Pharmaceutics

31 pages, 4667 KiB

Open AccessReview

Research Progress of Conjugated Nanomedicine for Cancer Treatment

by Bin Zhao, Sa Chen, Ye Hong, Liangliang Jia, Ying Zhou, Xinyu He, Ying Wang, Zhongmin Tian, Zhe Yang and Di Gao

Pharmaceutics 2022, 14(7), 1522; https://doi.org/10.3390/pharmaceutics14071522 - 21 Jul 2022

Cited by 10 | Viewed by 3577

Abstract

The conventional cancer therapeutic modalities include surgery, chemotherapy and radiotherapy. Although immunotherapy and targeted therapy are also widely used in cancer treatment, chemotherapy remains the cornerstone of tumor treatment. With the rapid development of nanotechnology, nanomedicine is believed to be an emerging field [...] Read more.

The conventional cancer therapeutic modalities include surgery, chemotherapy and radiotherapy. Although immunotherapy and targeted therapy are also widely used in cancer treatment, chemotherapy remains the cornerstone of tumor treatment. With the rapid development of nanotechnology, nanomedicine is believed to be an emerging field to further improve the efficacy of chemotherapy. Until now, there are more than 17 kinds of nanomedicine for cancer therapy approved globally. Thereinto, conjugated nanomedicine, as an important type of nanomedicine, can not only possess the targeted delivery of chemotherapeutics with great precision but also achieve controlled drug release to avoid adverse effects. Meanwhile, conjugated nanomedicine provides the platform for combining several different therapeutic approaches (chemotherapy, photothermal therapy, photodynamic therapy, thermodynamic therapy, immunotherapy, etc.) with the purpose of achieving synergistic effects during cancer treatment. Therefore, this review focuses on conjugated nanomedicine and its various applications in synergistic chemotherapy. Additionally, the further perspectives and challenges of the conjugated nanomedicine are also addressed, which clarifies the design direction of a new generation of conjugated nanomedicine and facilitates the translation of them from the bench to the bedside. Full article

(This article belongs to the Special Issue Bioconjugation and Nanomaterials for Clinical Translation)

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15 pages, 11002 KiB

Open AccessEditor’s ChoiceArticle

Preferences of Healthcare Professionals on 3D-Printed Tablets: A Pilot Study

by Odelia Goh, Wei Jiang Goh, Seng Han Lim, Grace S. Hoo, Raymond Liew and Tat Ming Ng

Pharmaceutics 2022, 14(7), 1521; https://doi.org/10.3390/pharmaceutics14071521 - 21 Jul 2022

Cited by 14 | Viewed by 3048

Abstract

An inaugural study was performed to understand the perceptions of healthcare professionals toward the potential benefits of 3D printing in Singapore. This study sought to increase awareness of 3D printing applications for viable clinical applications and to elucidate the current gaps in therapy [...] Read more.

An inaugural study was performed to understand the perceptions of healthcare professionals toward the potential benefits of 3D printing in Singapore. This study sought to increase awareness of 3D printing applications for viable clinical applications and to elucidate the current gaps in therapy where 3D printing could play a role. A common example would be the use of 3D printing to manufacture polypills, thereby reducing the daily pill burden of patients and possibly improving medication adherence. A qualitative descriptive survey with a single-centered cross-sectional design was performed at Tan Tock Seng Hospital, a tertiary referral hospital with 1700 beds. This study had a total of 55 respondents comprising doctors and pharmacists. Most of the respondents viewed the 3D printing of oral dosage forms favorably and agreed about the potential advantages this technology could offer. More than 60% of the respondents were also willing to prescribe 3D printed tablets to patients. Respondents’ concerns were grouped into three main categories: formulation considerations, manufacturing processes, and administrative issues. Viewed in its entirety, this study provides a valuable starting point for understanding the perceptions of healthcare professionals in adopting 3D printing technology. Full article

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

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13 pages, 3593 KiB

Open AccessArticle

Combination of Lanosterol and Nilvadipine Nanosuspensions Rescues Lens Opacification in Selenite-Induced Cataractic Rats

by Saori Deguchi, Reita Kadowaki, Hiroko Otake, Atsushi Taga, Yosuke Nakazawa, Manju Misra, Naoki Yamamoto, Hiroshi Sasaki and Noriaki Nagai

Pharmaceutics 2022, 14(7), 1520; https://doi.org/10.3390/pharmaceutics14071520 - 21 Jul 2022

Cited by 3 | Viewed by 2053

Abstract

It has recently been reported that lanosterol (LAN) plays a preventive role against lens opacification through the reversal of crystalline aggregation. However, the effect of LAN is not sufficient to restore lens transparency. In this study, we designed ophthalmic nanosuspensions (LAN-ONSs and NIL-ONSs) [...] Read more.

It has recently been reported that lanosterol (LAN) plays a preventive role against lens opacification through the reversal of crystalline aggregation. However, the effect of LAN is not sufficient to restore lens transparency. In this study, we designed ophthalmic nanosuspensions (LAN-ONSs and NIL-ONSs) based on LAN and nilvadipine (NIL), which can counteract cataract-related factors (e.g., enhanced Ca²⁺ and calpain levels), and investigated whether the combination of LAN-ONSs and NIL-ONSs can restore the nuclear lens opacity in sodium-selenite-induced cataractic rats (cataractic rats). The mean particle sizes of the LAN-ONSs and NIL-ONSs were 108.8 nm and 89.0 nm, respectively. The instillation of the LAN-ONSs or NIL-ONSs successfully delivered the drugs (LAN or NIL) into the lenses of the rats, although the instillation of LAN-ONSs or NIL-ONSs alone did not increase lens transparency in the cataractic rats. On the other hand, the cataract-related factors (enhanced Ca²⁺ and calpain levels) were significantly alleviated by the combination of LAN-ONSs and NIL-ONSs; furthermore, the perinuclear refractile ring in the lens nucleus and enhanced number of swollen fibers were attenuated by the LAN-ONS and NIL-ONS combination. Moreover, the opacity levels in the cataractic rats were reduced after treatment with the combination of LAN-ONSs and NIL-ONSs. It is possible that the combination of LAN and NIL will be useful for the treatment of lens opacification in the future. Full article

(This article belongs to the Special Issue Advanced Formulations for Non-invasive and Minimally Invasive Ocular Drug Delivery)

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20 pages, 1291 KiB

Open AccessReview

Nanoparticles in Endodontics Disinfection: State of the Art

by Xavier Roig-Soriano, Eliana B. Souto, Firas Elmsmari, Maria Luisa Garcia, Marta Espina, Fernando Duran-Sindreu, Elena Sánchez-López and Jose Antonio González Sánchez

Pharmaceutics 2022, 14(7), 1519; https://doi.org/10.3390/pharmaceutics14071519 - 21 Jul 2022

Cited by 13 | Viewed by 3259

Abstract

Endodontic-related diseases constitute the fourth most expensive pathologies in industrialized countries. Specifically, endodontics is the part of dentistry focused on treating disorders of the dental pulp and its consequences. In order to treat these problems, especially endodontic infections, dental barriers and complex root [...] Read more.

