Pharmaceutics

12 pages, 3763 KiB

Open AccessArticle

The Fast Track for Intestinal Tumor Cell Differentiation and In Vitro Intestinal Models by Inorganic Topographic Surfaces

by Matteo Centonze, Erwin J. W. Berenschot, Simona Serrati, Arturo Susarrey-Arce and Silke Krol

Pharmaceutics 2022, 14(1), 218; https://doi.org/10.3390/pharmaceutics14010218 - 17 Jan 2022

Cited by 2 | Viewed by 3782

Abstract

Three-dimensional (3D) complex in vitro cell systems are well suited to providing meaningful and translatable results in drug screening, toxicity measurements, and biological studies. Reliable complex gastrointestinal in vitro models as a testbed for oral drug administration and toxicity are very valuable in [...] Read more.

Three-dimensional (3D) complex in vitro cell systems are well suited to providing meaningful and translatable results in drug screening, toxicity measurements, and biological studies. Reliable complex gastrointestinal in vitro models as a testbed for oral drug administration and toxicity are very valuable in achieving predictive results for clinical trials and reducing animal testing. However, producing these models is time-consuming due to the lengthy differentiation of HT29 or other cells into mucus-producing goblet cells or other intestinal cell lineages. In the present work, HT29 cells were grown on an inorganic topographic surface decorated with a periodic pattern of micrometre-sized amorphous SiO₂ structures for up to 35 days. HT29 cells on topographic surfaces were compared to undifferentiated HT29 in glucose-containing medium on glass or culture dish and with HT29 cells differentiated for 30 days in the presence of methotrexate (HT29-MTX). The cells were stained with Alcian blue for mucus, antibodies for mucus 2 (goblet cells), villin (enterocytes), lysozyme (Paneth cells), and FITC-labeled lectins to identify different cells, glycomic profiles, and cell features. We observed that HT29 cells on topographic surfaces showed more similarities with the differentiated HT29-MTX than with undifferentiated HT29. They formed islands of cell clusters, as observed for HT29-MTX. Already after 2 days, the first mucus secretion was shown by Alcian blue stain and FITC-wheat germ agglutinin. After 4–6 days, mucus was observed on the cell surface and in the intercellular space. The cell layer was undulated, and in 3D reconstruction, the cells showed a clear polarisation with a strong actin signal to one membrane. The lectins and the antibody-staining confirmed the heterogeneous composition of differentiated HT29 cells on topographic surfaces after 6–8 days, or after 6–8 days following MTX differentiation (30 days). Full article

(This article belongs to the Special Issue Mucoadhesive and Mucosal Drug Delivery Systems)

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18 pages, 947 KiB

Open AccessReview

Drug Targeting and Nanomedicine: Lessons Learned from Liver Targeting and Opportunities for Drug Innovation

by Anna Salvati and Klaas Poelstra

Pharmaceutics 2022, 14(1), 217; https://doi.org/10.3390/pharmaceutics14010217 - 17 Jan 2022

Cited by 6 | Viewed by 3902

Abstract

Drug targeting and nanomedicine are different strategies for improving the delivery of drugs to their target. Several antibodies, immuno-drug conjugates and nanomedicines are already approved and used in clinics, demonstrating the potential of such approaches, including the recent examples of the DNA- and [...] Read more.

Drug targeting and nanomedicine are different strategies for improving the delivery of drugs to their target. Several antibodies, immuno-drug conjugates and nanomedicines are already approved and used in clinics, demonstrating the potential of such approaches, including the recent examples of the DNA- and RNA-based vaccines against COVID-19 infections. Nevertheless, targeting remains a major challenge in drug delivery and different aspects of how these objects are processed at organism and cell level still remain unclear, hampering the further development of efficient targeted drugs. In this review, we compare properties and advantages of smaller targeted drug constructs on the one hand, and larger nanomedicines carrying higher drug payload on the other hand. With examples from ongoing research in our Department and experiences from drug delivery to liver fibrosis, we illustrate opportunities in drug targeting and nanomedicine and current challenges that the field needs to address in order to further improve their success. Full article

(This article belongs to the Collection Drug Delivery in The Netherlands)

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17 pages, 2476 KiB

Open AccessArticle

Precise Dosing of Pramipexole for Low-Dosed Filament Production by Hot Melt Extrusion Applying Various Feeding Methods

by Rebecca Chamberlain, Hellen Windolf, Simon Geissler, Julian Quodbach and Jörg Breitkreutz

Pharmaceutics 2022, 14(1), 216; https://doi.org/10.3390/pharmaceutics14010216 - 17 Jan 2022

Cited by 19 | Viewed by 3003

Abstract

The aim of this research was the production of low-dosed filaments via hot-melt extrusion (HME) with the model drug pramipexole for the treatment of Parkinson’s disease. The active pharmaceutical ingredient (API) and one of the polymers polyvinyl alcohol (PVA) or basic butylated methacrylate [...] Read more.

The aim of this research was the production of low-dosed filaments via hot-melt extrusion (HME) with the model drug pramipexole for the treatment of Parkinson’s disease. The active pharmaceutical ingredient (API) and one of the polymers polyvinyl alcohol (PVA) or basic butylated methacrylate copolymer (bPMMA) were fed by various dosing techniques with the aim of achieving the smallest deviation (RSD) from the target concentration of 0.1% (w/w) pramipexole. It was found that deviation from target pramipexole concentration occurred due to degradation products in bPMMA formulations. Additionally, material temperature above 120 °C led to the formation of the anhydrous form of pramipexole within the extruded filaments and need to be considered in the calculation of the recovered API. This study clearly shows that even if equilibrium state of the extrusion parameters was reached, equilibrium condition for drug content was reached relatively late in the process. In addition, the RSD calculated by the Stange–Poole equation was proposed by us to predict the final content uniformity considering the sample size of the analyzed filament. The calculated RSD, depending on sample size and drug load, can serve as upper and lower limits of variation from target concentration and can be used to evaluate the deviations of drug content in equilibrium conditions of the HME process. The lowest deviations from target concentration in equilibrium condition for drug content were obtained in filaments extruded from previously prepared granule mixtures (RSD = 6.00%, acceptance value = 12.2). These promising results can be transferred to other API–excipient combinations to produce low-dosed filaments, which can be used for, e.g., fused filament 3D printing. The introduced calculation of the RSD by Stange–Poole equation can be used for precise determination of the homogeneity of an extruded batch. Full article

