to act as multifunctional ingredients (e.g., wetting and dispersion agents, emulsifiers, foaming and anti-foaming agents, lubricants, etc.) in a widerange of [...] Read more.
Surface active agents (SAAs) are molecules with the capacity to adsorb to solid surfaces and/or fluid interfaces, a property that allows them to act as multifunctional ingredients (e.g., wetting and dispersion agents, emulsifiers, foaming and anti-foaming agents, lubricants, etc.) in a widerange of the consumer products of various industrial sectors (e.g., pharmaceuticals, cosmetics, personal care, detergents, food, etc.). Given their widespread utilization, there is a continuously growing interest to explore their role in consumer products (relevant to promoting human health) and how such information can be utilized in order to synthesize better chemical derivatives. In this review article, weaimed to provide updated information on synthetic and biological (biosurfactants) SAAs and their health-promoting properties (e.g., anti-microbial, anti-oxidant, anti-viral, anti-inflammatory, anti-cancer and anti-aging) in an attempt to better define some of the underlying mechanism(s) by which they exert such properties. Full article
(This article belongs to the Special Issue Biosurfactants as Multifunctional Ingredients for Emerging Pharmaceutical Formulations)
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22 pages, 3781 KiB  
Article
Porous Nanostructure, Lipid Composition, and Degree of Drug Supersaturation Modulate In Vitro Fenofibrate Solubilization in Silica-Lipid Hybrids
by Ruba Almasri, Paul Joyce, Hayley B. Schultz, Nicky Thomas, Kristen E. Bremmell and Clive A. Prestidge
Pharmaceutics 2020, 12(7), 687; https://doi.org/10.3390/pharmaceutics12070687 - 21 Jul 2020
Cited by 6 | Viewed by 2956
Abstract
The unique nanostructured matrix obtained by silica-lipid hybrids (SLHs) is well known to improve the dissolution, absorption, and bioavailability of poorly water-soluble drugs (PWSDs). The aim of this study was to investigate the impact of: (i) drug load: 3–22.7% w/w, (ii) lipid [...] Read more.
The unique nanostructured matrix obtained by silica-lipid hybrids (SLHs) is well known to improve the dissolution, absorption, and bioavailability of poorly water-soluble drugs (PWSDs). The aim of this study was to investigate the impact of: (i) drug load: 3–22.7% w/w, (ii) lipid type: medium-chain triglyceride (Captex 300) and mono and diester of caprylic acid (Capmul PG8), and (iii) silica nanostructure: spray dried fumed silica (FS) and mesoporous silica (MPS), on the in vitro dissolution, solubilization, and solid-state stability of the model drug fenofibrate (FEN). Greater FEN crystallinity was detected at higher drug loads and within the MPS formulations. Furthermore, an increased rate and extent of dissolution was achieved by FS formulations when compared to crystalline FEN (5–10-fold), a commercial product; APO-fenofibrate (2.4–4-fold) and corresponding MPS formulations (2–4-fold). Precipitation of FEN during in vitro lipolysis restricted data interpretation, however a synergistic effect between MPS and Captex 300 in enhancing FEN aqueous solubilization was attained. It was concluded that a balance between in vitro performance and drug loading is key, and the optimum drug load was determined to be between 7–16% w/w, which corresponds to (200–400% equilibrium solubility in lipid Seq). This study provides valuable insight into the impact of key characteristics of SLHs, in constructing optimized solid-state lipid-based formulations for the oral delivery of PWSDs. Full article
(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)
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15 pages, 5230 KiB  
Article
Methiothepin Suppresses Human Ovarian Cancer Cell Growth by Repressing Mitochondrion-Mediated Metabolism and Inhibiting Angiogenesis In Vivo
by Jin-Young Lee, Changwon Yang, Whasun Lim and Gwonhwa Song
Pharmaceutics 2020, 12(7), 686; https://doi.org/10.3390/pharmaceutics12070686 - 20 Jul 2020
Cited by 8 | Viewed by 2559
Abstract
Ovarian cancer is the fifth leading cause of cancer-related deaths in women. Despite treatment, most patients experience relapse and the 5-year survival rate of ovarian cancer is less than 50%. Serotonin has cell growth-promoting functions in a variety of carcinomas, but the effect [...] Read more.
Ovarian cancer is the fifth leading cause of cancer-related deaths in women. Despite treatment, most patients experience relapse and the 5-year survival rate of ovarian cancer is less than 50%. Serotonin has cell growth-promoting functions in a variety of carcinomas, but the effect of serotonin receptor antagonists on ovarian cancer cells is unknown. In this study, it was confirmed that methiothepin, a serotonin receptor antagonist, suppresses the viability of, and induces apoptosis in, ovarian cancer cells. Methiothepin also induces mitochondrial dysfunction, represented by depolarization of the mitochondrial membrane and increased mitochondrion-specific Ca2+ levels, and causes metabolic disruption in cancer cells such as decreased ATP production and oxidative phosphorylation. Methiothepin also interferes with vascular development in transgenic zebrafish embryos. Combination treatment with methiothepin improves the anti-cancer effect of paclitaxel, a standard chemotherapeutic agent. In conclusion, this study revealed that methiothepin is a potential novel therapeutic agent for ovarian cancer treatment. Full article
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18 pages, 331 KiB  
Article
Approaches to Dose Finding in Neonates, Illustrating the Variability between Neonatal Drug Development Programs
by John N. Van den Anker, Susan McCune, Pieter Annaert, Gerri R. Baer, Yeruk Mulugeta, Ramy Abdelrahman, Kunyi Wu, Kevin M. Krudys, Jeffrey Fisher, William Slikker, Connie Chen, Gilbert J. Burckart and Karel Allegaert
Pharmaceutics 2020, 12(7), 685; https://doi.org/10.3390/pharmaceutics12070685 - 20 Jul 2020
Cited by 19 | Viewed by 3496
Abstract
Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be [...] Read more.
Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of efficacy from older children or adults to neonates is infrequently used. Even if a disease process is similar between neonates and children or adults, such as with anti-infectives, additional dosing and safety information will be necessary for labeling, recognizing that dosing in neonates is confounded by maturational PK in addition to body size. Full article
(This article belongs to the Special Issue Paediatric Drug Delivery)
31 pages, 4179 KiB  
Review
Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?
by Christian Gorzelanny, Christian Mess, Stefan W. Schneider, Volker Huck and Johanna M. Brandner
Pharmaceutics 2020, 12(7), 684; https://doi.org/10.3390/pharmaceutics12070684 - 20 Jul 2020
Cited by 105 | Viewed by 8524
Abstract
Although, drugs are required in the various skin compartments such as viable epidermis, dermis, or hair follicles, to efficiently treat skin diseases, drug delivery into and across the skin is still challenging. An improved understanding of skin barrier physiology is mandatory to optimize [...] Read more.
