Research

17 pages, 1959 KiB

Open AccessArticle

Mouse Type-I Interferon-Mannosylated Albumin Fusion Protein for the Treatment of Chronic Hepatitis

by Yuki Minayoshi, Hitoshi Maeda, Keisuke Hamasaki, Taisei Nagasaki, Mei Takano, Ryo Fukuda, Yuki Mizuta, Motohiko Tanaka, Yutaka Sasaki, Masaki Otagiri, Hiroshi Watanabe and Toru Maruyama

Pharmaceuticals 2024, 17(2), 260; https://doi.org/10.3390/ph17020260 - 19 Feb 2024

Viewed by 790

Abstract

Although a lot of effort has been put into creating drugs and combination therapies against chronic hepatitis, no effective treatment has been established. Type-I interferon is a promising therapeutic for chronic hepatitis due to its excellent anti-inflammatory effects through interferon receptors on hepatic [...] Read more.

Although a lot of effort has been put into creating drugs and combination therapies against chronic hepatitis, no effective treatment has been established. Type-I interferon is a promising therapeutic for chronic hepatitis due to its excellent anti-inflammatory effects through interferon receptors on hepatic macrophages. To develop a type-I IFN equipped with the ability to target hepatic macrophages through the macrophage mannose receptor, the present study designed a mouse type-I interferon-mannosylated albumin fusion protein using site-specific mutagenesis and albumin fusion technology. This fusion protein exhibited the induction of anti-inflammatory molecules, such as IL-10, IL-1Ra, and PD-1, in RAW264.7 cells, or hepatoprotective effects on carbon tetrachloride-induced chronic hepatitis mice. As expected, such biological and hepatoprotective actions were significantly superior to those of human fusion proteins. Furthermore, the repeated administration of mouse fusion protein to carbon tetrachloride-induced chronic hepatitis mice clearly suppressed the area of liver fibrosis and hepatic hydroxyproline contents, not only with a reduction in the levels of inflammatory cytokine (TNF-α) and fibrosis-related genes (TGF-β, Fibronectin, Snail, and Collagen 1α2), but also with a shift in the hepatic macrophage phenotype from inflammatory to anti-inflammatory. Therefore, type-I interferon-mannosylated albumin fusion protein has the potential as a new therapeutic agent for chronic hepatitis. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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14 pages, 2686 KiB

Open AccessArticle

Acute Kidney Injury Caused by Rhabdomyolysis Is Ameliorated by Serum Albumin-Based Supersulfide Donors through Antioxidative Pathways

by Mayumi Ikeda-Imafuku, Tatsuya Fukuta, Victor Tuan Giam Chuang, Tomohiro Sawa, Toru Maruyama, Masaki Otagiri, Tatsuhiro Ishida and Yu Ishima

Pharmaceuticals 2024, 17(1), 128; https://doi.org/10.3390/ph17010128 - 18 Jan 2024

Viewed by 875

Abstract

Oxidative stress is responsible for the onset and progression of various kinds of diseases including rhabdomyolysis-induced acute kidney injury (AKI). Antioxidants are, therefore, thought to aid in the recovery of illnesses linked to oxidative stress. Supersulfide species have been shown to have substantial [...] Read more.

Oxidative stress is responsible for the onset and progression of various kinds of diseases including rhabdomyolysis-induced acute kidney injury (AKI). Antioxidants are, therefore, thought to aid in the recovery of illnesses linked to oxidative stress. Supersulfide species have been shown to have substantial antioxidative activity; however, due to their limited bioavailability, few supersulfide donors have had their actions evaluated in vivo. In this study, human serum albumin (HSA) and N-acetyl-L-cysteine polysulfides (NACSn), which have polysulfides in an oxidized form, were conjugated to create a supersulfide donor. HSA is chosen to be a carrier of NACSn because of its extended blood circulation and high level of biocompatibility. In contrast to a supersulfide donor containing reduced polysulfide in HSA, the NACSn-conjugated HSAs exhibited stronger antioxidant activity than HSA and free NACSn without being uptaken by the cells in vitro. The supersulfide donor reduced the levels of blood urea nitrogen and serum creatinine significantly in a mouse model of rhabdomyolysis-induced AKI. Supersulfide donors significantly reduced the expression of oxidative stress markers in the kidney. These results indicate that the developed supersulfide donor has the therapeutic effect on rhabdomyolysis-induced AKI. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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12 pages, 1169 KiB