(This article belongs to the Special Issue Sustainable Materials and Technologies for Drug Delivery and Tissue Engineering)

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22 pages, 1680 KiB

Open AccessReview

BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia

by Gustavo P. Amarante-Mendes, Aamir Rana, Tarcila Santos Datoguia, Nelson Hamerschlak and Gabriela Brumatti

Pharmaceutics 2022, 14(1), 215; https://doi.org/10.3390/pharmaceutics14010215 - 17 Jan 2022

Cited by 42 | Viewed by 10450

Abstract

The constitutively active BCR-ABL1 tyrosine kinase, found in t(9;22)(q34;q11) chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and [...] Read more.

The constitutively active BCR-ABL1 tyrosine kinase, found in t(9;22)(q34;q11) chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, have revolutionized the treatment of BCR-ABL1-driven leukemia, particularly chronic myeloid leukemia (CML). However, TKIs do not cure CML patients, as some develop TKI resistance and the majority relapse upon withdrawal from treatment. Importantly, although BCR-ABL1 tyrosine kinase is necessary to initiate and establish the malignant phenotype of Ph-related leukemia, in the later advanced phase of the disease, BCR-ABL1-independent mechanisms are also in place. Here, we present an overview of the signaling pathways initiated by BCR-ABL1 and discuss the major challenges regarding immunologic/pharmacologic combined therapies. Full article

(This article belongs to the Special Issue Cancer Therapy Resistance: Choosing Kinase Inhibitors)

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21 pages, 6426 KiB

Open AccessArticle

Electrospraying as a Technique for the Controlled Synthesis of Biocompatible PLGA@Ag₂S and PLGA@Ag₂S@SPION Nanocarriers with Drug Release Capability

by Alexis Alvear-Jiménez, Irene Zabala Gutierrez, Yingli Shen, Gonzalo Villaverde, Laura Lozano-Chamizo, Pablo Guardia, Miguel Tinoco, Beatriz Garcia-Pinel, José Prados, Consolación Melguizo, Manuel López-Romero, Daniel Jaque, Marco Filice and Rafael Contreras-Cáceres

Pharmaceutics 2022, 14(1), 214; https://doi.org/10.3390/pharmaceutics14010214 - 17 Jan 2022

Cited by 9 | Viewed by 3801

Abstract

Ag₂S nanoparticles are near-infrared (NIR) probes providing emission in a specific spectral range (~1200 nm), and superparamagnetic iron oxide nanoparticles (SPION) are colloidal systems able to respond to an external magnetic field. A disadvantage of Ag₂S NPs is the [...] Read more.

Ag₂S nanoparticles are near-infrared (NIR) probes providing emission in a specific spectral range (~1200 nm), and superparamagnetic iron oxide nanoparticles (SPION) are colloidal systems able to respond to an external magnetic field. A disadvantage of Ag₂S NPs is the attenuated luminescent properties are reduced in aqueous media and human fluids. Concerning SPION, the main drawback is the generation of undesirable clusters that reduce particle stability. Here, we fabricate biocompatible hybrid nanosystems combining Ag₂S NPs and SPION by the electrospraying technique for drug delivery purposes. These nanostructures are composed of poly(lactic-co-glycolic acid) (PLGA) as the polymeric matrix in connection with both Ag₂S NPs and SPIONs. Initially, we fabricate a hybrid colloidal nanosystem composed of Ag₂S NPs in connection with PLGA (PLGA@Ag₂S) by three different routes, showing good photoluminescent (PL) properties with relatively high average decay times. Then, we incorporate SPIONs, obtaining a PLGA polymeric matrix containing both Ag₂S NPs and SPION (PLGA@Ag₂S@SPION). Interestingly, in this hybrid system, the location of Ag₂S NPs and SPIONs depends on the synthesis route performed during electrospraying. After a detailed characterization, we demonstrate the encapsulation and release capabilities, obtaining the kinetic release using a model chemotherapeutic drug (maslinic acid). Finally, we perform in vitro cytotoxicity assays using drug-loaded hybrid systems against several tumor cell lines. Full article

(This article belongs to the Special Issue Advanced Colloidal Systems for Multimodal Drug Delivery)

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18 pages, 3234 KiB

Open AccessArticle

Impact of Formulation Conditions on Lipid Nanoparticle Characteristics and Functional Delivery of CRISPR RNP for Gene Knock-Out and Correction

by Johanna Walther, Danny Wilbie, Vincent S. J. Tissingh, Mert Öktem, Heleen van der Veen, Bo Lou and Enrico Mastrobattista

Pharmaceutics 2022, 14(1), 213; https://doi.org/10.3390/pharmaceutics14010213 - 17 Jan 2022

Cited by 11 | Viewed by 5688

Abstract

The CRISPR-Cas9 system is an emerging therapeutic tool with the potential to correct diverse genetic disorders. However, for gene therapy applications, an efficient delivery vehicle is required, capable of delivering the CRISPR-Cas9 components into the cytosol of the intended target cell population. In [...] Read more.