Although, drugs are required in the various skin compartments such as viable epidermis, dermis, or hair follicles, to efficiently treat skin diseases, drug delivery into and across the skin is still challenging. An improved understanding of skin barrier physiology is mandatory to optimize drug penetration and permeation. The various barriers of the skin have to be known in detail, which means methods are needed to measure their functionality and outside-in or inside-out passage of molecules through the various barriers. In this review, we summarize our current knowledge about mechanical barriers, i.e., stratum corneum and tight junctions, in interfollicular epidermis, hair follicles and glands. Furthermore, we discuss the barrier properties of the basement membrane and dermal blood vessels. Barrier alterations found in skin of patients with atopic dermatitis are described. Finally, we critically compare the up-to-date applicability of several physical, biochemical and microscopic methods such as transepidermal water loss, impedance spectroscopy, Raman spectroscopy, immunohistochemical stainings, optical coherence microscopy and multiphoton microscopy to distinctly address the different barriers and to measure permeation through these barriers in vitro and in vivo. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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12 pages, 4708 KiB  
Article
PLGA Microspheres of hGH of Preserved Native State Prepared Using a Self-Regulated Process
by Jebun Nessa Diana, Ying Tao, Qiran Du, Meng Wang, Chinta Uday Kumar, Fei Wu and Tuo Jin
Pharmaceutics 2020, 12(7), 683; https://doi.org/10.3390/pharmaceutics12070683 - 20 Jul 2020
Cited by 7 | Viewed by 2832
Abstract
The challenges of formulating recombinant human growth hormone (rhGH) into sustained-release polymeric microspheres include two mutual causal factors, protein denaturing by the formulation process and severe initial burst release related with relative high dose. The stabilizers to protect the proteins must not evoke [...] Read more.
The challenges of formulating recombinant human growth hormone (rhGH) into sustained-release polymeric microspheres include two mutual causal factors, protein denaturing by the formulation process and severe initial burst release related with relative high dose. The stabilizers to protect the proteins must not evoke osmotic pressure inside the microspheres, and the contact of the protein with the interface between water and organic solution of the polymer must be minimized. To meet these criteria, rhGH was pre-formulated into polysaccharide particles via an aqueous–aqueous emulsion in the present study, followed by encapsulating the particles into microspheres through a self-regulated process to minimize the contact of the protein with the water–oil interface. Polysaccharides as the protein stabilizer did not evoke osmotic pressure as small sugar stabilizers, the cause of severe initial burst release. Reduced initial burst enabled reduced protein loading to 9% (from 22% of the once commercialized Nutropin depot), which in turn reduced the dosage form index from 80 to 8.7 and eased the initial burst. A series of physical chemical characterizations as well as biologic and pharmacokinetic assays confirmed that the present method is practically feasible for preparing microspheres of proteins. Full article
(This article belongs to the Special Issue Depot Delivery Systems: Recent Advances on Materials, Technologies, and Beyond)
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23 pages, 5181 KiB  
Article
Development and Characterization of Potential Ocular Mucoadhesive Nano Lipid Carriers Using Full Factorial Design
by Eszter L. Kiss, Szilvia Berkó, Attila Gácsi, Anita Kovács, Gábor Katona, Judit Soós, Erzsébet Csányi, Ilona Gróf, András Harazin, Mária A. Deli, György T. Balogh and Mária Budai-Szűcs
Pharmaceutics 2020, 12(7), 682; https://doi.org/10.3390/pharmaceutics12070682 - 20 Jul 2020
Cited by 12 | Viewed by 3127
Abstract
Generally, topically applied eye drops have low bioavailability due to short residence time and low penetration of the drug. The aim of the present study was to incorporate dexamethasone (DXM) into nano lipid carriers (NLC), which contain mucoadhesive polymer, in order to increase [...] Read more.
Generally, topically applied eye drops have low bioavailability due to short residence time and low penetration of the drug. The aim of the present study was to incorporate dexamethasone (DXM) into nano lipid carriers (NLC), which contain mucoadhesive polymer, in order to increase the bioavailability of the drug. A 23 factorial experimental design was applied, in which the three factors were the polymer, the DXM, and the emulsifier concentrations. The samples were analyzed for particle size, zeta potential, polydispersity index, and Span value. The significant factors were identified. The biocompatibility of the formulations was evaluated with human corneal toxicity tests and immunoassay analysis. The possible increase in bioavailability was analyzed by means of mucoadhesivity, in vitro drug diffusion, and different penetration tests, such as in vitro cornea PAMPA model, human corneal cell penetration, and ex vivo porcine corneal penetration using Raman mapping. The results indicated that DXM can be incorporated in stable mucoadhesive NLC systems, which are non-toxic and do not have any harmful effect on cell junctions. Mucoadhesive NLCs can create a depot on the surface of the cornea, which can predict improved bioavailability. Full article
(This article belongs to the Special Issue Mucoadhesive and Mucosal Drug Delivery Systems)
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15 pages, 2852 KiB  
Article
DoE-Assisted Development of a Novel Glycosaminoglycan-Based Injectable Formulation for Viscosupplementation
by Marta Cicognani, Silvia Rossi, Gabriele Vecchi, Andrea Maria Giori and Franca Ferrari
Pharmaceutics 2020, 12(7), 681; https://doi.org/10.3390/pharmaceutics12070681 - 20 Jul 2020
Cited by 2 | Viewed by 2798
Abstract
The aim of the present work was the development of a novel glycosaminoglycan (GAG)-based injectable formulation intended for intra-articular administration that should best mimic the healthy synovial fluid. Hyaluronic acid (HA) was chosen among GAG polymers, since it is the most abundant component [...] Read more.
The aim of the present work was the development of a novel glycosaminoglycan (GAG)-based injectable formulation intended for intra-articular administration that should best mimic the healthy synovial fluid. Hyaluronic acid (HA) was chosen among GAG polymers, since it is the most abundant component of the synovial fluid. A DoE (Design of Experiment) approach was used for the development of a formulation containing two HA (very high (VHMW) and low (LMW) molecular weight) grades. The rationale for this choice is that so far, no commercial product based on a single HA grade or even on binary HA mixture possesses optimal viscoelastic properties in comparison with healthy synovial fluid. A full factorial design was chosen to investigate the influence of concentration and relative fraction of the two polymer grades (retained as factors of the model) on formulation functional (viscosity and viscoelastic) properties, which are considered response variables. Thanks to the DoE approach, the composition of the optimized HA formulation was found. The addition to such formulation of an injectable grade fat-free soy phospholipid, which was rich in phosphatidylcholine (PC), resulted in improved lubrication properties. The final HA + PC formulation, packaged in pre-filled sterile syringes, was stable in long-term and accelerated ICH (International Council for Harmonisation) storage conditions. The overall results pointed out the formulation suitability for further steps of pharmaceutical developments, namely for the passage to pilot scale. Full article
(This article belongs to the Special Issue Gels and in Situ Gelling Formulations for Drug Delivery)
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18 pages, 3994 KiB  
Article
Oleic Acid Copolymer as A Novel Upconversion Nanomaterial to Make Doxorubicin-Loaded Nanomicelles with Dual Responsiveness to pH and NIR
by Jin Zhang, Xiaoyue Tang, Chuanqing Huang, Zeyu Liu and Yong Ye
Pharmaceutics 2020, 12(7), 680; https://doi.org/10.3390/pharmaceutics12070680 - 20 Jul 2020
Cited by 5 | Viewed by 3273
Abstract
Oleic acid (OA) as main component of plant oil is an important solvent but seldom used in the nanocarrier of anticancer drugs because of strong hydrophobicity and little drug release. In order to develop a new type of OA nanomaterial with dual responses [...] Read more.
