Pharmaceutics

22 pages, 4743 KB

Open AccessEditor’s ChoiceArticle

Ultrasound Triggers Hypericin Activation Leading to Multifaceted Anticancer Activity

by Federica Foglietta, Roberto Canaparo, Simone Cossari, Patrizia Panzanelli, Franco Dosio and Loredana Serpe

Pharmaceutics 2022, 14(5), 1102; https://doi.org/10.3390/pharmaceutics14051102 - 21 May 2022

Cited by 20 | Viewed by 3237

Abstract

The use of ultrasound (US) in combination with a responsive chemical agent (sonosensitizer) can selectively trigger the agent’s anticancer activity in a process called sonodynamic therapy (SDT). SDT shares some properties with photodynamic therapy (PDT), which has been clinically approved, but sets itself [...] Read more.

The use of ultrasound (US) in combination with a responsive chemical agent (sonosensitizer) can selectively trigger the agent’s anticancer activity in a process called sonodynamic therapy (SDT). SDT shares some properties with photodynamic therapy (PDT), which has been clinically approved, but sets itself apart because of its use of US rather than light to achieve better tissue penetration. SDT provides anticancer effects mainly via the sonosensitizer-mediated generation of reactive oxygen species (ROS), although the precise nature of the underpinning mechanism is still under debate. This work investigates the SDT anticancer activity of hypericin (Hyp) in vitro in two- (2D) and three-dimensional (3D) HT-29 colon cancer models, and uses PDT as a yardstick due to its well-known Hyp phototoxicity. The cancer cell uptake and cellular localization of Hyp were investigated first to determine the proper noncytotoxic concentration and incubation time of Hyp for SDT. Furthermore, ROS production, cell proliferation, and cell death were evaluated after Hyp was exposed to US. Since cancer relapse and transporter-mediated multidrug resistance (MDR) are important causes of cancer treatment failure, the US-mediated ability of Hyp to elicit immunogenic cell death (ICD) and overcome MDR was also investigated. SDT showed strong ROS-mediated anticancer activity 48 h after treatment in both the HT-29 models. Specific damage-associated molecular patterns that are consistent with ICD, such as calreticulin (CRT) exposure and high-mobility group box 1 protein (HMGB1) release, were observed after SDT with Hyp. Moreover, the expression of the ABC transporter, P-glycoprotein (P-gp), in HT-29/MDR cells was not able to hinder cancer cell responsiveness to SDT with Hyp. This work reveals, for the first time, the US responsiveness of Hyp with significant anticancer activity being displayed, making it a full-fledged sonosensitizer for the SDT of cancer. Full article

(This article belongs to the Special Issue Novel Strategies to Improve the Therapeutic Effects of Natural Anticancer Compounds)

► Show Figures

Graphical abstract

24 pages, 2467 KB

Open AccessEditor’s ChoiceReview

Controlled-Release Nanosystems with a Dual Function of Targeted Therapy and Radiotherapy in Colorectal Cancer

by Pedro Cruz-Nova, Alejandra Ancira-Cortez, Guillermina Ferro-Flores, Blanca Ocampo-García and Brenda Gibbens-Bandala

Pharmaceutics 2022, 14(5), 1095; https://doi.org/10.3390/pharmaceutics14051095 - 20 May 2022

Cited by 15 | Viewed by 4505

Abstract

Nanoparticles are excellent platforms for several biomedical applications, including cancer treatment. They can incorporate different molecules to produce combinations of chemotherapeutic agents, radionuclides, and targeting molecules to improve the therapeutic strategies against cancer. These specific nanosystems are designed to have minimal side effects [...] Read more.

Nanoparticles are excellent platforms for several biomedical applications, including cancer treatment. They can incorporate different molecules to produce combinations of chemotherapeutic agents, radionuclides, and targeting molecules to improve the therapeutic strategies against cancer. These specific nanosystems are designed to have minimal side effects on healthy cells and better treatment efficacy against cancer cells when compared to chemotherapeutics, external irradiation, or targeted radiotherapy alone. In colorectal cancer, some metal and polymeric nanoparticle platforms have been used to potentialize external radiation therapy and targeted drug delivery. Polymeric nanoparticles, liposomes, albumin-based nanoparticles, etc., conjugated with PEG and/or HLA, can be excellent platforms to increase blood circulation time and decrease side effects, in addition to the combination of chemo/radiotherapy, which increases therapeutic efficacy. Additionally, radiolabeled nanoparticles have been conjugated to target specific tissues and are mainly used as agents for diagnosis, drug/gene delivery systems, or plasmonic photothermal therapy enhancers. This review aims to analyze how nanosystems are shaping combinatorial therapy and evaluate their status in the treatment of colorectal cancer. Full article

(This article belongs to the Special Issue Novel Strategies for Cancer Targeted Delivery)

► Show Figures

Figure 1

19 pages, 5326 KB

Open AccessEditor’s ChoiceArticle

Three-Dimensional Printing of a Container Tablet: A New Paradigm for Multi-Drug-Containing Bioactive Self-Nanoemulsifying Drug-Delivery Systems (Bio-SNEDDSs)

by Vineet R. Kulkarni, Mohsin Kazi, Ahmad Abdul-Wahhab Shahba, Aakib Radhanpuri and Mohammed Maniruzzaman

Pharmaceutics 2022, 14(5), 1082; https://doi.org/10.3390/pharmaceutics14051082 - 18 May 2022

Cited by 23 | Viewed by 4571

Abstract

This research demonstrates the use of fused deposition modeling (FDM) 3D printing to control the delivery of multiple drugs containing bioactive self-nano emulsifying drug-delivery systems (SNEDDSs). Around two-thirds of the new chemical entities being introduced in the market are associated with some inherent [...] Read more.

This research demonstrates the use of fused deposition modeling (FDM) 3D printing to control the delivery of multiple drugs containing bioactive self-nano emulsifying drug-delivery systems (SNEDDSs). Around two-thirds of the new chemical entities being introduced in the market are associated with some inherent issues, such as poor solubility and high lipophilicity. SNEDDSs provide for an innovative and easy way to develop a delivery platform for such drugs. Combining this platform with FDM 3D printing would further aid in developing new strategies for delivering poorly soluble drugs and personalized drug-delivery systems with added therapeutic benefits. This study evaluates the performance of a 3D-printed container system containing curcumin (CUR)- and lansoprazole (LNS)-loaded SNEDDS. The SNEDDS showed 50% antioxidant activity (IC₅₀) at concentrations of around 330.1 µg/mL and 393.3 µg/mL in the DPPH and ABTS radical scavenging assay, respectively. These SNEDDSs were loaded with no degradation and leakage from the 3D-printed container. We were able to delay the release of the SNEDDS from the hollow prints while controlling the print wall thickness to achieve lag phases of 30 min and 60 min before the release from the 0.4 mm and 1 mm wall thicknesses, respectively. Combining these two innovative drug-delivery strategies demonstrates a novel option for tackling the problems associated with multi-drug delivery and delivery of drugs susceptible to degradation in, i.e., gastric pH for targeting disease conditions throughout the gastrointestinal tract (GIT). It is also envisaged that such delivery systems reported herein can be an ideal solution to deliver many challenging molecules, such as biologics, orally or near the target site in the future, thus opening a new paradigm for multi-drug-delivery systems. Full article

(This article belongs to the Special Issue Recent Progress in Formulation Approaches for Improving the Solubility and Bioavailability of Poorly Soluble Drugs)

► Show Figures

Graphical abstract

24 pages, 1500 KB

Open AccessEditor’s ChoiceReview

Advancements in Skin Delivery of Natural Bioactive Products for Wound Management: A Brief Review of Two Decades

by Cameron Ryall, Sanjukta Duarah, Shuo Chen, Haijun Yu and Jingyuan Wen

Pharmaceutics 2022, 14(5), 1072; https://doi.org/10.3390/pharmaceutics14051072 - 17 May 2022

Cited by 34 | Viewed by 6786

Abstract

Application of modern delivery techniques to natural bioactive products improves their permeability, bioavailability, and therapeutic efficacy. Many natural products have desirable biological properties applicable to wound healing but are limited by their inability to cross the stratum corneum to access the wound. Over [...] Read more.

Application of modern delivery techniques to natural bioactive products improves their permeability, bioavailability, and therapeutic efficacy. Many natural products have desirable biological properties applicable to wound healing but are limited by their inability to cross the stratum corneum to access the wound. Over the past two decades, modern systems such as microneedles, lipid-based vesicles, hydrogels, composite dressings, and responsive formulations have been applied to natural products such as curcumin or aloe vera to improve their delivery and efficacy. This article reviews which natural products and techniques have been formulated together in the past two decades and the success of these applications for wound healing. Many cultures prefer natural-product-based traditional therapies which are often cheaper and more available than their synthetic counterparts. Improving natural products’ effect can provide novel wound-healing therapies for those who trust traditional compounds over synthetic drugs to reduce medical inequalities. Full article

(This article belongs to the Special Issue Strategies to Enhance Drug Permeability across Biological Barriers)

► Show Figures

Graphical abstract

47 pages, 6754 KB

Open AccessEditor’s ChoiceReview

Potential of Microneedle Systems for COVID-19 Vaccination: Current Trends and Challenges

by Jasmin Hassan, Charlotte Haigh, Tanvir Ahmed, Md Jasim Uddin and Diganta B. Das

Pharmaceutics 2022, 14(5), 1066; https://doi.org/10.3390/pharmaceutics14051066 - 16 May 2022

Cited by 24 | Viewed by 7291

Abstract

To prevent the coronavirus disease 2019 (COVID-19) pandemic and aid restoration to prepandemic normality, global mass vaccination is urgently needed. Inducing herd immunity through mass vaccination has proven to be a highly effective strategy for preventing the spread of many infectious diseases, which [...] Read more.

To prevent the coronavirus disease 2019 (COVID-19) pandemic and aid restoration to prepandemic normality, global mass vaccination is urgently needed. Inducing herd immunity through mass vaccination has proven to be a highly effective strategy for preventing the spread of many infectious diseases, which protects the most vulnerable population groups that are unable to develop immunity, such as people with immunodeficiencies or weakened immune systems due to underlying medical or debilitating conditions. In achieving global outreach, the maintenance of the vaccine potency, transportation, and needle waste generation become major issues. Moreover, needle phobia and vaccine hesitancy act as hurdles to successful mass vaccination. The use of dissolvable microneedles for COVID-19 vaccination could act as a major paradigm shift in attaining the desired goal to vaccinate billions in the shortest time possible. In addressing these points, we discuss the potential of the use of dissolvable microneedles for COVID-19 vaccination based on the current literature. Full article

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

► Show Figures

Figure 1

19 pages, 3009 KB

Open AccessEditor’s ChoiceArticle

Microgels Formed by Spontaneous Click Chemistries Utilizing Microfluidic Flow Focusing for Cargo Release in Response to Endogenous or Exogenous Stimuli

by Paige J. LeValley, Amanda L. Parsons, Bryan P. Sutherland, Kristi L. Kiick, John S. Oakey and April M. Kloxin

Pharmaceutics 2022, 14(5), 1062; https://doi.org/10.3390/pharmaceutics14051062 - 15 May 2022

Cited by 3 | Viewed by 3700

Abstract

Protein therapeutics have become increasingly popular for the treatment of a variety of diseases owing to their specificity to targets of interest. However, challenges associated with them have limited their use for a range of ailments, including the limited options available for local [...] Read more.

Protein therapeutics have become increasingly popular for the treatment of a variety of diseases owing to their specificity to targets of interest. However, challenges associated with them have limited their use for a range of ailments, including the limited options available for local controlled delivery. To address this challenge, degradable hydrogel microparticles, or microgels, loaded with model biocargoes were created with tunable release profiles or triggered burst release using chemistries responsive to endogenous or exogeneous stimuli, respectively. Specifically, microfluidic flow-focusing was utilized to form homogenous microgels with different spontaneous click chemistries that afforded degradation either in response to redox environments for sustained cargo release or light for on-demand cargo release. The resulting microgels were an appropriate size to remain localized within tissues upon injection and were easily passed through a needle relevant for injection, providing means for localized delivery. Release of a model biopolymer was observed over the course of several weeks for redox-responsive formulations or triggered for immediate release from the light-responsive formulation. Overall, we demonstrate the ability of microgels to be formulated with different materials chemistries to achieve various therapeutic release modalities, providing new tools for creation of more complex protein release profiles to improve therapeutic regimens. Full article

(This article belongs to the Special Issue Hydrogels in Pharmaceutical and Biomedical Applications)

► Show Figures

Graphical abstract

20 pages, 13838 KB

Open AccessEditor’s ChoiceArticle

Dextran-Coated Iron Oxide Nanoparticles Loaded with Curcumin for Antimicrobial Therapies

by Cristina Chircov, Raluca-Elena Ștefan, Georgiana Dolete, Adriana Andrei, Alina Maria Holban, Ovidiu-Cristian Oprea, Bogdan Stefan Vasile, Ionela Andreea Neacșu and Bianca Tihăuan

Pharmaceutics 2022, 14(5), 1057; https://doi.org/10.3390/pharmaceutics14051057 - 14 May 2022

Cited by 42 | Viewed by 5281

Abstract

The current trend in antimicrobial-agent development focuses on the use of natural compounds that limit the toxicity of conventional drugs and provide a potential solution to the antimicrobial resistance crisis. Curcumin represents a natural bioactive compound with well-known antimicrobial, anticancer, and antioxidant properties. [...] Read more.