The CRISPR-Cas9 system is an emerging therapeutic tool with the potential to correct diverse genetic disorders. However, for gene therapy applications, an efficient delivery vehicle is required, capable of delivering the CRISPR-Cas9 components into the cytosol of the intended target cell population. In this study, we optimized the formulation conditions of lipid nanoparticles (LNP) for delivery of ready-made CRISPR-Cas9 ribonucleic protein (RNP). The buffer composition during complexation and relative DOTAP concentrations were varied for LNP encapsulating in-house produced Cas9 RNP alone or Cas9 RNP with additional template DNA for gene correction. The LNP were characterized for size, surface charge, and plasma interaction through asymmetric flow field flow fractionation (AF4). Particles were functionally screened on fluorescent reporter cell lines for gene knock-out and gene correction. This revealed incompatibility of RNP with citrate buffer and PBS. We demonstrated that LNP for gene knock-out did not necessarily require DOTAP, while LNP for gene correction were only active with a low concentration of DOTAP. The AF4 studies additionally revealed that LNP interact with plasma, however, remain stable, whereby HDR template seems to favor stability of LNP. Under optimal formulation conditions, we achieved gene knock-out and gene correction efficiencies as high as 80% and 20%, respectively, at nanomolar concentrations of the CRISPR-Cas9 RNP. Full article

(This article belongs to the Collection Drug Delivery in The Netherlands)

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18 pages, 5124 KiB

Open AccessReview

Molecular Engineering of Peptide–Drug Conjugates for Therapeutics

by Yu Fang and Huaimin Wang

Pharmaceutics 2022, 14(1), 212; https://doi.org/10.3390/pharmaceutics14010212 - 17 Jan 2022

Cited by 14 | Viewed by 3817

Abstract

In recent years, hundreds of novel small molecular drugs used for different treatments have been studied in the three phases of clinical trials around the world. However, less than 10% of them are eventually used due to diverse problems. Even some traditional drugs [...] Read more.

In recent years, hundreds of novel small molecular drugs used for different treatments have been studied in the three phases of clinical trials around the world. However, less than 10% of them are eventually used due to diverse problems. Even some traditional drugs that have been approved by the Food and Drug Administration (FDA) have faced similar dilemmas. For instance, many drugs have poor water solubility, are easily hydrolyzed, or possess undesirable toxicity, while a variety of cancer cells develop drug resistance (DR) or multiple drug resistance (MDR) towards chemotherapeutic agents after long-term therapy. In order to improve the efficacy and efficiency of drugs, research has been directed forward towards the creation of assemblies of peptide–drug conjugates (PDCs) which have proven to possess wide potential for overcoming such complications based on their excellent biocompatibility, controllable biodegradability, site-selective targeting, and comparably low cytotoxicity. In this review, we focus on the recent developments and advances made in the creation of self-assembled nanostructures of PDCs for cancer therapy, on the chemical and physical properties of such drugs and peptides, and how they are arranged together to form diverse supramolecular nanostructures. Additionally, we cover certain mechanisms regarding how peptides or their derivatives enhance the efficiency and efficacy of those selected drugs and provide a brief discussion regarding the perspectives and remaining challenges in this intriguing field. Full article

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16 pages, 2131 KiB

Open AccessArticle

Anticancer Activity of Urease Mimetic Cobalt (III) Complexes on A549-Lung Cancer Cells: Targeting the Acidic Microenvironment

by Bhawna Uprety, Rahul Chandran, Charmaine Arderne and Heidi Abrahamse

Pharmaceutics 2022, 14(1), 211; https://doi.org/10.3390/pharmaceutics14010211 - 17 Jan 2022

Cited by 5 | Viewed by 2772

Abstract

Tumour cells maintain a local hypoxic and acidic microenvironment which plays a crucial role in cancer progression and drug resistance. Urease is a metallohydrolases that catalyses the hydrolysis of urea into ammonia and carbon dioxide, causing an abrupt increase of pH. This enzymatic [...] Read more.

Tumour cells maintain a local hypoxic and acidic microenvironment which plays a crucial role in cancer progression and drug resistance. Urease is a metallohydrolases that catalyses the hydrolysis of urea into ammonia and carbon dioxide, causing an abrupt increase of pH. This enzymatic activity can be employed to target the acidic tumour microenvironment. In this study, we present the anticancer activities of urease mimetic cobalt (III) complexes on A549 cells. The cells were treated with different doses of cobalt (III) complexes to observe the cytotoxicity. The change in cellular morphology was observed using an inverted microscope. The cell death induced by these complexes was analysed through ATP proliferation, LDH release and caspase 3/7 activity. The effect of extracellular alkalinization by the cobalt (III) complexes on the efficacy of the weakly basic drug, doxorubicin (dox) was also evaluated. This combination therapy of dox with cobalt (III) complexes resulted in enhanced apoptosis in A549 cells, as evidenced by elevated caspase 3/7 activity in treated groups. The study confirms the urease mimicking anticancer activity of cobalt (III) complexes by neutralizing the tumour microenvironment. This study will motivate the applications of transition metal-based enzyme mimics in targeting the tumour microenvironment for effective anticancer treatments. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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19 pages, 3005 KiB

Open AccessArticle

Design and Characterisation of pH-Responsive Photosensitiser-Loaded Nano-Transfersomes for Enhanced Photodynamic Therapy

by Sooho Yeo, Il Yoon and Woo Kyoung Lee

Pharmaceutics 2022, 14(1), 210; https://doi.org/10.3390/pharmaceutics14010210 - 16 Jan 2022

Cited by 10 | Viewed by 2811

Abstract

Photodynamic therapy (PDT) is a non-invasive and tumour-specific therapy. Photosensitizers (PSs) (essential ingredients in PDT) aggregate easily owing to their lipophilic properties. The aim of this study was to synthesise a PS (methyl pheophorbide a, MPa) and design a biocompatible lipid-based nanocarrier to [...] Read more.