Endodontic-related diseases constitute the fourth most expensive pathologies in industrialized countries. Specifically, endodontics is the part of dentistry focused on treating disorders of the dental pulp and its consequences. In order to treat these problems, especially endodontic infections, dental barriers and complex root canal anatomy should be overcome. This constitutes an unmet medical need since the rate of successful disinfection with the currently marketed drugs is around 85%. Therefore, nanoparticles constitute a suitable alternative in order to deliver active compounds effectively to the target site, increasing their therapeutic efficacy. Therefore, in the present review, an overview of dental anatomy and the barriers that should be overcome for effective disinfection will be summarized. In addition, the versatility of nanoparticles for drug delivery and their specific uses in dentistry are comprehensively discussed. Finally, the latest findings, potential applications and state of the art nanoparticles with special emphasis on biodegradable nanoparticles used for endodontic disinfection are also reviewed. Full article

(This article belongs to the Special Issue Controlled Release of Nanostructured Drug Systems (Volume II))

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14 pages, 5272 KiB

Open AccessArticle

Dual-Drug Loaded Separable Microneedles for Efficient Rheumatoid Arthritis Therapy

by Mengchen An, Mengxiao Shi, Jingjing Su, Yueru Wei, Rongrong Luo, Pengchao Sun and Yongxing Zhao

Pharmaceutics 2022, 14(7), 1518; https://doi.org/10.3390/pharmaceutics14071518 - 21 Jul 2022

Cited by 10 | Viewed by 3748

Abstract

Although the inhibitors of the interleukin-6 receptor (IL-6R) and tumor necrosis factor-α (TNF-α) have achieved a certain success in the clinical treatment of rheumatoid arthritis (RA), great effort should be made to overcome side effects and to improve patient compliance. The present research [...] Read more.

Although the inhibitors of the interleukin-6 receptor (IL-6R) and tumor necrosis factor-α (TNF-α) have achieved a certain success in the clinical treatment of rheumatoid arthritis (RA), great effort should be made to overcome side effects and to improve patient compliance. The present research aimed to address these problems by the co-delivery of tocilizumab (TCZ)—an inhibitor of IL-6R—and an aptamer Apt1-67, which specifically inhibits TNF receptor 1 via separable microneedles (MN). MN were featured with a sustained release of TCZ from needle tips and a rapid release of Apt1-67 from needle bodies by using methacrylate groups grafted hyaluronic acid as the fillings of needle tips and polyvinyl alcohol/polyvinyl pyrrolidone as the fillings of needle bodies. Our results demonstrated that TCZ and Apt1-67 were distributed in MN as expected, and they could be released to the surroundings in the skin. In vivo studies revealed that combined medication via MN (TCZ/Apt1-67@MN) was superior to MN loaded with a single drug. Compared with subcutaneous injection, TCZ/Apt1-67@MN was of great advantage in inhibiting bone erosion and alleviating symptoms of CIA mice. This study not only provides a novel approach for combined medication with different release properties but also supplies a strategy for improving drug efficacy. Full article

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

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14 pages, 2847 KiB

Open AccessArticle

Saporin Toxin Delivered by Engineered Colloidal Nanoparticles Is Strongly Effective against Cancer Cells

by Lucia Salvioni, Filippo Testa, Linda Barbieri, Marco Giustra, Jessica Armida Bertolini, Giulia Tomaino, Paolo Tortora, Davide Prosperi and Miriam Colombo

Pharmaceutics 2022, 14(7), 1517; https://doi.org/10.3390/pharmaceutics14071517 - 21 Jul 2022

Cited by 3 | Viewed by 2215

Abstract

Ribosome-inactivating proteins, including Saporin toxin, have found application in the search for innovative alternative cancer therapies to conventional chemo- and radiotherapy. Saporin’s main mechanism of action involves the inhibition of cytoplasmic protein synthesis. Its strong theoretical efficacy is counterbalanced by negligible cell uptake [...] Read more.

Ribosome-inactivating proteins, including Saporin toxin, have found application in the search for innovative alternative cancer therapies to conventional chemo- and radiotherapy. Saporin’s main mechanism of action involves the inhibition of cytoplasmic protein synthesis. Its strong theoretical efficacy is counterbalanced by negligible cell uptake and diffusion into the cytosol. In this work, we demonstrate that by immobilizing Saporin on iron oxide nanoparticles coated with an amphiphilic polymer, which promotes nanoconjugate endosomal escape, a strong cytotoxic effect mediated by ribosomal functional inactivation can be achieved. Cancer cell death was mediated by apoptosis dependent on nanoparticle concentration but independent of surface ligand density. The cytotoxic activity of Saporin-conjugated colloidal nanoparticles proved to be selective against three different cancer cell lines in comparison with healthy fibroblasts. Full article

(This article belongs to the Special Issue Metal Nanoparticles for Cancer Therapy)

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3 pages, 161 KiB

Open AccessEditorial

New Advances in the Understanding of Proteases as Diagnostic and Pharmaceutical Targets in Homeostatic and Pathologic Conditions

by Andrey A. Zamyatnin, Jr. and Alessandro Parodi

Pharmaceutics 2022, 14(7), 1516; https://doi.org/10.3390/pharmaceutics14071516 - 21 Jul 2022

Cited by 1 | Viewed by 1379

Abstract

Protease biology represents a hot topic in biomedical research because of their pivotal role in regulating cell and tissue homeostasis, regeneration and pathogenesis [...] Full article

(This article belongs to the Special Issue New Advances in the Understanding of Proteases as Diagnostic and Pharmaceutical Targets in Homeostatic and Pathologic Conditions)

31 pages, 22154 KiB

Open AccessArticle

Development of a Personalized Tumor Neoantigen Based Vaccine Formulation (FRAME-001) for Use in a Phase II Trial for the Treatment of Advanced Non-Small Cell Lung Cancer

by Linette T. Oosting, Katka Franke, Michael V. Martin, Wigard P. Kloosterman, Jennifer A. Jamieson, Laura A. Glenn, Miranda W. de Jager, Jacoba van Zanten, Derk P. Allersma and Bahez Gareb

Pharmaceutics 2022, 14(7), 1515; https://doi.org/10.3390/pharmaceutics14071515 - 21 Jul 2022

Cited by 8 | Viewed by 3726

Abstract

Stage III–IV non-small cell lung cancer (NSCLC) is a devastating disease characterized by a poor prognosis. NSCLC tumors carry genetic mutations, which can lead to the expression of altered protein sequences. Peptides originating from mutated proteins and bound to MHC molecules on the [...] Read more.

Stage III–IV non-small cell lung cancer (NSCLC) is a devastating disease characterized by a poor prognosis. NSCLC tumors carry genetic mutations, which can lead to the expression of altered protein sequences. Peptides originating from mutated proteins and bound to MHC molecules on the tumor cell surface are referred to as neoantigens, as they are tumor-specific and not expressed in normal cells. Due to their tumor specificity, neoantigens have a strong potential to induce an anti-tumor immune response and have been investigated for development of personalized therapeutic cancer vaccines. The current study describes the development of a clinical grade neoantigen vaccine formulation (FRAME-001) intended as immunotherapy in advanced NSCLC in combination with the immune checkpoint inhibitor pembrolizumab. The detection of aberrant tumor-specific transcripts as well as an algorithm to select immunogenic neoantigen peptides are described. Subsequently, selected neoantigen peptides were synthesized with a high throughput synthesis platform and aseptically formulated under good manufacturing practice (GMP) conditions into four aqueous peptides mixtures that each contained six neoantigen peptides. A validated stability-indicating analytical method was developed in which we considered the personalized nature of the formulation. An extensive stability study performed either at −25 °C or −80 °C showed that the formulation was stable for up to 32 weeks. The formulation was mixed with the vaccine adjuvant Montanide ISA 51 VG, which yielded the final vaccine emulsion. The stability of the vaccine emulsion was demonstrated using microscopic examination, differential light scattering, and the water-drop test. The presented data show that FRAME-001 is a feasible personalized vaccine formulation for the treatment of stage III–IV NSCLC. The presented data may give guidance in the development of novel personalized therapeutic vaccines since this formulation strategy could be used for any cancer indication. Full article

(This article belongs to the Special Issue Drug Formulation and Process Optimization)

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16 pages, 5851 KiB

Open AccessArticle

Quality Control Dissolution Data Is Biopredictive for a Modified Release Ropinirole Formulation: Virtual Experiment with the Use of Re-Developed and Verified PBPK Model

by Olha Shuklinova, Przemysław Dorożyński, Piotr Kulinowski and Sebastian Polak

Pharmaceutics 2022, 14(7), 1514; https://doi.org/10.3390/pharmaceutics14071514 - 21 Jul 2022

Cited by 6 | Viewed by 2141

Abstract

Physiologically based pharmacokinetic and absorption modeling are being used by industry and regulatory bodies to address various scientifically challenging questions. While there is high confidence in the prediction of exposure for the BCS class I drugs administered as immediate-release formulations, in the case [...] Read more.