Oleic acid (OA) as main component of plant oil is an important solvent but seldom used in the nanocarrier of anticancer drugs because of strong hydrophobicity and little drug release. In order to develop a new type of OA nanomaterial with dual responses to pH and near infrared light (NIR) to achieve the intelligent delivery of anticancer drugs. The novel OA copolymer (mPEG-PEI-(NBS, OA)) was synthesized by grafting OA and o-nitrobenzyl succinate (NBS) onto mPEGylated polyethyleneimine (mPEG-PEI) by amidation reaction. It was further conjugated with NaYF4:Yb3+/Er3+ nanoparticles, and encapsulated doxorubicin (DOX) through self-assembly to make upconversion nanomicelles with dual response to pH and NIR. Drug release behavior of DOX, physicochemical characteristics of the nanomicelles were evaluated, along with its cytotoxic profile, as well as the degree of cellular uptake in A549 cells. The encapsulation efficiency and drug loading capacity of DOX in the nanomicelles were 73.84% ± 0.58% and 4.62% ± 0.28%, respectively, and the encapsulated DOX was quickly released in an acidic environment exposed to irradiation at 980 nm. The blank nanomicelles exhibited low cytotoxicity and excellent biocompatibility by MTT assay against A549 cells. The DOX-loaded nanomicelles showed remarkable cytotoxicity to A549 cells under NIR, and promoted the cellular uptake of DOX into the cytoplasm and nucleus of cancer cells. OA copolymer can effectively deliver DOX to cancer cells and achieve tumor targeting through a dual response to pH and NIR. Full article
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16 pages, 2241 KiB  
Article
Silicon Nanofluidic Membrane for Electrostatic Control of Drugs and Analytes Elution
by Nicola Di Trani, Antonia Silvestri, Yu Wang, Danilo Demarchi, Xuewu Liu and Alessandro Grattoni
Pharmaceutics 2020, 12(7), 679; https://doi.org/10.3390/pharmaceutics12070679 - 19 Jul 2020
Cited by 12 | Viewed by 3408
Abstract
Individualized long-term management of chronic pathologies remains an elusive goal despite recent progress in drug formulation and implantable devices. The lack of advanced systems for therapeutic administration that can be controlled and tailored based on patient needs precludes optimal management of pathologies, such [...] Read more.
Individualized long-term management of chronic pathologies remains an elusive goal despite recent progress in drug formulation and implantable devices. The lack of advanced systems for therapeutic administration that can be controlled and tailored based on patient needs precludes optimal management of pathologies, such as diabetes, hypertension, rheumatoid arthritis. Several triggered systems for drug delivery have been demonstrated. However, they mostly rely on continuous external stimuli, which hinder their application for long-term treatments. In this work, we investigated a silicon nanofluidic technology that incorporates a gate electrode and examined its ability to achieve reproducible control of drug release. Silicon carbide (SiC) was used to coat the membrane surface, including nanochannels, ensuring biocompatibility and chemical inertness for long-term stability for in vivo deployment. With the application of a small voltage (≤ 3 V DC) to the buried polysilicon electrode, we showed in vitro repeatable modulation of membrane permeability of two model analytes—methotrexate and quantum dots. Methotrexate is a first-line therapeutic approach for rheumatoid arthritis; quantum dots represent multi-functional nanoparticles with broad applicability from bio-labeling to targeted drug delivery. Importantly, SiC coating demonstrated optimal properties as a gate dielectric, which rendered our membrane relevant for multiple applications beyond drug delivery, such as lab on a chip and micro total analysis systems (µTAS). Full article
(This article belongs to the Special Issue Mesoporous Materials for Drug Delivery and Theranostics)
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13 pages, 421 KiB  
Article
Y-Site Physical Compatibility of Numeta G13E with Drugs Frequently Used at Neonatal Intensive Care
by Katerina Nezvalova-Henriksen, Niklas Nilsson, Camilla Tomine Østerberg, Vigdis Staven Berge and Ingunn Tho
Pharmaceutics 2020, 12(7), 677; https://doi.org/10.3390/pharmaceutics12070677 - 18 Jul 2020
Cited by 9 | Viewed by 3372
Abstract
Preterm neonates require parenteral nutrition (PN) in addition to intravenous drug therapy. Due to limited venous access, drugs are often co-administered with PN via the same lumen. If incompatible, precipitation and emulsion destabilization may occur with the consequent risk of embolism and hyper-immune [...] Read more.
Preterm neonates require parenteral nutrition (PN) in addition to intravenous drug therapy. Due to limited venous access, drugs are often co-administered with PN via the same lumen. If incompatible, precipitation and emulsion destabilization may occur with the consequent risk of embolism and hyper-immune reactions. Information on intravenous compatibility is scarce. Our aim was to analyse the compatibility of Numeta G13E with paracetamol, vancomycin and fentanyl because of the frequency of their use. A panel of methods was chosen to assess precipitation (sub-visual particle counting, turbidity measurement, Tyndall beam effect and pH measurement) and emulsion destabilization (mean droplet diameter measurement and sub-visual counting of oil droplets, followed by estimation of PFAT5 (percentage of fat residing in globules larger than 5 µm) and pH measurement). Samples in clinically relevant mixing ratios were tested immediately and after 4 h. All samples of drugs mixed with Numeta G13E were compared to unmixed controls. None of the tested drugs precipitated in contact with Numeta G13E, and we did not see any sign of emulsion destabilization when clinically relevant mixing ratios were applied. These results are reassuring. However, when contact time exceeds the established norm, caution in the form of filter utilisation and close inspection is advised. Full article
(This article belongs to the Special Issue Paediatric Drug Delivery)
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18 pages, 2235 KiB  
Article
Antimicrobial Essential Oil Formulation: Chitosan Coated Nanoemulsions for Nose to Brain Delivery
by Federica Rinaldi, Alessandra Oliva, Manuela Sabatino, Anna Imbriano, Patrizia N. Hanieh, Stefania Garzoli, Claudio M. Mastroianni, Massimiliano De Angelis, Maria Claudia Miele, Marcela Arnaut, Federica Di Timoteo, Carlotta Marianecci, Rino Ragno and Maria Carafa
Pharmaceutics 2020, 12(7), 678; https://doi.org/10.3390/pharmaceutics12070678 - 17 Jul 2020
Cited by 30 | Viewed by 3338
Abstract
Brain infections as meningitis and encephalitis are attracting a great interest. Challenges in the treatment of these diseases are mainly represented by the blood brain barrier (BBB) that impairs the efficient delivery of even very potent drugs to reach the brain. The nose [...] Read more.