The current trend in antimicrobial-agent development focuses on the use of natural compounds that limit the toxicity of conventional drugs and provide a potential solution to the antimicrobial resistance crisis. Curcumin represents a natural bioactive compound with well-known antimicrobial, anticancer, and antioxidant properties. However, its hydrophobicity considerably limits the possibility of body administration. Therefore, dextran-coated iron oxide nanoparticles can be used as efficient drug-delivery supports that could overcome this limitation. The iron oxide nanoparticles were synthesized through the microwave-assisted hydrothermal method by varying the treatment parameters (pressure and reaction time). The nanoparticles were subsequently coated with dextran and used for the loading of curcumin (in various concentrations). The drug-delivery systems were characterized through X-ray diffraction (XRD) coupled with Rietveld refinement, transmission electron microscopy (TEM), high-resolution TEM (HR-TEM), selected area electron diffraction (SAED), dynamic light scattering (DLS) and zeta potential, thermogravimetry and differential scanning calorimetry (TG-DSC), vibrating sample magnetometry (VSM), and UV-Vis spectrophotometry, as well as regarding their antimicrobial efficiency and biocompatibility using the appropriate assays. The results demonstrate a promising antimicrobial efficiency, as well as an increased possibility of controlling the properties of the resulted nanosystems. Thus, the present study represents an important step forward toward the development of highly efficient antimicrobial drug-delivery systems. Full article

(This article belongs to the Special Issue Nanomaterials and Novel Biologics to Manage Bacterial Infections)

► Show Figures

Figure 1

16 pages, 3926 KB

Open AccessEditor’s ChoiceArticle

A Hot-Melt Extrusion Risk Assessment Classification System for Amorphous Solid Dispersion Formulation Development

by Samuel O. Kyeremateng, Kristin Voges, Stefanie Dohrn, Ekaterina Sobich, Ute Lander, Stefan Weber, David Gessner, Rachel C. Evans and Matthias Degenhardt

Pharmaceutics 2022, 14(5), 1044; https://doi.org/10.3390/pharmaceutics14051044 - 12 May 2022

Cited by 22 | Viewed by 5630

Abstract

Several literature publications have described the potential application of active pharmaceutical ingredient (API)–polymer phase diagrams to identify appropriate temperature ranges for processing amorphous solid dispersion (ASD) formulations via the hot-melt extrusion (HME) technique. However, systematic investigations and reliable applications of the phase diagram [...] Read more.

Several literature publications have described the potential application of active pharmaceutical ingredient (API)–polymer phase diagrams to identify appropriate temperature ranges for processing amorphous solid dispersion (ASD) formulations via the hot-melt extrusion (HME) technique. However, systematic investigations and reliable applications of the phase diagram as a risk assessment tool for HME are non-existent. Accordingly, within AbbVie, an HME risk classification system (HCS) based on API–polymer phase diagrams has been developed as a material-sparing tool for the early risk assessment of especially high melting temperature APIs, which are typically considered unsuitable for HME. The essence of the HCS is to provide an API risk categorization framework for the development of ASDs via the HME process. The proposed classification system is based on the recognition that the manufacture of crystal-free ASD using the HME process fundamentally depends on the ability of the melt temperature to reach the API’s thermodynamic solubility temperature or above. Furthermore, we explored the API–polymer phase diagram as a simple tool for process design space selection pertaining to API or polymer thermal degradation regions and glass transition temperature-related dissolution kinetics limitations. Application of the HCS was demonstrated via HME experiments with two high melting temperature APIs, sulfamerazine and telmisartan, with the polymers Copovidone and Soluplus. Analysis of the resulting ASDs in terms of the residual crystallinity and degradation showed excellent agreement with the preassigned HCS class. Within AbbVie, the HCS concept has been successfully applied to more than 60 different APIs over the last 8 years as a robust validated risk assessment and quality-by-design (QbD) tool for the development of HME ASDs. Full article

(This article belongs to the Special Issue Amorphous Solid Dispersions: Rational Selection of a Manufacturing Process)

► Show Figures

Graphical abstract

18 pages, 8399 KB

Open AccessEditor’s ChoiceArticle

Tissue Adhesive, Self-Healing, Biocompatible, Hemostasis, and Antibacterial Properties of Fungal-Derived Carboxymethyl Chitosan-Polydopamine Hydrogels

by Kummara Madhusudana Rao, Kannan Badri Narayanan, Uluvangada Thammaiah Uthappa, Pil-Hoon Park, Inho Choi and Sung Soo Han

Pharmaceutics 2022, 14(5), 1028; https://doi.org/10.3390/pharmaceutics14051028 - 10 May 2022

Cited by 45 | Viewed by 5912

Abstract

In this work, fungal mushroom-derived carboxymethyl chitosan-polydopamine hydrogels (FCMCS-PDA) with multifunctionality (tissue adhesive, hemostasis, self-healing, and antibacterial properties) were developed for wound dressing applications. The hydrogel is obtained through dynamic Schiff base cross-linking and hydrogen bonds between FCMCS-PDA and covalently cross-linked polyacrylamide (PAM) [...] Read more.

In this work, fungal mushroom-derived carboxymethyl chitosan-polydopamine hydrogels (FCMCS-PDA) with multifunctionality (tissue adhesive, hemostasis, self-healing, and antibacterial properties) were developed for wound dressing applications. The hydrogel is obtained through dynamic Schiff base cross-linking and hydrogen bonds between FCMCS-PDA and covalently cross-linked polyacrylamide (PAM) networks. The FCMCS-PDA-PAM hydrogels have a good swelling ratio, biodegradable properties, excellent mechanical properties, and a highly interconnected porous structure with PDA microfibrils. Interestingly, the PDA microfibrils were formed along with FCMCS fibers in the hydrogel networks, which has a high impact on the biological performance of hydrogels. The maximum adhesion strength of the hydrogel to porcine skin was achieved at about 29.6 ± 2.9 kPa. The hydrogel had good self-healing and recoverable properties. The PDA-containing hydrogels show good antibacterial properties on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) bacteria. Moreover, the adhesive hydrogels depicted good viability and attachment of skin fibroblasts and keratinocyte cells. Importantly, FCMCS and PDA combined resulted in fast blood coagulation within 60 s. Hence, the adhesive hydrogel with multifunctionality has excellent potential as a wound dressing material for infected wounds. Full article

(This article belongs to the Special Issue Rational Design and Characterization of Hydrogels to Improve Pharmaceutical and Biomedical Applicability)

► Show Figures

Figure 1

20 pages, 6468 KB

Open AccessEditor’s ChoiceArticle

Glioblastoma-Derived Exosomes as Nanopharmaceutics for Improved Glioma Treatment

by Hyeji Lee, Kanghye Bae, Ah-Rum Baek, Eun-Bin Kwon, Yeoun-Hee Kim, Sung-Wook Nam, Gang Ho Lee and Yongmin Chang

Pharmaceutics 2022, 14(5), 1002; https://doi.org/10.3390/pharmaceutics14051002 - 6 May 2022

Cited by 37 | Viewed by 5611

Abstract

The use of cancer-derived exosomes has been studied in several cancer types, but the cancer-targeting efficacy of glioma-derived exosomes has not been investigated in depth for malignant glioblastoma (GBM) cells. In this study, exosomes were derived from U87MG human glioblastoma cells, and selumetinib, [...] Read more.

The use of cancer-derived exosomes has been studied in several cancer types, but the cancer-targeting efficacy of glioma-derived exosomes has not been investigated in depth for malignant glioblastoma (GBM) cells. In this study, exosomes were derived from U87MG human glioblastoma cells, and selumetinib, a new anticancer drug, was loaded into the exosomes. We observed the tropism of GBM-derived exosomes in vitro and in vivo. We found that the tropism of GBM-derived exosomes is in contrast to the behavior of non-exosome-enveloped drugs and non-GBM-specific exosomes in vitro and in vivo in an animal GBM model. We found that the tropism exhibited by GBM-derived exosomes can be utilized to shuttle selumetinib, with no specific targeting moiety, to GBM tumor sites. Therefore, our findings indicated that GBM-derived exosomes loaded with selumetinib had a specific antitumor effect on U87MG cells and were non-toxic to normal brain cells. These exosomes offer improved therapeutic prospects for glioblastoma therapy. Full article

(This article belongs to the Special Issue Nanopharmaceuticals for Image-Guided Cancer Therapy and Diagnosis)

► Show Figures

Figure 1

23 pages, 1917 KB

Open AccessEditor’s ChoiceReview

Semi-Automated Therapeutic Drug Monitoring as a Pillar toward Personalized Medicine for Tuberculosis Management

by Rannissa Puspita Jayanti, Nguyen Phuoc Long, Nguyen Ky Phat, Yong-Soon Cho and Jae-Gook Shin

Pharmaceutics 2022, 14(5), 990; https://doi.org/10.3390/pharmaceutics14050990 - 5 May 2022

Cited by 13 | Viewed by 4469

Abstract

Standard tuberculosis (TB) management has failed to control the growing number of drug-resistant TB cases worldwide. Therefore, innovative approaches are required to eradicate TB. Model-informed precision dosing and therapeutic drug monitoring (TDM) have become promising tools for adjusting anti-TB drug doses corresponding with [...] Read more.

Standard tuberculosis (TB) management has failed to control the growing number of drug-resistant TB cases worldwide. Therefore, innovative approaches are required to eradicate TB. Model-informed precision dosing and therapeutic drug monitoring (TDM) have become promising tools for adjusting anti-TB drug doses corresponding with individual pharmacokinetic profiles. These are crucial to improving the treatment outcome of the patients, particularly for those with complex comorbidity and a high risk of treatment failure. Despite the actual benefits of TDM at the bedside, conventional TDM encounters several hurdles related to laborious, time-consuming, and costly processes. Herein, we review the current practice of TDM and discuss the main obstacles that impede it from successful clinical implementation. Moreover, we propose a semi-automated TDM approach to further enhance precision medicine for TB management. Full article

(This article belongs to the Special Issue Adding Model-Informed Precision Dosing to Precision Medicine to Improve Patient Drug Treatment Outcomes)

► Show Figures

Figure 1

38 pages, 1737 KB

Open AccessEditor’s ChoiceReview

Vesicular Nanocarriers for Phytocompounds in Wound Care: Preparation and Characterization

by Diana Antonia Safta, Cătălina Bogdan and Mirela Liliana Moldovan

Pharmaceutics 2022, 14(5), 991; https://doi.org/10.3390/pharmaceutics14050991 - 5 May 2022

Cited by 38 | Viewed by 5252

Abstract

The need to develop wound healing preparations is a pressing challenge given the limitations of the current treatment and the rising prevalence of impaired healing wounds. Although herbal extracts have been used for many years to treat skin disorders, due to their wound [...] Read more.

The need to develop wound healing preparations is a pressing challenge given the limitations of the current treatment and the rising prevalence of impaired healing wounds. Although herbal extracts have been used for many years to treat skin disorders, due to their wound healing, anti-inflammatory, antimicrobial, and antioxidant effects, their efficacy can be questionable because of their poor bioavailability and stability issues. Nanotechnology offers an opportunity to revolutionize wound healing therapies by including herbal compounds in nanosystems. Particularly, vesicular nanosystems exhibit beneficial properties, such as biocompatibility, targeted and sustained delivery capacity, and increased phytocompounds’ bioavailability and protection, conferring them a great potential for future applications in wound care. This review summarizes the beneficial effects of phytocompounds in wound healing and emphasizes the advantages of their entrapment in vesicular nanosystems. Different types of lipid nanocarriers are presented (liposomes, niosomes, transferosomes, ethosomes, cubosomes, and their derivates’ systems), highlighting their applications as carriers for phytocompounds in wound care, with the presentation of the state-of-art in this field. The methods of preparation, characterization, and evaluation are also described, underlining the properties that ensure good in vitro and in vivo performance. Finally, future directions of topical systems in which vesicle-bearing herbal extracts or phytocompounds can be incorporated are pointed out, as their development is emerging as a promising strategy. Full article

(This article belongs to the Special Issue Nanotechnology-Enabled Strategies to Enhance Topical Bioavailability)

► Show Figures

Figure 1

20 pages, 5842 KB

Open AccessEditor’s ChoiceArticle

Formulation and Biological Evaluation of Mesoporous Silica Nanoparticles Loaded with Combinations of Sortase A Inhibitors and Antimicrobial Peptides

by Sitah Alharthi, Zyta M. Ziora, Taskeen Janjua, Amirali Popat and Peter M. Moyle

Pharmaceutics 2022, 14(5), 986; https://doi.org/10.3390/pharmaceutics14050986 - 4 May 2022

Cited by 17 | Viewed by 3650

Abstract

This study aimed to develop synergistic therapies to treat superbug infections through the encapsulation of sortase A inhibitors (SrtAIs; trans-chalcone (TC), curcumin (CUR), quercetin (QC), or berberine chloride (BR)) into MCM-41 mesoporous silica nanoparticles (MSNs) or a phosphonate-modified analogue (MCM-41-PO₃⁻ [...] Read more.