Physiologically based pharmacokinetic and absorption modeling are being used by industry and regulatory bodies to address various scientifically challenging questions. While there is high confidence in the prediction of exposure for the BCS class I drugs administered as immediate-release formulations, in the case of prolonged-release formulations, special attention should be given to the input dissolution data. Our goal was to develop and verify a PBPK model for a BCS class I compound, ropinirole, and check the biopredictiveness of the dissolution data for the prolonged-release formulation administered by Parkinson’s patients. The model was built based on quality control dissolution data reported in the certificates of analysis and verified with the use of data derived from five clinical trial reports. The simulated pharmacokinetic parameters being within a two-fold range of the observed values confirmed acceptable model performance, in vivo relevance of the in vitro dissolution profiles, and indirectly indicated ropinirole stable release from the formulation in the patients’ gastro-intestinal tract. Ropinirole PBPK model will be used for exploring potential clinical scenarios while developing a new formulation. Full article

(This article belongs to the Special Issue In Silico Pharmacology for Evidence-Based and Precision Medicine)

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14 pages, 5105 KiB

Open AccessArticle

Unraveling the Antibiofilm Activity of a New Nanogold Resin for Dentures and Epithesis

by Vera Ivanovic, Danica Popovic, Sanja Petrovic, Rebeka Rudolf, Peter Majerič, Milos Lazarevic, Igor Djordjevic, Vojkan Lazic and Milena Radunovic

Pharmaceutics 2022, 14(7), 1513; https://doi.org/10.3390/pharmaceutics14071513 - 21 Jul 2022

Cited by 8 | Viewed by 1892

Abstract

Dentures and epitheses are mostly made from poly(methyl methacrylate) (PMMA), which does not show antimicrobial properties. They present reservoirs of microorganisms grown in biofilms. The aim of this study is to prepare a PMMA enriched with gold nanoparticles (AuNPs)-PMMA/AuNPs and the examination of [...] Read more.

Dentures and epitheses are mostly made from poly(methyl methacrylate) (PMMA), which does not show antimicrobial properties. They present reservoirs of microorganisms grown in biofilms. The aim of this study is to prepare a PMMA enriched with gold nanoparticles (AuNPs)-PMMA/AuNPs and the examination of its physical, mechanical and antimicrobial properties. The AuNPS were synthetized from HAuCl₄ using the ultrasonic spray pyrolysis method with lyophilization. The PMMA/AuNP samples were compared to PMMA samples. Density was measured by pycnometer. Microhardness was evaluated using the Vickers hardness test. Monomicrobial biofilm formation (Streptococcus mitis, Candida albicans, Staphylococcus aureus and Escherichia coli) was measured by colony-forming units (CFUs) and MTT test and visualized by SEM. AuNP release was measured indirectly (the CFUs of the medium around the sample). The density and microhardness of the PMMA/AuNPs were similar to those of the PMMA. CFU and MTT values for the biofilms formed on the PMMA for each of the tested species were higher than those of the biofilms formed on the PMMA/AuNPs. The CFUs of the medium around the sample were similar for both materials. PMMA/AuNPs showed a significant reduction in the monomicrobial biofilms of all tested species. AuNPs are not released from PMMA/AuNPs. Density, indirect measurement of residual monomer and dentures weight were similar between PMMA and PMMA/AuNPs. Microhardness, as a measure of the wear resistance, was also similar between tested discs. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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17 pages, 5552 KiB

Open AccessArticle

Effects of Lipid Shape and Interactions on the Conformation, Dynamics, and Curvature of Ultrasound-Responsive Liposomes

by Hwankyu Lee, Hyungwon Moon and Hyun-Ryoung Kim

Pharmaceutics 2022, 14(7), 1512; https://doi.org/10.3390/pharmaceutics14071512 - 21 Jul 2022

Cited by 4 | Viewed by 2264

Abstract

We perform coarse-grained molecular dynamics simulations of bilayers composed of various lipids and cholesterol at their different ratios. Simulations show that cholesterol-lipid interactions restrict the lateral dynamics of bilayers but also promote bilayer curvature, indicating that these opposite effects simultaneously occur and thus [...] Read more.

We perform coarse-grained molecular dynamics simulations of bilayers composed of various lipids and cholesterol at their different ratios. Simulations show that cholesterol-lipid interactions restrict the lateral dynamics of bilayers but also promote bilayer curvature, indicating that these opposite effects simultaneously occur and thus cannot significantly influence bilayer stability. In contrast, lyso-lipids effectively pack the vacancy in the bilayer composed of cone-shaped lipids and thus reduce bilayer dynamics and curvature, showing that bilayers are more significantly stabilized by lyso-lipids than by cholesterol, in agreement with experiments. In particular, the bilayer composed of cone-shaped lipids shows higher dynamics and curvature than does the bilayer composed of cylindrical-shaped lipids. To mimic ultrasound, a high external pressure was applied in the direction of bilayer normal, showing the formation of small pores that are surrounded by hydrophilic lipid headgroups, which can allow the release of drug molecules encapsulated into the liposome. These findings help to explain experimental observations regarding that liposomes are more significantly stabilized by lyso-lipids than by cholesterol, and that the liposome with cone-shaped lipids more effectively releases drug molecules upon applying ultrasound than does the liposome with cylindrical-shaped lipids. Full article

(This article belongs to the Special Issue Recent Trends on Liposome Technology: From Emerging Synthesis Strategies to Advanced Lipid Nanosystems for Drug Delivery)

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17 pages, 7803 KiB

Open AccessArticle

The Synergistic Inhibition of Coronavirus Replication and Induced Cytokine Production by Ciclesonide and the Tylophorine-Based Compound Dbq33b

by Yue-Zhi Lee, Hsing-Yu Hsu, Cheng-Wei Yang, Yi-Ling Lin, Sui-Yuan Chang, Ruey-Bing Yang, Jian-Jong Liang, Tai-Ling Chao, Chun-Che Liao, Han-Chieh Kao, Jang-Yang Chang, Huey-Kang Sytwu, Chiung-Tong Chen and Shiow-Ju Lee

Pharmaceutics 2022, 14(7), 1511; https://doi.org/10.3390/pharmaceutics14071511 - 21 Jul 2022

Cited by 2 | Viewed by 2238 | Correction

Abstract

Ciclesonide is an inhaled corticosteroid used to treat asthma and has been repurposed as a treatment for mildly ill COVID-19 patients, but its precise mechanism of action is unclear. Herein, we report that ciclesonide blocks the coronavirus-induced production of the cytokines IL-6, IL-8, [...] Read more.