Brain infections as meningitis and encephalitis are attracting a great interest. Challenges in the treatment of these diseases are mainly represented by the blood brain barrier (BBB) that impairs the efficient delivery of even very potent drugs to reach the brain. The nose to the brain administration route, is a non-invasive alternative for a quick onset of action, and enables the transport of numerous medicinal agents straight to the brain thus workarounding the BBB through the highly vascularized olfactory region. In this report, Thymus vulgaris and Syzygium aromaticum essential oils (EOs) were selected to be included in chitosan coated nanoemulsions (NEs). The EOs were firstly analyzed to determine their chemical composition, then used to prepare NEs, that were deeply characterized in order to evaluate their use in intranasal administration. An in vitro evaluation against a collection of clinical isolated bacterial strains was carried out for both free and nanoemulsioned EOs. Chitosan coated NEs showed to be a potential and effective intranasal formulation against multi-drug resistant Gram-negative bacteria such as methicillin-susceptible Staphylococcus aureus and multi-drug resistant Gram-negative microorganisms including carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae. Full article
(This article belongs to the Special Issue Natural Products in Drug Delivery Systems)
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15 pages, 5275 KiB  
Article
mTHPC-Loaded Extracellular Vesicles Significantly Improve mTHPC Diffusion and Photodynamic Activity in Preclinical Models
by Marie Millard, Solène Posty, Max Piffoux, Jordane Jasniewski, Henri-Pierre Lassalle, Ilya Yakavets, Florence Gazeau, Claire Wilhelm, Amanda K. A. Silva and Lina Bezdetnaya
Pharmaceutics 2020, 12(7), 676; https://doi.org/10.3390/pharmaceutics12070676 - 17 Jul 2020
Cited by 17 | Viewed by 2758
Abstract
Extracellular vesicles (EVs), derived from the cell, display a phospholipid bilayer membrane that protects the cargo molecules from degradation and contributes to increasing their stability in the bloodstream and tumor targeting. EVs are interesting in regard to the delivery of photosensitizers (PSs) used [...] Read more.
Extracellular vesicles (EVs), derived from the cell, display a phospholipid bilayer membrane that protects the cargo molecules from degradation and contributes to increasing their stability in the bloodstream and tumor targeting. EVs are interesting in regard to the delivery of photosensitizers (PSs) used in the photodynamic therapy (PDT), as they allow us to overcome the limitations observed with liposomes. In fact, liposomal formulation of meta-tetra(hydroxyphenyl)chlorin (mTHPC) (Foslip®), one of the most potent clinically approved PSs, is rapidly destroyed in circulation, thus decreasing in vivo PDT efficacy. mTHPC-EV uptake was evaluated in vitro in a 3D human colon HT-29 microtumor and in vivo study was performed in HT-29 xenografted mice. The obtained data were compared with Foslip®. After intravenous injection of the mTHPC formulations, biodistribution, pharmacokinetics and PDT-induced tumor regrowth were evaluated. In a 3D model of cells, mTHPC-EV uptake featured a deeper penetration after 24h incubation compared to liposomal mTHPC. In vivo results showed a considerable improvement of 33% tumor cure with PDT treatment applied 24h after injection, while 0% was observed after Foslip®/PDT. Moreover, 47 days were required to obtain ten times the initial tumor volume after mTHPC-EVs/PDT compared to 30 days for liposomal mTHPC. In conclusion, compared to Foslip®, mTHPC-EVs improved mTHPC biodistribution and PDT efficacy in vivo. We deduced that a major determinant factor for the improved in vivo PDT efficacy is the deep mTHPC intratumor penetration. Full article
(This article belongs to the Special Issue Nanopharmaceuticals for Image-Guided Cancer Therapy and Diagnosis)
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17 pages, 10666 KiB  
Article
NIR Stimulus-Responsive PdPt Bimetallic Nanoparticles for Drug Delivery and Chemo-Photothermal Therapy
by Chun Chu, Zhihong Bao, Meng Sun, Xiaowei Wang, Hongyan Zhang, Weiguo Chen, Yang Sui, Ji Li, Yuanyuan Zhuang and Dongkai Wang
Pharmaceutics 2020, 12(7), 675; https://doi.org/10.3390/pharmaceutics12070675 - 17 Jul 2020
Cited by 9 | Viewed by 2614
Abstract
The combination of chemotherapy and phototherapy has attracted increasing attention for cancer treatment in recent years. In the current study, porous PdPt bimetallic nanoparticles (NPs) were synthesized and used as delivery carriers for the anti-cancer drug doxorubicin (DOX). DOX@PdPt NPs were modified with [...] Read more.
The combination of chemotherapy and phototherapy has attracted increasing attention for cancer treatment in recent years. In the current study, porous PdPt bimetallic nanoparticles (NPs) were synthesized and used as delivery carriers for the anti-cancer drug doxorubicin (DOX). DOX@PdPt NPs were modified with thiol functionalized hyaluronic acid (HA-SH) to generate DOX@PdPt@HA NPs with an average size of 105.2 ± 6.7 nm. Characterization and in vivo and in vitro assessment of anti-tumor effects of DOX@PdPt@HA NPs were further performed. The prepared DOX@PdPt@HA NPs presented a high photothermal conversion efficiency of 49.1% under the irradiation of a single 808 nm near-infrared (NIR) laser. Moreover, NIR laser irradiation-induced photothermal effect triggered the release of DOX from DOX@PdPt@HA NPs. The combined chemo-photothermal treatment of NIR-irradiated DOX@PdPt@HA NPs exerted a stronger inhibitory effect on cell viability than that of DOX or NIR-irradiated PdPt@HA NPs in mouse mammary carcinoma 4T1 cells in vitro. Further, the in vivo combination therapy, which used NIR-irradiated DOX@PdPt@HA NPs in a mouse tumor model established by subcutaneous inoculation of 4T1 cells, was demonstrated to achieve a remarkable tumor-growth inhibition in comparison with chemotherapy or photothermal therapy alone. Results of immunohistochemical staining for caspase-3 and Ki-67 indicated the increased apoptosis and decreased proliferation of tumor cells contributed to the anti-tumor effect of chemo-photothermal treatment. In addition, DOX@PdPt@HA NPs induced negligible toxicity in vivo. Hence, the developed nanoplatform demonstrates great potential for applications in photothermal therapy, drug delivery and controlled release. Full article
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18 pages, 3011 KiB  
Article
Formulation of Sustained Release Hydrophilic Matrix Tablets of Tolcapone with the Application of Sedem Diagram: Influence of Tolcapone’s Particle Size on Sustained Release
by Anna Nardi-Ricart, Isaac Nofrerias-Roig, Marc Suñé-Pou, Pilar Pérez-Lozano, Montse Miñarro-Carmona, Encarna García-Montoya, Josep R. Ticó-Grau, Raul Insa Boronat and Josep M. Suñé-Negre
Pharmaceutics 2020, 12(7), 674; https://doi.org/10.3390/pharmaceutics12070674 - 17 Jul 2020
Cited by 16 | Viewed by 3734
Abstract
Hydrophilic matrix tablets are a type of sustained release dosage form characterized by distributing a drug in a matrix that is usually polymeric. Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase. In recent years, it has been shown that [...] Read more.