This study aimed to develop synergistic therapies to treat superbug infections through the encapsulation of sortase A inhibitors (SrtAIs; trans-chalcone (TC), curcumin (CUR), quercetin (QC), or berberine chloride (BR)) into MCM-41 mesoporous silica nanoparticles (MSNs) or a phosphonate-modified analogue (MCM-41-PO₃⁻) to overcome their poor aqueous solubility. A resazurin-modified minimum inhibitory concentration (MIC) and checkerboard assays, to measure SrtAI synergy in combination with leading antimicrobial peptides (AMPs; pexiganan (PEX), indolicidin (INDO), and [I5, R8] mastoparan (MASTO)), were determined against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The results demonstrated that the MCM-41 and MCM-41-PO₃⁻ formulations significantly improved the aqueous solubility of each SrtAI. The MICs for SrtAI/MCM-41-PO₃⁻ formulations were lower compared to the SrtAI/MCM-41 formulations against tested bacterial strains, except for the cases of BR/MCM-41 and QC/MCM-41 against P. aeruginosa. Furthermore, the following combinations demonstrated synergy: PEX with TC/MCM-41 (against all strains) or TC/MCM-41-PO₃⁻ (against all strains except P. aeruginosa); PEX with BR/MCM-41 or BR/MCM-41-PO₃⁻ (against MSSA and MRSA); INDO with QC/MCM-41 or QC/MCM-41-PO₃⁻ (against MRSA); and MASTO with CUR/MCM-41 (against E. coli). These combinations also reduced each components’ toxicity against human embryonic kidney cells. In conclusion, MCM-41 MSNs provide a platform to enhance SrtAI solubility and demonstrated antimicrobial synergy with AMPs and reduced toxicity, providing novel superbug treatment opportunities. Full article

(This article belongs to the Special Issue Design of Mesoporous Materials for Biomedical Application)

► Show Figures

Figure 1

32 pages, 2842 KB

Open AccessEditor’s ChoiceReview

Metallic Engineered Nanomaterials and Ocular Toxicity: A Current Perspective

by Krista M. Cosert, Soohyun Kim, Iman Jalilian, Maggie Chang, Brooke L. Gates, Kent E. Pinkerton, Laura S. Van Winkle, Vijay Krishna Raghunathan, Brian C. Leonard and Sara M. Thomasy

Pharmaceutics 2022, 14(5), 981; https://doi.org/10.3390/pharmaceutics14050981 - 3 May 2022

Cited by 18 | Viewed by 6127

Abstract

The ocular surface, comprised of the transparent cornea, conjunctiva, and protective tear film, forms a protective barrier defending deeper structures of the eye from particulate matter and mechanical trauma. This barrier is routinely exposed to a multitude of naturally occurring and engineered nanomaterials [...] Read more.

The ocular surface, comprised of the transparent cornea, conjunctiva, and protective tear film, forms a protective barrier defending deeper structures of the eye from particulate matter and mechanical trauma. This barrier is routinely exposed to a multitude of naturally occurring and engineered nanomaterials (ENM). Metallic ENMs are particularly ubiquitous in commercial products with a high risk of ocular exposure, such as cosmetics and sunscreens. Additionally, there are several therapeutic uses for metallic ENMs owing to their attractive magnetic, antimicrobial, and functionalization properties. The increasing commercial and therapeutic applications of metallic ENMs come with a high risk of ocular exposure with poorly understood consequences to the health of the eye. While the toxicity of metallic ENMs exposure has been rigorously studied in other tissues and organs, further studies are necessary to understand the potential for adverse effects and inform product usage for individuals whose ocular health may be compromised by injury, disease, or surgical intervention. This review provides an update of current literature on the ocular toxicity of metallic ENMs in vitro and in vivo, as well as the risks and benefits of therapeutic applications of metallic ENMs in ophthalmology. Full article

(This article belongs to the Special Issue Nanotechnology in Ocular Drug Delivery)

► Show Figures

Figure 1

26 pages, 5238 KB

Open AccessEditor’s ChoiceArticle

Importance of Spray–Wall Interaction and Post-Deposition Liquid Motion in the Transport and Delivery of Pharmaceutical Nasal Sprays

by Arun V. Kolanjiyil, Ali Alfaifi, Ghali Aladwani, Laleh Golshahi and Worth Longest

Pharmaceutics 2022, 14(5), 956; https://doi.org/10.3390/pharmaceutics14050956 - 28 Apr 2022

Cited by 19 | Viewed by 4185

Abstract

Nasal sprays, which produce relatively large pharmaceutical droplets and have high momentum, are primarily used to deliver locally acting drugs to the nasal mucosa. Depending on spray pump administration conditions and insertion angles, nasal sprays may interact with the nasal surface in ways [...] Read more.

Nasal sprays, which produce relatively large pharmaceutical droplets and have high momentum, are primarily used to deliver locally acting drugs to the nasal mucosa. Depending on spray pump administration conditions and insertion angles, nasal sprays may interact with the nasal surface in ways that creates complex droplet–wall interactions followed by significant liquid motion after initial wall contact. Additionally, liquid motion can occur after deposition as the spray liquid moves in bulk along the nasal surface. It is difficult or impossible to capture these conditions with commonly used computational fluid dynamics (CFD) models of spray droplet transport that typically employ a deposit-on-touch boundary condition. Hence, an updated CFD framework with a new spray–wall interaction (SWI) model in tandem with a post-deposition liquid motion (PDLM) model was developed and applied to evaluate nasal spray delivery for Flonase and Flonase Sensimist products. For both nasal spray products, CFD revealed significant effects of the spray momentum on surface liquid motion, as well as motion of the surface film due to airflow generated shear stress and gravity. With Flonase, these factors substantially influenced the final resting place of the liquid. For Flonase Sensimist, anterior and posterior liquid movements were approximately balanced over time. As a result, comparisons with concurrent in vitro experimental results were substantially improved for Flonase compared with the traditional deposit-on-touch boundary condition. The new SWI-PDLM model highlights the dynamicenvironment that occurs when a nasal spray interacts with a nasal wall surface and can be used to better understand the delivery of current nasal spray products as well as to develop new nasal drug delivery strategies with improved regional targeting. Full article

► Show Figures

Figure 1

30 pages, 5885 KB

Open AccessEditor’s ChoiceReview

Fluorescent Nanosystems for Drug Tracking and Theranostics: Recent Applications in the Ocular Field

by Elide Zingale, Alessia Romeo, Salvatore Rizzo, Cinzia Cimino, Angela Bonaccorso, Claudia Carbone, Teresa Musumeci and Rosario Pignatello

Pharmaceutics 2022, 14(5), 955; https://doi.org/10.3390/pharmaceutics14050955 - 28 Apr 2022

Cited by 19 | Viewed by 4553

Abstract

The greatest challenge associated with topical drug delivery for the treatment of diseases affecting the posterior segment of the eye is to overcome the poor bioavailability of the carried molecules. Nanomedicine offers the possibility to overcome obstacles related to physiological mechanisms and ocular [...] Read more.

The greatest challenge associated with topical drug delivery for the treatment of diseases affecting the posterior segment of the eye is to overcome the poor bioavailability of the carried molecules. Nanomedicine offers the possibility to overcome obstacles related to physiological mechanisms and ocular barriers by exploiting different ocular routes. Functionalization of nanosystems by fluorescent probes could be a useful strategy to understand the pathway taken by nanocarriers into the ocular globe and to improve the desired targeting accuracy. The application of fluorescence to decorate nanocarrier surfaces or the encapsulation of fluorophore molecules makes the nanosystems a light probe useful in the landscape of diagnostics and theranostics. In this review, a state of the art on ocular routes of administration is reported, with a focus on pathways undertaken after topical application. Numerous studies are reported in the first section, confirming that the use of fluorescent within nanoparticles is already spread for tracking and biodistribution studies. The first section presents fluorescent molecules used for tracking nanosystems’ cellular internalization and permeation of ocular tissues; discussions on the classification of nanosystems according to their nature (lipid-based, polymer-based, metallic-based and protein-based) follows. The following sections are dedicated to diagnostic and theranostic uses, respectively, which represent an innovation in the ocular field obtained by combining dual goals in a single administration system. For its great potential, this application of fluorescent nanoparticles would experience a great development in the near future. Finally, a brief overview is dedicated to the use of fluorescent markers in clinical trials and the market in the ocular field. Full article

(This article belongs to the Special Issue Nanoparticles in Ocular Drug Delivery Systems)

► Show Figures

Figure 1

19 pages, 10410 KB

Open AccessEditor’s ChoiceArticle

Combined Release of Antiseptic and Antibiotic Drugs from Visible Light Polymerized Biodegradable Nanocomposite Hydrogels for Periodontitis Treatment

by Jozsef Bako, Ferenc Toth, Jozsef Gall, Renato Kovacs, Attila Csík, Istvan Varga, Anton Sculean, Romana Zelko and Csaba Hegedus

Pharmaceutics 2022, 14(5), 957; https://doi.org/10.3390/pharmaceutics14050957 - 28 Apr 2022

Cited by 22 | Viewed by 3826

Abstract

The in situ application of the combination of different types of drugs revolutionized the area of periodontal therapy. The purpose of this study was to develop nanocomposite hydrogel (NCHG) as a pH-sensitive drug delivery system. To achieve local applicability of the NCHG in [...] Read more.

The in situ application of the combination of different types of drugs revolutionized the area of periodontal therapy. The purpose of this study was to develop nanocomposite hydrogel (NCHG) as a pH-sensitive drug delivery system. To achieve local applicability of the NCHG in dental practice, routinely used blue-light photopolymerization was chosen for preparation. The setting time was 60 s, which resulted in stable hydrogel structures. Universal Britton–Robinson buffer solutions were used to investigate the effect of pH in the range 4–12 on the release of drugs that can be used in the periodontal pocket. Metronidazole was released from the NCHGs within 12 h, but chlorhexidine showed a much longer elution time with strong pH dependence, which lasted more than 7 days as it was corroborated by the bactericidal effect. The biocompatibility of the NCHGs was proven by Alamar-blue test and the effectiveness of drug release in the acidic medium was also demonstrated. This fast photo-polymerizable NCHG can help to establish a locally applicable combined drug delivery system which can be loaded with the required amount of medicines and can reduce the side effects of the systemic use of drugs that have to be used in high doses to reach an ideal concentration locally. Full article

(This article belongs to the Special Issue Hydrogels in Drug Delivery: Progress and Challenges)

► Show Figures

Graphical abstract

26 pages, 3004 KB

Open AccessEditor’s ChoiceReview

Advances in the Synthesis and Application of Magnetic Ferrite Nanoparticles for Cancer Therapy

by Seipati Rosemary Mokhosi, Wendy Mdlalose, Amos Nhlapo and Moganavelli Singh

Pharmaceutics 2022, 14(5), 937; https://doi.org/10.3390/pharmaceutics14050937 - 26 Apr 2022

Cited by 76 | Viewed by 7918

Abstract

Cancer is among the leading causes of mortality globally, with nearly 10 million deaths in 2020. The emergence of nanotechnology has revolutionised treatment strategies in medicine, with rigorous research focusing on designing multi-functional nanoparticles (NPs) that are biocompatible, non-toxic, and target-specific. Iron-oxide-based NPs [...] Read more.

Cancer is among the leading causes of mortality globally, with nearly 10 million deaths in 2020. The emergence of nanotechnology has revolutionised treatment strategies in medicine, with rigorous research focusing on designing multi-functional nanoparticles (NPs) that are biocompatible, non-toxic, and target-specific. Iron-oxide-based NPs have been successfully employed in theranostics as imaging agents and drug delivery vehicles for anti-cancer treatment. Substituted iron-oxides (MFe₂O₄) have emerged as potential nanocarriers due to their unique and attractive properties such as size and magnetic tunability, ease of synthesis, and manipulatable properties. Current research explores their potential use in hyperthermia and as drug delivery vehicles for cancer therapy. Significantly, there are considerations in applying iron-oxide-based NPs for enhanced biocompatibility, biodegradability, colloidal stability, lowered toxicity, and more efficient and targeted delivery. This review covers iron-oxide-based NPs in cancer therapy, focusing on recent research advances in the use of ferrites. Methods for the synthesis of cubic spinel ferrites and the requirements for their considerations as potential nanocarriers in cancer therapy are discussed. The review highlights surface modifications, where functionalisation with specific biomolecules can deliver better efficiency. Finally, the challenges and solutions for the use of ferrites in cancer therapy are summarised. Full article

(This article belongs to the Special Issue Novel Strategies for Cancer Targeted Delivery)

► Show Figures

Figure 1

22 pages, 5937 KB

Open AccessEditor’s ChoiceArticle

3D Printed Mini-Floating-Polypill for Parkinson’s Disease: Combination of Levodopa, Benserazide, and Pramipexole in Various Dosing for Personalized Therapy

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

Pharmaceutics 2022, 14(5), 931; https://doi.org/10.3390/pharmaceutics14050931 - 25 Apr 2022

Cited by 47 | Viewed by 6162

Abstract

Therapy for Parkinson’s disease is quite challenging. Numerous drugs are available for symptomatic treatment, and levodopa (LD), in combination with a dopa decarboxylase inhibitor (e.g., benserazide (BZ)), has been the drug of choice for years. As the disease progresses, therapy must be supplemented [...] Read more.