Ciclesonide is an inhaled corticosteroid used to treat asthma and has been repurposed as a treatment for mildly ill COVID-19 patients, but its precise mechanism of action is unclear. Herein, we report that ciclesonide blocks the coronavirus-induced production of the cytokines IL-6, IL-8, and MCP-1 by increasing IκBα protein levels and significantly decreasing p65 nuclear translocation. Furthermore, we found that the combination of ciclesonide and dbq33b, a potent tylophorine-based coronavirus inhibitor that affects coronavirus-induced NF-κB activation a little, additively and synergistically decreased coronavirus-induced IL-6, IL-8, and MCP-1 cytokine levels, and synergistically inhibited the replication of both HCoV-OC43 and SARS-CoV-2. Collectively, the combination of ciclesonide and dbq33b merits consideration as a treatment for COVID-19 patients who may otherwise be overwhelmed by high viral loads and an NF-κB-mediated cytokine storm. Full article

(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)

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12 pages, 3359 KiB

Open AccessArticle

Enhanced Oral Bioavailability of MT-102, a New Anti-inflammatory Agent, via a Ternary Solid Dispersion Formulation

by Rajiv Bajracharya, Jae Geun Song, Sang Hoon Lee, Seong Hoon Jeong and Hyo-Kyung Han

Pharmaceutics 2022, 14(7), 1510; https://doi.org/10.3390/pharmaceutics14071510 - 21 Jul 2022

Cited by 8 | Viewed by 2185

Abstract

This study aimed to develop a solid dispersion (SD) of MT-102, a new anti-inflammatory agent, to improve its oral bioavailability. The ternary SD formulations of MT-102 (a poorly soluble extract of Isatis indigotica and Juglans mandshurica) were prepared using a solvent evaporation [...] Read more.

This study aimed to develop a solid dispersion (SD) of MT-102, a new anti-inflammatory agent, to improve its oral bioavailability. The ternary SD formulations of MT-102 (a poorly soluble extract of Isatis indigotica and Juglans mandshurica) were prepared using a solvent evaporation method with various drug/excipient ratios. Following that, the effectiveness of various SDs as an oral formulation of MT-102 was investigated using indirubin as a marker component. By forming SDs with hydrophilic polymers, the aqueous solubility of indirubin was significantly increased. SD-F4, containing drug, poloxamer 407 (P407), and povidone K30 (PVP K30) at a 1:2:2 weight ratio, exhibited the optimal dissolution profiles in the acidic to neutral pH range. Compared to pure MT-102 and a physical mixture, SD-F4 increased indirubin’s dissolution from MT-102 by approximately 9.86-fold and 2.21-fold, respectively. Additionally, SD-F4 caused the sticky extract to solidify, resulting in improved flowability and handling. As a result, compared to pure MT-102, the oral administration of SD-F4 significantly improved the systemic exposure of MT-102 in rats. Overall, the ternary SD formulation of MT-102 with a blended mixture of P407 and PVP K30 appeared to be effective at improving the dissolution and oral absorption of MT-102. 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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17 pages, 1706 KiB

Open AccessArticle

HDAC Inhibition Regulates Cardiac Function by Increasing Myofilament Calcium Sensitivity and Decreasing Diastolic Tension

by Deborah M. Eaton, Thomas G. Martin, Michael Kasa, Natasa Djalinac, Senka Ljubojevic-Holzer, Dirk Von Lewinski, Maria Pöttler, Theerachat Kampaengsri, Andreas Krumphuber, Katharina Scharer, Heinrich Maechler, Andreas Zirlik, Timothy A. McKinsey, Jonathan A. Kirk, Steven R. Houser, Peter P. Rainer and Markus Wallner

Pharmaceutics 2022, 14(7), 1509; https://doi.org/10.3390/pharmaceutics14071509 - 21 Jul 2022

Cited by 4 | Viewed by 2787

Abstract

We recently established a large animal model that recapitulates key clinical features of heart failure with preserved ejection fraction (HFpEF) and tested the effects of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). SAHA reversed and prevented the development of cardiopulmonary impairment. This study [...] Read more.

We recently established a large animal model that recapitulates key clinical features of heart failure with preserved ejection fraction (HFpEF) and tested the effects of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). SAHA reversed and prevented the development of cardiopulmonary impairment. This study evaluated the effects of SAHA at the level of cardiomyocyte and contractile protein function to understand how it modulates cardiac function. Both isolated adult feline ventricular cardiomyocytes (AFVM) and left ventricle (LV) trabeculae isolated from non-failing donors were treated with SAHA or vehicle before recording functional data. Skinned myocytes were isolated from AFVM and human trabeculae to assess myofilament function. SAHA-treated AFVM had increased contractility and improved relaxation kinetics but no difference in peak calcium transients, with increased calcium sensitivity and decreased passive stiffness of myofilaments. Mass spectrometry analysis revealed increased acetylation of the myosin regulatory light chain with SAHA treatment. SAHA-treated human trabeculae had decreased diastolic tension and increased developed force. Myofilaments isolated from human trabeculae had increased calcium sensitivity and decreased passive stiffness. These findings suggest that SAHA has an important role in the direct control of cardiac function at the level of the cardiomyocyte and myofilament by increasing myofilament calcium sensitivity and reducing diastolic tension. Full article

(This article belongs to the Special Issue Modern Pharmaceutics for Cardiovascular Diseases)

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14 pages, 3451 KiB

Open AccessArticle

Molecular and Nano-Structural Optimization of Nanoparticulate Mn²⁺-Hexarhenium Cluster Complexes for Optimal Balance of High T₁- and T₂-Weighted Contrast Ability with Low Hemoagglutination and Cytotoxicity

by Bulat Salavatovich Akhmadeev, Irek R. Nizameev, Kirill V. Kholin, Alexandra D. Voloshina, Tatyana P. Gerasimova, Aidar T. Gubaidullin, Marsil K. Kadirov, Ildus E. Ismaev, Konstantin A. Brylev, Rustem R. Zairov and Asiya R. Mustafina

Pharmaceutics 2022, 14(7), 1508; https://doi.org/10.3390/pharmaceutics14071508 - 20 Jul 2022

Cited by 8 | Viewed by 1884

Abstract

The present work introduces rational design of nanoparticulate Mn(II)-based contrast agents through both variation of the μ₃ (inner) ligands within a series of hexarhenium cluster complexes [{Re₆(μ₃-Q)₈}(CN)₆]⁴⁻ (Re₆Q₈, [...] Read more.

The present work introduces rational design of nanoparticulate Mn(II)-based contrast agents through both variation of the μ₃ (inner) ligands within a series of hexarhenium cluster complexes [{Re₆(μ₃-Q)₈}(CN)₆]⁴⁻ (Re₆Q₈, Q = S²⁻, Se²⁻ or Te²⁻) and interfacial decoration of the nanoparticles (NPs) K_4−2xMn_xRe₆Q₈ (x = 1.3 − 1.8) by a series of pluronics (F-68, P-123, F-127). The results highlight an impact of the ligand and pluronic for the optimal colloid behavior of the NPs allowing high colloid stability in ambient conditions and efficient phase separation under the centrifugation. It has been revealed that the K_4−2xMn_xRe₆Se₈ NPs and those decorated by F-127 are optimal from the viewpoint of magnetic relaxivities r₁ and r₂ (8.9 and 10.9 mM⁻¹s⁻¹, respectively, at 0.47 T) and low hemoagglutination activity. The insignificant leaching of Mn²⁺ ions from the NPs correlates with their insignificant effect on the cell viability of both M-HeLa and Chang Liver cell lines. The T₁- and T₂-weighted contrast ability of F-127–K_4−2xMn_xRe₆Q₈ NPs was demonstrated through the measurements of phantoms at whole body 1.5 T scanner. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles for Therapy and Diagnosis in Nanomedicine)

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19 pages, 1875 KiB

Open AccessArticle

Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia

by Giorgio Aquila, Yannick Regin, Xabier Murgia, Fabrizio Salomone, Costanza Casiraghi, Chiara Catozzi, Enrica Scalera, Matteo Storti, Francesca Stretti, Giancarlo Aquino, Giorgia Cavatorta, Roberta Volta, Carmelina Di Pasquale, Caterina Amato, Fabio Bignami, Davide Amidani, Barbara Pioselli, Elisa Sgarbi, Paolo Ronchi, Giuseppe Mazzola, Ignacio Valenzuela and Jaan Toelen Show full author list Hide full author list

Pharmaceutics 2022, 14(7), 1507; https://doi.org/10.3390/pharmaceutics14071507 - 20 Jul 2022

Cited by 1 | Viewed by 3194

Abstract

Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated [...] Read more.

Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated the PPARγ selectivity, epithelial permeability, and lung tissue binding of three types of TZDs in vitro (rosiglitazone (RGZ), pioglitazone, and DRF-2546), followed by an in vivo study in preterm rabbits exposed to hyperoxia (95% oxygen) to investigate the pharmacokinetics and the pulmonary outcomes of daily RGZ administration. In addition, blood lipids and a comparative lung proteomics analysis were also performed on Day 7. All TZDs showed high epithelial permeability through Caco-2 monolayers and high plasma and lung tissue binding; however, RGZ showed the highest affinity for PPARγ. The pharmacokinetic profiling of RGZ (1 mg/kg) revealed an equivalent biodistribution after either intratracheal or intraperitoneal administration, with detectable levels in lungs and plasma after 24 h. However, daily RGZ doses of 1 mg/kg did not improve lung function in preterm rabbits exposed to hyperoxia, and daily 10 mg/kg doses were even associated with a significant lung function worsening, which could be partially explained by the upregulation of lung inflammation and lipid metabolism pathways revealed by the proteomic analysis. Notably, daily postnatal RGZ produced an aberrant modulation of serum lipids, particularly in rabbit pups treated with the 10 mg/kg dose. In conclusion, daily postnatal RGZ did not improve lung function and caused dyslipidemia in preterm rabbits exposed to hyperoxia. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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63 pages, 20579 KiB

Open AccessReview

Polymeric Nanosystems Applied for Metal-Based Drugs and Photosensitizers Delivery: The State of the Art and Recent Advancements

by Kele Cristina Ferreira Dantas, Jânia dos Santos Rosário and Priscila Pereira Silva-Caldeira

Pharmaceutics 2022, 14(7), 1506; https://doi.org/10.3390/pharmaceutics14071506 - 20 Jul 2022

Cited by 11 | Viewed by 3279

Abstract

Nanotechnology-based approaches for targeting the delivery and controlled release of metal-based therapeutic agents have revealed significant potential as tools for enhancing the therapeutic effect of metal-based agents and minimizing their systemic toxicities. In this context, a series of polymer-based nanosized systems designed to [...] Read more.

Nanotechnology-based approaches for targeting the delivery and controlled release of metal-based therapeutic agents have revealed significant potential as tools for enhancing the therapeutic effect of metal-based agents and minimizing their systemic toxicities. In this context, a series of polymer-based nanosized systems designed to physically load or covalently conjugate metal-based therapeutic agents have been remarkably improving their bioavailability and anticancer efficacy. Initially, the polymeric nanocarriers were applied for platinum-based chemotherapeutic agents resulting in some nanoformulations currently in clinical tests and even in medical applications. At present, these nanoassemblies have been slowly expanding for nonplatinum-containing metal-based chemotherapeutic agents. Interestingly, for metal-based photosensitizers (PS) applied in photodynamic therapy (PDT), especially for cancer treatment, strategies employing polymeric nanocarriers have been investigated for almost 30 years. In this review, we address the polymeric nanocarrier-assisted metal-based therapeutics agent delivery systems with a specific focus on non-platinum systems; we explore some biological and physicochemical aspects of the polymer–metallodrug assembly. Finally, we summarize some recent advances in polymeric nanosystems coupled with metal-based compounds that present potential for successful clinical applications as chemotherapeutic or photosensitizing agents. We hope this review can provide a fertile ground for the innovative design of polymeric nanosystems for targeting the delivery and controlled release of metal-containing therapeutic agents. Full article

(This article belongs to the Special Issue Functional Polymers in Drug Delivery)

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18 pages, 6389 KiB

Open AccessArticle

Novel Cyclic Peptides for Targeting EGFR and EGRvIII Mutation for Drug Delivery

by Olga Furman, Alisa Zaporozhets, Dror Tobi, Andrii Bazylevich, Michael A. Firer, Leonid Patsenker, Gary Gellerman and Bat Chen R. Lubin

Pharmaceutics 2022, 14(7), 1505; https://doi.org/10.3390/pharmaceutics14071505 - 20 Jul 2022

Cited by 17 | Viewed by 3054

Abstract

The epidermal growth factor–epidermal growth factor receptor (EGF-EGFR) pathway has become the main focus of selective chemotherapeutic intervention. As a result, two classes of EGFR inhibitors have been clinically approved, namely monoclonal antibodies and small molecule kinase inhibitors. Despite an initial good response [...] Read more.

The epidermal growth factor–epidermal growth factor receptor (EGF-EGFR) pathway has become the main focus of selective chemotherapeutic intervention. As a result, two classes of EGFR inhibitors have been clinically approved, namely monoclonal antibodies and small molecule kinase inhibitors. Despite an initial good response rate to these drugs, most patients develop drug resistance. Therefore, new treatment approaches are needed. In this work, we aimed to find a new EGFR-specific, short cyclic peptide, which could be used for targeted drug delivery. Phage display peptide technology and biopanning were applied to three EGFR expressing cells, including cells expressing the EGFRvIII mutation. DNA from the internalized phage was extracted and the peptide inserts were sequenced using next-generation sequencing (NGS). Eleven peptides were selected for further investigation using binding, internalization, and competition assays, and the results were confirmed by confocal microscopy and peptide docking. Among these eleven peptides, seven showed specific and selective binding and internalization into EGFR positive (EGFR+ve) cells, with two of them—P6 and P9—also demonstrating high specificity for non-small cell lung cancer (NSCLC) and glioblastoma cells, respectively. These peptides were chemically conjugated to camptothecin (CPT). The conjugates were more cytotoxic to EGFR+ve cells than free CPT. Our results describe a novel cyclic peptide, which can be used for targeted drug delivery to cells overexpressing the EGFR and EGFRvIII mutation. Full article

(This article belongs to the Special Issue Application of Peptide-Drug-Conjugates in the Treatment of Cancer and Microbial Infections)

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18 pages, 3255 KiB

Open AccessArticle

Multiparticulate Systems of Meloxicam for Colonic Administration in Cancer or Autoimmune Diseases

by Eva Navarro-Ruíz, Covadonga Álvarez-Álvarez, M Ángeles Peña, Carlos Torrado-Salmerón, Zaid Dahma and Paloma Marina de la Torre-Iglesias

Pharmaceutics 2022, 14(7), 1504; https://doi.org/10.3390/pharmaceutics14071504 - 20 Jul 2022

Cited by 4 | Viewed by 2295

Abstract

The aim of this research is the development of new colonic release systems of meloxicam (MLX) a non-steroidal anti-inflammatory drug (NSAIDs) with pH and time-dependent vehicles for cancer or autoimmune diseases. The colon has a higher pH than the rest of the gastrointestinal [...] Read more.