Hydrophilic matrix tablets are a type of sustained release dosage form characterized by distributing a drug in a matrix that is usually polymeric. Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase. In recent years, it has been shown that tolcapone is a potent inhibitor of the amyloid aggregation process of the transthyretin protein, and acts by stabilizing the structure of the protein, reducing the progression of familial amyloid polyneuropathy. The main objective of this study was to obtain a sustained release tablet of tolcapone for oral administration with a preferred dosage regimen of 1 administration every 12 or 24 h and manufactured, preferably, by direct compression. The SeDeM Diagram method has been used for the formulation development of hydrophilic matrix tablets. Given the characteristics of tolcapone, the excipient selected for the formation of the polymeric matrix was a high viscosity hydroxypropylmethylcellulose (Methocel® K100M CR). A decrease in the particle size of tolcapone resulted in a slower dissolution release of the formulation when the concentration of the polymer Methocel® K100M CR was below 29%. These surprising and novel results have given rise to patent number WO/2018/019997. Full article
(This article belongs to the Special Issue Matrix Tablets for Oral Controlled Release)
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17 pages, 1523 KiB  
Article
IPEC-J2 rMdr1a, a New Cell Line with Functional Expression of Rat P-glycoprotein Encoded by Rat Mdr1a for Drug Screening Purposes
by Lasse Saaby, Josefine Trasborg, Mikkel A. Rasmussen, Bjørn Holst and Birger Brodin
Pharmaceutics 2020, 12(7), 673; https://doi.org/10.3390/pharmaceutics12070673 - 17 Jul 2020
Cited by 1 | Viewed by 3069
Abstract
The efflux pump P-glycoprotein (P-gp) affects drug distribution after absorption in humans and animals. P-gp is encoded by the multidrug resistance gene (MDR1) gene in humans, while rodents (the most common preclinical animal model) express the two isoforms Mdr1a and Mdr1b. Differences in [...] Read more.
The efflux pump P-glycoprotein (P-gp) affects drug distribution after absorption in humans and animals. P-gp is encoded by the multidrug resistance gene (MDR1) gene in humans, while rodents (the most common preclinical animal model) express the two isoforms Mdr1a and Mdr1b. Differences in substrate selectivity has also been reported. Our aim was to generate an in vitro cell model with tight barrier properties, expressing functional rat Mdr1a P-gp, as an in vitro tool for investigating species differences. The IPEC-J2 cell line forms extremely tight monolayers and was transfected with a plasmid carrying the rat Mdr1a gene sequence. Expression and P-gp localization at the apical membrane was demonstrated with Western blots and immunocytochemistry. Function of P-gp was shown through digoxin transport experiments in the presence and absence of the P-gp inhibitor zosuquidar. Bidirectional transport experiments across monolayers of the IPEC-J2 rMDR1a cell line and the IPEC-J2 MDR1 cell line, expressing human P-gp, showed comparable magnitude of transport in both the absorptive and efflux direction. We conclude that the newly established IPEC-J2 rMdr1a cell line, in combination with our previously established cell line IPEC-J2 MDR1, has the potential to be a strong in vitro tool to compare P-gp substrate profiles of rat and human P-gp. Full article
(This article belongs to the Special Issue Drug Transporters in Absorption, Disposition and Elimination)
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18 pages, 2051 KiB  
Review
Food Effects on Oral Drug Absorption: Application of Physiologically-Based Pharmacokinetic Modeling as a Predictive Tool
by Lisa Cheng and Harvey Wong
Pharmaceutics 2020, 12(7), 672; https://doi.org/10.3390/pharmaceutics12070672 - 17 Jul 2020
Cited by 66 | Viewed by 7819
Abstract
The bioavailability of an orally administered small molecule is often dictated by drug-specific physicochemical characteristics and is influenced by many biological processes. For example, in fed or fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to predict [...] Read more.
The bioavailability of an orally administered small molecule is often dictated by drug-specific physicochemical characteristics and is influenced by many biological processes. For example, in fed or fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to predict the oral absorption. As such, the effects of food on the pharmacokinetics of compounds in the various biopharmaceutics classification system (BCS) classes need to be assessed. The consumption of food leads to physiological changes, including fluctuations in the gastric and intestinal pH, a delay in gastric emptying, an increased bile secretion, and an increased splanchnic and hepatic blood flow. Despite the significant impact of a drug’s absorption and dissolution, food effects have not been fully studied and are often overlooked. Physiologically-based pharmacokinetic (PBPK) models can be used to mechanistically simulate a compound’s pharmacokinetics under fed or fasted conditions, while integrating drug properties such as solubility and permeability. This review discusses the PBPK models published in the literature predicting the food effects, the models’ strengths and shortcomings, as well as future steps to mitigate the current knowledge gap. We observed gaps in knowledge which limits the ability of PBPK models to predict the negative food effects and food effects in the pediatric population. Overall, the further development of PBPK models to predict food effects will provide a mechanistic basis to understand a drug’s behavior in fed and fasted conditions, and will help enable the drug development process. Full article
(This article belongs to the Special Issue Mechanistic In Vitro and In Silico Modeling of Oral Drug Absorption)
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23 pages, 5443 KiB  
Article
Study on Ajuga reptans Extract: A Natural Antioxidant in Microencapsulated Powder Form as an Active Ingredient for Nutraceutical or Pharmaceutical Purposes
by Tiziana Esposito, Francesca Sansone, Giulia Auriemma, Silvia Franceschelli, Michela Pecoraro, Patrizia Picerno, Rita P. Aquino and Teresa Mencherini
Pharmaceutics 2020, 12(7), 671; https://doi.org/10.3390/pharmaceutics12070671 - 17 Jul 2020
Cited by 14 | Viewed by 2991
Abstract
The administration of natural antioxidants is considered to be a prevention strategy for chronic diseases and a useful tool for the healthcare system to reduce the administration of expensive and often not effective treatments. The chemical characterization of a methanolic extract (AJ) of [...] Read more.