Photodynamic therapy (PDT) is a non-invasive and tumour-specific therapy. Photosensitizers (PSs) (essential ingredients in PDT) aggregate easily owing to their lipophilic properties. The aim of this study was to synthesise a PS (methyl pheophorbide a, MPa) and design a biocompatible lipid-based nanocarrier to improve its bioavailability and pharmacological effects. MPa-loaded nano-transfersomes were fabricated by sonication. The characteristics of synthesised PS and nano-transfersomes were assessed. The effects of PDT were evaluated by 1,3-diphenylisobenzofuran assay and by measuring photo-cytotoxicity against HeLa and A549 cell lines. The mean particle size and zeta potential for nano-transfersomes ranged from 95.84 to 267.53 nm and −19.53 to −45.08 mV, respectively. Nano-transfersomes exhibited sustained drug release for 48 h in a physiological environment (as against burst release in an acidic environment), which enables its use as a pH-responsive drug release system in PDT with enhanced photodynamic activity and reduced side effects. The formulations showed light cytotoxicity, but no dark toxicity, which meant that light irradiation resulted in anti-cancer effects. Additionally, formulations with the smallest size exhibited photodynamic activity to a larger extent than those with the highest loading capacity or free MPa. These results suggest that our MPa-loaded nano-transfersome system is a promising anti-cancer strategy for PDT. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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35 pages, 19836 KiB

Open AccessReview

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

by Dusan Ruzic, Nemanja Djoković, Tatjana Srdić-Rajić, Cesar Echeverria, Katarina Nikolic and Juan F. Santibanez

Pharmaceutics 2022, 14(1), 209; https://doi.org/10.3390/pharmaceutics14010209 - 16 Jan 2022

Cited by 32 | Viewed by 4591

Abstract

The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. [...] Read more.

The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies. Full article

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

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25 pages, 6600 KiB

Open AccessEditor’s ChoiceArticle

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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16 pages, 2848 KiB

Open AccessEditor’s ChoiceArticle

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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12 pages, 3657 KiB

Open AccessArticle

Strong Antimicrobial Activity of Highly Stable Nanocomposite Containing AgNPs Based on Water-Soluble Triazole-Sulfonate Copolymer

by Alexander Pozdnyakov, Artem Emel’yanov, Anastasiya Ivanova, Nadezhda Kuznetsova, Tat’yana Semenova, Yuliya Bolgova, Svetlana Korzhova, Olga Trofimova, Tat’yana Fadeeva and Galina Prozorova

Pharmaceutics 2022, 14(1), 206; https://doi.org/10.3390/pharmaceutics14010206 - 16 Jan 2022

Cited by 9 | Viewed by 1951

Abstract

A new hydrophilic polymeric nanocomposite containing AgNPs was synthesized by chemical reduction of metal ions in an aqueous medium in the presence of the copolymer. A new water-soluble copolymer of 1-vinyl-1,2,4-triazole and vinylsulfonic acid sodium salt (poly(VT-co-Na-VSA)) was obtained by free-radical copolymerization and [...] Read more.

A new hydrophilic polymeric nanocomposite containing AgNPs was synthesized by chemical reduction of metal ions in an aqueous medium in the presence of the copolymer. A new water-soluble copolymer of 1-vinyl-1,2,4-triazole and vinylsulfonic acid sodium salt (poly(VT-co-Na-VSA)) was obtained by free-radical copolymerization and was used as a stabilizing precursor agent. The structural, dimensional, and morphological properties of the nanocomposite were studied by UV–Vis, FTIR, X-ray diffraction, atomic absorption, transmission and scanning electron microscopy, dynamic and electrophoretic light scattering, gel permeation chromatography, thermogravimetric analysis, and differential scanning calorimetry. Hydrodynamic diameter of macroclubs for the copolymer was 171 nm, and for the nanocomposite it was 694 nm. Zeta potential for the copolymer was −63.8 mV, and for the nanocomposite it was −70.4 mV. The nanocomposite had strong antimicrobial activity towards Gram-negative and Gram-positive microorganisms: MIC and MBC values were in the range of 0.25–4.0 and 0.5–8.0 μg/mL, respectively. Full article

(This article belongs to the Special Issue Advances in Nanostructured Materials between Pharmaceutics and Biomedicine 2.0)

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20 pages, 11414 KiB

Open AccessArticle

Formulation, Preparation, Characterization, and Evaluation of Dicarboxylic Ionic Liquid Donepezil Transdermal Patches

by Linh Dinh, Soohun Lee, Sharif Md Abuzar, Heejun Park and Sung-Joo Hwang

Pharmaceutics 2022, 14(1), 205; https://doi.org/10.3390/pharmaceutics14010205 - 16 Jan 2022

Cited by 13 | Viewed by 5050

Abstract

Donepezil (DPZ) is generally administered orally to treat Alzheimer’s disease (AD). However, oral administration can cause gastrointestinal side effects. Therefore, to enhance compliance, a new way to deliver DPZ from transdermal patch was developed. Ionic bonds were created by dissolving dicarboxylic acid and [...] Read more.

Donepezil (DPZ) is generally administered orally to treat Alzheimer’s disease (AD). However, oral administration can cause gastrointestinal side effects. Therefore, to enhance compliance, a new way to deliver DPZ from transdermal patch was developed. Ionic bonds were created by dissolving dicarboxylic acid and DPZ in ethanol, resulting in a stable ionic liquid (IL) state. The synthesized ILs were characterized by differential scanning calorimetry, optical microscope, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. The DPZ ILs were then transformed to a suitable drug-in-adhesive patch for transdermal delivery of DPZ. The novel DPZ ILs patch inhibits crystallization of the IL, indicating coherent design. Moreover, DPZ ILs and DPZ IL patch formulations performed excellent skin permeability compared to that of the DPZ free-base patch in both in vitro and ex vivo skin permeability studies. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)

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25 pages, 2613 KiB

Open AccessReview

Biomedical Applications of Iron Oxide Nanoparticles: Current Insights Progress and Perspectives

by María Gabriela Montiel Schneider, María Julia Martín, Jessica Otarola, Ekaterina Vakarelska, Vasil Simeonov, Verónica Lassalle and Miroslava Nedyalkova

Pharmaceutics 2022, 14(1), 204; https://doi.org/10.3390/pharmaceutics14010204 - 16 Jan 2022

Cited by 128 | Viewed by 9227

Abstract

The enormous development of nanomaterials technology and the immediate response of many areas of science, research, and practice to their possible application has led to the publication of thousands of scientific papers, books, and reports. This vast amount of information requires careful classification [...] Read more.