Therapy for Parkinson’s disease is quite challenging. Numerous drugs are available for symptomatic treatment, and levodopa (LD), in combination with a dopa decarboxylase inhibitor (e.g., benserazide (BZ)), has been the drug of choice for years. As the disease progresses, therapy must be supplemented with a dopamine agonist (e.g., pramipexole (PDM)). Side effects increase, as do the required dose and dosing intervals. For these specific requirements of drug therapy, the 3D printing method fused deposition modelling (FDM) was applied in this study for personalized therapy. Hot melt extrusion was utilized to produce two different compositions into filaments: PDM and polyvinyl alcohol for rapid drug release and a fixed combination of LD/BZ (4:1) in an ethylene-vinyl acetate copolymer matrix for prolonged drug release. Since LD is absorbed in the upper gastrointestinal tract, a formulation that floats in gastric fluid was desired to prolong API absorption. Using the FDM 3D printing process, different polypill geometries were printed from both filaments, with variable dosages. Dosage forms with 15–180 mg LD could be printed, showing similar release rates (f₂ > 50). In addition, a mini drug delivery dosage form was printed that released 75% LD/BZ within 750 min and could be used as a gastric retentive drug delivery system due to the floating properties of the composition. The floating mini-polypill was designed to accommodate patients’ swallowing difficulties and to allow for individualized dosing with an API release over a longer period of time. Full article

(This article belongs to the Special Issue The Evolution of Pharmaceutical Three-Dimensional Printing)

► Show Figures

Graphical abstract

20 pages, 3008 KB

Open AccessEditor’s ChoiceArticle

Polyaphron Formulations Stabilised with Different Water-Soluble Polymers for Ocular Drug Delivery

by Roman V. Moiseev, Fraser Steele and Vitaliy V. Khutoryanskiy

Pharmaceutics 2022, 14(5), 926; https://doi.org/10.3390/pharmaceutics14050926 - 24 Apr 2022

Cited by 18 | Viewed by 4555

Abstract

As drug delivery to the eye has evolved over the last decades, researchers have explored more effective treatments for ocular diseases. Despite this, delivering drugs to the cornea remains one of the most problematic issues in ophthalmology due to the poor permeability of [...] Read more.

As drug delivery to the eye has evolved over the last decades, researchers have explored more effective treatments for ocular diseases. Despite this, delivering drugs to the cornea remains one of the most problematic issues in ophthalmology due to the poor permeability of the cornea and tear clearance mechanisms. In this study, four different types of polyaphron formulations are prepared with 10% poloxamer 188 (P188), 10% poly(2-ethyl-2-oxazoline), 1% polyquaternium 10, and 3% sodium carboxymethylcellulose solutions mixed with 1% Brij® L4 in a caprylic/capric triglycerides solution. Their physicochemical characteristics, rheological properties, and stability are assessed. Additionally, a polyaphron with 3% polyquaternium 10 was prepared for the assessment of ex vivo corneal retention along with four other polyaphrons. The best retention on the ex vivo cornea was displayed by the 3% polyquaternium 10-based formulation. The 10% poloxamer 188 along with 1% polyquaternium 10-based polyaphrons appeared to be the most stable among the four prepared formulations. A toxicological evaluation of these formulations was performed using a slug mucosal irritation test and bovine corneal opacity and permeability assay, with all four polyaphrons proving good biocompatibility with ocular tissues. The developed drug delivery systems demonstrated an excellent potential for ocular drug delivery. Full article

(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)

► Show Figures

Figure 1

21 pages, 7624 KB

Open AccessEditor’s ChoiceArticle

Compression Modulus and Apparent Density of Polymeric Excipients during Compression—Impact on Tabletability

by Barbara V. Schönfeld, Ulrich Westedt and Karl G. Wagner

Pharmaceutics 2022, 14(5), 913; https://doi.org/10.3390/pharmaceutics14050913 - 22 Apr 2022

Cited by 8 | Viewed by 5097

Abstract

The present study focuses on the compaction behavior of polymeric excipients during compression in comparison to nonpolymeric excipients and its consequences on commonly used Heckel analysis. Compression analysis at compaction pressures (CPs) from 50 to 500 MPa was performed using a compaction simulator. [...] Read more.

The present study focuses on the compaction behavior of polymeric excipients during compression in comparison to nonpolymeric excipients and its consequences on commonly used Heckel analysis. Compression analysis at compaction pressures (CPs) from 50 to 500 MPa was performed using a compaction simulator. This study demonstrates that the particle density, measured via helium pycnometer (ρ_par), of polymeric excipients (Kollidon^®VA64, Soluplus^®, AQOAT^®AS-MMP, Starch1500^®, Avicel^®PH101) was already exceeded at low CPs (<200 MPa), whereas the ρ_par was either never reached for brittle fillers such as DI-CAFOS^®A60 and tricalcium citrate or exceeded at CPs above 350 MPa (FlowLac^®100, Pearlitol^®100SD). We hypothesized that the threshold for exceeding ρ_par is linked with predominantly elastic deformation. This was confirmed by the start of linear increase in elastic recovery in-die (ER_in-die) with exceeding particle density, and in addition, by the applicability in calculating the elastic modulus via the equation of the linear increase in ER_in-die. Last, the evaluation of “density under pressure” as an alternative to the ρ_par for Heckel analysis showed comparable conclusions for compression behavior based on the calculated yield pressures. However, the applicability of Heckel analysis for polymeric excipients was questioned in principle. In conclusion, the knowledge of the threshold provides guidance for the selection of suitable excipients in the formulation development to mitigate the risk of tablet defects related to stored elastic energy, such as capping and lamination. Full article

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

► Show Figures

Graphical abstract

22 pages, 2676 KB

Open AccessEditor’s ChoiceArticle

Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions

by Helena Leonie Hanae Loer, Denise Türk, José David Gómez-Mantilla, Dominik Selzer and Thorsten Lehr

Pharmaceutics 2022, 14(5), 915; https://doi.org/10.3390/pharmaceutics14050915 - 22 Apr 2022

Cited by 12 | Viewed by 7553

Abstract

The antiplatelet agent clopidogrel is listed by the FDA as a strong clinical index inhibitor of cytochrome P450 (CYP) 2C8 and weak clinical inhibitor of CYP2B6. Moreover, clopidogrel is a substrate of—among others—CYP2C19 and CYP3A4. This work presents the development of a whole-body [...] Read more.

The antiplatelet agent clopidogrel is listed by the FDA as a strong clinical index inhibitor of cytochrome P450 (CYP) 2C8 and weak clinical inhibitor of CYP2B6. Moreover, clopidogrel is a substrate of—among others—CYP2C19 and CYP3A4. This work presents the development of a whole-body physiologically based pharmacokinetic (PBPK) model of clopidogrel including the relevant metabolites, clopidogrel carboxylic acid, clopidogrel acyl glucuronide, 2-oxo-clopidogrel, and the active thiol metabolite, with subsequent application for drug–gene interaction (DGI) and drug–drug interaction (DDI) predictions. Model building was performed in PK-Sim^® using 66 plasma concentration-time profiles of clopidogrel and its metabolites. The comprehensive parent-metabolite model covers biotransformation via carboxylesterase (CES) 1, CES2, CYP2C19, CYP3A4, and uridine 5′-diphospho-glucuronosyltransferase 2B7. Moreover, CYP2C19 was incorporated for normal, intermediate, and poor metabolizer phenotypes. Good predictive performance of the model was demonstrated for the DGI involving CYP2C19, with 17/19 predicted DGI AUC_last and 19/19 predicted DGI C_max ratios within 2-fold of their observed values. Furthermore, DDIs involving bupropion, omeprazole, montelukast, pioglitazone, repaglinide, and rifampicin showed 13/13 predicted DDI AUC_last and 13/13 predicted DDI C_max ratios within 2-fold of their observed ratios. After publication, the model will be made publicly accessible in the Open Systems Pharmacology repository. Full article

(This article belongs to the Special Issue Drug–Drug Interactions (Volume II))

► Show Figures

Figure 1

26 pages, 4997 KB

Open AccessEditor’s ChoiceReview

Nanotheranostics for Image-Guided Cancer Treatment

by Isabel S. Dennahy, Zheng Han, William M. MacCuaig, Hunter M. Chalfant, Anna Condacse, Jordan M. Hagood, Juan C. Claros-Sorto, Wajeeha Razaq, Jennifer Holter-Chakrabarty, Ronald Squires, Barish H. Edil, Ajay Jain and Lacey R. McNally

Pharmaceutics 2022, 14(5), 917; https://doi.org/10.3390/pharmaceutics14050917 - 22 Apr 2022

Cited by 36 | Viewed by 5914

Abstract

Image-guided nanotheranostics have the potential to represent a new paradigm in the treatment of cancer. Recent developments in modern imaging and nanoparticle design offer an answer to many of the issues associated with conventional chemotherapy, including their indiscriminate side effects and susceptibility to [...] Read more.

Image-guided nanotheranostics have the potential to represent a new paradigm in the treatment of cancer. Recent developments in modern imaging and nanoparticle design offer an answer to many of the issues associated with conventional chemotherapy, including their indiscriminate side effects and susceptibility to drug resistance. Imaging is one of the tools best poised to enable tailoring of cancer therapies. The field of image-guided nanotheranostics has the potential to harness the precision of modern imaging techniques and use this to direct, dictate, and follow site-specific drug delivery, all of which can be used to further tailor cancer therapies on both the individual and population level. The use of image-guided drug delivery has exploded in preclinical and clinical trials although the clinical translation is incipient. This review will focus on traditional mechanisms of targeted drug delivery in cancer, including the use of molecular targeting, as well as the foundations of designing nanotheranostics, with a focus on current clinical applications of nanotheranostics in cancer. A variety of specially engineered and targeted drug carriers, along with strategies of labeling nanoparticles to endow detectability in different imaging modalities will be reviewed. It will also introduce newer concepts of image-guided drug delivery, which may circumvent many of the issues seen with other techniques. Finally, we will review the current barriers to clinical translation of image-guided nanotheranostics and how these may be overcome. Full article

(This article belongs to the Special Issue Novel Strategies for Cancer Targeted Delivery)

► Show Figures

Figure 1

13 pages, 783 KB

Open AccessEditor’s ChoiceReview

Retinal Diseases: The Next Frontier in Pharmacodelivery

by Assaf Ben-Arzi, Rita Ehrlich and Ron Neumann

Pharmaceutics 2022, 14(5), 904; https://doi.org/10.3390/pharmaceutics14050904 - 21 Apr 2022

Cited by 11 | Viewed by 5234

Abstract

The future continuous growth of the global older population augments the burden of retinal diseases worldwide. Retinal characteristics isolating and protecting the sensitive neuro-retina from the rest of the ocular tissues challenge drug delivery and promote research and development toward new horizons. In [...] Read more.

The future continuous growth of the global older population augments the burden of retinal diseases worldwide. Retinal characteristics isolating and protecting the sensitive neuro-retina from the rest of the ocular tissues challenge drug delivery and promote research and development toward new horizons. In this review, we wish to describe the unmet medical needs, discuss the novel modes of delivery, and disclose to the reader a spectrum of older-to-novel drug delivery technologies, innovations, and the frontier of pharmacodelivery to the retina. Treating the main retinal diseases in the everlasting war against blindness and its associated morbidity has been growing steadily over the last two decades. Implants, new angiogenesis inhibitor agents, micro- and nano-carriers, and the anchored port delivery system are becoming new tools in this war. The revolution and evolution of new delivery methods might be just a few steps ahead, yet its assimilation in our daily clinical work may take time, due to medical, economical, and regulatory elements that need to be met in order to allow successful development and market utilization of new technologies. Therefore, further work is warranted, as detailed in this Pharmaceutics Special Issue. Full article

(This article belongs to the Special Issue Recent Advances in Retinal Drug Delivery)

► Show Figures

Graphical abstract

30 pages, 6490 KB

Open AccessEditor’s ChoiceArticle

Inclusion of a Phytomedicinal Flavonoid in Biocompatible Surface-Modified Chylomicron Mimic Nanovesicles with Improved Oral Bioavailability and Virucidal Activity: Molecular Modeling and Pharmacodynamic Studies

by Mohamed Y. Zakaria, Paris E. Georghiou, Joseph H. Banoub and Botros Y. Beshay

Pharmaceutics 2022, 14(5), 905; https://doi.org/10.3390/pharmaceutics14050905 - 21 Apr 2022

Cited by 25 | Viewed by 3153

Abstract

Morin hydrate (MH) is a widely-used Asian phytomedicinal flavonoid with a wide range of reported therapeutic activities. However, MH has limited oral bioavailability due to its low aqueous solubility and intestinal permeability, which in turn hinders its potential antiviral activity. The study reported [...] Read more.