The administration of natural antioxidants is considered to be a prevention strategy for chronic diseases and a useful tool for the healthcare system to reduce the administration of expensive and often not effective treatments. The chemical characterization of a methanolic extract (AJ) of Ajuga reptans L. was performed, and its antioxidant activity was evaluated. AJ and the major compounds, characterized by chromatographic techniques as phenylpropanoids and iridoids, were able to reduce the Reactive Oxygen Species levels in cancer cell lines (melanoma, A375, cervical cancer, HeLa, and alveolar adenocarcinoma, A549), stimulated by E. coli lipopolysaccharide. However, a clinical translation of these results encountered a significant limitation represented by the poor water solubility and bioavailability of the extract and compounds. Consequently, a hydro-soluble powder system (AJEP3) was developed by spray-drying encapsulating AJ into a multi-component solid matrix that is based on L-proline and hydroxyethylcellulose as loading and coating agents, and lecithin as solubility enhancer. The technological approach led to a satisfactory process yield (71.5%), encapsulation efficiency (99.9%), and stability. The in vitro water dissolution rate of the bioactive compounds appeared to be improved with respect to the extract, suggesting higher feasibility in the manufacturing and administration; even the in vitro biological activity of the produced multi-component AJEP3 was clearly enhanced. Full article
(This article belongs to the Special Issue Herbal Extracts and Natural Compounds: Nutraceutical and Pharmaceutical Aspects)
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16 pages, 3858 KiB  
Article
Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir
by Tom de Waal, Jari Rubbens, Michael Grimm, Vincent Vandecaveye, Jan Tack, Werner Weitschies, Joachim Brouwers and Patrick Augustijns
Pharmaceutics 2020, 12(7), 670; https://doi.org/10.3390/pharmaceutics12070670 - 17 Jul 2020
Cited by 15 | Viewed by 3284
Abstract
Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even [...] Read more.
Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even though duodenal concentrations were not affected. The present study explored if a PPI-induced decrease in gastrointestinal (GI) fluid volume might contribute to the reduced absorption of ritonavir. In an exploratory cross-over study, five volunteers were given a Norvir tablet (100 mg ritonavir) orally, once without PPI pre-treatment and once after a three-day pre-treatment with the PPI esomeprazole. Blood samples were collected for eight hours to assess ritonavir absorption and magnetic resonance imaging (MRI) was used to determine the gastric and duodenal fluid volumes during the first three hours after administration of the tablet. The results confirmed that PPI intake reduced ritonavir plasma concentrations by 40%. The gastric residual volume and gastric fluid volume decreased by 41% and 44% respectively, while the duodenal fluid volume was reduced by 33%. These data suggest that the PPI esomeprazole lowers the available fluid volume for dissolution, which may limit the amount of ritonavir that can be absorbed. Although additional factors may play a role, the effect of PPI intake on the GI fluid volume should be considered when simulating the absorption of poorly soluble drugs like ritonavir in real-life conditions. Full article
(This article belongs to the Special Issue Mechanistic In Vitro and In Silico Modeling of Oral Drug Absorption)
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68 pages, 2844 KiB  
Review
Nanosystems for the Encapsulation of Natural Products: The Case of Chitosan Biopolymer as a Matrix
by Anastasia Detsi, Eleni Kavetsou, Ioanna Kostopoulou, Ioanna Pitterou, Antonella Rozaria Nefeli Pontillo, Andromachi Tzani, Paris Christodoulou, Aristeia Siliachli and Panagiotis Zoumpoulakis
Pharmaceutics 2020, 12(7), 669; https://doi.org/10.3390/pharmaceutics12070669 - 16 Jul 2020
Cited by 95 | Viewed by 7106
Abstract
Chitosan is a cationic natural polysaccharide, which has emerged as an increasingly interesting biomaterialover the past few years. It constitutes a novel perspective in drug delivery systems and nanocarriers’ formulations due to its beneficial properties, including biocompatibility, biodegradability and low toxicity. The potentiality [...] Read more.
Chitosan is a cationic natural polysaccharide, which has emerged as an increasingly interesting biomaterialover the past few years. It constitutes a novel perspective in drug delivery systems and nanocarriers’ formulations due to its beneficial properties, including biocompatibility, biodegradability and low toxicity. The potentiality of chemical or enzymatic modifications of the biopolymer, as well as its complementary use with other polymers, further attract the scientific community, offering improved and combined properties in the final materials. As a result, chitosan has been extensively used as a matrix for the encapsulation of several valuable compounds. In this review article, the advantageous character of chitosan as a matrix for nanosystemsis presented, focusing on the encapsulation of natural products. A five-year literature review is attempted covering the use of chitosan and modified chitosan as matrices and coatings for the encapsulation of natural extracts, essential oils or pure naturally occurring bioactive compounds are discussed. Full article
(This article belongs to the Special Issue Chitosan Nanoparticles in Drug Delivery)
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13 pages, 2658 KiB  
Article
Locally Applied Slow-Release of Minocycline Microspheres in the Treatment of Peri-Implant Mucositis: An Experimental In Vivo Study
by Sung-Wook Yoon, Myong-Ji Kim, Kyeong-Won Paeng, Kyeong Ae Yu, Chong-Kil Lee, Young Woo Song, Jae-Kook Cha, Mariano Sanz and Ui-Won Jung
Pharmaceutics 2020, 12(7), 668; https://doi.org/10.3390/pharmaceutics12070668 - 16 Jul 2020
Cited by 7 | Viewed by 2759
Abstract
Background: The objective of this is preclinical investigation was to evaluate the differential drug sustainability and pharmacodynamic properties of two local minocycline microsphere carriers: chitosan-coated alginate (CA) and poly(meth)acrylate-glycerin (PG). Methods: Four dental implants were placed unilaterally in the edentulous mandible of six [...] Read more.
Background: The objective of this is preclinical investigation was to evaluate the differential drug sustainability and pharmacodynamic properties of two local minocycline microsphere carriers: chitosan-coated alginate (CA) and poly(meth)acrylate-glycerin (PG). Methods: Four dental implants were placed unilaterally in the edentulous mandible of six beagle dogs. Each implant was randomly assigned to receive one of the following four treatments: (i) CA (CA-based minocycline), (ii) placebo (CA substrate without minocycline), (iii) PG (PG-based minocycline) and (iv) control (mechanical debridement only). After inducing peri-implant mucositis, the randomly assigned treatments were administered into the gingival sulcus twice at a 4-week interval using a plastic-tipped syringe. Drug sustainability and pharmacodynamic (clinical, radiographical and cell marker intensity) evaluations were performed after each administration. Results: The CA microspheres remained longer around the healing abutment compared to the PG microspheres at both administrations and a longer bacteriostatic effect was observed from CA (7.0 ± 5.7 days) compared to PG (1.2 ± 2.6 days). The efficacy of the applied therapies based on clinical, radiographical and histological analyses were comparable across all treatment groups. Conclusions: CA microspheres showed longer carrier and bacteriostatic effect sustainability when compared to PG microspheres, however, longer drug sustainability did not lead to improved treatment outcomes. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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17 pages, 7319 KiB  
Article
Avoiding the Pitfalls of siRNA Delivery to the Retinal Pigment Epithelium with Physiologically Relevant Cell Models
by Eva Ramsay, Manuela Raviña, Sanjay Sarkhel, Sarah Hehir, Neil R. Cameron, Tanja Ilmarinen, Heli Skottman, Jørgen Kjems, Arto Urtti, Marika Ruponen and Astrid Subrizi
Pharmaceutics 2020, 12(7), 667; https://doi.org/10.3390/pharmaceutics12070667 - 16 Jul 2020
Cited by 7 | Viewed by 3062
Abstract
Inflammation is involved in the pathogenesis of several age-related ocular diseases, such as macular degeneration (AMD), diabetic retinopathy, and glaucoma. The delivery of anti-inflammatory siRNA to the retinal pigment epithelium (RPE) may become a promising therapeutic option for the treatment of inflammation, if [...] Read more.