The enormous development of nanomaterials technology and the immediate response of many areas of science, research, and practice to their possible application has led to the publication of thousands of scientific papers, books, and reports. This vast amount of information requires careful classification and order, especially for specifically targeted practical needs. Therefore, the present review aims to summarize to some extent the role of iron oxide nanoparticles in biomedical research. Summarizing the fundamental properties of the magnetic iron oxide nanoparticles, the review’s next focus was to classify research studies related to applying these particles for cancer diagnostics and therapy (similar to photothermal therapy, hyperthermia), in nano theranostics, multimodal therapy. Special attention is paid to research studies dealing with the opportunities of combining different nanomaterials to achieve optimal systems for biomedical application. In this regard, original data about the synthesis and characterization of nanolipidic magnetic hybrid systems are included as an example. The last section of the review is dedicated to the capacities of magnetite-based magnetic nanoparticles for the management of oncological diseases. Full article

(This article belongs to the Special Issue Development of Novel Tumor-Targeting Nanoparticles)

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21 pages, 3852 KiB

Open AccessEditor’s ChoiceArticle

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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18 pages, 1608 KiB

Open AccessEditor’s ChoiceReview

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 13 | 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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8 pages, 1300 KiB

Open AccessArticle

⁷⁷Se-Enriched Selenoglycoside Enables Significant Enhancement in NMR Spectroscopic Monitoring of Glycan–Protein Interactions

by István Timári, Sára Balla, Krisztina Fehér, Katalin E. Kövér and László Szilágyi

Pharmaceutics 2022, 14(1), 201; https://doi.org/10.3390/pharmaceutics14010201 - 15 Jan 2022

Cited by 5 | Viewed by 2231

Abstract

Detailed investigation of ligand–protein interactions is essential for better understanding of biological processes at the molecular level. Among these binding interactions, the recognition of glycans by lectins is of particular importance in several diseases, such as cancer; therefore, inhibition of glycan-lectin/galectin interactions represents [...] Read more.

Detailed investigation of ligand–protein interactions is essential for better understanding of biological processes at the molecular level. Among these binding interactions, the recognition of glycans by lectins is of particular importance in several diseases, such as cancer; therefore, inhibition of glycan-lectin/galectin interactions represents a promising perspective towards developing therapeutics controlling cancer development. The recent introduction of ⁷⁷Se NMR spectroscopy for monitoring the binding of a selenoglycoside to galectins prompted interest to optimize the sensitivity by increasing the ⁷⁷Se content from the natural 7.63% abundance to 99%. Here, we report a convenient synthesis of ⁷⁷Se-enriched selenodigalactoside (SeDG), which is a potent ligand of the medically relevant human galectin-3 protein, and proof of the expected sensitivity gain in 2D ¹H, ⁷⁷Se correlation NMR experiments. Our work opens perspectives for adding isotopically enriched selenoglycans for rapid monitoring of lectin-binding of selenated as well as non-selenated ligands and for ligand screening in competition experiments. Full article

(This article belongs to the Special Issue Selenium, Trace Elements and Transition Metals in Anticancer Drug Discovery)

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20 pages, 3840 KiB

Open AccessArticle

Safe and Effective Cynomolgus Monkey GLP—Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders

by Sebastian Peters, Eva Wirkert, Sabrina Kuespert, Rosmarie Heydn, Siw Johannesen, Anita Friedrich, Susanne Mailänder, Sven Korte, Lars Mecklenburg, Ludwig Aigner, Tim-Henrik Bruun and Ulrich Bogdahn

Pharmaceutics 2022, 14(1), 200; https://doi.org/10.3390/pharmaceutics14010200 - 15 Jan 2022

Cited by 4 | Viewed by 3698

Abstract

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and [...] Read more.

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFβ system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide “NVP-13”, targeting TGFBR2, effectively reduced its expression and lowered TGFβ signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13. Full article

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19 pages, 19149 KiB

Open AccessEditor’s ChoiceArticle

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 Methocel^TM 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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11 pages, 582 KiB

Open AccessArticle

Swallowability of Minitablets among Children Aged 6–23 Months: An Exploratory, Randomized Crossover Study

by Nao Mitsui, Noriko Hida, Taro Kamiya, Taigi Yamazaki, Kazuki Miyazaki, Kiyomi Saito, Jumpei Saito, Akimasa Yamatani, Yoichi Ishikawa, Hidefumi Nakamura, Akihiro Nakamura and Tsutomu Harada

Pharmaceutics 2022, 14(1), 198; https://doi.org/10.3390/pharmaceutics14010198 - 15 Jan 2022

Cited by 10 | Viewed by 2631

Abstract

Minitablets have garnered interest as a new paediatric formulation that is easier to swallow than liquid formulations. In Japan, besides the latter, fine granules are frequently used for children. We examined the swallowability of multiple drug-free minitablets and compared it with that of [...] Read more.