The aim of this research is the development of new colonic release systems of meloxicam (MLX) a non-steroidal anti-inflammatory drug (NSAIDs) with pH and time-dependent vehicles for cancer or autoimmune diseases. The colon has a higher pH than the rest of the gastrointestinal tract (GIT) and this can be used as a modified release strategy. Eudragit^® polymers are the most widely used synthetic products in the design of colonic release formulations because they might offer mucoadhesiveness and pH-dependent release. Colonic delivery systems produced with pH-dependent and permeable polymers (FS-30D) or with pH-independent and low permeability polymers (NM-30D), must dissolve at a pH range of 6.0–7.0 to delay the release of the drug and prevent degradation in the GIT, before reaching the colon. The conditions prepared to simulate a gastrointestinal transit showed the CNM multiparticulate system, composed of Eudragit^® NM and cellulose, as the best release option for MLX with a more sustained release with respect to the other formulations. CNM formulation followed Higuchi and First-order release kinetics, thus MLX release was controlled by a combination of diffusion and polymers swelling/eroding processes. Full article

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

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11 pages, 2602 KiB

Open AccessArticle

Opening the Blood Brain Barrier with an Electropermanent Magnet System

by Sahar Jafari, Ittai S. Baum, Oleg G. Udalov, Yichien Lee, Olga Rodriguez, Stanley T. Fricke, Maryam Jafari, Mostafa Amini, Roland Probst, Xinyao Tang, Cheng Chen, David J. Ariando, Anjana Hevaganinge, Lamar O. Mair, Christopher Albanese and Irving N. Weinberg

Pharmaceutics 2022, 14(7), 1503; https://doi.org/10.3390/pharmaceutics14071503 - 20 Jul 2022

Cited by 2 | Viewed by 3041

Abstract

Opening the blood brain barrier (BBB) under imaging guidance may be useful for the treatment of many brain disorders. Rapidly applied magnetic fields have the potential to generate electric fields in brain tissue that, if properly timed, may enable safe and effective BBB [...] Read more.

Opening the blood brain barrier (BBB) under imaging guidance may be useful for the treatment of many brain disorders. Rapidly applied magnetic fields have the potential to generate electric fields in brain tissue that, if properly timed, may enable safe and effective BBB opening. By tuning magnetic pulses generated by a novel electropermanent magnet (EPM) array, we demonstrate the opening of tight junctions in a BBB model culture in vitro, and show that induced monophasic electrical pulses are more effective than biphasic ones. We confirmed, with in vivo contrast-enhanced MRI, that the BBB can be opened with monophasic pulses. As electropermanent magnets have demonstrated efficacy at tuning B0 fields for magnetic resonance imaging studies, our results suggest the possibility of implementing an EPM-based hybrid theragnostic device that could both image the brain and enhance drug transport across the BBB in a single sitting. Full article

(This article belongs to the Special Issue Novel Approaches for Overcoming Biological Barriers)

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15 pages, 2097 KiB

Open AccessArticle

Reducing the Kidney Uptake of High Contrast CXCR4 PET Imaging Agents via Linker Modifications

by Daniel Kwon, Zhengxing Zhang, Jutta Zeisler, Hsiou-Ting Kuo, Kuo-Shyan Lin and Francois Benard

Pharmaceutics 2022, 14(7), 1502; https://doi.org/10.3390/pharmaceutics14071502 - 20 Jul 2022

Cited by 6 | Viewed by 2227

Abstract

Purpose: The C-X-C chemokine receptor 4 (CXCR4) is highly expressed in many subtypes of cancers, notably in several kidney-based malignancies. We synthesized, labeled, and assessed a series of radiotracers based on a previous high contrast PET imaging radiopharmaceutical [⁶⁸Ga]Ga-BL02, with modifications [...] Read more.

Purpose: The C-X-C chemokine receptor 4 (CXCR4) is highly expressed in many subtypes of cancers, notably in several kidney-based malignancies. We synthesized, labeled, and assessed a series of radiotracers based on a previous high contrast PET imaging radiopharmaceutical [⁶⁸Ga]Ga-BL02, with modifications to its linker and metal chelator, in order to improve its tumor-to-kidney contrast ratio. Methods: Based on the design of BL02, a piperidine-based cationic linker (BL06) and several anionic linkers (tri-Aad (BL17); tri-D-Glu (BL20); tri-Asp (BL25); and tri-cysteic acid (BL31)) were substituted for the triglutamate linker. Additionally, the DOTA chelator was swapped for a DOTAGA chelator (BL30). Each radiotracer was labeled with ⁶⁸Ga and evaluated in CXCR4-expressing Daudi xenograft mice with biodistribution and/or PET imaging studies. Results: Of all the evaluated radiotracers, [⁶⁸Ga]Ga-BL31 showed the most promising biodistribution profile, with a lower kidney uptake compared to [⁶⁸Ga]Ga-BL02, while retaining the high imaging contrast capabilities of [⁶⁸Ga]Ga-BL02. [⁶⁸Ga]Ga-BL31 also compared favorably to [⁶⁸Ga]Ga-Pentixafor, with superior imaging contrast in all non-target organs. The other anionic linker-based radiotracers showed either equivocal or worse contrast ratios compared to [⁶⁸Ga]Ga-BL02; however, [⁶⁸Ga]Ga-BL25 also showed lower kidney uptake, as compared to that of [⁶⁸Ga]Ga-BL02. Meanwhile, [⁶⁸Ga]Ga-BL06 had high non-target organ uptake and relatively lower tumor uptake, while [⁶⁸Ga]Ga-BL30 showed significantly increased kidney uptake and similar tumor uptake values. Conclusions: [⁶⁸Ga]Ga-BL31 is an optimized CXCR4-targeting radiopharmaceutical with lower kidney retention that has clinical potential for PET imaging and radioligand therapy. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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27 pages, 2190 KiB

Open AccessEditor’s ChoiceReview

Transport Mechanisms at the Blood–Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs

by Patrick T. Ronaldson and Thomas P. Davis

Pharmaceutics 2022, 14(7), 1501; https://doi.org/10.3390/pharmaceutics14071501 - 20 Jul 2022

Cited by 14 | Viewed by 4310

Abstract

Ischemic stroke is a primary origin of morbidity and mortality in the United States and around the world. Indeed, several research projects have attempted to discover new drugs or repurpose existing therapeutics to advance stroke pharmacotherapy. Many of these preclinical stroke studies have [...] Read more.

Ischemic stroke is a primary origin of morbidity and mortality in the United States and around the world. Indeed, several research projects have attempted to discover new drugs or repurpose existing therapeutics to advance stroke pharmacotherapy. Many of these preclinical stroke studies have reported positive results for neuroprotective agents; however, only one compound (3K3A-activated protein C (3K3A-APC)) has advanced to Phase III clinical trial evaluation. One reason for these many failures is the lack of consideration of transport mechanisms at the blood–brain barrier (BBB) and neurovascular unit (NVU). These endogenous transport processes function as a “gateway” that is a primary determinant of efficacious brain concentrations for centrally acting drugs. Despite the knowledge that some neuroprotective agents (i.e., statins and memantine) are substrates for these endogenous BBB transporters, preclinical stroke studies have largely ignored the role of transporters in CNS drug disposition. Here, we review the current knowledge on specific BBB transporters that either limit drug uptake into the brain (i.e., ATP-binding cassette (ABC) transporters) or can be targeted for optimized drug delivery (i.e., solute carrier (SLC) transporters). Additionally, we highlight the current knowledge on transporter expression in astrocytes, microglia, pericytes, and neurons with an emphasis on transport mechanisms in these cell types that can influence drug distribution within the brain. Full article

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

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17 pages, 1000 KiB

Open AccessReview

Research Progress and Potential Applications of Spermidine in Ocular Diseases

by Wentao Han, Haoyu Li and Baihua Chen

Pharmaceutics 2022, 14(7), 1500; https://doi.org/10.3390/pharmaceutics14071500 - 19 Jul 2022

Cited by 8 | Viewed by 3568

Abstract

Spermidine, a natural polyamine, exists in almost all human tissues, exhibiting broad properties like anti-aging, autophagy induction, anti-inflammation, anti-oxidation, cell proliferation activation, and ion channel regulation. Considering that spermidine is already present in human nutrition, recent studies targeting supplementing exogenous sources of this [...] Read more.