Inflammation is involved in the pathogenesis of several age-related ocular diseases, such as macular degeneration (AMD), diabetic retinopathy, and glaucoma. The delivery of anti-inflammatory siRNA to the retinal pigment epithelium (RPE) may become a promising therapeutic option for the treatment of inflammation, if the efficient delivery of siRNA to target cells is accomplished. Unfortunately, so far, the siRNA delivery system selection performed in dividing RPE cells in vitro has been a poor predictor of the in vivo efficacy. Our study evaluates the silencing efficiency of polyplexes, lipoplexes, and lipidoid-siRNA complexes in dividing RPE cells as well as in physiologically relevant RPE cell models. We find that RPE cell differentiation alters their endocytic activity and causes a decrease in the uptake of siRNA complexes. In addition, we determine that melanosomal sequestration is another significant and previously unexplored barrier to gene silencing in pigmented cells. In summary, this study highlights the importance of choosing a physiologically relevant RPE cell model for the selection of siRNA delivery systems. Such cell models are expected to enable the identification of carriers with a high probability of success in vivo, and thus propel the development of siRNA therapeutics for ocular disease. Full article
(This article belongs to the Special Issue Advances in the Delivery of DNA and RNA Therapeutics to the Eye)
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14 pages, 2514 KiB  
Article
Optimized Polyethylene Glycolylated Polymer–Lipid Hybrid Nanoparticles as a Potential Breast Cancer Treatment
by Salam Massadeh, Mustafa E Omer, Asmaa Alterawi, Rizwan Ali, Fayez H Alanazi, Fares Almutairi, Wejdan Almotairi, Faris F Alobaidi, Khulud Alhelal, Mansour S Almutairi, Abdulaziz Almalik, Aiman A. Obaidat, Manal Alaamery and Alaa Eldeen Yassin
Pharmaceutics 2020, 12(7), 666; https://doi.org/10.3390/pharmaceutics12070666 - 15 Jul 2020
Cited by 20 | Viewed by 3876
Abstract
Purpose: The aim of this work is to optimize a polyethylene glycolated (PEGylated) polymer–lipid hybrid nanoparticulate system for the delivery of anastrozole (ANS) to enhance its biopharmaceutical attributes and overall efficacy. Methods: ANS loaded PEGylated polymer–lipid hybrid nanoparticles (PLNPs) were prepared by a [...] Read more.
Purpose: The aim of this work is to optimize a polyethylene glycolated (PEGylated) polymer–lipid hybrid nanoparticulate system for the delivery of anastrozole (ANS) to enhance its biopharmaceutical attributes and overall efficacy. Methods: ANS loaded PEGylated polymer–lipid hybrid nanoparticles (PLNPs) were prepared by a direct emulsification solvent evaporation method. The physical incorporation of PEG was optimized using variable ratios. The produced particles were evaluated to discern their particle size and shape, zeta-potential, entrapment efficiency, and physical stability. The drug-release profiles were studied, and the kinetic model was analyzed. The anticancer activity of the ANS PLNPs on estrogen-positive breast cancer cell lines was determined using flow cytometry. Results: The prepared ANS-PLNPs showed particle sizes in the range of 193.6 ± 2.9 to 218.2 ± 1.9 nm, with good particle size uniformity (i.e., poly-dispersity index of around 0.1). Furthermore, they exhibited relatively low zeta-potential values ranging from −0.50 ± 0.52 to 6.01 ± 4.74. The transmission electron microscopy images showed spherical shape of ANS-PLNPs and the compliance with the sizes were revealed by light scattering. The differential scanning calorimetry DSC patterns of the ANS PLNPs revealed a disappearance of the characteristic sharp melting peak of pure ANS, supporting the incorporation of the drug into the polymeric matrices of the nanoparticles. Flow cytometry showed the apoptosis of MCF-7 cell lines in the presence of ANS-PLNPs. Conclusion: PEGylated polymeric nanoparticles presented a stable encapsulated system with which to incorporate an anticancer drug (ANS) with a high percentage of entrapment efficiency (around 80%), good size uniformity, and induction of apoptosis in MCF-7 cells. Full article
(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)
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18 pages, 1785 KiB  
Review
Micro/Nanorobot: A Promising Targeted Drug Delivery System
by Mengyi Hu, Xuemei Ge, Xuan Chen, Wenwei Mao, Xiuping Qian and Wei-En Yuan
Pharmaceutics 2020, 12(7), 665; https://doi.org/10.3390/pharmaceutics12070665 - 15 Jul 2020
Cited by 74 | Viewed by 9630
Abstract
Micro/nanorobot, as a research field, has attracted interest in recent years. It has great potential in medical treatment, as it can be applied in targeted drug delivery, surgical operation, disease diagnosis, etc. Differently from traditional drug delivery, which relies on blood circulation to [...] Read more.
Micro/nanorobot, as a research field, has attracted interest in recent years. It has great potential in medical treatment, as it can be applied in targeted drug delivery, surgical operation, disease diagnosis, etc. Differently from traditional drug delivery, which relies on blood circulation to reach the target, the designed micro/nanorobots can move autonomously, which makes it possible to deliver drugs to the hard-to-reach areas. Micro/nanorobots were driven by exogenous power (magnetic fields, light energy, acoustic fields, electric fields, etc.) or endogenous power (chemical reaction energy). Cell-based micro/nanorobots and DNA origami without autonomous movement ability were also introduced in this article. Although micro/nanorobots have excellent prospects, the current research is mainly based on in vitro experiments; in vivo research is still in its infancy. Further biological experiments are required to verify in vivo drug delivery effects of micro/nanorobots. This paper mainly discusses the research status, challenges, and future development of micro/nanorobots. Full article
(This article belongs to the Special Issue Nanocarriers for Drug Delivery Systems)
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23 pages, 3842 KiB  
Article
Analytical Techniques for the Assessment of Drug-Lipid Interactions and the Active Substance Distribution in Liquid Dispersions of Solid Lipid Microparticles (SLM) Produced de novo and Reconstituted from Spray-Dried Powders
by Eliza Wolska, Małgorzata Sznitowska, Katarzyna Krzemińska and Maria Ferreira Monteiro
Pharmaceutics 2020, 12(7), 664; https://doi.org/10.3390/pharmaceutics12070664 - 15 Jul 2020
Cited by 11 | Viewed by 2567
Abstract
Solid lipid microparticles (SLM) can be presented as liquid suspension or spray-dried powder. The main challenge in SLM technology is to precisely determine the location of the active substance (API) in the different compartments of the formulation and its changes during SLM processing. [...] Read more.