Minitablets have garnered interest as a new paediatric formulation that is easier to swallow than liquid formulations. In Japan, besides the latter, fine granules are frequently used for children. We examined the swallowability of multiple drug-free minitablets and compared it with that of fine granules and liquid formulations in 40 children of two age groups (n = 20 each, aged 6–11 and 12–23 months). We compared the percentage of children who could swallow minitablets without chewing with that of children who could swallow fine granules or liquid formulations without leftover. The children who visited the paediatric department of Showa University Hospital were enrolled. Their caregivers were allowed to choose the administration method. In total, 37 out of 40 caregivers dispersed the fine granules in water. Significantly more children (80%, 95% CI: 56–94%) aged 6–11 months could swallow the minitablets than those who could swallow all the dispersed fine granules and liquid formulations (22%, 95% CI: 6–47% and 35%, 95% CI: 15–59%, respectively). No significant differences were observed in children aged 12–23 months. Hence, minitablets may be easier to swallow than dispersed fine granules and liquid formulations in children aged 6–11 months. Full article

(This article belongs to the Special Issue Advance in Development of Patient-Centric Dosage Form)

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14 pages, 5619 KiB

Open AccessArticle

Dasatinib Nanoemulsion and Nanocrystal for Enhanced Oral Drug Delivery

by Chuanqi Wang, Manting Wang, Peng Chen, Jiexin Wang and Yuan Le

Pharmaceutics 2022, 14(1), 197; https://doi.org/10.3390/pharmaceutics14010197 - 15 Jan 2022

Cited by 18 | Viewed by 3308

Abstract

In this work, dasatinib (DAS) nanoemulsion and nanocrystal are produced by high-gravity technology that approaches to practical mass production. The drug nanoformulations were systematically characterized and evaluated. At a low high-gravity level (β) = 47, nanoemulsion droplets were 16.15 ± 0.42 nm with [...] Read more.

In this work, dasatinib (DAS) nanoemulsion and nanocrystal are produced by high-gravity technology that approaches to practical mass production. The drug nanoformulations were systematically characterized and evaluated. At a low high-gravity level (β) = 47, nanoemulsion droplets were 16.15 ± 0.42 nm with a PDI of 0.122 ± 0.021. The nanoemulsion’s size and active pharmaceutical ingredient (API) content remained stable at long-term (4 months) freeze–thaw and dilution experiments. At a high β = 188, the as-prepared nanocrystal was lamellar with a short diameter of about 200 nm and a long diameter of about 750 nm. In vitro performances demonstrated the nanoemulsion displayed higher cytotoxicity on MDA-MB-231 tumor cells, Caco-2 cell permeability and drug release than that of the nanocrystal, indicating that nanoemulsion should be an ideal alternative for dasatinib oral administration. Full article

(This article belongs to the Special Issue Nanotechnology-Based Approaches for Enhancing Oral Administration of Drugs)

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13 pages, 1727 KiB

Open AccessArticle

Induction of Immunogenic Cell Death by Photodynamic Therapy Mediated by Aluminum-Phthalocyanine in Nanoemulsion

by Mosar Corrêa Rodrigues, Wellington Tavares de Sousa Júnior, Thayná Mundim, Camilla Lepesqueur Costa Vale, Jaqueline Vaz de Oliveira, Rayane Ganassin, Thyago José Arruda Pacheco, José Athayde Vasconcelos Morais, João Paulo Figueiró Longo, Ricardo Bentes Azevedo and Luis Alexandre Muehlmann

Pharmaceutics 2022, 14(1), 196; https://doi.org/10.3390/pharmaceutics14010196 - 14 Jan 2022

Cited by 24 | Viewed by 3146

Abstract

Photodynamic therapy (PDT) has been clinically employed to treat mainly superficial cancer, such as basal cell carcinoma. This approach can eliminate tumors by direct cytotoxicity, tumor ischemia, or by triggering an immune response against tumor cells. Among the immune-related mechanisms of PDT, the [...] Read more.

Photodynamic therapy (PDT) has been clinically employed to treat mainly superficial cancer, such as basal cell carcinoma. This approach can eliminate tumors by direct cytotoxicity, tumor ischemia, or by triggering an immune response against tumor cells. Among the immune-related mechanisms of PDT, the induction of immunogenic cell death (ICD) in target cells is to be cited. ICD is an apoptosis modality distinguished by the emission of damage-associated molecular patterns (DAMP). Therefore, this study aimed to analyze the immunogenicity of CT26 and 4T1 treated with PDT mediated by aluminum-phthalocyanine in nanoemulsion (PDT-AlPc-NE). Different PDT-AlPc-NE protocols with varying doses of energy and AlPc concentrations were tested. The death mechanism and the emission of DAMPs–CRT, HSP70, HSP90, HMGB1, and IL-1β–were analyzed in cells treated in vitro with PDT. Then, the immunogenicity of these cells was assessed in an in vivo vaccination-challenge model with BALB/c mice. CT26 and 4T1 cells treated in vitro with PDT mediated by AlPc IC₅₀ and a light dose of 25 J/cm² exhibited the hallmarks of ICD, i.e., these cells died by apoptosis and exposed DAMPs. Mice injected with these IC₅₀ PDT-treated cells showed, in comparison to the control, increased resistance to the development of tumors in a subsequent challenge with viable cells. Mice injected with 4T1 and CT26 cells treated with higher or lower concentrations of photosensitizer and light doses exhibited a significantly lower resistance to tumor development than those injected with IC₅₀ PDT-treated cells. The results presented in this study suggest that both the photosensitizer concentration and light dose affect the immunogenicity of the PDT-treated cells. This event can affect the therapy outcomes in vivo. Full article

(This article belongs to the Special Issue Application of Nanomedicine in Immunotherapy: Recent Advances and Prospects)

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18 pages, 11329 KiB

Open AccessArticle

Towards Complete Tumor Resection: Novel Dual-Modality Probes for Improved Image-Guided Surgery of GRPR-Expressing Prostate Cancer

by Maryana Handula, Marjolein Verhoeven, Kuo-Ting Chen, Joost Haeck, Marion de Jong, Simone U. Dalm and Yann Seimbille

Pharmaceutics 2022, 14(1), 195; https://doi.org/10.3390/pharmaceutics14010195 - 14 Jan 2022

Cited by 7 | Viewed by 2812

Abstract

Nuclear and optical dual-modality probes can be of great assistance in prostate cancer localization, providing the means for both preoperative nuclear imaging and intraoperative surgical guidance. We developed a series of probes based on the backbone of the established GRPR-targeting radiotracer NeoB. The [...] Read more.