Open AccessArticle

Brain Delivery of Cisplatin Using Microbubbles in Combination with Ultrasound as an Effective Therapy for Glioblastoma

by Fumiko Hagiwara, Daiki Omata, Lisa Munakata, Saori Kageyama, Kazuo Maruyama, Nobuki Kudo and Ryo Suzuki

Pharmaceuticals 2023, 16(11), 1599; https://doi.org/10.3390/ph16111599 - 13 Nov 2023

Viewed by 1059

Abstract

Glioblastoma is a highly invasive and fatal disease. Temozolomide, a blood–brain barrier (BBB)-penetrant therapeutic agent currently used for glioblastoma, does not exhibit sufficient therapeutic effect. Cisplatin (CDDP), a versatile anticancer drug, is not considered a therapeutic option for glioblastoma due to its low [...] Read more.

Glioblastoma is a highly invasive and fatal disease. Temozolomide, a blood–brain barrier (BBB)-penetrant therapeutic agent currently used for glioblastoma, does not exhibit sufficient therapeutic effect. Cisplatin (CDDP), a versatile anticancer drug, is not considered a therapeutic option for glioblastoma due to its low BBB permeability. We previously investigated the utility of microbubbles (MBs) in combination with ultrasound (US) in promoting BBB permeability and reported the efficacy of drug delivery to the brain using a minimally invasive approach. This study aimed to evaluate the feasibility of CDDP delivery to the brain using the combination of MBs and US for the treatment of glioblastoma. We used mice that were implanted with glioma-261 GFP-Luc cells expressing luciferase as the glioblastoma model. In this model, after tumor inoculation, the BBB opening was induced using MBs and US, and CDDP was simultaneously administered. We found that the CDDP concentrations were higher at the glioblastoma site where the US was applied, although CDDP normally cannot pass through the BBB. Furthermore, the survival was longer in mice treated with CDDP delivered via MBs and US than in those treated with CDDP alone or those that were left untreated. These results suggest that the combination of MBs and US is an effective antitumor drug delivery system based on BBB opening in glioblastoma therapy. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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23 pages, 7293 KiB

Open AccessArticle

Verubulin (Azixa) Analogues with Increased Saturation: Synthesis, SAR and Encapsulation in Biocompatible Nanocontainers Based on Ca²⁺ or Mg²⁺ Cross-Linked Alginate

by Kseniya N. Sedenkova, Denis N. Leschukov, Yuri K. Grishin, Nikolay A. Zefirov, Yulia A. Gracheva, Dmitry A. Skvortsov, Yanislav S. Hrytseniuk, Lilja A. Vasilyeva, Elena A. Spirkova, Pavel N. Shevtsov, Elena F. Shevtsova, Alina R. Lukmanova, Vasily V. Spiridonov, Alina A. Markova, Minh T. Nguyen, Alexander A. Shtil, Olga N. Zefirova, Alexander A. Yaroslavov, Elena R. Milaeva and Elena B. Averina

Pharmaceuticals 2023, 16(10), 1499; https://doi.org/10.3390/ph16101499 - 21 Oct 2023

Viewed by 1247

Abstract

Tubulin-targeting agents attract undiminished attention as promising compounds for the design of anti-cancer drugs. Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. In the present work, a series of verubulin analogues containing a cyclohexane or cycloheptane ring 1,2-annulated with pyrimidine [...] Read more.

Tubulin-targeting agents attract undiminished attention as promising compounds for the design of anti-cancer drugs. Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. In the present work, a series of verubulin analogues containing a cyclohexane or cycloheptane ring 1,2-annulated with pyrimidine moiety and various substituents in positions 2 and 4 of pyrimidine were obtained and their cytotoxicity towards cancer and non-cancerous cell lines was estimated. The investigated compounds revealed activity against various cancer cell lines with IC₅₀ down to 1–4 nM. According to fluorescent microscopy data, compounds that showed cytotoxicity in the MTT test disrupt the normal cytoskeleton of the cell in a pattern similar to that for combretastatin A-4. The hit compound (N-(4-methoxyphenyl)-N,2-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine) was encapsulated in biocompatible nanocontainers based on Ca²⁺ or Mg²⁺ cross-linked alginate and it was demonstrated that its cytotoxic activity was preserved after encapsulation. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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15 pages, 1248 KiB