Morin hydrate (MH) is a widely-used Asian phytomedicinal flavonoid with a wide range of reported therapeutic activities. However, MH has limited oral bioavailability due to its low aqueous solubility and intestinal permeability, which in turn hinders its potential antiviral activity. The study reported herein was designed to encapsulate MH in polyethyleneglycolated (PEGylated) chylomicrons (PCMs) and to boost its antiviral activity and biological availability for oral administration using a rat experimental model. The PEGylated edge activator combined with the conventional components of chylomicrons (CMs) amplify the transport of the drug across the intestine and its circulation period, hence its therapeutic impact. The implementation of variables in the in vitro characterization of the vesicles was investigated. Using Design Expert^® software, a 2⁴ factorial design was conducted, and the resulting PCM formulations were fabricated utilizing a thin-film hydration technique. The efficacy of the formulations was assessed according to their zeta potential (ZP), entrapment efficiency percentage (EE%), amount of drug released after 8 h (Q8h), and particle size (PS) data. Formulation F9, which was deemed to be the optimal formula, used compritol as the lipidic core together in defined amounts with phosphatidylcholine (PC) and Brij52. Computer-aided studies revealed that MH alone in a suspension had both diminished intestinal permeability and absorption, but was enhanced when loaded in PCMs. This was affirmed by the superiority of formulation F9 results in ex vivo permeation and pharmacokinetic studies. Furthermore, formulation F9 had a superior safety profile and antiviral activity over a pure MH suspension. Molecular-docking studies revealed the capability of MH to inhibit MERS-CoV 3CL^pro, the enzyme shown to exhibit a crucial role in viral replication. Additionally, F9 suppressed both MERS-CoV-induced histopathological alteration in lung tissue and resulting oxidative and inflammatory biomarkers. Collectively, the results reported herein affirmed the potential of PCMs as nanocarriers for the effective oral administration of MH as an antiviral. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Gregory Gregoriadis: Liposomes for the Delivery of Drugs and Vaccines)

► Show Figures

Graphical abstract

38 pages, 3693 KB

Open AccessEditor’s ChoiceReview

Redesigning of Cell-Penetrating Peptides to Improve Their Efficacy as a Drug Delivery System

by Ildikó Szabó, Mo’ath Yousef, Dóra Soltész, Csaba Bató, Gábor Mező and Zoltán Bánóczi

Pharmaceutics 2022, 14(5), 907; https://doi.org/10.3390/pharmaceutics14050907 - 21 Apr 2022

Cited by 52 | Viewed by 8435

Abstract

Cell-penetrating peptides (CPP) are promising tools for the transport of a broad range of compounds into cells. Since the discovery of the first members of this peptide family, many other peptides have been identified; nowadays, dozens of these peptides are known. These peptides [...] Read more.

Cell-penetrating peptides (CPP) are promising tools for the transport of a broad range of compounds into cells. Since the discovery of the first members of this peptide family, many other peptides have been identified; nowadays, dozens of these peptides are known. These peptides sometimes have very different chemical–physical properties, but they have similar drawbacks; e.g., non-specific internalization, fast elimination from the body, intracellular/vesicular entrapment. Although our knowledge regarding the mechanism and structure–activity relationship of internalization is growing, the prediction and design of the cell-penetrating properties are challenging. In this review, we focus on the different modifications of well-known CPPs to avoid their drawbacks, as well as how these modifications may increase their internalization and/or change the mechanism of penetration. Full article

(This article belongs to the Special Issue Drug Discovery and Drug Delivery System for Biological Application)

► Show Figures

Figure 1

16 pages, 2384 KB

Open AccessEditor’s ChoiceArticle

Polymeric Nanocapsules Containing Fennel Essential Oil: Their Preparation, Physicochemical Characterization, Stability over Time and in Simulated Gastrointestinal Conditions

by Giuseppe Granata, Carla Riccobene, Edoardo Napoli and Corrada Geraci

Pharmaceutics 2022, 14(4), 873; https://doi.org/10.3390/pharmaceutics14040873 - 16 Apr 2022

Cited by 23 | Viewed by 4671

Abstract

Plant essential oils, a source of biologically active compounds, represent a promising segment in the pharmaceutical market. However, their volatility, hydrophobicity, poor stability, and low toxicity limit direct use in pharmaceutical-related applications. Nanoencapsulation is a technique that allows overcoming these obstacles by improving [...] Read more.

Plant essential oils, a source of biologically active compounds, represent a promising segment in the pharmaceutical market. However, their volatility, hydrophobicity, poor stability, and low toxicity limit direct use in pharmaceutical-related applications. Nanoencapsulation is a technique that allows overcoming these obstacles by improving bioaccessibility and bioavailability. Nanocapsules (NCs) based on biodegradable and biocompatible poly(ɛ-caprolactone) containing Foeniculum vulgare Mill. essential oil (FEO), known for its biological activities, were successfully prepared by interfacial deposition of the preformed polymer method. The composition of FEO (trans-anethole chemotype) was determined by gas chromatography analyses. The FEO presence inside the NCs was confirmed by nuclear magnetic resonance experiments. The FEO-NCs showed nanometer size (210 nm), low polydispersity index (0.10), negative zeta potential (−15 mV), non-Newtonian rheological behavior, and high efficiency of encapsulation (93%). Moreover, parameters such as FEO-NC particle size, bioactive compound retention, and FEO composition were monitored for 30 days at storage temperatures of 4 and 40 °C, confirming the robustness of the nanosystem. Finally, FEO-NCs were resistant to the simulated gastric digestion and showed an effective bioaccessibility of 29% in simulated intestinal digestion. Based on the results obtained, this FEO-NC nanosystem could find interesting applications in the nutraceutical and pharmaceutical sectors. Full article

(This article belongs to the Special Issue Essential Oils in Pharmaceutical Products)

► Show Figures

Graphical abstract

17 pages, 6111 KB

Open AccessEditor’s ChoiceArticle

Assessment of the Extrusion Process and Printability of Suspension-Type Drug-Loaded Affinisol^TM Filaments for 3D Printing

by Gloria Mora-Castaño, Mónica Millán-Jiménez, Vicente Linares and Isidoro Caraballo

Pharmaceutics 2022, 14(4), 871; https://doi.org/10.3390/pharmaceutics14040871 - 15 Apr 2022

Cited by 26 | Viewed by 4517

Abstract

Three-dimensional (3D) printing technology enables the design of new drug delivery systems for personalised medicine. Polymers that can be molten are needed to obtain extruded filaments for Fused Deposition Modelling (FDM), one of the most frequently employed techniques for 3D printing. The aim [...] Read more.

Three-dimensional (3D) printing technology enables the design of new drug delivery systems for personalised medicine. Polymers that can be molten are needed to obtain extruded filaments for Fused Deposition Modelling (FDM), one of the most frequently employed techniques for 3D printing. The aim of this work was to evaluate the extrusion process and the physical appearance of filaments made of a hydrophilic polymer and a non-molten model drug. Metformin was used as model drug and Affinisol™ 15LV as the main carrier. Drug-loaded filaments were obtained by using a single-screw extruder and, subsequently, their printability was tested. Blends containing up to a 60% and 50% drug load with 5% and 7.5% of auxiliary excipients, respectively, were successfully extruded. Between the obtained filaments, those containing up to 50% of the drug were suitable for use in FDM 3D printing. The studied parameters, including residence time, flow speed, brittleness, and fractal dimension, reflect a critical point in the extrusion process at between 30–40% drug load. This finding could be essential for understanding the behaviour of filaments containing a non-molten component. Full article

(This article belongs to the Special Issue Additive Manufacturing Approaches to Produce Drug Delivery Systems)

► Show Figures

Figure 1

23 pages, 4536 KB

Open AccessEditor’s ChoiceArticle

Puzzle out Machine Learning Model-Explaining Disintegration Process in ODTs

by Jakub Szlęk, Mohammad Hassan Khalid, Adam Pacławski, Natalia Czub and Aleksander Mendyk

Pharmaceutics 2022, 14(4), 859; https://doi.org/10.3390/pharmaceutics14040859 - 13 Apr 2022

Cited by 19 | Viewed by 4533

Abstract

Tablets are the most common dosage form of pharmaceutical products. While tablets represent the majority of marketed pharmaceutical products, there remain a significant number of patients who find it difficult to swallow conventional tablets. Such difficulties lead to reduced patient compliance. Orally disintegrating [...] Read more.

Tablets are the most common dosage form of pharmaceutical products. While tablets represent the majority of marketed pharmaceutical products, there remain a significant number of patients who find it difficult to swallow conventional tablets. Such difficulties lead to reduced patient compliance. Orally disintegrating tablets (ODT), sometimes called oral dispersible tablets, are the dosage form of choice for patients with swallowing difficulties. ODTs are defined as a solid dosage form for rapid disintegration prior to swallowing. The disintegration time, therefore, is one of the most important and optimizable critical quality attributes (CQAs) for ODTs. Current strategies to optimize ODT disintegration times are based on a conventional trial-and-error method whereby a small number of samples are used as proxies for the compliance of whole batches. We present an alternative machine learning approach to optimize the disintegration time based on a wide variety of machine learning (ML) models through the H2O AutoML platform. ML models are presented with inputs from a database originally presented by Han et al., which was enhanced and curated to include chemical descriptors representing active pharmaceutical ingredient (API) characteristics. A deep learning model with a 10-fold cross-validation NRMSE of 8.1% and an R² of 0.84 was obtained. The critical parameters influencing the disintegration of the directly compressed ODTs were ascertained using the SHAP method to explain ML model predictions. A reusable, open-source tool, the ODT calculator, is now available at Heroku platform. Full article

(This article belongs to the Special Issue Computational Intelligence (CI) Tools in Drug Discovery and Design)

► Show Figures

Graphical abstract

13 pages, 1049 KB

Open AccessEditor’s ChoiceArticle

Pharmacokinetics of Tildipirosin in Plasma, Milk, and Somatic Cells Following Intravenous, Intramuscular, and Subcutaneous Administration in Dairy Goats

by Juan Sebastián Galecio, Pedro Marín, Verónica Hernandis, María Botía and Elisa Escudero

Pharmaceutics 2022, 14(4), 860; https://doi.org/10.3390/pharmaceutics14040860 - 13 Apr 2022

Cited by 6 | Viewed by 2755

Abstract

Tildipirosin is a macrolide currently authorized for treating respiratory diseases in cattle and swine. The disposition kinetics of tildipirosin in plasma, milk, and somatic cells were investigated in dairy goats. Tildipirosin was administered at a single dose of 2 mg/kg by intravenous (IV) [...] Read more.

Tildipirosin is a macrolide currently authorized for treating respiratory diseases in cattle and swine. The disposition kinetics of tildipirosin in plasma, milk, and somatic cells were investigated in dairy goats. Tildipirosin was administered at a single dose of 2 mg/kg by intravenous (IV) and 4 mg/kg by intramuscular (IM) and subcutaneous (SC) routes. Concentrations of tildipirosin were determined by an HPLC method with UV detection. Pharmacokinetic parameters were estimated by non-compartmental analysis. Muscle damage, cardiotoxicity, and inflammation were evaluated. After IV administration, the apparent volume of distribution in the steady state was 7.2 L/kg and clearance 0.64 L/h/kg. Plasma and milk half-lives were 6.2 and 58.3 h, respectively, indicating nine times longer persistence of tildipirosin in milk than in plasma. Moreover, if somatic cells are considered, persistence and exposure measured by the area under concentration–time curve (AUC) significantly exceeded those obtained in plasma. Similarly, longer half-lives in whole milk and somatic cells compared to plasma were observed after IM and SC administration. No adverse effects were observed. In brief, tildipirosin should be reserved for cases where other suitable antibiotics have been unsuccessful, discarding milk production of treated animals for at least 45 days or treating goats at the dry-off period. Full article

(This article belongs to the Special Issue Specific Drug Disposition in Veterinary Medicine)

► Show Figures

Figure 1

22 pages, 5678 KB

Open AccessEditor’s ChoiceArticle

Cu-Doped Hollow Bioactive Glass Nanoparticles for Bone Infection Treatment

by Javier Jiménez-Holguín, Sandra Sánchez-Salcedo, Mónica Cicuéndez, María Vallet-Regí and Antonio J. Salinas

Pharmaceutics 2022, 14(4), 845; https://doi.org/10.3390/pharmaceutics14040845 - 12 Apr 2022

Cited by 21 | Viewed by 3866

Abstract

In search of new approaches to treat bone infection and prevent drug resistance development, a nanosystem based on hollow bioactive glass nanoparticles (HBGN) of composition 79.5SiO₂-(18-x)CaO-2.5P₂O₅-xCuO (x = 0, 2.5 or 5 mol-% CuO) was developed. The [...] Read more.

In search of new approaches to treat bone infection and prevent drug resistance development, a nanosystem based on hollow bioactive glass nanoparticles (HBGN) of composition 79.5SiO₂-(18-x)CaO-2.5P₂O₅-xCuO (x = 0, 2.5 or 5 mol-% CuO) was developed. The objective of the study was to evaluate the capacity of the HBGN to be used as a nanocarrier of the broad-spectrum antibiotic danofloxacin and source of bactericidal Cu²⁺ ions. Core-shell nanoparticles with specific surface areas close to 800 m²/g and pore volumes around 1 cm³/g were obtained by using hexadecyltrimethylammonium bromide (CTAB) and poly(styrene)-block-poly(acrylic acid) (PS-b-PAA) as structure-directing agents. Flow cytometry studies showed the cytocompatibility of the nanoparticles in MC3T3-E1 pre-osteoblastic cell cultures. Ion release studies confirmed the release of non-cytotoxic concentrations of Cu²⁺ ions within the therapeutic range. Moreover, it was shown that the inclusion of copper in the system resulted in a more gradual release of danofloxacin that was extended over one week. The bactericidal activity of the nanosystem was evaluated with E. coli and S. aureus strains. Nanoparticles with copper were not able to reduce bacterial viability by themselves and Cu-free HBGN failed to reduce bacterial growth, despite releasing higher antibiotic concentrations. However, HBGN enriched with copper and danofloxacin drastically reduced bacterial growth in sessile, planktonic and biofilm states, which was attributed to a synergistic effect between the action of Cu²⁺ ions and danofloxacin. Therefore, the nanosystem here investigated is a promising candidate as an alternative for the local treatment of bone infections. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

► Show Figures

Graphical abstract

38 pages, 9775 KB

Open AccessEditor’s ChoiceReview

Significance of Polymers with “Allyl” Functionality in Biomedicine: An Emerging Class of Functional Polymers

by Mijanur Rahman, Aliaa Ali, Erica Sjöholm, Sebastian Soindinsalo, Carl-Eric Wilén, Kuldeep Kumar Bansal and Jessica M. Rosenholm

Pharmaceutics 2022, 14(4), 798; https://doi.org/10.3390/pharmaceutics14040798 - 6 Apr 2022

Cited by 9 | Viewed by 6232

Abstract

In recent years, polymer-based advanced drug delivery and tissue engineering have grown and expanded steadily. At present, most of the polymeric research has focused on improving existing polymers or developing new biomaterials with tunable properties. Polymers with free functional groups offer the diverse [...] Read more.