Nuclear and optical dual-modality probes can be of great assistance in prostate cancer localization, providing the means for both preoperative nuclear imaging and intraoperative surgical guidance. We developed a series of probes based on the backbone of the established GRPR-targeting radiotracer NeoB. The inverse electron demand of the Diels–Alder reaction was used to integrate the sulfo-cyanine 5 dye. Indium-111 radiolabeling, stability studies and a competition binding assay were carried out. Pilot biodistribution and imaging studies were performed in PC-3 tumor-bearing mice, using the best two dual-labeled probes. The dual-modality probes were radiolabeled with a high yield (>92%), were proven to be hydrophilic and demonstrated high stability in mouse serum (>94% intact labeled ligand at 4 h). The binding affinity for the GRPR was in the nanomolar range (21.9–118.7 nM). SPECT/CT images at 2 h p.i. clearly visualized the tumor xenograft and biodistribution studies, after scanning confirmed the high tumor uptake (8.47 ± 0.46%ID/g and 6.90 ± 0.81%ID/g for probe [¹¹¹In]In-12 and [¹¹¹In]In-15, respectively). Receptor specificity was illustrated with blocking studies, and co-localization of the radioactive and fluorescent signal was verified by ex vivo fluorescent imaging. Although optimal tumor-to-blood and tumor-to-kidney ratios might not yet have been reached due to the prolonged blood circulation, our probes are promising candidates for the preoperative and intraoperative visualization of GRPR-positive prostate cancer. Full article

(This article belongs to the Special Issue Advances in the Development and Application of Targeted Radiopharmaceuticals for Cancer Management)

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22 pages, 2324 KiB

Open AccessArticle

In Vitro Evaluation of Curcumin- and Quercetin-Loaded Nanoemulsions for Intranasal Administration: Effect of Surface Charge and Viscosity

by Gustavo Vaz, Adryana Clementino, Evgenia Mitsou, Elena Ferrari, Francesca Buttini, Cristina Sissa, Aristotelis Xenakis, Fabio Sonvico and Cristiana Lima Dora

Pharmaceutics 2022, 14(1), 194; https://doi.org/10.3390/pharmaceutics14010194 - 14 Jan 2022

Cited by 16 | Viewed by 3283

Abstract

The nose-to-brain delivery of neuroprotective natural compounds is an appealing approach for the treatment of neurodegenerative diseases. Nanoemulsions containing curcumin (CUR) and quercetin (QU) were prepared by high-pressure homogenization and characterized physicochemically and structurally. A negative (CQ_NE−), a positive (CQ_NE+), and a gel [...] Read more.

The nose-to-brain delivery of neuroprotective natural compounds is an appealing approach for the treatment of neurodegenerative diseases. Nanoemulsions containing curcumin (CUR) and quercetin (QU) were prepared by high-pressure homogenization and characterized physicochemically and structurally. A negative (CQ_NE−), a positive (CQ_NE+), and a gel (CQ_NEgel) formulation were developed. The mean particle size of the CQ_NE− and CQ_NE+ was below 120 nm, while this increased to 240 nm for the CQ_NEgel. The formulations showed high encapsulation efficiency and protected the CUR/QU from biological/chemical degradation. Electron paramagnetic resonance spectroscopy showed that the CUR/QU were located at the interface of the oil phase in the proximity of the surfactant layer. The cytotoxicity studies showed that the formulations containing CUR/QU protected human nasal cells from the toxicity evidenced for blank NEs. No permeation across an in vitro model nasal epithelium was evidenced for CUR/QU, probably due to their poor water-solubility and instability in physiological buffers. However, the nasal cells’ drug uptake showed that the total amount of CUR/QU in the cells was related to the NE characteristics (CQ_NE− > CQ_NE+ > CQ_NEgel). The method used allowed the obtainment of nanocarriers of an appropriate size for nasal administration. The treatment of the cells showed the protection of cellular viability, holding promise as an anti-inflammatory treatment able to prevent neurodegenerative diseases. Full article

(This article belongs to the Special Issue Up-to-Date Pharmaceutical Applications of Micro/Nanoemulsions)

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14 pages, 3088 KiB

Open AccessArticle

Tumor-Targeted Fluorescence Imaging and Mechanisms of Tumor Cell-Derived Carbon Nanodots

by Taotao Huo, Wenshuai Li, Dong Liang and Rongqin Huang

Pharmaceutics 2022, 14(1), 193; https://doi.org/10.3390/pharmaceutics14010193 - 14 Jan 2022

Cited by 1 | Viewed by 2132

Abstract

An ideal cancer diagnostic probe should possess precise tumor-targeted accumulation with negligible sojourn in normal tissues. Herein, tumor cell-derived carbon nanodots (C-CND_U87 and C-CND_HepG2) about 3~7 nm were prepared by a solvothermal method with stable fluorescence and negligible cytotoxicity. More [...] Read more.