Solid lipid microparticles (SLM) can be presented as liquid suspension or spray-dried powder. The main challenge in SLM technology is to precisely determine the location of the active substance (API) in the different compartments of the formulation and its changes during SLM processing. Therefore, the purpose of the research was to assess the distribution of the API and to investigate the nature of the API-lipid interaction when the formulation was subjected to spray drying, with an indication of the most suitable techniques for this purpose. SLM were prepared with two various lipids (Compritol or stearic acid) and two model APIs: cyclosporine (0.1% and 1% w/w) and spironolactone (0.1% and 0.5% w/w). Physicochemical characterizations of the formulations, before and after spray drying, were performed by differential scanning calorimetry (DSC), atomic force microscopy (AFM), Raman spectroscopy and nuclear magnetic resonance (NMR). The API distribution between the SLM matrix, SLM surface and the aqueous phase was determined, and the release study was performed. It was demonstrated that, in general, the spray drying did not affect the drug release and drug distribution; however, some changes were observed in the SLM with Compritol and when the API concentration was lower. Only in the SLM with stearic acid was a change in the DSC curves noted. Measurements with the AFM technique proved to be a useful method for detecting differences in the surface properties between the placebo and API-loaded SLM, while the Raman spectroscopy did not show such evident differences. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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83 pages, 4451 KiB  
Review
Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy
by Lukas Amon, Lukas Hatscher, Lukas Heger, Diana Dudziak and Christian H. K. Lehmann
Pharmaceutics 2020, 12(7), 663; https://doi.org/10.3390/pharmaceutics12070663 - 14 Jul 2020
Cited by 22 | Viewed by 5421
Abstract
The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the [...] Read more.
The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases. Full article
(This article belongs to the Special Issue Dendritic Cell Vaccines)
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12 pages, 3481 KiB  
Article
Enhanced Viability of Probiotics against Gastric Acid by One-Step Coating Process with Poly-L-Lysine: In Vitro and In Vivo Evaluation
by Shwe Phyu Hlaing, Jihyun Kim, Juho Lee, Dongmin Kwak, Hyunwoo Kim and Jin-Wook Yoo
Pharmaceutics 2020, 12(7), 662; https://doi.org/10.3390/pharmaceutics12070662 - 14 Jul 2020
Cited by 13 | Viewed by 3029
Abstract
Due to their low acid tolerance, a majority of probiotics face diculties with regard to
surviving in the gastric environment long enough to reach the intestinal surfaces where they colonize
and provide health benefits. We prepared a probiotic delivery system that can enhance [...] Read more.
Due to their low acid tolerance, a majority of probiotics face diculties with regard to
surviving in the gastric environment long enough to reach the intestinal surfaces where they colonize
and provide health benefits. We prepared a probiotic delivery system that can enhance their viability
in acidic conditions by developing a one-step poly-L-lysine (PLL) coating process. We determined
whether the coating process was successful by measuring the zeta potential and observing it with
confocal scanning microscopy. PLL-coated L. plantarum (PLL-LP), incubated in a solution of pH 2 for
2 h, exhibited a higher viability (6.86 0.12 log CFU/mL of viable cells) than non-coated L. plantarum
(non-coated LP), which exhibited only 2.7 1.23 log CFU/mL of viable cells. In addition, a higher
amount of L. plantarum was detected in the feces of mice orally administered PLL-LP (6.2 0.4 log
CFU/g of feces) than in the feces of the control groups. In addition to enhancing probiotic viability in
pH 2 solution, the PLL coating showed no eect on the probiotic growth pattern and the viability of
either freeze-dried L. plantarum or L. plantarum, stored at ?20 C and 4 C, respectively. Overall, these
results indicated that the PLL coating is a promising potential probiotic delivery system. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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24 pages, 4859 KiB  
Article
Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood–Brain Barrier Adherence, Uptake, and Permeation
by Mie Kristensen, Krzysztof Kucharz, Eduardo Felipe Alves Fernandes, Kristian Strømgaard, Morten Schallburg Nielsen, Hans Christian Cederberg Helms, Anders Bach, Malte Ulrikkaholm Tofte-Hansen, Blanca Irene Aldana Garcia, Martin Lauritzen and Birger Brodin
Pharmaceutics 2020, 12(7), 661; https://doi.org/10.3390/pharmaceutics12070661 - 14 Jul 2020
Cited by 21 | Viewed by 5420
Abstract
Novel stroke therapies are needed. Inhibition of the interaction between the postsynaptic density-95 (PSD-95)/disc large/ZO-1 (PDZ) domains of PSD-95 and the N-methyl-D-aspartate (NMDA) receptor has been suggested as a strategy for relieving neuronal damage. The peptides NR2B9c and N-dimer have been [...] Read more.
Novel stroke therapies are needed. Inhibition of the interaction between the postsynaptic density-95 (PSD-95)/disc large/ZO-1 (PDZ) domains of PSD-95 and the N-methyl-D-aspartate (NMDA) receptor has been suggested as a strategy for relieving neuronal damage. The peptides NR2B9c and N-dimer have been designed to hinder this interaction; they are conjugated to the cell-penetrating peptide Tat to facilitate blood–brain barrier (BBB) permeation and neuronal uptake. Tat-N-dimer exhibits 1000-fold better target affinity than Tat-NR2B9c, but the same magnitude of improvement is not observed in terms of therapeutic effect. Differences in BBB permeation by Tat-NR2B9c and Tat-N-dimer may explain this difference, but studies providing a direct comparison of Tat-NR2B9c and Tat-N-dimer are lacking. The aim of the present study was therefore to compare the BBB uptake and permeation of Tat-NR2B9c and Tat-N-dimer. The peptides were conjugated to the fluorophore TAMRA and their chemical stability assessed. Endothelial membrane association and cell uptake, and transendothelial permeation were estimated using co-cultures of primary bovine brain capillary endothelial cells and rat astrocytes. In vivo BBB permeation was demonstrated in mice using two-photon microscopy imaging. Tissue distribution was evaluated in mice demonstrating brain accumulation of TAMRA-Tat (0.4% ID/g), TAMRA-Tat-NR2B9c (0.3% ID/g), and TAMRA-Tat-N-dimer (0.25% ID/g). In conclusion, we demonstrate that attachment of NR2B9c or N-dimer to Tat affects both the chemical stability and the ability of the resulting construct to interact with and permeate the BBB. Full article
(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)
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