Spermidine, a natural polyamine, exists in almost all human tissues, exhibiting broad properties like anti-aging, autophagy induction, anti-inflammation, anti-oxidation, cell proliferation activation, and ion channel regulation. Considering that spermidine is already present in human nutrition, recent studies targeting supplementing exogenous sources of this polyamine appear feasible. The protective role of spermidine in various systems has been illuminated in the literature, while recent progress of spermidine administration in ocular diseases remains to be clarified. This study shows the current landscape of studies on spermidine and its potential to become a promising therapeutic agent to treat ocular diseases: glaucoma, optic nerve injury, age-related macular degeneration (AMD), cataracts, dry eye syndrome, and bacterial keratitis. It also has the potential to become a potent biomarker to predict keratoconus (KC), cataracts, uveitis, glaucoma, proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and retinopathy of prematurity (ROP). We also summarize the routes of administration and the effects of spermidine at different doses. Full article

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11 pages, 287 KiB

Open AccessReview

Efficacy and Safety of Topical Morphine: A Narrative Review

by Krzysztof Nosek, Wojciech Leppert, Łukasz Puchała and Krzysztof Łoń

Pharmaceutics 2022, 14(7), 1499; https://doi.org/10.3390/pharmaceutics14071499 - 19 Jul 2022

Cited by 9 | Viewed by 4008

Abstract

Background. Opioids are the cornerstone of the therapy used in both acute and chronic pain syndromes to treat pain of moderate to severe intensity. The knowledge that opioid receptors also occur in other tissues outside the central nervous system has created a possibility [...] Read more.

Background. Opioids are the cornerstone of the therapy used in both acute and chronic pain syndromes to treat pain of moderate to severe intensity. The knowledge that opioid receptors also occur in other tissues outside the central nervous system has created a possibility for the topical use of opioids. Thus, local analgesia may be obtained without systemic adverse effects. Methods. A narrative review of scientific papers discussing the topical use of morphine was conducted. For this purpose, the PubMed, Google Scholar, Cochrane Library, and Mendeley databases were searched. Results. The current knowledge on topical morphine does not allow for its recommended use in everyday medical practice, but suggests it may be effective, particularly in the treatment of ulcers and erosions of inflammatory etiology and painful skin lesions including persistent post-mastectomy pain due to breast cancer. Conclusions. Topical morphine has its place beside other analgesics. An important issue is the practical possibility to meet the demand for topical formulations, which is limited by technical difficulties. Full article

(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)

25 pages, 5991 KiB

Open AccessArticle

Perfluorocarbon Nanodroplets as Potential Nanocarriers for Brain Delivery Assisted by Focused Ultrasound-Mediated Blood–Brain Barrier Disruption

by Charlotte Bérard, Stéphane Desgranges, Noé Dumas, Anthony Novell, Benoit Larrat, Mourad Hamimed, Nicolas Taulier, Marie-Anne Estève, Florian Correard and Christiane Contino-Pépin

Pharmaceutics 2022, 14(7), 1498; https://doi.org/10.3390/pharmaceutics14071498 - 19 Jul 2022

Cited by 12 | Viewed by 3234

Abstract

The management of brain diseases remains a challenge, particularly because of the difficulty for drugs to cross the blood–brain barrier. Among strategies developed to improve drug delivery, nano-sized emulsions (i.e., nanoemulsions), employed as nanocarriers, have been described. Moreover, focused ultrasound-mediated blood–brain barrier disruption [...] Read more.

The management of brain diseases remains a challenge, particularly because of the difficulty for drugs to cross the blood–brain barrier. Among strategies developed to improve drug delivery, nano-sized emulsions (i.e., nanoemulsions), employed as nanocarriers, have been described. Moreover, focused ultrasound-mediated blood–brain barrier disruption using microbubbles is an attractive method to overcome this barrier, showing promising results in clinical trials. Therefore, nanoemulsions combined with this technology represent a real opportunity to bypass the constraints imposed by the blood–brain barrier and improve the treatment of brain diseases. In this work, a stable freeze-dried emulsion of perfluorooctyl bromide nanodroplets stabilized with home-made fluorinated surfactants able to carry hydrophobic agents is developed. This formulation is biocompatible and droplets composing the emulsion are internalized in multiple cell lines. After intravenous administration in mice, droplets are eliminated from the bloodstream in 24 h (blood half-life (t_1/2) = 3.11 h) and no long-term toxicity is expected since they are completely excreted from mice’ bodies after 72 h. In addition, intracerebral accumulation of tagged droplets is safely and significantly increased after focused ultrasound-mediated blood–brain barrier disruption. Thus, the proposed nanoemulsion appears as a promising nanocarrier for a successful focused ultrasound-mediated brain delivery of hydrophobic agents. Full article

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16 pages, 4792 KiB

Open AccessArticle

Development of a Mucoadhesive Vehicle Based on Lyophilized Liposomes for Drug Delivery through the Sublingual Mucosa

by María José De Jesús Valle, Aranzazu Zarzuelo Castañeda, Cristina Maderuelo, Alejandro Cencerrado Treviño, Jorge Loureiro, Paula Coutinho and Amparo Sánchez Navarro

Pharmaceutics 2022, 14(7), 1497; https://doi.org/10.3390/pharmaceutics14071497 - 19 Jul 2022

Cited by 3 | Viewed by 2296

Abstract

A pharmaceutical vehicle based on lyophilized liposomes is proposed for the buccal administration of drugs aimed at systemic delivery through the sublingual mucosa. Liposomes made of egg phosphatidylcholine and cholesterol (7/3 molar ratio) were prepared and lyophilized in the presence of different additive [...] Read more.

A pharmaceutical vehicle based on lyophilized liposomes is proposed for the buccal administration of drugs aimed at systemic delivery through the sublingual mucosa. Liposomes made of egg phosphatidylcholine and cholesterol (7/3 molar ratio) were prepared and lyophilized in the presence of different additive mixtures with mucoadhesive and taste-masking properties. Palatability was assayed on healthy volunteers. The lyophilization cycle was optimized, and the lyophilized product was compressed to obtain round and capsule-shaped tables that were evaluated in healthy volunteers. Tablets were also assayed regarding weight and thickness uniformities, swelling index and liposome release. The results proved that lyophilized liposomes in unidirectional round tablets have palatability, small size, comfortability and buccal retention adequate for sublingual administration. In contact with water fluids, the tablets swelled, and rehydrated liposomes were released at a slower rate than permeation efficiency determined using a biomimetic membrane. Permeability efficiency values of 0.72 ± 0.34 µg/cm²/min and 4.18 ± 0.95 µg/cm²/min were obtained for the liposomes with and without additives, respectively. Altogether, the results point to the vehicle proposed as a liposomal formulation suitable for systemic drug delivery through the sublingual mucosa. Full article

(This article belongs to the Special Issue Liposomes for Transmucosal Drug Delivery)

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21 pages, 5809 KiB

Open AccessArticle

Tuning Design Parameters of ICAM-1-Targeted 3DNA Nanocarriers to Optimize Pulmonary Targeting Depending on Drug Type

by Nikša Roki, Melani Solomon, Jessica Bowers, Lori Getts, Robert C. Getts and Silvia Muro

Pharmaceutics 2022, 14(7), 1496; https://doi.org/10.3390/pharmaceutics14071496 - 19 Jul 2022

Cited by 1 | Viewed by 2017

Abstract

3DNA holds promise as a carrier for drugs that can be intercalated into its core or linked to surface arms. Coupling 3DNA to an antibody targeting intercellular adhesion molecule 1 (ICAM-1) results in high lung-specific biodistributions in vivo. While the role of individual [...] Read more.