Open AccessArticle

Evaluation of Anti-Inflammatory and Anti-Tubercular Activity of 4-Methyl-7-Substituted Coumarin Hybrids and Their Structure Activity Relationships

by Muthipeedika Nibin Joy, Mallikarjuna R. Guda and Grigory V. Zyryanov

Pharmaceuticals 2023, 16(9), 1326; https://doi.org/10.3390/ph16091326 - 19 Sep 2023

Viewed by 1094

Abstract

Four sets of previously synthesized 4-methyl-7-substituted coumarin derivatives were screened for their in vitro anti-inflammatory and anti-tubercular activities. The anti-inflammatory potential of 3a–t, 5a–o, 6a–n, and 7a–f synthesized compounds was evaluated by [...] Read more.

Four sets of previously synthesized 4-methyl-7-substituted coumarin derivatives were screened for their in vitro anti-inflammatory and anti-tubercular activities. The anti-inflammatory potential of 3a–t, 5a–o, 6a–n, and 7a–f synthesized compounds was evaluated by an anti-denaturation assay using diclofenac sodium as the reference standard. Evaluation of the anti-tuberculous activity of the mentioned compounds was performed by the Resazurin test method against four different TB strains using rifampicin and isoniazid as reference drugs. Based on the anti-inflammatory results, compounds 3o, 5f, 6c, and 7d proved to be the most active compounds in their respective series. Additionally, compounds 3k–n, 5b–d, 6d–f, 6k, 7a, and 7f were found to be the most potent anti-tuberculous agents. In fact, most of the screened compounds exhibited promising activity profiles compared to the respective standard drugs. The structure–activity connections revealed a few intriguing aspects, indicating that the presence of electron-donating and nitrogen-rich fragments boost the anti-inflammatory effects of the examined compounds. However, the presence of electron-withdrawing substituents was required to boost the anti-tubercular activity of the evaluated compounds. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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29 pages, 5462 KiB

Open AccessArticle

Cytotoxic and Infection-Controlled Investigations of Novel Dihydropyridine Hybrids: An Efficient Synthesis and Molecular-Docking Studies

by Mallikarjuna R. Guda, Grigory. V. Zyryanov, Amit Dubey, Venkata Subbaiah Munagapati and Jet-Chau Wen

Pharmaceuticals 2023, 16(8), 1159; https://doi.org/10.3390/ph16081159 - 15 Aug 2023

Cited by 1 | Viewed by 965

Abstract

A sequence of novel 1,4-dihydropyridines (DHP) and their hybrids was developed using a multicomponent strategy under environmentally benign conditions. In addition, computational studies were performed, and the ligand–protein interactions calculated in different bacteria and two fungal strains. Para-hydroxy-linked DHP (5f) showed [...] Read more.

A sequence of novel 1,4-dihydropyridines (DHP) and their hybrids was developed using a multicomponent strategy under environmentally benign conditions. In addition, computational studies were performed, and the ligand–protein interactions calculated in different bacteria and two fungal strains. Para-hydroxy-linked DHP (5f) showed the best binding energies of 3.591, 3.916, 8.499 and 6.895 kcal/mol against various pathogens used and other substances received a good docking score. The pathogen resistance potential of the synthesized targets against four bacteria and two fungi showed that whole DHP substances exhibit different levels of resistance to each microorganism. Gram-positive bacteria, which are highly sensitive to all molecules, and the MTCC-1884-encoded fungus strongly rejected the studied compounds compared to comparator drugs. In particular, the 5f candidate showed remarkable antimicrobial activity, followed by the substances 5a, 5b, 5j, 5k and 5l. Furthermore, MIC and MBC/MFC properties showed that 5f had a minimum bacterial concentration of 12.5 μg/mL against E. coli and against two fungal pathogens, with its killing activity being effective even at low concentrations. On the other hand, whole motifs were tested for their cytotoxic activity, revealing that the methoxy and hydroxy-linked compounds (5h) showed greater cytotoxic potency, followed by the two hydroxy linked compounds (5d and 5f). Overall, this synthetic approach used represents a prototype for future nature-favored synthesis methods and these biological results serve as a guide for future therapeutic drug research. However, the computer results play an important role in the further development of biological experiments. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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17 pages, 3270 KiB