An ideal cancer diagnostic probe should possess precise tumor-targeted accumulation with negligible sojourn in normal tissues. Herein, tumor cell-derived carbon nanodots (C-CND_U87 and C-CND_HepG2) about 3~7 nm were prepared by a solvothermal method with stable fluorescence and negligible cytotoxicity. More interestingly, due to the differences in gene expression of cancers, C-CND structurally mimicked the corresponding precursors during carbonization in which carbon nanodots were functionalized with α-amino and carboxyl groups with different densities on their edges. With inherent homology and homing effect, C-CND were highly enriched in precursor tumor tissues. Mechanistic studies showed that under the mediation of the original configuration of α-amino and carboxyl groups, C-CND specifically bound to the large neutral amino acid transporter 1 (LAT1, overexpressed in cancer cells), achieving specific tumor fluorescence imaging. This work provided a new vision about tumor cell architecture-mimicked carbon nanodots for tumor-targeted fluorescence imaging. Full article

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14 pages, 3539 KiB

Open AccessEditor’s ChoiceArticle

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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26 pages, 2276 KiB

Open AccessReview

Nanofiber Systems as Herbal Bioactive Compounds Carriers: Current Applications in Healthcare

by Kathya Huesca-Urióstegui, Elsy J. García-Valderrama, Janet A. Gutierrez-Uribe, Marilena Antunes-Ricardo and Daniel Guajardo-Flores

Pharmaceutics 2022, 14(1), 191; https://doi.org/10.3390/pharmaceutics14010191 - 14 Jan 2022

Cited by 25 | Viewed by 3734

Abstract

Nanofibers have emerged as a potential novel platform due to their physicochemical properties for healthcare applications. Nanofibers’ advantages rely on their high specific surface-area-to-volume and highly porous mesh. Their peculiar assembly allows cell accommodation, nutrient infiltration, gas exchange, waste excretion, high drug release [...] Read more.

Nanofibers have emerged as a potential novel platform due to their physicochemical properties for healthcare applications. Nanofibers’ advantages rely on their high specific surface-area-to-volume and highly porous mesh. Their peculiar assembly allows cell accommodation, nutrient infiltration, gas exchange, waste excretion, high drug release rate, and stable structure. This review provided comprehensive information on the design and development of natural-based polymer nanofibers with the incorporation of herbal medicines for the treatment of common diseases and their in vivo studies. Natural and synthetic polymers have been widely used for the fabrication of nanofibers capable of mimicking extracellular matrix structure. Among them, natural polymers are preferred because of their biocompatibility, biodegradability, and similarity with extracellular matrix proteins. Herbal bioactive compounds from natural extracts have raised special interest due to their prominent beneficial properties in healthcare. Nanofiber properties allow these systems to serve as bioactive compound carriers to generate functional matrices with antimicrobial, anti-inflammatory, antioxidant, antiseptic, anti-viral, and other properties which have been studied in vitro and in vivo, mostly to prove their wound healing capacity and anti-inflammation properties. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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17 pages, 1311 KiB

Open AccessReview

The Role of Glucosinolates from Cruciferous Vegetables (Brassicaceae) in Gastrointestinal Cancers: From Prevention to Therapeutics

by Catarina Melim, Maria R. Lauro, Isabel M. Pires, Paulo J. Oliveira and Célia Cabral

Pharmaceutics 2022, 14(1), 190; https://doi.org/10.3390/pharmaceutics14010190 - 14 Jan 2022

Cited by 28 | Viewed by 6069

Abstract

The gastrointestinal (GI) tract is composed of rapidly renewing cells, which increase the likelihood of cancer. Colorectal cancer is one of the most frequently diagnosed GI cancers and currently stands in second place regarding cancer-related mortality. Unfortunately, the treatment of GI is limited, [...] Read more.

The gastrointestinal (GI) tract is composed of rapidly renewing cells, which increase the likelihood of cancer. Colorectal cancer is one of the most frequently diagnosed GI cancers and currently stands in second place regarding cancer-related mortality. Unfortunately, the treatment of GI is limited, and few developments have occurred in the field over the years. With this in mind, new therapeutic strategies involving biologically active phytocompounds are being evaluated as anti-cancer agents. Vegetables such as broccoli, brussels sprouts, cabbage, cauliflower, and radish, all belonging to the Brassicaceae family, are high in dietary fibre, minerals, vitamins, carotenoids, polyphenols, and glucosinolates. The latter compound is a secondary metabolite characteristic of this family and, when biologically active, has demonstrated anti-cancer properties. This article reviews the literature regarding the potential of Cruciferous vegetables in the prevention and/or treatment of GI cancers and the relevance of appropriate compound formulations for improving the stability and bioaccessibility of the major Cruciferous compounds, with a particular focus on glucosinolates. Full article

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

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21 pages, 1684 KiB

Open AccessReview

²¹²Pb: Production Approaches and Targeted Therapy Applications

by Konstantin V. Kokov, Bayirta V. Egorova, Marina N. German, Ilya D. Klabukov, Michael E. Krasheninnikov, Antonius A. Larkin-Kondrov, Kseniya A. Makoveeva, Michael V. Ovchinnikov, Maria V. Sidorova and Dmitry Y. Chuvilin

Pharmaceutics 2022, 14(1), 189; https://doi.org/10.3390/pharmaceutics14010189 - 13 Jan 2022

Cited by 34 | Viewed by 6847

Abstract

Over the last decade, targeted alpha therapy has demonstrated its high effectiveness in treating various oncological diseases. Lead-212, with a convenient half-life of 10.64 h, and daughter alpha-emitter short-lived ²¹²Bi (T_1/2 = 1 h), provides the possibility for the synthesis [...] Read more.

Over the last decade, targeted alpha therapy has demonstrated its high effectiveness in treating various oncological diseases. Lead-212, with a convenient half-life of 10.64 h, and daughter alpha-emitter short-lived ²¹²Bi (T_1/2 = 1 h), provides the possibility for the synthesis and purification of complex radiopharmaceuticals with minimum loss of radioactivity during preparation. As a benefit for clinical implementation, it can be milked from a radionuclide generator in different ways. The main approaches applied for these purposes are considered and described in this review, including chromatographic, solution, and other techniques to isolate ²¹²Pb from its parent radionuclide. Furthermore, molecules used for lead’s binding and radiochemical features of preparation and stability of compounds labeled with ²¹²Pb are discussed. The results of preclinical studies with an estimation of therapeutic and tolerant doses as well as recently initiated clinical trials of targeted radiopharmaceuticals are presented. Full article

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

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Pharmaceutics, Volume 14, Issue 1 (January 2022) – 218 articles

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