3DNA holds promise as a carrier for drugs that can be intercalated into its core or linked to surface arms. Coupling 3DNA to an antibody targeting intercellular adhesion molecule 1 (ICAM-1) results in high lung-specific biodistributions in vivo. While the role of individual parameters on ICAM-1 targeting has been studied for other nanocarriers, it has never been examined for 3DNA or in a manner capable of revealing the hierarchic interplay among said parameters. In this study, we used 2-layer vs. 4-layer anti-ICAM 3DNA and radiotracing to examine biodistribution in mice. We found that, below saturating conditions and within the ranges tested, the density of targeting antibodies on 3DNA is the most relevant parameter driving lung targeting over liver clearance, compared to the number of antibodies per carrier, total antibody dose, 3DNA dose, 3DNA size, or the administered concentration, which influenced the dose in organs but not the lung specific-over-liver clearance ratio. Data predicts that lung-specific delivery of intercalating (core loaded) drugs can be tuned using this biodistribution pattern, while that of arm-linked (surface loaded) drugs requires a careful parametric balance because increasing anti-ICAM density reduces the number of 3DNA arms available for drug loading. Full article

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

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20 pages, 2627 KiB

Open AccessArticle

Nanodevices for the Efficient Codelivery of CRISPR-Cas9 Editing Machinery and an Entrapped Cargo: A Proposal for Dual Anti-Inflammatory Therapy

by Alba García-Fernández, Gema Vivo-Llorca, Mónica Sancho, Alicia Belén García-Jareño, Laura Ramírez-Jiménez, Eloísa Barber-Cano, José Ramón Murguía, Mar Orzáez, Félix Sancenón and Ramón Martínez-Máñez

Pharmaceutics 2022, 14(7), 1495; https://doi.org/10.3390/pharmaceutics14071495 - 19 Jul 2022

Cited by 13 | Viewed by 2899

Abstract

In this article, we report one of the few examples of nanoparticles capable of simultaneously delivering CRISPR-Cas9 gene-editing machinery and releasing drugs for one-shot treatments. Considering the complexity of inflammation in diseases, the synergistic effect of nanoparticles for gene-editing/drug therapy is evaluated in [...] Read more.

In this article, we report one of the few examples of nanoparticles capable of simultaneously delivering CRISPR-Cas9 gene-editing machinery and releasing drugs for one-shot treatments. Considering the complexity of inflammation in diseases, the synergistic effect of nanoparticles for gene-editing/drug therapy is evaluated in an in vitro inflammatory model as proof of concept. Mesoporous silica nanoparticles (MSNs), able to deliver the CRISPR/Cas9 machinery to edit gasdermin D (GSDMD), a key protein involved in inflammatory cell death, and the anti-inflammatory drug VX-765 (^GSDMD45CRISPR-VX-MSNs), were prepared. Nanoparticles allow high cargo loading and CRISPR-Cas9 plasmid protection and, thus, achieve the controlled codelivery of CRISPR-Cas9 and the drug in cells. Nanoparticles exhibit GSDMD gene editing by downregulating inflammatory cell death and achieving a combined effect on decreasing the inflammatory response by the codelivery of VX-765. Taken together, our results show the potential of MSNs as a versatile platform by allowing multiple combinations for gene editing and drug therapy to prepare advanced nanodevices to meet possible biomedical needs. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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10 pages, 1985 KiB

Open AccessArticle

Urea-Based Patches with Controlled Release for Potential Atopic Dermatitis Treatment

by Zuzanna J. Krysiak and Urszula Stachewicz

Pharmaceutics 2022, 14(7), 1494; https://doi.org/10.3390/pharmaceutics14071494 - 19 Jul 2022

Cited by 12 | Viewed by 3217

Abstract

Skin diseases such as atopic dermatitis (AD) are widespread and affect people all over the world. Current treatments for dry and itchy skin are mostly focused on pharmaceutical solutions, while supportive therapies such as ointments bring immediate relief. Electrospun membranes are commonly used [...] Read more.

Skin diseases such as atopic dermatitis (AD) are widespread and affect people all over the world. Current treatments for dry and itchy skin are mostly focused on pharmaceutical solutions, while supportive therapies such as ointments bring immediate relief. Electrospun membranes are commonly used as a drug delivery system, as they have a high surface to volume area, resulting in high loading capacity. Within this study we present the manufacturing strategies of skin patches using polymer membranes with active substances for treating various skin problems. Here, we manufactured the skin patches using electrospun poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate) (PVB) fibers blended and electrosprayed with urea. The highest cumulative release of urea was obtained from the PVB patches manufactured via blend electrospinning with 5% of the urea incorporated in the fiber. The maximum concentration of released urea was acquired after 30 min, which was followed up by 6 h of constant release level. The simultaneous electrospinning and electrospraying limited the urea deposition and resulted in the lowest urea incorporation followed by the low release level. The urea-based patches, manufactured via blend electrospinning, exhibited a great potential as overnight treatment for various skin problems and their development can bring new trends to the textile-based therapies for AD. Full article

(This article belongs to the Special Issue Electrospun Fibers: Advancement in Drug Delivery, Controlled Release, and Tissue Regeneration)

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15 pages, 2679 KiB

Open AccessArticle

Preparation and Characterisation of a Cyclodextrin-Complexed Mānuka Honey Microemulsion for Eyelid Application

by Ilva D. Rupenthal, Priyanka Agarwal, Benedict Uy, Jaeun Kim, Angela A. Cunningham, Ali Seyfoddin, Simon Swift and Jennifer P. Craig

Pharmaceutics 2022, 14(7), 1493; https://doi.org/10.3390/pharmaceutics14071493 - 19 Jul 2022

Cited by 3 | Viewed by 2142

Abstract

Honey has been widely purported as a natural remedy due to its antimicrobial and anti-inflammatory effects. In recent years, several studies have suggested that the considerably high methylglyoxal (MGO) concentration in Mānuka honey (MH) makes it particularly effective to manage bacterial overload, such [...] Read more.

Honey has been widely purported as a natural remedy due to its antimicrobial and anti-inflammatory effects. In recent years, several studies have suggested that the considerably high methylglyoxal (MGO) concentration in Mānuka honey (MH) makes it particularly effective to manage bacterial overload, such as that observed in blepharitis. However, the poor solubility, high viscosity, and osmolarity of aqueous honey solutions, especially at the high MGO concentrations studied in the literature, render the formulation of an acceptable dosage form for topical application to the eyelids challenging. Here, the antibacterial properties of raw MH and alpha-cyclodextrin (α-CD)-complexed MH were evaluated at relatively low MGO concentrations, and a liquid crystalline-forming microemulsion containing α-CD-complexed MH was formulated. After determining pH and osmolarity, ocular tolerability was assessed using human primary corneal epithelial cells and chorioallantoic membranes, while the antibacterial efficacy was further evaluated in vitro. The α-CD–MH complex had significantly greater antibacterial activity against Staphylococcus aureus than either constituent alone, which was evident even when formulated as a microemulsion. Moreover, the final formulation had a physiologically acceptable pH and osmolarity for eyelid application and was well-tolerated when diluted 1:10 with artificial tear fluid, as expected to be the case after accidental exposure to the ocular surface in the clinical setting. Thus, a safe and efficient MH dosage form was developed for topical application to the eyelids, which can potentially be used to support optimal eyelid health in the management of blepharitis. Full article

(This article belongs to the Special Issue Cyclodextrins and Their Inclusion Complexes for Pharmaceutical Uses)

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