Open AccessArticle

In Vitro and In Vivo Functional Viability, and Biocompatibility Evaluation of Bovine Serum Albumin-Ingrained Microemulsion: A Model Based on Sesame Oil as the Payload for Developing an Efficient Drug Delivery Platform

by Atiaf Rhyaf, Hala Naji, Hassan Al-Karagoly, Salim Albukhaty, Ghassan M. Sulaiman, Abdulaziz Arif A. Alshammari, Hamdoon A. Mohammed, Majid Jabir and Riaz A. Khan

Pharmaceuticals 2023, 16(4), 582; https://doi.org/10.3390/ph16040582 - 12 Apr 2023

Cited by 6 | Viewed by 1943

Abstract

Combination of bovine serum albumin with microemulsions as constituting ingredient biopolymer has long been regarded an innovative method to address the surface functionalization and stability issues in the targeted payload deliveries, thereupon producing effectively modified microemulsions, which are superior in loading capacity, transitional [...] Read more.

Combination of bovine serum albumin with microemulsions as constituting ingredient biopolymer has long been regarded an innovative method to address the surface functionalization and stability issues in the targeted payload deliveries, thereupon producing effectively modified microemulsions, which are superior in loading capacity, transitional and shelf-stability, as well as site-directed/site-preferred delivery, has become a favored option. The current study aimed to develop an efficient, suitable and functional microemulsion system encapsulating sesame oil (SO) as a model payload towards developing an efficient delivery platform. UV-VIS, FT-IR, and FE-SEM were used to characterize, and analyze the developed carrier. Physicochemical properties assessments of the microemulsion by dynamic light scattering size distributions, zeta-potential, and electron micrographic analyses were performed. The mechanical properties for rheological behavior were also studied. The HFF-2 cell line and hemolysis assays were conducted to ascertain the cell viability, and in vitro biocompatibility. The in vivo toxicity was determined based on a predicted median lethal dose (LD₅₀) model, wherein the liver enzymes’ functions were also tested to assess and confirm the predicted toxicity. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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12 pages, 3268 KiB

Open AccessArticle

Increasing Skeletal Muscle Mass in Mice by Non-Invasive Intramuscular Delivery of Myostatin Inhibitory Peptide by Iontophoresis

by Kohki Michiue, Kentaro Takayama, Atsuhiko Taniguchi, Yoshio Hayashi and Kentaro Kogure

Pharmaceuticals 2023, 16(3), 397; https://doi.org/10.3390/ph16030397 - 06 Mar 2023

Viewed by 1877

Abstract

Sarcopenia is a major public health issue that affects older adults. Myostatin inhibitory-D-peptide-35 (MID-35) can increase skeletal muscle and is a candidate therapeutic agent, but a non-invasive and accessible technology for the intramuscular delivery of MID-35 is required. Recently, we succeeded in the [...] Read more.

Sarcopenia is a major public health issue that affects older adults. Myostatin inhibitory-D-peptide-35 (MID-35) can increase skeletal muscle and is a candidate therapeutic agent, but a non-invasive and accessible technology for the intramuscular delivery of MID-35 is required. Recently, we succeeded in the intradermal delivery of various macromolecules, such as siRNA and antibodies, by iontophoresis (ItP), a non-invasive transdermal drug delivery technology that uses weak electricity. Thus, we expected that ItP could deliver MID-35 non-invasively from the skin surface to skeletal muscle. In the present study, ItP was performed with a fluorescently labeled peptide on mouse hind leg skin. Fluorescent signal was observed in both skin and skeletal muscle. This result suggested that the peptide was effectively delivered to skeletal muscle from skin surface by ItP. Then, the effect of MID-35/ItP on skeletal muscle mass was evaluated. The skeletal muscle mass increased 1.25 times with ItP of MID-35. In addition, the percentage of new and mature muscle fibers tended to increase, and ItP delivery of MID-35 showed a tendency to induce alterations in the levels of mRNA of genes downstream of myostatin. In conclusion, ItP of myostatin inhibitory peptide is a potentially useful strategy for treating sarcopenia. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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