In recent years, polymer-based advanced drug delivery and tissue engineering have grown and expanded steadily. At present, most of the polymeric research has focused on improving existing polymers or developing new biomaterials with tunable properties. Polymers with free functional groups offer the diverse characteristics needed for optimal tissue regeneration and controlled drug delivery. Allyl-terminated polymers, characterized by the presence of a double bond, are a unique class of polymers. These polymers allow the insertion of a broad diversity of architectures and functionalities via different chemical reactions. In this review article, we shed light on various synthesis methodologies utilized for generating allyl-terminated polymers, macromonomers, and polymer precursors, as well as their post-synthesis modifications. In addition, the biomedical applications of these polymers reported in the literature, such as targeted and controlled drug delivery, improvement i aqueous solubility and stability of drugs, tissue engineering, and antimicrobial coatings, are summarized. Full article

(This article belongs to the Collection Feature Papers in Pharmaceutical Technology)

► Show Figures

Figure 1

29 pages, 2054 KB

Open AccessEditor’s ChoiceReview

Application of Nanomaterials in the Prevention, Detection, and Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA)

by John Hulme

Pharmaceutics 2022, 14(4), 805; https://doi.org/10.3390/pharmaceutics14040805 - 6 Apr 2022

Cited by 29 | Viewed by 6139

Abstract

Due to differences in geographic surveillance systems, chemical sanitization practices, and antibiotic stewardship (AS) implementation employed during the COVID-19 pandemic, many experts have expressed concerns regarding a future surge in global antimicrobial resistance (AMR). A potential beneficiary of these differences is the Gram-positive [...] Read more.

Due to differences in geographic surveillance systems, chemical sanitization practices, and antibiotic stewardship (AS) implementation employed during the COVID-19 pandemic, many experts have expressed concerns regarding a future surge in global antimicrobial resistance (AMR). A potential beneficiary of these differences is the Gram-positive bacteria MRSA. MRSA is a bacterial pathogen with a high potential for mutational resistance, allowing it to engage various AMR mechanisms circumventing conventional antibiotic therapies and the host’s immune response. Coupled with a lack of novel FDA-approved antibiotics reaching the clinic, the onus is on researchers to develop alternative treatment tools to mitigate against an increase in pathogenic resistance. Mitigation strategies can take the form of synthetic or biomimetic nanomaterials/vesicles employed in vaccines, rapid diagnostics, antibiotic delivery, and nanotherapeutics. This review seeks to discuss the current potential of the aforementioned nanomaterials in detecting and treating MRSA. Full article

(This article belongs to the Special Issue Nanotechnology Applied in Prevention, Diagnosis and Treatment of Infectious Diseases)

► Show Figures

Figure 1

19 pages, 2868 KB

Open AccessEditor’s ChoiceArticle

Thiolated Chitosan Conjugated Liposomes for Oral Delivery of Selenium Nanoparticles

by Atiđa Selmani, Elisabeth Seibert, Carolin Tetyczka, Doris Kuehnelt, Ivan Vidakovic, Karin Kornmueller, Markus Absenger-Novak, Borna Radatović, Ivana Vinković Vrček, Gerd Leitinger, Eleonore Fröhlich, Andreas Bernkop-Schnürch, Eva Roblegg and Ruth Prassl

Pharmaceutics 2022, 14(4), 803; https://doi.org/10.3390/pharmaceutics14040803 - 6 Apr 2022

Cited by 14 | Viewed by 4317

Abstract

This study aimed to design a hybrid oral liposomal delivery system for selenium nanoparticles (Lip-SeNPs) to improve the bioavailability of selenium. Thiolated chitosan, a multifunctional polymer with mucoadhesive properties, was used for surface functionalization of Lip-SeNPs. Selenium nanoparticle (SeNP)-loaded liposomes were manufactured by [...] Read more.

This study aimed to design a hybrid oral liposomal delivery system for selenium nanoparticles (Lip-SeNPs) to improve the bioavailability of selenium. Thiolated chitosan, a multifunctional polymer with mucoadhesive properties, was used for surface functionalization of Lip-SeNPs. Selenium nanoparticle (SeNP)-loaded liposomes were manufactured by a single step microfluidics-assisted chemical reduction and assembling process. Subsequently, chitosan-N-acetylcysteine was covalently conjugated to the preformed Lip-SeNPs. The Lip-SeNPs were characterized in terms of composition, morphology, size, zeta potential, lipid organization, loading efficiency and radical scavenging activity. A co-culture system (Caco-2:HT29-MTX) that integrates mucus secreting and enterocyte-like cell types was used as a model of the human intestinal epithelium to determine adsorption, mucus penetration, release and transport properties of Lip-SeNPs in vitro. Thiolated Lip-SeNPs were positively charged with an average size of about 250 nm. Thiolated Lip-SeNPs tightly adhered to the mucus layer without penetrating the enterocytes. This finding was consistent with ex vivo adsorption studies using freshly excised porcine small intestinal tissues. Due to the improved mucoadhesion and retention in a simulated microenvironment of the small intestine, thiolated Lip-SeNPs might be a promising tool for oral selenium delivery. Full article

(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)

► Show Figures

Graphical abstract

22 pages, 17488 KB

Open AccessEditor’s ChoiceReview

Advantageous Reactivity of Unstable Metal Complexes: Potential Applications of Metal-Based Anticancer Drugs for Intratumoral Injections

by Aviva Levina, Debbie C. Crans and Peter A. Lay

Pharmaceutics 2022, 14(4), 790; https://doi.org/10.3390/pharmaceutics14040790 - 4 Apr 2022

Cited by 31 | Viewed by 4344

Abstract

Injections of highly cytotoxic or immunomodulating drugs directly into the inoperable tumor is a procedure that is increasingly applied in the clinic and uses established Pt-based drugs. It is advantageous for less stable anticancer metal complexes that fail administration by the standard intravenous [...] Read more.

Injections of highly cytotoxic or immunomodulating drugs directly into the inoperable tumor is a procedure that is increasingly applied in the clinic and uses established Pt-based drugs. It is advantageous for less stable anticancer metal complexes that fail administration by the standard intravenous route. Such hydrophobic metal-containing complexes are rapidly taken up into cancer cells and cause cell death, while the release of their relatively non-toxic decomposition products into the blood has low systemic toxicity and, in some cases, may even be beneficial. This concept was recently proposed for V(V) complexes with hydrophobic organic ligands, but it can potentially be applied to other metal complexes, such as Ti(IV), Ga(III) and Ru(III) complexes, some of which were previously unsuccessful in human clinical trials when administered via intravenous injections. The potential beneficial effects include antidiabetic, neuroprotective and tissue-regenerating activities for V(V/IV); antimicrobial activities for Ga(III); and antimetastatic and potentially immunogenic activities for Ru(III). Utilizing organic ligands with limited stability under biological conditions, such as Schiff bases, further enhances the tuning of the reactivities of the metal complexes under the conditions of intratumoral injections. However, nanocarrier formulations are likely to be required for the delivery of unstable metal complexes into the tumor. Full article

(This article belongs to the Special Issue Multifunctional Bioinorganic Metal Ions in Pharmaceutical Applications)

► Show Figures

Figure 1

21 pages, 2820 KB

Open AccessEditor’s ChoiceArticle

Cyclooxygenase-Inhibiting Platinum(IV) Prodrugs with Potent Anticancer Activity

by Aleen Khoury, Jennette A. Sakoff, Jayne Gilbert, Kieran F. Scott, Shawan Karan, Christopher P. Gordon and Janice R. Aldrich-Wright

Pharmaceutics 2022, 14(4), 787; https://doi.org/10.3390/pharmaceutics14040787 - 3 Apr 2022

Cited by 23 | Viewed by 3909

Abstract

Platinum(IV) prodrugs of the [Pt(P_L)(A_L)(COXi)(OH)]²⁺ type scaffold (where P_L is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A_L is 1S,2S-diaminocyclohexane, and COXi is a COX inhibitor, either indomethacin or aspirin) were synthesised and characterised, and their [...] Read more.

Platinum(IV) prodrugs of the [Pt(P_L)(A_L)(COXi)(OH)]²⁺ type scaffold (where P_L is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A_L is 1S,2S-diaminocyclohexane, and COXi is a COX inhibitor, either indomethacin or aspirin) were synthesised and characterised, and their biological activity was explored. MTT assays showed that these complexes exhibit outstanding activity against a range of cancer cell lines, and nanomolar activities were observed. The most potent complex, 4, exhibited a GI₅₀ of 3 nM in the Du145 prostate cancer cell line and was observed to display a 1614-fold increased activity against the HT29 colon cancer cell line relative to cisplatin. ICP-MS studies showed a linear correlation between increased cellular accumulation of the complexes and increased cytotoxicity, while an enzyme immunoassay showed that 1 and 2 inhibited COX-2 at 14 and 1.4 µM, respectively, which is comparable to the inhibition exhibited by indomethacin. These results suggest that while the cytotoxicity of prodrugs 1–4 was influenced by cellular uptake, it was not entirely dependent on either COX inhibition or lipophilicity. Full article

(This article belongs to the Special Issue Multifunctional Bioinorganic Metal Ions in Pharmaceutical Applications)

► Show Figures

Graphical abstract

22 pages, 7385 KB

Open AccessEditor’s ChoiceArticle

Bio-Hybrid Hydrogels Incorporated into a System of Salicylic Acid-pH/Thermosensitive Nanocarriers Intended for Cutaneous Wound-Healing Processes

by Katarzyna Bialik-Wąs, Małgorzata Miastkowska, Paulina Sapuła, Klaudia Pluta, Dagmara Malina, Jarosław Chwastowski and Mateusz Barczewski

Pharmaceutics 2022, 14(4), 773; https://doi.org/10.3390/pharmaceutics14040773 - 1 Apr 2022

Cited by 14 | Viewed by 3801

Abstract

In this paper, the preparation method of bio-hybrid hydrogels incorporated into a system of salicylic acid-pH/thermosensitive nanocarriers to speed up the wound-healing process was developed. This combination creates a dual drug delivery system, which releases the model hydrophobic active substance—salicylic acid—in a gradual [...] Read more.

In this paper, the preparation method of bio-hybrid hydrogels incorporated into a system of salicylic acid-pH/thermosensitive nanocarriers to speed up the wound-healing process was developed. This combination creates a dual drug delivery system, which releases the model hydrophobic active substance—salicylic acid—in a gradual and controlled manner for an extended time. Our research team has determined the various properties of bio-hybrid hydrogels based on their physicochemical (swelling degree, and degradation), structural (FT-IR), morphological (SEM), and mechanical (elongation tests) traits. Moreover, empty pH/thermosensitive nanocarriers and their salicylic acid-containing systems were characterized using the following methods: DLS, TG/DTG, and DSC. Additionally, salicylic acid release profiles directly from thermosensitive nanocarriers were compared to the bio-hybrid matrix. These studies were conducted in PBS (pH = 7.4) for 7 days using the USP4 method. To evaluate the antibacterial properties of the obtained materials, the inhibition of growth of Staphylococcus aureus, Escherichia coli, Candida albicans, and Aspergillus niger—as the main microorganisms responsible for human infections—were tested. The obtained results indicated that the pH/thermosensitive nanocarrier–salicylic acid system and bio-hybrid hydrogels are characterized by antibacterial activity against both S. aureus and E. coli. Full article

(This article belongs to the Special Issue Advanced Bio-Hybrid Materials for Drug Delivery Systems - New Trends and Perspectives)

► Show Figures

Figure 1

17 pages, 3539 KB

Open AccessEditor’s ChoiceArticle

Toxicokinetics of β-Amanitin in Mice and In Vitro Drug–Drug Interaction Potential

by Young Yoon Bang, Im-Sook Song, Min Seo Lee, Chang Ho Lim, Yong-Yeon Cho, Joo Young Lee, Han Chang Kang and Hye Suk Lee

Pharmaceutics 2022, 14(4), 774; https://doi.org/10.3390/pharmaceutics14040774 - 1 Apr 2022

Cited by 16 | Viewed by 3794

Abstract

The toxicokinetics of β-amanitin, a toxic bicyclic octapeptide present abundantly in Amanitaceae mushrooms, was evaluated in mice after intravenous (iv) and oral administration. The area under plasma concentration curves (AUC) following iv injection increased in proportion to doses of 0.2, 0.4, and 0.8 [...] Read more.

The toxicokinetics of β-amanitin, a toxic bicyclic octapeptide present abundantly in Amanitaceae mushrooms, was evaluated in mice after intravenous (iv) and oral administration. The area under plasma concentration curves (AUC) following iv injection increased in proportion to doses of 0.2, 0.4, and 0.8 mg/kg. β-amanitin disappeared rapidly from plasma with a half-life of 18.3–33.6 min, and 52.3% of the iv dose was recovered as a parent form. After oral administration, the AUC again increased in proportion with doses of 2, 5, and 10 mg/kg. Absolute bioavailability was 7.3–9.4%, which resulted in 72.4% of fecal recovery from orally administered β-amanitin. Tissue-to-plasma AUC ratios of orally administered β-amanitin were the highest in the intestine and stomach. It also readily distributed to kidney > spleen > lung > liver ≈ heart. Distribution to intestines, kidneys, and the liver is in agreement with previously reported target organs after acute amatoxin poisoning. In addition, β-amanitin weakly or negligibly inhibited major cytochrome P450 and 5′-diphospho-glucuronosyltransferase activities in human liver microsomes and suppressed drug transport functions in mammalian cells that overexpress transporters, suggesting the remote drug interaction potentials caused by β-amanitin exposure. Full article

(This article belongs to the Special Issue Pharmacokinetic Properties in Drug Development)

► Show Figures

Figure 1

40 pages, 4988 KB

Open AccessEditor’s ChoiceReview

Inorganic Nanoparticles in Bone Healing Applications

by Alexandra-Cristina Burdușel, Oana Gherasim, Ecaterina Andronescu, Alexandru Mihai Grumezescu and Anton Ficai

Pharmaceutics 2022, 14(4), 770; https://doi.org/10.3390/pharmaceutics14040770 - 31 Mar 2022

Cited by 44 | Viewed by 6675

Abstract

Modern biomedicine aims to develop integrated solutions that use medical, biotechnological, materials science, and engineering concepts to create functional alternatives for the specific, selective, and accurate management of medical conditions. In the particular case of tissue engineering, designing a model that simulates all [...] Read more.

Modern biomedicine aims to develop integrated solutions that use medical, biotechnological, materials science, and engineering concepts to create functional alternatives for the specific, selective, and accurate management of medical conditions. In the particular case of tissue engineering, designing a model that simulates all tissue qualities and fulfills all tissue requirements is a continuous challenge in the field of bone regeneration. The therapeutic protocols used for bone healing applications are limited by the hierarchical nature and extensive vascularization of osseous tissue, especially in large bone lesions. In this regard, nanotechnology paves the way for a new era in bone treatment, repair and regeneration, by enabling the fabrication of complex nanostructures that are similar to those found in the natural bone and which exhibit multifunctional bioactivity. This review aims to lay out the tremendous outcomes of using inorganic nanoparticles in bone healing applications, including bone repair and regeneration, and modern therapeutic strategies for bone-related pathologies. Full article

(This article belongs to the Special Issue Pharmaceutics beyond Liposomes: Versatile Carriers and Templates from Bioceramic and Mineral Materials for Drug Delivery and Tissue Engineering)

► Show Figures

Figure 1

22 pages, 6156 KB

Open AccessEditor’s ChoiceArticle

Polymeric Microneedles for Transdermal Delivery of Rivastigmine: Design and Application in Skin Mimetic Model

by Tânia M. T. Guimarães, Tânia Moniz, Cláudia Nunes, Maya Margaritova Zaharieva, Mila Kaleva, Krassimira Yoncheva, Hristo Najdenski, Sofia A. Costa Lima and Salette Reis

Pharmaceutics 2022, 14(4), 752; https://doi.org/10.3390/pharmaceutics14040752 - 30 Mar 2022

Cited by 19 | Viewed by 4230

Abstract

In the last years, microneedles (MNs) have been considered a valuable, painless, and minimally invasive approach for controlled transdermal drug delivery (TDD). Rivastigmine (RV), a drug administered to patients suffering from dementia, is currently delivered by oral or transdermal routes; however, both present [...] Read more.

In the last years, microneedles (MNs) have been considered a valuable, painless, and minimally invasive approach for controlled transdermal drug delivery (TDD). Rivastigmine (RV), a drug administered to patients suffering from dementia, is currently delivered by oral or transdermal routes; however, both present limitations, mainly gastrointestinal adverse symptoms or local skin irritation and drug losses, respectively, for each route. Given this, the objective of the present work was to develop and evaluate the potential of polymeric MNs for RV transdermal delivery in a controlled manner. Polymeric MNs with two needle heights and different compositions were developed with calcein as a fluorescent model molecule. Morphology and mechanical characterisation were accessed. Skin permeation experiments showed the ability of the devices to deliver calcein and confirmed that the arrays were able to efficiently pierce the skin. To obtain a new TDD anti-dementia therapeutic solution, RV was loaded in 800 µm polymeric MNs of alginate and alginate/k-carrageenan MNs. In the presence of RV, the MN’s morphology was maintained; however, the presence of RV influenced the compression force. Skin permeation studies revealed that RV-loaded MNs allowed a more efficient controlled release of the drug than the commercial patch. In vivo, skin irritation tests in rabbits revealed that the developed MNs were innocuous upon removal, in contrast with the evidence found for Exelon^®, the commercial patch, which caused slight mechanical damage to the skin. The herein-produced MNs demonstrated a more controlled release of the drug, being the more suitable option for the transdermal delivery of RV. Full article

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

► Show Figures

Graphical abstract

15 pages, 1137 KB

Open AccessEditor’s ChoiceArticle

Modernising Orodispersible Film Characterisation to Improve Palatability and Acceptability Using a Toolbox of Techniques

by Neel Desai, Marc Masen, Philippa Cann, Ben Hanson, Catherine Tuleu and Mine Orlu

Pharmaceutics 2022, 14(4), 732; https://doi.org/10.3390/pharmaceutics14040732 - 29 Mar 2022

Cited by 12 | Viewed by 4088

Abstract

Orodispersible films (ODFs) have been widely used in paediatric, geriatric and dysphagic patients due to ease of administration and precise and flexible dose adjustments. ODF fabrication has seen significant advancements with the move towards more technologically advanced production methods. The acceptability of ODFs [...] Read more.

Orodispersible films (ODFs) have been widely used in paediatric, geriatric and dysphagic patients due to ease of administration and precise and flexible dose adjustments. ODF fabrication has seen significant advancements with the move towards more technologically advanced production methods. The acceptability of ODFs is dependent upon film composition and process of formation, which affects disintegration, taste, texture and mouthfeel. There is currently a lack of testing to accurately assess ODFs for these important acceptability sensory perceptions. This study produced four ODFs formed of polyvinyl alcohol and sodium carboxymethylcellulose using 3D printing. These were assessed using three in vitro methods: Petri dish and oral cavity model (OCM) methods for disintegration and bio-tribology for disintegration and oral perception. Increasing polymer molecular weight (MW) exponentially increased disintegration time in the Petri dish and OCM methods. Higher MW films adhered to the OCM upper palate. Bio-tribology analysis showed that films of higher MW disintegrated quickest and had lower coefficient of friction, perhaps demonstrating good oral perception but also stickiness, with higher viscosity. These techniques, part of a toolbox, may enable formulators to design, test and reformulate ODFs that both disintegrate rapidly and may be better perceived when consumed, improving overall treatment acceptability. Full article

(This article belongs to the Special Issue ODX Formulations for Drug Delivery and Other Approaches to Overcome Swallowing Problems)

► Show Figures

Figure 1

30 pages, 1341 KB

Open AccessEditor’s ChoiceReview

Mesenchymal Stem Cell-Derived Extracellular Vesicles as Non-Coding RNA Therapeutic Vehicles in Autoimmune Diseases

by Olga Martinez-Arroyo, Ana Ortega, Maria J. Forner and Raquel Cortes

Pharmaceutics 2022, 14(4), 733; https://doi.org/10.3390/pharmaceutics14040733 - 29 Mar 2022

Cited by 20 | Viewed by 6757

Abstract

Autoimmune diseases (ADs) are characterized by the activation of the immune system against self-antigens. More common in women than in men and with an early onset, their incidence is increasing worldwide, and this, combined with their chronic nature, is contributing to an enlarged [...] Read more.

Autoimmune diseases (ADs) are characterized by the activation of the immune system against self-antigens. More common in women than in men and with an early onset, their incidence is increasing worldwide, and this, combined with their chronic nature, is contributing to an enlarged medical and economic burden. Conventional immunosuppressive agents are designed to alleviate symptoms but do not constitute an effective therapy, highlighting a need to develop new alternatives. In this regard, mesenchymal stem cells (MSCs) have demonstrated powerful immunosuppressive and regenerative effects. MSC-derived extracellular vesicles (MSC-EVs) have shown some advantages, such as less immunogenicity, and are proposed as novel therapies for ADs. In this review, we summarize current perspectives on therapeutic options for ADs based on MSCs and MSC-EVs, focusing particularly on their mechanism of action exerted through their non-coding RNA (ncRNA) cargo. A complete state-of-the-art review was performed, centralized on some of the most severe ADs (rheumatoid arthritis, autoimmune type 1 diabetes mellitus, and systemic lupus erythematosus), giving evidence that a promising field is evolving to overcome the current knowledge and provide new therapeutic possibilities centered on MSC-EVs and their role as ncRNA delivery vehicles for AD gene therapy. Full article

(This article belongs to the Special Issue Extracellular Vesicles as Non-coding RNA Delivery Systems in Inflammatory and Immunological Diseases)

► Show Figures

Figure 1

28 pages, 13308 KB

Open AccessEditor’s ChoiceReview

Emerging Albumin-Binding Anticancer Drugs for Tumor-Targeted Drug Delivery: Current Understandings and Clinical Translation

by Hanhee Cho, Seong Ik Jeon, Cheol-Hee Ahn, Man Kyu Shim and Kwangmeyung Kim

Pharmaceutics 2022, 14(4), 728; https://doi.org/10.3390/pharmaceutics14040728 - 28 Mar 2022

Cited by 96 | Viewed by 12054

Abstract

Albumin has shown remarkable promise as a natural drug carrier by improving pharmacokinetic (PK) profiles of anticancer drugs for tumor-targeted delivery. The exogenous or endogenous albumin enhances the circulatory half-lives of anticancer drugs and passively target the tumors by the enhanced permeability and [...] Read more.

Albumin has shown remarkable promise as a natural drug carrier by improving pharmacokinetic (PK) profiles of anticancer drugs for tumor-targeted delivery. The exogenous or endogenous albumin enhances the circulatory half-lives of anticancer drugs and passively target the tumors by the enhanced permeability and retention (EPR) effect. Thus, the albumin-based drug delivery leads to a potent antitumor efficacy in various preclinical models, and several candidates have been evaluated clinically. The most successful example is Abraxane, an exogenous human serum albumin (HSA)-bound paclitaxel formulation approved by the FDA and used to treat locally advanced or metastatic tumors. However, additional clinical translation of exogenous albumin formulations has not been approved to date because of their unexpectedly low delivery efficiency, which can increase the risk of systemic toxicity. To overcome these limitations, several prodrugs binding endogenous albumin covalently have been investigated owing to distinct advantages for a safe and more effective drug delivery. In this review, we give account of the different albumin-based drug delivery systems, from laboratory investigations to clinical applications, and their potential challenges, and the outlook for clinical translation is discussed. In addition, recent advances and progress of albumin-binding drugs to move more closely to the clinical settings are outlined. Full article

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

► Show Figures

Figure 1

27 pages, 2166 KB

Open AccessEditor’s ChoiceReview

An Overview of siRNA Delivery Strategies for Urological Cancers

by Nadia Halib, Nicola Pavan, Carlo Trombetta, Barbara Dapas, Rossella Farra, Bruna Scaggiante, Mario Grassi and Gabriele Grassi

Pharmaceutics 2022, 14(4), 718; https://doi.org/10.3390/pharmaceutics14040718 - 27 Mar 2022

Cited by 10 | Viewed by 4141

Abstract

The treatment of urological cancers has been significantly improved in recent years. However, for the advanced stages of these cancers and/or for those developing resistance, novel therapeutic options need to be developed. Among the innovative strategies, the use of small interfering RNA (siRNA) [...] Read more.

The treatment of urological cancers has been significantly improved in recent years. However, for the advanced stages of these cancers and/or for those developing resistance, novel therapeutic options need to be developed. Among the innovative strategies, the use of small interfering RNA (siRNA) seems to be of great therapeutic interest. siRNAs are double-stranded RNA molecules which can specifically target virtually any mRNA of pathological genes. For this reason, siRNAs have a great therapeutic potential for human diseases including urological cancers. However, the fragile nature of siRNAs in the biological environment imposes the development of appropriate delivery systems to protect them. Thus, ensuring siRNA reaches its deep tissue target while maintaining structural and functional integrity represents one of the major challenges. To reach this goal, siRNA-based therapies require the development of fine, tailor-made delivery systems. Polymeric nanoparticles, lipid nanoparticles, nanobubbles and magnetic nanoparticles are among nano-delivery systems studied recently to meet this demand. In this review, after an introduction about the main features of urological tumors, we describe siRNA characteristics together with representative delivery systems developed for urology applications; the examples reported are subdivided on the basis of the different delivery materials and on the different urological cancers. Full article

(This article belongs to the Special Issue Smart Polymeric Nanocarriers for Drug and Gene Delivery)

► Show Figures

Figure 1

17 pages, 4537 KB

Open AccessEditor’s ChoiceArticle

Injectable Hydrogel Based on Protein-Polyester Microporous Network as an Implantable Niche for Active Cell Recruitment

by V.H. Giang Phan, Mohanapriya Murugesan, Panchanathan Manivasagan, Thanh Loc Nguyen, Thuy-Hien Phan, Cuong Hung Luu, Duy-Khiet Ho, Yi Li, Jaeyun Kim, Doo Sung Lee and Thavasyappan Thambi

Pharmaceutics 2022, 14(4), 709; https://doi.org/10.3390/pharmaceutics14040709 - 26 Mar 2022

Cited by 19 | Viewed by 4498

Abstract

Despite the potential of hydrogel-based localized cancer therapies, their efficacy can be limited by cancer recurrence. Therefore, it is of great significance to develop a hydrogel system that can provoke robust and durable immune response in the human body. This study has developed [...] Read more.

Despite the potential of hydrogel-based localized cancer therapies, their efficacy can be limited by cancer recurrence. Therefore, it is of great significance to develop a hydrogel system that can provoke robust and durable immune response in the human body. This study has developed an injectable protein-polymer-based porous hydrogel network composed of lysozyme and poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide (PCLA) (Lys-PCLA) bioconjugate for the active recruitment dendritic cells (DCs). The Lys-PCLA bioconjugates are prepared using thiol-ene reaction between thiolated lysozyme (Lys-SH) and acrylated PCLA (PCLA-Ac). The free-flowing Lys-PCLA bioconjugate sols at low temperature transformed to immovable gel at the physiological condition and exhibited stability upon dilution with buffers. According to the in vitro toxicity test, the Lys-PCLA bioconjugate and PCLA copolymer were non-toxic to RAW 263.7 cells at higher concentrations (1000 µg/mL). In addition, subcutaneous administration of Lys-PCLA bioconjugate sols formed stable hydrogel depot instantly, which suggested the in situ gel forming ability of the bioconjugate. Moreover, the Lys-PCLA bioconjugate hydrogel depot formed at the interface between subcutaneous tissue and dermis layers allowed the active migration and recruitment of DCs. As suggested by these results, the in-situ forming injectable Lys-PCLA bioconjugate hydrogel depot may serve as an implantable immune niche for the recruitment and modification of DCs. Full article

(This article belongs to the Special Issue Hydrogels in Drug Delivery: Progress and Challenges)

► Show Figures

Figure 1

29 pages, 7583 KB

Open AccessEditor’s ChoiceReview

Liposome-Tethered Gold Nanoparticles Triggered by Pulsed NIR Light for Rapid Liposome Contents Release and Endosome Escape

by Anisha Veeren, Maria O. Ogunyankin, Jeong Eun Shin and Joseph A. Zasadzinski

Pharmaceutics 2022, 14(4), 701; https://doi.org/10.3390/pharmaceutics14040701 - 25 Mar 2022

Cited by 23 | Viewed by 4988

Abstract

Remote triggering of contents release with micron spatial and sub-second temporal resolution has been a long-time goal of medical and technical applications of liposomes. Liposomes can sequester a variety of bioactive water-soluble ions, ligands and enzymes, and oligonucleotides. The bilayer that separates the [...] Read more.

Remote triggering of contents release with micron spatial and sub-second temporal resolution has been a long-time goal of medical and technical applications of liposomes. Liposomes can sequester a variety of bioactive water-soluble ions, ligands and enzymes, and oligonucleotides. The bilayer that separates the liposome interior from the exterior solution provides a physical barrier to contents release and degradation. Tethering plasmon-resonant, hollow gold nanoshells to the liposomes, or growing gold nanoparticles directly on the liposome exterior, allows liposome contents to be released by nanosecond or shorter pulses of near-infrared light (NIR). Gold nanoshells or nanoparticles strongly adsorb NIR light; cells, tissues, and physiological media are transparent to NIR, allowing penetration depths of millimeters to centimeters. Nano to picosecond pulses of NIR light rapidly heat the gold nanoshells, inducing the formation of vapor nanobubbles, similar to cavitation bubbles. The collapse of the nanobubbles generates mechanical forces that rupture bilayer membranes to rapidly release liposome contents at the preferred location and time. Here, we review the syntheses, characterization, and applications of liposomes coupled to plasmon-resonant gold nanostructures for delivering a variety of biologically important contents in vitro and in vivo with sub-micron spatial control and sub-second temporal control. 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)

► Show Figures

Figure 1

39 pages, 1463 KB

Open AccessEditor’s ChoiceReview

Drug Nanocrystals: Focus on Brain Delivery from Therapeutic to Diagnostic Applications

by Elide Zingale, Angela Bonaccorso, Claudia Carbone, Teresa Musumeci and Rosario Pignatello

Pharmaceutics 2022, 14(4), 691; https://doi.org/10.3390/pharmaceutics14040691 - 23 Mar 2022

Cited by 33 | Viewed by 6742

Abstract

The development of new drugs is often hindered by low solubility in water, a problem common to nearly 90% of natural and/or synthetic molecules in the discovery pipeline. Nanocrystalline drug technology involves the reduction in the bulk particle size down to the nanosize [...] Read more.

The development of new drugs is often hindered by low solubility in water, a problem common to nearly 90% of natural and/or synthetic molecules in the discovery pipeline. Nanocrystalline drug technology involves the reduction in the bulk particle size down to the nanosize range, thus modifying its physico-chemical properties with beneficial effects on drug bioavailability. Nanocrystals (NCs) are carrier-free drug particles surrounded by a stabilizer and suspended in an aqueous medium. Due to high drug loading, NCs maintain a potent therapeutic concentration to produce desirable pharmacological action, particularly useful in the treatment of central nervous system (CNS) diseases. In addition to the therapeutic purpose, NC technology can be applied for diagnostic scope. This review aims to provide an overview of NC application by different administration routes, especially focusing on brain targeting, and with a particular attention to therapeutic and diagnostic fields. NC therapeutic applications are analyzed for the most common CNS pathologies (i.e., Parkinson’s disease, psychosis, Alzheimer’s disease, etc.). Recently, a growing interest has emerged from the use of colloidal fluorescent NCs for brain diagnostics. Therefore, the use of NCs in the imaging of brain vessels and tumor cells is also discussed. Finally, the clinical effectiveness of NCs is leading to an increasing number of FDA-approved products, among which the NCs approved for neurological disorders have increased. Full article

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

► Show Figures

Graphical abstract

16 pages, 1745 KB

Open AccessEditor’s ChoiceArticle

Interaction of Antifungal Drugs with CYP3A- and OATP1B-Mediated Venetoclax Elimination

by Eric D. Eisenmann, Dominique A. Garrison, Zahra Talebi, Yan Jin, Josie A. Silvaroli, Jin-Gyu Kim, Alex Sparreboom, Michael R. Savona, Alice S. Mims and Sharyn D. Baker

Pharmaceutics 2022, 14(4), 694; https://doi.org/10.3390/pharmaceutics14040694 - 23 Mar 2022

Cited by 16 | Viewed by 4811

Abstract

Venetoclax, a BCL-2 inhibitor used to treat certain hematological cancers, exhibits low oral bioavailability and high interpatient pharmacokinetic variability. Venetoclax is commonly administered with prophylactic antifungal drugs that may result in drug interactions, of which the underlying mechanisms remain poorly understood. We hypothesized [...] Read more.

Venetoclax, a BCL-2 inhibitor used to treat certain hematological cancers, exhibits low oral bioavailability and high interpatient pharmacokinetic variability. Venetoclax is commonly administered with prophylactic antifungal drugs that may result in drug interactions, of which the underlying mechanisms remain poorly understood. We hypothesized that antifungal drugs may increase venetoclax exposure through inhibition of both CYP3A-mediated metabolism and OATP1B-mediated transport. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms, or OATP1B2 that received venetoclax alone or in combination with ketoconazole or micafungin. In mice lacking all CYP3A isoforms, venetoclax AUC was increased by 1.8-fold, and pretreatment with the antifungal ketoconazole further increased venetoclax exposure by 1.6-fold, despite the absence of CYP3A. Ensuing experiments demonstrated that the deficiency of OATP1B-type transporters is also associated with increases in venetoclax exposure, and that many antifungal drugs, including micafungin, posaconazole, and isavuconazole, are inhibitors of this transport mechanism both in vitro and in vivo. These studies have identified OATP1B-mediated transport as a previously unrecognized contributor to the elimination of venetoclax that is sensitive to inhibition by various clinically-relevant antifungal drugs. Additional consideration is warranted when venetoclax is administered together with agents that inhibit both CYP3A-mediated metabolism and OATP1B-mediated transport. Full article

(This article belongs to the Special Issue Drug–Drug Interactions (Volume II))

► Show Figures

Graphical abstract

26 pages, 5448 KB

Open AccessEditor’s ChoiceArticle

Novel Methacrylate-Based Multilayer Nanofilms with Incorporated FePt-Based Nanoparticles and the Anticancer Drug 5-Fluorouracil for Skin Cancer Treatment

by Kristijan Skok, Tanja Zidarič, Kristjan Orthaber, Matevž Pristovnik, Nina Kostevšek, Kristina Žužek Rožman, Sašo Šturm, Lidija Gradišnik, Uroš Maver and Tina Maver

Pharmaceutics 2022, 14(4), 689; https://doi.org/10.3390/pharmaceutics14040689 - 22 Mar 2022

Cited by 16 | Viewed by 4118

Abstract

Despite medical advances, skin-associated disorders continue to pose a unique challenge to physicians worldwide. Skin cancer is one of the most common forms of cancer, with more than one million new cases reported each year. Currently, surgical excision is its primary treatment; however, [...] Read more.

Despite medical advances, skin-associated disorders continue to pose a unique challenge to physicians worldwide. Skin cancer is one of the most common forms of cancer, with more than one million new cases reported each year. Currently, surgical excision is its primary treatment; however, this can be impractical or even contradictory in certain situations. An interesting potential alternative could lie in topical treatment solutions. The goal of our study was to develop novel multilayer nanofilms consisting of a combination of polyhydroxyethyl methacrylate (PHEMA), polyhydroxypropyl methacrylate (PHPMA), sodium deoxycholate (NaDOC) with incorporated superparamagnetic iron–platinum nanoparticles (FePt NPs), and the potent anticancer drug (5-fluorouracil), for theranostic skin cancer treatment. All multilayer systems were prepared by spin-coating and characterised by atomic force microscopy, infrared spectroscopy, and contact angle measurement. The magnetic properties of the incorporated FePt NPs were evaluated using magnetisation measurement, while their size was determined using transmission electron microscopy (TEM). Drug release performance was tested in vitro, and formulation safety was evaluated on human-skin-derived fibroblasts. Finally, the efficacy for skin cancer treatment was tested on our own basal-cell carcinoma cell line. Full article

(This article belongs to the Special Issue Novel Strategies for Cancer Targeted Delivery)

► Show Figures

Figure 1

12 pages, 1831 KB

Open AccessEditor’s ChoiceArticle

Redox-Responsive Crosslinked Mixed Micelles for Controllable Release of Caffeic Acid Phenethyl Ester

by Katya Kamenova, Georgy Grancharov, Vasilena Kortenova and Petar D. Petrov

Pharmaceutics 2022, 14(3), 679; https://doi.org/10.3390/pharmaceutics14030679 - 20 Mar 2022

Cited by 9 | Viewed by 3511

Abstract

We report the elaboration of redox-responsive functional micellar nanocarriers designed for triggered release of caffeic acid phenethyl ester (CAPE) in cancer therapy. Three-layered micelles, comprising a poly(ε-caprolactone) (PCL) core, a middle poly(acrylic acid)/poly(ethylene oxide) (PAA/PEO) layer and a PEO outer corona, were prepared [...] Read more.

We report the elaboration of redox-responsive functional micellar nanocarriers designed for triggered release of caffeic acid phenethyl ester (CAPE) in cancer therapy. Three-layered micelles, comprising a poly(ε-caprolactone) (PCL) core, a middle poly(acrylic acid)/poly(ethylene oxide) (PAA/PEO) layer and a PEO outer corona, were prepared by co-assembly of PEO₁₁₃-b-PCL₃₅-b-PEO₁₁₃ and PAA₁₃-b-PCL₃₅-b-PAA₁₃ amphiphilic triblock copolymers in aqueous media. The preformed micelles were loaded with CAPE via hydrophobic interactions between the drug molecules and PCL core, and subsequently crosslinked by reaction of carboxyl groups from PAA and a disulfide crosslinking agent. The reaction of crosslinking took place in the middle layer of the nanocarriers without changing the encapsulation efficiency (EE~90%) of the system. The crosslinked polymeric micelles (CPMs) exhibited superior structural stability and did not release CAPE in phosphate buffer (pH 7.4). However, in weak acidic media and in the presence of 10 mM reducing agent (dithiothreitol, DTT), the payload was released at a high rate from CPMs due to the breakup of disulfide linkages. The physicochemical properties of the nanocarriers were investigated by dynamic and electrophoretic light scattering (DLS and ELS) and atomic force microscopy (AFM). The rapid release of CAPE under intracellular-like conditions and the lack of premature drug release in media resembling the blood stream (neutral pH) make the developed CPMs a promising candidate for controllable drug release in the microenvironment of tumors. Full article

(This article belongs to the Special Issue Advances of Colloidal Systems in Drug Delivery and Therapeutic Application)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI