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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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20 pages, 5663 KB  
Article
A Novel Poly(ε-Caprolactone)-Based Photo-Crosslinkable Liquid Copolymer as a Versatile Drug Delivery Platform
by Marcus Flowers, Nicole Mertens, Amanda Billups, Brenda M. Ogle and Chun Wang
Pharmaceutics 2024, 16(11), 1380; https://doi.org/10.3390/pharmaceutics16111380 - 27 Oct 2024
Viewed by 2378
Abstract
Background/Objectives: Hydrophobic semi-solid or liquid biodegradable polymers have shown unique advantages as injectable matrices for sustained release of a wide range of drugs. Here we report the design, synthesis, and characterization of a new low-melt liquid copolymer based on poly(ε-caprolactone) (PCL) and [...] Read more.
Background/Objectives: Hydrophobic semi-solid or liquid biodegradable polymers have shown unique advantages as injectable matrices for sustained release of a wide range of drugs. Here we report the design, synthesis, and characterization of a new low-melt liquid copolymer based on poly(ε-caprolactone) (PCL) and establish its utility as a versatile delivery platform. Methods: The copolymer, mPA20, consisting of short PCL blocks connected via acid-labile acetal linkages, was synthesized using a one-pot reaction and its properties were comprehensively characterized. Results: mPA20 is an amorphous, injectable liquid at physiological temperature and can undergo pH-sensitive hydrolytic degradation. mPA20 bearing methacrylate end groups can be photo-crosslinked into solid matrices with tunable mechanical properties. A hydrophobic fluorophore, Nile Red (NR), was solubilized in mPA20 without any solvent. Sustained release of NR into aqueous medium was achieved using mPA20, either as an injectable liquid depot or a photo-crosslinked solid matrix. Further, mPA20 self-emulsified in water to form nanodroplets, which were subsequently photo-crosslinked into nanogels. Both the nanodroplets and nanogels mediated efficient intracellular delivery of NR with no cytotoxicity. Conclusions: mPA20, a new photo-crosslinkable, hydrophobic liquid copolymer with pH-sensitive degradability, is highly adaptable as either an injectable or implantable depot or nanoscale carrier for the controlled release and intracellular delivery of poorly soluble drugs. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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31 pages, 3958 KB  
Review
Emerging Cationic Nanovaccines
by Ana Maria Carmona-Ribeiro and Yunys Pérez-Betancourt
Pharmaceutics 2024, 16(11), 1362; https://doi.org/10.3390/pharmaceutics16111362 - 25 Oct 2024
Cited by 5 | Viewed by 2692
Abstract
Cationic vaccines of nanometric sizes can directly perform the delivery of antigen(s) and immunomodulator(s) to dendritic cells in the lymph nodes. The positively charged nanovaccines are taken up by antigen-presenting cells (APCs) of the lymphatic system often originating the cellular immunological defense required [...] Read more.
Cationic vaccines of nanometric sizes can directly perform the delivery of antigen(s) and immunomodulator(s) to dendritic cells in the lymph nodes. The positively charged nanovaccines are taken up by antigen-presenting cells (APCs) of the lymphatic system often originating the cellular immunological defense required to fight intracellular microbial infections and the proliferation of cancers. Cationic molecules imparting the positive charges to nanovaccines exhibit a dose-dependent toxicity which needs to be systematically addressed. Against the coronavirus, mRNA cationic nanovaccines evolved rapidly. Nowadays cationic nanovaccines have been formulated against several infections with the advantage of cationic compounds granting protection of nucleic acids in vivo against biodegradation by nucleases. Up to the threshold concentration of cationic molecules for nanovaccine delivery, cationic nanovaccines perform well eliciting the desired Th 1 improved immune response in the absence of cytotoxicity. A second strategy in the literature involves dilution of cationic components in biocompatible polymeric matrixes. Polymeric nanoparticles incorporating cationic molecules at reduced concentrations for the cationic component often result in an absence of toxic effects. The progress in vaccinology against cancer involves in situ designs for cationic nanovaccines. The lysis of transformed cancer cells releases several tumoral antigens, which in the presence of cationic nanoadjuvants can be systemically presented for the prevention of metastatic cancer. In addition, these local cationic nanovaccines allow immunotherapeutic tumor treatment. Full article
(This article belongs to the Special Issue Applications of Nanomaterials in Immunotherapies)
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51 pages, 3047 KB  
Review
The Impact of COVID-19 on RNA Therapeutics: A Surge in Lipid Nanoparticles and Alternative Delivery Systems
by Nargish Parvin, Tapas K. Mandal and Sang-Woo Joo
Pharmaceutics 2024, 16(11), 1366; https://doi.org/10.3390/pharmaceutics16111366 - 25 Oct 2024
Cited by 11 | Viewed by 5333
Abstract
The COVID-19 pandemic has significantly accelerated progress in RNA-based therapeutics, particularly through the successful development and global rollout of mRNA vaccines. This review delves into the transformative impact of the pandemic on RNA therapeutics, with a strong focus on lipid nanoparticles (LNPs) as [...] Read more.
The COVID-19 pandemic has significantly accelerated progress in RNA-based therapeutics, particularly through the successful development and global rollout of mRNA vaccines. This review delves into the transformative impact of the pandemic on RNA therapeutics, with a strong focus on lipid nanoparticles (LNPs) as a pivotal delivery platform. LNPs have proven to be critical in enhancing the stability, bioavailability, and targeted delivery of mRNA, facilitating the unprecedented success of vaccines like those developed by Pfizer-BioNTech and Moderna. Beyond vaccines, LNP technology is being explored for broader therapeutic applications, including treatments for cancer, rare genetic disorders, and infectious diseases. This review also discusses emerging RNA delivery systems, such as polymeric nanoparticles and viral vectors, which offer alternative strategies to overcome existing challenges related to stability, immune responses, and tissue-specific targeting. Additionally, we examine the pandemic’s influence on regulatory processes, including the fast-tracked approvals for RNA therapies, and the surge in research funding that has spurred further innovation in the field. Public acceptance of RNA-based treatments has also grown, laying the groundwork for future developments in personalized medicine. By providing an in-depth analysis of these advancements, this review highlights the long-term impact of COVID-19 on the evolution of RNA therapeutics and the future of precision drug delivery technologies. Full article
(This article belongs to the Special Issue Advanced Materials Science and Technology in Drug Delivery)
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27 pages, 8072 KB  
Article
Preparation of Ibuprofen-Loaded Inhalable γCD-MOFs by Freeze-Drying Using the QbD Approach
by Anett Motzwickler-Németh, Petra Party, Péter Simon, Milena Sorrenti, Rita Ambrus and Ildikó Csóka
Pharmaceutics 2024, 16(11), 1361; https://doi.org/10.3390/pharmaceutics16111361 - 24 Oct 2024
Cited by 7 | Viewed by 1762
Abstract
Background/Objectives: Research on cyclodextrin-based metal-organic frameworks (CD-MOFs) is still in its infancy, but their potential for use in drug delivery—expressly in the lung—seems promising. We aimed to use the freeze-drying method to create a novel approach for preparing CD-MOFs. MOFs consisting of γ-cyclodextrin [...] Read more.
Background/Objectives: Research on cyclodextrin-based metal-organic frameworks (CD-MOFs) is still in its infancy, but their potential for use in drug delivery—expressly in the lung—seems promising. We aimed to use the freeze-drying method to create a novel approach for preparing CD-MOFs. MOFs consisting of γ-cyclodextrin (γCD) and potassium cations (K+) were employed to encapsulate the poorly water-soluble model drug Ibuprofen (IBU) for the treatment of cystic fibrosis (CF). Methods: Using the LeanQbD® software (v2022), we designed the experiments based on the Quality by Design (QbD) concept. According to QbD, we identified the three most critical factors, which were the molar ratio of the IBU to the γCD, incubation time, and the percentage of the organic solvent. light-, scanning electron microscope (SEM) and laser diffraction were utilized to observe the morphology and particle size of the samples. In addition, the products were characterized by Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (NMR). Results: Based on characterizations, we concluded that a γCD-MOF/IBU complex was also formed using the freeze-drying method. Using formulations with optimal aerodynamic properties, we achieved 38.10 ± 5.06 and 47.18 ± 4.18 Fine Particle Fraction% (FPF%) based on the Andersen Cascade Impactor measurement. With these formulations, we achieved a fast dissolution profile and increased IBU solubility. Conclusions: This research successfully demonstrates the innovative use of freeze-drying to produce γCD-MOFs for inhalable IBU delivery. The method enabled to modify the particle size, which was crucial for successful pulmonary intake, emphasizing the need for further investigation of these formulations as effective delivery systems. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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16 pages, 2988 KB  
Article
Customizable Self-Microemulsifying Rectal Suppositories by Semisolid Extrusion 3D Printing
by Hye Jin Park and Dong Wuk Kim
Pharmaceutics 2024, 16(11), 1359; https://doi.org/10.3390/pharmaceutics16111359 - 24 Oct 2024
Cited by 5 | Viewed by 3182
Abstract
Objectives: This study aims to create an innovative self-microemulsifying drug delivery system (SMEDDS) suppository for ibuprofen (IBU) using semisolid extrusion (SSE) three-dimensional (3D) printing technology. Methods: Based on solubility studies and the ability to form a transparent microemulsion upon dilution, a [...] Read more.
Objectives: This study aims to create an innovative self-microemulsifying drug delivery system (SMEDDS) suppository for ibuprofen (IBU) using semisolid extrusion (SSE) three-dimensional (3D) printing technology. Methods: Based on solubility studies and the ability to form a transparent microemulsion upon dilution, a selected oil, surfactant, and co-surfactant were utilized to prepare SMEDDS-3DPS containing IBU. The optimal formulation consisted of 10% Triacetin, 80% Gelucire 48/16, and 10% Tetraethylene glycol. SSE 3D printing was employed to create three different-sized suppositories with varying drug contents. These suppositories were assessed for their physicochemical properties, content uniformity, and dissolution profiles. Results: The prepared mixture exhibited suitable physical properties for printing, with nano-sized emulsion droplets providing a large surface area for improved drug absorption in the rectum. Characterization techniques such as differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy indicated that IBU was present in the formulation in an amorphous state. Additionally, in vitro dissolution tests demonstrated that SMEDDS-3DPS had a significantly higher initial dissolution rate compared with IBU powder. Conclusions: This research suggests that SMEDDS-3DPS, as a rectal IBU dosage form, can enhance the rectal bioavailability of IBU. It demonstrates the versatility of 3D printing as a novel manufacturing method for lipid-based suppositories and highlights the simplicity and adaptability of SSE 3D printing technology in producing customized suppositories tailored to individual patient needs, surpassing traditional methods. Full article
(This article belongs to the Special Issue 3D Printing of Drug Delivery Systems)
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14 pages, 4946 KB  
Article
Pediatric Orally Disintegrating Tablets (ODTs) with Enhanced Palatability Based on Propranolol HCl Coground with Hydroxypropyl-β-Cyclodextrin
by Marzia Cirri, Paola A. Mura, Francesca Maestrelli, Simona Benedetti and Susanna Buratti
Pharmaceutics 2024, 16(11), 1351; https://doi.org/10.3390/pharmaceutics16111351 - 23 Oct 2024
Cited by 4 | Viewed by 2856
Abstract
Background: Propranolol, largely prescribed as an antihypertensive and antiarrhythmic drug in pediatrics, is characterized by a bitter taste and an astringent aftertaste. Currently, the therapy requires crushing of tablets for adults and their dispersion in water many times a day, leading to loss [...] Read more.
Background: Propranolol, largely prescribed as an antihypertensive and antiarrhythmic drug in pediatrics, is characterized by a bitter taste and an astringent aftertaste. Currently, the therapy requires crushing of tablets for adults and their dispersion in water many times a day, leading to loss of dosing accuracy, low palatability, and poor compliance for both patients and caregivers. Objectives: This work aimed to exploit cyclodextrin complexation by cogrinding to develop orally disintegrating tablets (ODTs) endowed with reliable dosing accuracy, good palatability and safety, ease of swallowability, and ultimately better compliance for both pediatric patients and caregivers. Results: Different formulation variables and process parameters were evaluated in preparing ODTs. The technological and morphological characterization and disintegration tests were performed according to official and alternative tests to select the ODT formulation based on the drug Hydroxypropyl-β-cyclodextrin (HPβCD) coground complex form containing Pearlitol® Flash as the diluent and 8% Explotab® as the superdisintegrant, which demonstrated the highest % drug dissolution in simulated saliva and acceptable in vitro palatability assessed by the electronic tongue, confirming the good taste-masking power of HPβCD towards propranolol. Conclusions: Such a new dosage form of propranolol could represent a valid alternative to the common extemporaneous preparations, overcoming the lack of solid formulations of propranolol intended for pediatric use. Full article
(This article belongs to the Special Issue Orally Disintegrating Dosage Forms Based on Cyclodextrins and Hydrophilic Polymers)
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18 pages, 2665 KB  
Article
The Key Role of Wettability and Boundary Layer in Dissolution Rate Test
by Alice Biasin, Federico Pribac, Erica Franceschinis, Angelo Cortesi, Lucia Grassi, Dario Voinovich, Italo Colombo, Gabriele Grassi, Gesmi Milcovich, Mario Grassi and Michela Abrami
Pharmaceutics 2024, 16(10), 1335; https://doi.org/10.3390/pharmaceutics16101335 - 18 Oct 2024
Cited by 1 | Viewed by 1919
Abstract
Background/Objectives: The present work proposes a mathematical model able to describe the dissolution of poly-disperse drug spherical particles in a solution (Dissolution Rate Test—DRT). DRT is a pivotal test performed in the pharmaceutical field to qualitatively assess drug bioavailability. Methods: The proposed mathematical [...] Read more.
Background/Objectives: The present work proposes a mathematical model able to describe the dissolution of poly-disperse drug spherical particles in a solution (Dissolution Rate Test—DRT). DRT is a pivotal test performed in the pharmaceutical field to qualitatively assess drug bioavailability. Methods: The proposed mathematical model relies on the key hallmarks of DRT, such as particle size distribution, solubility, wettability, hydrodynamic conditions in the dissolving liquid of finite dimensions, and possible re-crystallization during the dissolution process. The spherical shape of the drug particles was the only cue simplification applied. Two model drugs were considered to check model robustness: theophylline (both soluble and wettable) and praziquantel (both poorly soluble and wettable). Results: The DRT data analysis within the proposed model allows us to understand that for theophylline, the main resistance to dissolution is due to the boundary layer surrounding drug particles, whereas wettability plays a negligible role. Conversely, the effect of low wettability cannot be neglected for praziquantel. These results are validated by the determination of drug wettability performed while measuring the solid–liquid contact angle on four liquids with decreasing polarities. Moreover, the percentage of drug polarity was determined. Conclusions: The proposed mathematical model confirms the importance of the different physical phenomena leading the dissolution of poly-disperse solid drug particles in a solution. Although a comprehensive mathematical model was proposed and applied, the DRT data of theophylline and praziquantel was successfully fitted by means of just two fitting parameters. Full article
(This article belongs to the Special Issue Mathematical Modeling in Drug Delivery)
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16 pages, 5063 KB  
Article
Respiratory Delivery of Lacticaseibacillus rhamnosus GG by Vibrating-Mesh and Jet Nebulisation
by Alex Seungyeon Byun, Luis Vitetta, Hak-Kim Chan and Philip Chi Lip Kwok
Pharmaceutics 2024, 16(10), 1326; https://doi.org/10.3390/pharmaceutics16101326 - 14 Oct 2024
Cited by 1 | Viewed by 3900
Abstract
Background: The use of probiotic bacteria to improve lung health has been gaining interest. Although the oral delivery of probiotics and their effects are well documented, there is currently limited knowledge on the respiratory delivery of probiotics. Objectives: This study aimed to investigate [...] Read more.
Background: The use of probiotic bacteria to improve lung health has been gaining interest. Although the oral delivery of probiotics and their effects are well documented, there is currently limited knowledge on the respiratory delivery of probiotics. Objectives: This study aimed to investigate whether nebulisation is suitable for delivering Lacticaseibacillus rhamnosus GG (LGG) into the lungs for the potential treatment of bacterial pulmonary infections. Methods: It compared the dose output and aerosol performance of a vibrating-mesh nebuliser (VMN) and a jet nebuliser (JN) in nebulising LGG suspended in de Man Rogosa Sharpe (MRS) broth, phosphate-buffered saline (PBS), or normal saline (0.9% w/v sodium chloride in water). Results: The VMN consistently produced a higher output than the JN for all liquid media, indicating that VMN was more efficient. The fine-particle fractions of both nebulisers were comparable for a given medium. The highest fine-particle fraction was achieved with LGG suspended in MRS broth for both nebulisers (20.5 ± 2.8% for VMN; 18.7 ± 3.4% for JN). This suggests that the aerosol performance of nebulised probiotics may depend on the medium in which the probiotic bacteria were suspended. Conclusions: Therefore, this study demonstrated that the nebulisation efficiency of LGG depended on the nebuliser type and liquid medium of the probiotic suspension. Full article
(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections, 2nd Edition)
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27 pages, 2107 KB  
Review
Artificial Intelligence (AI) Applications in Drug Discovery and Drug Delivery: Revolutionizing Personalized Medicine
by Dolores R. Serrano, Francis C. Luciano, Brayan J. Anaya, Baris Ongoren, Aytug Kara, Gracia Molina, Bianca I. Ramirez, Sergio A. Sánchez-Guirales, Jesus A. Simon, Greta Tomietto, Chrysi Rapti, Helga K. Ruiz, Satyavati Rawat, Dinesh Kumar and Aikaterini Lalatsa
Pharmaceutics 2024, 16(10), 1328; https://doi.org/10.3390/pharmaceutics16101328 - 14 Oct 2024
Cited by 193 | Viewed by 42074
Abstract
Artificial intelligence (AI) encompasses a broad spectrum of techniques that have been utilized by pharmaceutical companies for decades, including machine learning, deep learning, and other advanced computational methods. These innovations have unlocked unprecedented opportunities for the acceleration of drug discovery and delivery, the [...] Read more.
Artificial intelligence (AI) encompasses a broad spectrum of techniques that have been utilized by pharmaceutical companies for decades, including machine learning, deep learning, and other advanced computational methods. These innovations have unlocked unprecedented opportunities for the acceleration of drug discovery and delivery, the optimization of treatment regimens, and the improvement of patient outcomes. AI is swiftly transforming the pharmaceutical industry, revolutionizing everything from drug development and discovery to personalized medicine, including target identification and validation, selection of excipients, prediction of the synthetic route, supply chain optimization, monitoring during continuous manufacturing processes, or predictive maintenance, among others. While the integration of AI promises to enhance efficiency, reduce costs, and improve both medicines and patient health, it also raises important questions from a regulatory point of view. In this review article, we will present a comprehensive overview of AI’s applications in the pharmaceutical industry, covering areas such as drug discovery, target optimization, personalized medicine, drug safety, and more. By analyzing current research trends and case studies, we aim to shed light on AI’s transformative impact on the pharmaceutical industry and its broader implications for healthcare. Full article
(This article belongs to the Special Issue Computational Intelligence (CI) Tools in Applications of Pharmaceutics)
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17 pages, 1313 KB  
Review
Serum Albumin in Nasal Drug Delivery Systems: Exploring the Role and Application
by Sandra Aulia Mardikasari, Gábor Katona and Ildikó Csóka
Pharmaceutics 2024, 16(10), 1322; https://doi.org/10.3390/pharmaceutics16101322 - 11 Oct 2024
Cited by 8 | Viewed by 4976
Abstract
The application of serum albumin in various types of formulations has emerged as a valuable option in biomedical research, especially in the field of nasal drug delivery systems. A serum albumin-based carrier system has been employed due to several benefits, such as enhancing [...] Read more.
The application of serum albumin in various types of formulations has emerged as a valuable option in biomedical research, especially in the field of nasal drug delivery systems. A serum albumin-based carrier system has been employed due to several benefits, such as enhancing drug solubility and stability, generating the desired controlled release profile, and developing favorable properties with respect to the challenges in nasal conditions, which, in this case, involves hindering rapid elimination due to nasal mucociliary clearance. Accordingly, considering the important role of serum albumin, in-depth knowledge related to its utilization in preparing nasal drug formulation is highly encouraged. This review aimed to explore the potential application of serum albumin in fabricating nasal drug formulations and its crucial role and functionality regarding the binding interaction with nasal mucin, which significantly determines the successful administration of nasal drug formulations. Full article
(This article belongs to the Special Issue Topical Advisory Panel Members' Collection Series: Nanocarriers for Alternative Drug Delivery)
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15 pages, 1828 KB  
Article
Model-Informed Precision Dosing for Personalized Ustekinumab Treatment in Plaque Psoriasis
by Karine Rodríguez-Fernández, Javier Zarzoso-Foj, Marina Saez-Bello, Almudena Mateu-Puchades, Antonio Martorell-Calatayud, Matilde Merino-Sanjuan, Elena Gras-Colomer, Monica Climente-Martí and Victor Mangas-Sanjuan
Pharmaceutics 2024, 16(10), 1295; https://doi.org/10.3390/pharmaceutics16101295 - 4 Oct 2024
Cited by 3 | Viewed by 2277
Abstract
Background/Objectives: Implementing model-informed precision dosing (MIPD) strategies guided by population pharmacokinetic/pharmacodynamic (PK/PD) models could enhance the management of inflammatory diseases such as psoriasis. However, the extent of individual experimental data gathered during MIPD significantly influences the uncertainty in estimating individual PK/PD parameters, affecting [...] Read more.
Background/Objectives: Implementing model-informed precision dosing (MIPD) strategies guided by population pharmacokinetic/pharmacodynamic (PK/PD) models could enhance the management of inflammatory diseases such as psoriasis. However, the extent of individual experimental data gathered during MIPD significantly influences the uncertainty in estimating individual PK/PD parameters, affecting clinical dose selection decisions. Methods: This study proposes a methodology to individualize ustekinumab (UTK) dosing strategies for 23 Spanish patients with moderate to severe chronic plaque psoriasis., considering the uncertainty of individual parameters within a population PK/PD model. Results: An indirect response model from previous research was used to describe the PK/PD relationship between UTK serum concentrations and the Psoriasis Area and Severity Index (PASI) score. A maximum inhibition drug effect (Imax) model was selected, and a first-order remission constant rate of psoriatic skin lesion (kout = 0.016 d−1) was estimated. Conclusions: The MIPD approach predicted that 35% and 26% of the patients would need an optimized and intensified dosage regimen, respectively, compared to the regimen typically used in clinical practice. This analysis demonstrated its utility as a tool for selecting personalized UTK dosing regimens in clinical practice in order to optimize the probability of achieving targeted clinical outcomes in patients with psoriasis. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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14 pages, 2945 KB  
Article
Application of the Thermal Analysis of Frozen Aqueous Solutions to Assess the Miscibility of Hyaluronic Acid and Polymers Used for Dissolving Microneedles
by Ken-ichi Izutsu, Hiroyuki Yoshida, Yasuhiro Abe, Eiichi Yamamoto, Yoji Sato and Daisuke Ando
Pharmaceutics 2024, 16(10), 1280; https://doi.org/10.3390/pharmaceutics16101280 - 30 Sep 2024
Cited by 1 | Viewed by 1950
Abstract
Background: The combination of multiple polymers is anticipated to serve as a means to diversify the physical properties and functionalities of dissolving microneedles. The mixing state of components is considered as a crucial factor in determining their suitability. Objectives: The purpose of this [...] Read more.
Background: The combination of multiple polymers is anticipated to serve as a means to diversify the physical properties and functionalities of dissolving microneedles. The mixing state of components is considered as a crucial factor in determining their suitability. Objectives: The purpose of this study was to elucidate whether thermal analysis of frozen aqueous solutions can appropriately predict the miscibility of hyaluronic acid (HA) and other polymers used for dissolving microneedles prepared by a micromolding method. Methods: Aliquots of aqueous polymer solutions were applied for thermal analysis by heating the samples from −70 °C at 5 °C/min to obtain the transition temperature of amorphous polymers and/or the crystallization/melting peaks of polymers (e.g., polyethylene glycol (PEG)). Films and dissolving microneedles were prepared by air-drying of the aqueous polymer solutions to assess the polymer miscibility in the solids. Results: The frozen aqueous single-solute HA solutions exhibited a clear Tg′ (the glass transition temperature of maximally freeze-concentrated solutes) at approximately −20 °C. The combination of HA with several polymers (e.g., dextran FP40, DEAE-dextran, dextran sulfate, and gelatin) showed a single Tg′ transition at temperatures that shifted according to their mass ratio, which strongly suggested the mixing of the freeze-concentrated solutes. By contrast, the observation of two Tg′ transitions in a scan strongly suggested the separation of HA and polyvinylpyrrolidone (PVP) or HA and polyacrylic acid (PAA) into different freeze-concentrated phases, each of which was rich in an amorphous polymer. The combination of HA and PEG exhibited the individual physical changes of the polymers. The polymer combinations that showed phase separation in the frozen solution formed opaque films and microneedles upon their preparation by air-drying. Coacervation occurring in certain polymer combinations was also suggested as a factor contributing to the formation of cloudy films. Conclusions: Freezing aqueous polymer solutions creates a highly concentrated polymer environment that mimics the matrix of dissolving microneedles prepared through air drying. This study demonstrated that thermal analysis of the frozen solution offers insights into the mixing state of condensed polymers, which can be useful for predicting the physical properties of microneedles. Full article
(This article belongs to the Special Issue Microarray Patches for Transdermal Drug Delivery)
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15 pages, 4021 KB  
Article
Feasibility of a High-Dose Inhaled Indomethacin Dry Powder with Dual Deposition for Pulmonary and Oral Delivery
by Jamie E. Spahn, Amr Hefnawy, Feng Zhang and Hugh D. C. Smyth
Pharmaceutics 2024, 16(10), 1269; https://doi.org/10.3390/pharmaceutics16101269 - 28 Sep 2024
Cited by 1 | Viewed by 1843
Abstract
In this study we have developed a high-dose dry powder inhaler formulation of indomethacin using a novel approach to carrier-based formulations. Specifically, larger drug particles serve as the carrier for the smaller micronized drug particles, such that an inhaled dose is combined with [...] Read more.
In this study we have developed a high-dose dry powder inhaler formulation of indomethacin using a novel approach to carrier-based formulations. Specifically, larger drug particles serve as the carrier for the smaller micronized drug particles, such that an inhaled dose is combined with an oral dose. To study this system, the aerosol performance of a standard indomethacin–lactose formulation was compared to carrier-free micronized indomethacin and a drug-as-carrier formulation (a micronized indomethacin–coarse indomethacin blend). Indomethacin with lactose showed a very poor aerosol performance, indicating high adhesion between the drug and carrier. The performance of the carrier-free micronized drug was significantly better, indicating low cohesion. Coarse drug particles as a carrier allowed improved powder flow and aerosol performance while also providing a potential secondary route of absorption of indomethacin, namely oral. An optimal formulation ratio of 1:1 (w/w) fine indomethacin–coarse indomethacin was developed in this study. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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23 pages, 2778 KB  
Review
Self-Tumor Antigens in Solid Tumors Turned into Vaccines by α-gal Micelle Immunotherapy
by Uri Galili
Pharmaceutics 2024, 16(10), 1263; https://doi.org/10.3390/pharmaceutics16101263 - 27 Sep 2024
Cited by 4 | Viewed by 2752
Abstract
A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in [...] Read more.
A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in situ targeting of tumor cells for robust uptake by APCs, without the need to identify and characterize the TAs. This is feasible by the intra-tumoral injection of α-gal micelles comprised of glycolipids presenting the carbohydrate-antigen “α-gal epitope” (Galα1-3Galβ1-4GlcNAc-R). Humans produce a natural antibody called “anti-Gal” (constituting ~1% of immunoglobulins), which binds to α-gal epitopes. Tumor-injected α-gal micelles spontaneously insert into tumor cell membranes, so that multiple α-gal epitopes are presented on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in the killing of tumor cells, and the recruitment of multiple APCs (dendritic cells and macrophages) into treated tumors by the chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into a personalized TA vaccine, the recruited APC phagocytose anti-Gal opsonized tumor cells and cell membranes, process the internalized TAs and transport them to regional lymph-nodes. TA peptides presented on APCs activate TA-specific T cells to proliferate and destroy the metastatic tumor cells presenting the TAs. Studies in anti-Gal-producing mice demonstrated the induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic α-gal micelles into primary tumors. This treatment was further found to synergize with checkpoint inhibitor therapy by the anti-PD1 antibody. Phase-1 clinical trials indicated that α-gal micelle immunotherapy is safe and can induce the infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that, in addition to converting treated metastases into an autologous TA vaccine, this treatment should be considered as a neoadjuvant therapy, administering α-gal micelles into primary tumors immediately following their detection. Such an immunotherapy will convert tumors into a personalized anti-TA vaccine for the period prior to their resection. Full article
(This article belongs to the Special Issue Nanomedicines for Overcoming Tumor Immunotherapy Tolerance)
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13 pages, 966 KB  
Review
Topical Application of Centella asiatica in Wound Healing: Recent Insights into Mechanisms and Clinical Efficacy
by Katarzyna Witkowska, Magdalena Paczkowska-Walendowska, Ewa Garbiec and Judyta Cielecka-Piontek
Pharmaceutics 2024, 16(10), 1252; https://doi.org/10.3390/pharmaceutics16101252 - 26 Sep 2024
Cited by 32 | Viewed by 25419
Abstract
Centella asiatica, widely known as Gotu kola, is a traditional herb celebrated for its benefits in skin health and wound healing. Recent research has provided new insights into its efficacy, particularly through topical applications. This review highlights the plant’s mechanisms, focusing [...] Read more.
Centella asiatica, widely known as Gotu kola, is a traditional herb celebrated for its benefits in skin health and wound healing. Recent research has provided new insights into its efficacy, particularly through topical applications. This review highlights the plant’s mechanisms, focusing on its active compounds such as asiaticoside, madecassoside, asiatic acid, and madecassic acid, which enhance collagen synthesis, modulate inflammation, and offer antioxidant protection. Clinical trials have been collected and summarized that innovative delivery systems, such as hydrogels, nanostructures or microneedles, can accelerate wound healing, reduce wound size, and improve recovery times in various wound types, including diabetic ulcers and burns. Future research will likely refine these technologies and explore new applications, reinforcing the role of C. asiatica in contemporary wound care. Advances in formulation and delivery will continue to enhance the plant’s therapeutic potential, offering promising solutions for effective wound management. Full article
(This article belongs to the Special Issue Therapeutic Approaches for Wound-Associated Skin Diseases)
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22 pages, 6892 KB  
Review
Review on Photoacoustic Monitoring after Drug Delivery: From Label-Free Biomarkers to Pharmacokinetics Agents
by Jiwoong Kim, Seongwook Choi, Chulhong Kim, Jeesu Kim and Byullee Park
Pharmaceutics 2024, 16(10), 1240; https://doi.org/10.3390/pharmaceutics16101240 - 24 Sep 2024
Cited by 9 | Viewed by 2890
Abstract
Photoacoustic imaging (PAI) is an emerging noninvasive and label-free method for capturing the vasculature, hemodynamics, and physiological responses following drug delivery. PAI combines the advantages of optical and acoustic imaging to provide high-resolution images with multiparametric information. In recent decades, PAI’s abilities have [...] Read more.
Photoacoustic imaging (PAI) is an emerging noninvasive and label-free method for capturing the vasculature, hemodynamics, and physiological responses following drug delivery. PAI combines the advantages of optical and acoustic imaging to provide high-resolution images with multiparametric information. In recent decades, PAI’s abilities have been used to determine reactivity after the administration of various drugs. This study investigates photoacoustic imaging as a label-free method of monitoring drug delivery responses by observing changes in the vascular system and oxygen saturation levels across various biological tissues. In addition, we discuss photoacoustic studies that monitor the biodistribution and pharmacokinetics of exogenous contrast agents, offering contrast-enhanced imaging of diseased regions. Finally, we demonstrate the crucial role of photoacoustic imaging in understanding drug delivery mechanisms and treatment processes. Full article
(This article belongs to the Special Issue Advanced Materials Science and Technology in Drug Delivery)
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23 pages, 4533 KB  
Article
Exploring Cationic Guar Gum: Innovative Hydrogels and Films for Enhanced Wound Healing
by Kamila Gabrieli Dallabrida, Willer Cezar Braz, Crisleine Marchiori, Thainá Mayer Alves, Luiza Stolz Cruz, Giovanna Araujo de Morais Trindade, Patrícia Machado, Lucas Saldanha da Rosa, Najeh Maissar Khalil, Fabiane Gomes de Moraes Rego, André Ricardo Fajardo, Luana Mota Ferreira, Marcel Henrique Marcondes Sari and Jéssica Brandão Reolon
Pharmaceutics 2024, 16(9), 1233; https://doi.org/10.3390/pharmaceutics16091233 - 22 Sep 2024
Cited by 13 | Viewed by 4013
Abstract
Background/Objectives: This study developed and characterized hydrogels (HG-CGG) and films (F-CGG) based on cationic guar gum (CGG) for application in wound healing. Methods: HG-CGG (2% w/v) was prepared by gum thickening and evaluated for pH, stability, spreadability, and viscosity. F-CGG [...] Read more.
Background/Objectives: This study developed and characterized hydrogels (HG-CGG) and films (F-CGG) based on cationic guar gum (CGG) for application in wound healing. Methods: HG-CGG (2% w/v) was prepared by gum thickening and evaluated for pH, stability, spreadability, and viscosity. F-CGG was obtained using an aqueous dispersion of CGG (6% w/v) and the solvent casting method. F-CGG was characterized for thickness, weight uniformity, morphology, mechanical properties, hydrophilicity, and swelling potential. Both formulations were evaluated for bioadhesive potential on intact and injured porcine skin, as well as antioxidant activity. F-CGG was further studied for biocompatibility using hemolysis and cell viability assays (L929 fibroblasts), and its wound-healing potential by the scratch assay. Results: HG-CGG showed adequate viscosity and spreadability profiles for wound coverage, but its bioadhesive strength was reduced on injured skin. In contrast, F-CGG maintained consistent bioadhesive strength regardless of skin condition (6554.14 ± 540.57 dyne/cm2 on injured skin), presenting appropriate mechanical properties (flexible, transparent, thin, and resistant) and a high swelling capacity (2032 ± 211% after 6 h). F-CGG demonstrated superior antioxidant potential compared to HG-CGG (20.50 mg/mL ABTS+ radical scavenging activity), in addition to exhibiting low hemolytic potential and no cytotoxicity to fibroblasts. F-CGG promoted the proliferation of L929 cells in vitro, supporting wound healing. Conclusions: Therefore, CGG proved to be a promising material for developing formulations with properties suitable for cutaneous use. F-CGG combines bioadhesion, antioxidant activity, biocompatibility, cell proliferation, and potential wound healing, making it promising for advanced wound treatment. Full article
(This article belongs to the Special Issue Research on the Development of Nano-Based Polymeric Films for Drugs and Their Derivatives)
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15 pages, 2077 KB  
Article
Oral Gels as an Alternative to Liquid Pediatric Suspensions Compounded from Commercial Tablets
by Monika Trofimiuk, Małgorzata Sznitowska and Katarzyna Winnicka
Pharmaceutics 2024, 16(9), 1229; https://doi.org/10.3390/pharmaceutics16091229 - 20 Sep 2024
Cited by 1 | Viewed by 2213
Abstract
The aim of the study was to propose pharmacy-compounded oral gels as a new and alternative dosage form that is attractive to children as having a better masking taste than syrups and reducing the risk of spilling. The application and physical properties of [...] Read more.
The aim of the study was to propose pharmacy-compounded oral gels as a new and alternative dosage form that is attractive to children as having a better masking taste than syrups and reducing the risk of spilling. The application and physical properties of the gels prepared with cellulose derivatives (hydroxyethylcellulose and carmellose sodium) or carbomers were evaluated. The results of the study showed the most suitable consistency, viscosity, and organoleptic properties for gels prepared with carbomer and cellulose derivatives at concentrations of 0.75% and 2.0%, respectively. The microbial stability of the gels was guaranteed by the use of methylparaben and potassium sorbate. VAL (valsartan) and CC (candesartan cilexetil) tablets, often used off-label in children, were pulverized and suspended in the hydrogel bases, resulting in final drug concentrations of 4 mg/g and 1 mg/g, respectively. There was no significant change in viscosity and consistency parameters when the pulverized tablets were added, and only small changes in viscosity and consistency were observed during 35 days of storage, especially in the gels with sodium carmellose and candesartan. On the basis of the drug assay, an expiry date of 25 °C was recommended: 35 days for valsartan and 14 days for candesartan preparations. Full article
(This article belongs to the Special Issue Extemporaneous Formulations: Filling the Gap in the Pharmaceutical Industry with Personalized Medicines)
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15 pages, 4031 KB  
Article
Magnetic Nanoparticles with On-Site Azide and Alkyne Functionalized Polymer Coating in a Single Step through a Solvothermal Process
by Romualdo Mora-Cabello, David Fuentes-Ríos, Lidia Gago, Laura Cabeza, Ana Moscoso, Consolación Melguizo, José Prados, Francisco Sarabia and Juan Manuel López-Romero
Pharmaceutics 2024, 16(9), 1226; https://doi.org/10.3390/pharmaceutics16091226 - 19 Sep 2024
Cited by 5 | Viewed by 2380
Abstract
Background/Objectives: Magnetic Fe3O4 nanoparticles (MNPs) are becoming more important every day. We prepared MNPs in a simple one-step reaction by following the solvothermal method, assisted by azide and alkyne functionalized polyethylene glycol (PEG400) polymers, as well as by PEG6000 [...] Read more.
Background/Objectives: Magnetic Fe3O4 nanoparticles (MNPs) are becoming more important every day. We prepared MNPs in a simple one-step reaction by following the solvothermal method, assisted by azide and alkyne functionalized polyethylene glycol (PEG400) polymers, as well as by PEG6000 and the polyol β-cyclodextrin (βCD), which played a crucial role as electrostatic stabilizers, providing polymeric/polyol coatings around the magnetic cores. Methods: The composition, morphology, and magnetic properties of the nanospheres were analyzed using Transmission Electron and Atomic Force Microscopies (TEM, AFM), Nuclear Magnetic Resonance (NMR), X-ray Diffraction Diffractometry (XRD), Fourier-Transform Infrared Spectroscopy (FT-IR), Matrix-Assisted Laser Desorption/Ionization (MALDI) and Vibrating Sample Magnetometry (VSM). Results: The obtained nanoparticles (@Fe3O4-PEGs and @Fe3O4-βCD) showed diameters between 90 and 250 nm, depending on the polymer used and the Fe3O4·6H2O precursor concentration, typically, 0.13 M at 200 °C and 24 h of reaction. MNPs exhibited superparamagnetism with high saturation mass magnetization at room temperature, reaching values of 59.9 emu/g (@Fe3O4-PEG6000), and no ferromagnetism. Likewise, they showed temperature elevation after applying an alternating magnetic field (AMF), obtaining Specific Absorption Rate (SAR) values of up to 51.87 ± 2.23 W/g for @Fe3O4-PEG6000. Additionally, the formed systems are susceptible to click chemistry, as was demonstrated in the case of the cannabidiol-propargyl derivative (CBD-Pro), which was synthesized and covalently attached to the azide functionalized surface of @Fe3O4-PEG400-N3. Prepared MNPs are highly dispersible in water, PBS, and citrate buffer, remaining in suspension for over 2 weeks, and non-toxic in the T84 human colon cancer cell line, Conclusions: indicating that they are ideal candidates for biomedical applications. Full article
(This article belongs to the Special Issue Recent Advances in Biomedical Applications of Magnetic Nanomaterials)
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20 pages, 14709 KB  
Article
Characterizing Extracellular Vesicles Generated from the Integra CELLine Culture System and Their Endocytic Pathways for Intracellular Drug Delivery
by Tianjiao Geng, Lei Tian, Song Yee Paek, Euphemia Leung, Lawrence W. Chamley and Zimei Wu
Pharmaceutics 2024, 16(9), 1206; https://doi.org/10.3390/pharmaceutics16091206 - 13 Sep 2024
Cited by 1 | Viewed by 2633
Abstract
Extracellular vesicles (EVs) have attracted great attention as promising intracellular drug delivery carriers. While the endocytic pathways of small EVs (sEVs, <200 nm) have been reported, there is limited understanding of large EVs (lEVs, >200 nm), despite their potential applications for drug delivery. [...] Read more.
Extracellular vesicles (EVs) have attracted great attention as promising intracellular drug delivery carriers. While the endocytic pathways of small EVs (sEVs, <200 nm) have been reported, there is limited understanding of large EVs (lEVs, >200 nm), despite their potential applications for drug delivery. Additionally, the low yield of EVs during isolation remains a major challenge in their application. Herein, we aimed to compare the endocytic pathways of sEVs and lEVs using MIA PaCa-2 pancreatic cancer cell-derived EVs as models and to explore the efficiency of their production. The cellular uptake of EVs by MIA PaCa-2 cells was assessed and the pathways were investigated with the aid of endocytic inhibitors. The yield and protein content of sEVs and lEVs from the Integra CELLine culture system and the conventional flasks were compared. Our findings revealed that both sEVs and lEVs produced by the Integra CELLine system entered their parental cells via multiple routes, including caveolin-mediated endocytosis, clathrin-mediated endocytosis, and actin-dependent phagocytosis or macropinocytosis. Notably, caveolin- and clathrin-mediated endocytosis were more prominent in the uptake of sEVs, while actin-dependent phagocytosis and macropinocytosis were significant for both sEVs and lEVs. Compared with conventional flasks, the Integra CELLine system demonstrated a 9-fold increase in sEVs yield and a 6.5-fold increase in lEVs yield, along with 3- to 4-fold higher protein content per 1010 EVs. Given that different endocytic pathways led to distinct intracellular trafficking routes, this study highlights the unique potentials of sEVs and lEVs for intracellular cargo delivery. The Integra CELLine proves to be a highly productive and cost-effective system for generating EVs with favourable properties for drug delivery. Full article
(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)
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13 pages, 1958 KB  
Article
Assessing α-Bisabolol as a Transmucosal Permeation Enhancer of Buccal Local Anesthetics
by Renê Oliveira do Couto, Douglas Vieira Thomaz, Maira Perez Ferreira Duarte, Renata Fonseca Vianna Lopez, Vinícius Pedrazzi, Osvaldo de Freitas and Gianluca Martino Tartaglia
Pharmaceutics 2024, 16(9), 1198; https://doi.org/10.3390/pharmaceutics16091198 - 12 Sep 2024
Cited by 1 | Viewed by 2241
Abstract
Needle-free buccal anesthesia improves dental treatment outcomes for both patients and dentists. In this study, we report on an assessment of the enhancement effects of α-bisabolol on the in vitro transmucosal permeation of prilocaine hydrochloride (PCl) and lidocaine hydrochloride (LCl) from needleless buccal [...] Read more.
Needle-free buccal anesthesia improves dental treatment outcomes for both patients and dentists. In this study, we report on an assessment of the enhancement effects of α-bisabolol on the in vitro transmucosal permeation of prilocaine hydrochloride (PCl) and lidocaine hydrochloride (LCl) from needleless buccal films. We also evaluated the mechanical properties of the film, which consisted of Methocel™ K100 LV as the film-forming polymer (3% m·m−1), PEG 400 as a cosolvent (15% m·m−1 based on drug loading), α-bisabolol (15 and 30% m·m−1 based on drug loading), and the drugs combined at a 1:1 ratio (15 mg·unit−1). The porcine esophageal epithelium was used as a membrane barrier, and artificial saliva was the release medium. After a 1 h experiment at 25 ± 2 °C, α-bisabolol significantly decreased, rather than enhanced, the permeation fluxes (five-fold), permeability coefficients (seven-fold), and retentions (two-fold) of both PCl and LCl through the epithelium, regardless of the concentration. Moreover, the resistance and flexibility of the films markedly decreased compared to those without α-bisabolol. Therefore, under the experimental conditions, using α-bisabolol as a buccal permeation enhancer for the hydrophilic local anesthetics PCl and LCl from buccal films is not feasible. Full article
(This article belongs to the Special Issue Site-Specific Drug Delivery: Formulation Strategies and Regulatory Challenges)
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39 pages, 2469 KB  
Review
Exploring the Therapeutic Implications of Co-Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer
by Mafalda Calheiros-Lobo, João P. N. Silva, Bárbara Pinto, Luís Monteiro, Patrícia M. A. Silva and Hassan Bousbaa
Pharmaceutics 2024, 16(9), 1196; https://doi.org/10.3390/pharmaceutics16091196 - 11 Sep 2024
Cited by 3 | Viewed by 2559
Abstract
Head and neck cancer (HNC), the sixth most common cancer worldwide, is increasing in incidence, with oral squamous cell carcinoma (OSCC) as the predominant subtype. OSCC mainly affects middle-aged to elderly males, often occurring on the posterior lateral border of the tongue, leading [...] Read more.
Head and neck cancer (HNC), the sixth most common cancer worldwide, is increasing in incidence, with oral squamous cell carcinoma (OSCC) as the predominant subtype. OSCC mainly affects middle-aged to elderly males, often occurring on the posterior lateral border of the tongue, leading to significant disfigurement and functional impairments, such as swallowing and speech difficulties. Despite advancements in understanding OSCC’s genetic and epigenetic variations, survival rates for advanced stages remain low, highlighting the need for new treatment options. Primary treatment includes surgery, often combined with radiotherapy (RT) and chemotherapy (CT). Cetuximab-based chemotherapy, targeting the overexpressed epidermal growth factor receptor (EGFR) in 80–90% of HNCs, is commonly used but correlates with poor prognosis. Additionally, monopolar spindle 1 (MPS1), a spindle assembly checkpoint (SAC) component, is a significant target due to its role in genomic fidelity during mitosis and its overexpression in several cancers. This review explores EGFR and MPS1 as therapeutic targets in HNC, analyzing their molecular mechanisms and the effects of their inhibition on cancer cells. It also highlights the promise of combinatorial approaches, such as microtubule-targeting agents (MTAs) and antimitotic agents, in improving HNC therapies, patient outcomes, and survival rates. Full article
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28 pages, 7409 KB  
Review
Advances in Nanoparticles as Non-Viral Vectors for Efficient Delivery of CRISPR/Cas9
by Minse Kim, Youngwoo Hwang, Seongyu Lim, Hyeon-Ki Jang and Hyun-Ouk Kim
Pharmaceutics 2024, 16(9), 1197; https://doi.org/10.3390/pharmaceutics16091197 - 11 Sep 2024
Cited by 33 | Viewed by 8224
Abstract
The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is a gene-editing technology. Nanoparticle delivery systems have attracted attention because of the limitations of conventional viral vectors. In this review, we assess the efficiency of various nanoparticles, including lipid-based, polymer-based, inorganic, and extracellular [...] Read more.
The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is a gene-editing technology. Nanoparticle delivery systems have attracted attention because of the limitations of conventional viral vectors. In this review, we assess the efficiency of various nanoparticles, including lipid-based, polymer-based, inorganic, and extracellular vesicle-based systems, as non-viral vectors for CRISPR/Cas9 delivery. We discuss their advantages, limitations, and current challenges. By summarizing recent advancements and highlighting key strategies, this review aims to provide a comprehensive overview of the role of non-viral delivery systems in advancing CRISPR/Cas9 technology for clinical applications and gene therapy. Full article
(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)
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15 pages, 2434 KB  
Article
Powder Self-Emulsifying Drug Delivery System for Mitotane: In Vitro and In Vivo Evaluation
by Mohamed Skiba, Valentin Lefébure, Frederic Bounoure, Nicolas Milon, Michael Thomas, Herve Lefebvre and Lahiani-Skiba Malika
Pharmaceutics 2024, 16(9), 1194; https://doi.org/10.3390/pharmaceutics16091194 - 11 Sep 2024
Cited by 4 | Viewed by 2096
Abstract
Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p′-dichlorodimethyl dichloroethane [o,p′-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, [...] Read more.
Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p′-dichlorodimethyl dichloroethane [o,p′-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, Cushing’s syndrome. However, the efficacy of mitotane is limited by its low oral bioavailability, caused by its extremely poor aqueous solubility. This research explores the development of a new powder self-emulsifying drug delivery system (P-SEDDS) for mitotane to improve its oral bioavailability. The study focuses on the new concept of a mitotane-loaded P-SEDDS to overcome the challenges associated with its limited solubility and high logP, thereby improving its therapeutic efficacy, reducing off-target toxicity, and avoiding first-pass metabolism. The P-SEDDS formulations were meticulously designed using only α-cyclodextrin and oil, with the goal of achieving a stable and efficient P-SEDDS. The optimized formulation was characterized for pharmaceutical properties, and its pharmacokinetic behavior was examined in rats. The results demonstrated a significant enhancement in the bioavailability of mitotane when delivered through the P-SEDDS, attributed to the increased dissolution velocity and improved absorption of the poorly water-soluble drug. The results suggest that a mitotane-loaded P-SEDDS has distinctly enhanced in vitro and in vivo performance compared with conventional mitotane formulations (Lysodren®), which leads to the conclusion that the P-SEDDS formulation could be a viable and effective strategy for improving the dissolution rate and bioavailability of poorly aqueous-soluble ingredients. Full article
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37 pages, 5256 KB  
Review
Emerging Trends in Dissolving-Microneedle Technology for Antimicrobial Skin-Infection Therapies
by Rui Luo, Huihui Xu, Qiaoni Lin, Jiaying Chi, Tingzhi Liu, Bingrui Jin, Jiayu Ou, Zejun Xu, Tingting Peng, Guilan Quan and Chao Lu
Pharmaceutics 2024, 16(9), 1188; https://doi.org/10.3390/pharmaceutics16091188 - 8 Sep 2024
Cited by 10 | Viewed by 5394
Abstract
Skin and soft-tissue infections require significant consideration because of their prolonged treatment duration and propensity to rapidly progress, resulting in severe complications. The primary challenge in their treatment stems from the involvement of drug-resistant microorganisms that can form impermeable biofilms, as well as [...] Read more.
Skin and soft-tissue infections require significant consideration because of their prolonged treatment duration and propensity to rapidly progress, resulting in severe complications. The primary challenge in their treatment stems from the involvement of drug-resistant microorganisms that can form impermeable biofilms, as well as the possibility of infection extending deep into tissues, thereby complicating drug delivery. Dissolving microneedle patches are an innovative transdermal drug-delivery system that effectively enhances drug penetration through the stratum corneum barrier, thereby increasing drug concentration at the site of infection. They offer highly efficient, safe, and patient-friendly alternatives to conventional topical formulations. This comprehensive review focuses on recent advances and emerging trends in dissolving-microneedle technology for antimicrobial skin-infection therapy. Conventional antibiotic microneedles are compared with those based on emerging antimicrobial agents, such as quorum-sensing inhibitors, antimicrobial peptides, and antimicrobial-matrix materials. The review also highlights the potential of innovative microneedles incorporating chemodynamic, nanoenzyme antimicrobial, photodynamic, and photothermal antibacterial therapies. This review explores the advantages of various antimicrobial therapies and emphasizes the potential of their combined application to improve the efficacy of microneedles. Finally, this review analyzes the druggability of different antimicrobial microneedles and discusses possible future developments. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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33 pages, 2551 KB  
Review
Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer
by Ryunosuke Hoshi, Kristyna A. Gorospe, Hagar I. Labouta, Taha Azad, Warren L. Lee and Kelsie L. Thu
Pharmaceutics 2024, 16(9), 1181; https://doi.org/10.3390/pharmaceutics16091181 - 7 Sep 2024
Cited by 8 | Viewed by 4299
Abstract
The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)+ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8+ T cells activates downstream signaling pathways [...] Read more.
The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)+ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8+ T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them. Full article
(This article belongs to the Special Issue Drug Repurposing and Delivery Systems for Immunotherapy)
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28 pages, 2664 KB  
Review
Exploring Protein-Based Carriers in Drug Delivery: A Review
by Claudia Ferraro, Marco Dattilo, Francesco Patitucci, Sabrina Prete, Giuseppe Scopelliti, Ortensia Ilaria Parisi and Francesco Puoci
Pharmaceutics 2024, 16(9), 1172; https://doi.org/10.3390/pharmaceutics16091172 - 5 Sep 2024
Cited by 25 | Viewed by 4986
Abstract
Drug delivery systems (DDSs) represent an emerging focus for many researchers and they are becoming progressively crucial in the development of new treatments. Great attention is given to all the challenges that a drug has to overcome during its journey across barriers and [...] Read more.
Drug delivery systems (DDSs) represent an emerging focus for many researchers and they are becoming progressively crucial in the development of new treatments. Great attention is given to all the challenges that a drug has to overcome during its journey across barriers and tissues and all the pharmacokinetics modulations that are needed in order to reach the targeting sites. The goal of these pathways is the delivery of drugs in a controlled way, optimizing their bioavailability and minimizing side effects. Recent innovations in DDSs include various nanotechnology-based approaches, such as nanoparticles, nanofibers and micelles, which provide effective targeted delivery and sustained release of therapeutics. In this context, protein-based drug delivery systems are gaining significant attention in the pharmaceutical field due to their potential to revolutionize targeted and efficient drug delivery. As natural biomolecules, proteins offer distinct advantages, including safety, biocompatibility and biodegradability, making them a fascinating alternative to synthetic polymers. Moreover, protein-based carriers, including those derived from gelatin, albumin, collagen, gliadin and silk proteins, demonstrate exceptional stability under physiological conditions, and they allow for controlled and sustained drug release, enhancing therapeutic efficacy. This review provides a comprehensive overview of the current trends, challenges, and future perspectives in protein-based drug delivery, focusing on the types of proteins adopted and the techniques that are being developed to enhance their functionality in terms of drug affinity and targeting capabilities, underscoring their potential to significantly impact modern therapeutics. Full article
(This article belongs to the Special Issue The 15th Anniversary of Pharmaceutics—Advances and Future Trends in Drug Delivery)
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25 pages, 5468 KB  
Review
A Descriptive Review on the Potential Use of Diatom Biosilica as a Powerful Functional Biomaterial: A Natural Drug Delivery System
by Sunggu Kang, Yeeun Woo, Yoseph Seo, Daehyeon Yoo, Daeryul Kwon, Hyunjun Park, Sang Deuk Lee, Hah Young Yoo and Taek Lee
Pharmaceutics 2024, 16(9), 1171; https://doi.org/10.3390/pharmaceutics16091171 - 5 Sep 2024
Cited by 13 | Viewed by 3473
Abstract
Although various chemically synthesized materials are essential in medicine, food, and agriculture, they can exert unexpected side effects on the environment and human health by releasing certain toxic chemicals. Therefore, eco-friendly and biocompatible biomaterials based on natural resources are being actively explored. Recently, [...] Read more.
Although various chemically synthesized materials are essential in medicine, food, and agriculture, they can exert unexpected side effects on the environment and human health by releasing certain toxic chemicals. Therefore, eco-friendly and biocompatible biomaterials based on natural resources are being actively explored. Recently, biosilica derived from diatoms has attracted attention in various biomedical fields, including drug delivery systems (DDS), due to its uniform porous nano-pattern, hierarchical structure, and abundant silanol functional groups. Importantly, the structural characteristics of diatom biosilica improve the solubility of poorly soluble substances and enable sustained release of loaded drugs. Additionally, diatom biosilica predominantly comprises SiO2, has high biocompatibility, and can easily hybridize with other DDS platforms, including hydrogels and cationic DDS, owing to its strong negative charge and abundant silanol groups. This review explores the potential applications of various diatom biosilica-based DDS in various biomedical fields, with a particular focus on hybrid DDS utilizing them. Full article
(This article belongs to the Special Issue Lipid-Based Nanoparticulate Drug Delivery Systems: Preparation, Biomedical Applications, and Evaluation)
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14 pages, 2411 KB  
Article
Reactive Oxygen Species-Regulated Conjugates Based on Poly(jasmine) Lactone for Simultaneous Delivery of Doxorubicin and Docetaxel
by Jyoti Verma, Vishal Kumar, Carl-Eric Wilen, Jessica M. Rosenholm and Kuldeep K. Bansal
Pharmaceutics 2024, 16(9), 1164; https://doi.org/10.3390/pharmaceutics16091164 - 3 Sep 2024
Cited by 2 | Viewed by 2194
Abstract
In cancer therapy, it is essential to selectively release cytotoxic agents into the tumor to prevent the adverse effects associated with anticancer drugs. Thus, in this study, a stimuli-sensitive polymer–drug conjugate was synthesized for selective drug release. Doxorubicin (DOX) and docetaxel (DTX) were [...] Read more.
In cancer therapy, it is essential to selectively release cytotoxic agents into the tumor to prevent the adverse effects associated with anticancer drugs. Thus, in this study, a stimuli-sensitive polymer–drug conjugate was synthesized for selective drug release. Doxorubicin (DOX) and docetaxel (DTX) were conjugated onto novel poly(jasmine lactone) based copolymer via a thioketal (TK) linker. In addition, a photosensitizer (chlorin e6) was attached to the polymer, which served as a reactive oxygen species generator to cleave the TK linker. The conjugate is readily self-assembled into micelles less than 100 nm in size. Micelles demonstrate a notable increase in their ability to cause cell death when exposed to near-infrared (NIR) light on MDA-MB-231 breast cancer cells. The increase in cytotoxicity is higher than that observed with the combination of free DOX and DTX. The accumulation of DOX in the nucleus after release from the micelles (laser irradiation) was also confirmed by confocal microscopy. In the absence of light, micelles did not show any toxicity while the free drugs were found toxic irrespective of the light exposure. The obtained results suggest the targeted drug delivery potential of micelles regulated by the external stimuli, i.e., NIR light. Full article
(This article belongs to the Special Issue Functional Nanomaterials for Drug Delivery in Photodynamic Therapy)
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32 pages, 4110 KB  
Review
Platinum Group Metals Nanoparticles in Breast Cancer Therapy
by Sibusiso Alven, Sendibitiyosi Gandidzanwa, Basabele Ngalo, Olwethu Poswayo, Tatenda Madanhire, Blessing A. Aderibigbe and Zenixole Tshentu
Pharmaceutics 2024, 16(9), 1162; https://doi.org/10.3390/pharmaceutics16091162 - 3 Sep 2024
Cited by 6 | Viewed by 4083
Abstract
Despite various methods currently used in cancer therapy, breast cancer remains the leading cause of morbidity and mortality worldwide. Current therapeutics face limitations such as multidrug resistance, drug toxicity and off-target effects, poor drug bioavailability and biocompatibility, and inefficient drug delivery. Nanotechnology has [...] Read more.
Despite various methods currently used in cancer therapy, breast cancer remains the leading cause of morbidity and mortality worldwide. Current therapeutics face limitations such as multidrug resistance, drug toxicity and off-target effects, poor drug bioavailability and biocompatibility, and inefficient drug delivery. Nanotechnology has emerged as a promising approach to cancer diagnosis, imaging, and therapy. Several preclinical studies have demonstrated that compounds and nanoparticles formulated from platinum group metals (PGMs) effectively treat breast cancer. PGMs are chemically stable, easy to functionalise, versatile, and tunable. They can target hypoxic microenvironments, catalyse the production of reactive oxygen species, and offer the potential for combination therapy. PGM nanoparticles can be incorporated with anticancer drugs to improve efficacy and can be attached to targeting moieties to enhance tumour-targeting efficiency. This review focuses on the therapeutic outcomes of platinum group metal nanoparticles (PGMNs) against various breast cancer cells and briefly discusses clinical trials of these nanoparticles in breast cancer treatment. It further illustrates the potential applications of PGMNs in breast cancer and presents opportunities for future PGM-based nanomaterial applications in combatting breast cancer. Full article
(This article belongs to the Special Issue Nanomedicines in Cancer Therapy)
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22 pages, 728 KB  
Review
Lipid-Based Nanocarriers: Bridging Diagnosis and Cancer Therapy
by Alessandra Giordano, Anna Chiara Provenza, Giorgio Reverchon, Lucia Baldino and Ernesto Reverchon
Pharmaceutics 2024, 16(9), 1158; https://doi.org/10.3390/pharmaceutics16091158 - 1 Sep 2024
Cited by 25 | Viewed by 5450
Abstract
Theranostics is a growing field that matches diagnostics and therapeutics. In this approach, drugs and techniques are uniquely coupled to diagnose and treat medical conditions synergically or sequentially. By integrating diagnostic and treatment functions in a single platform, the aim of theranostics is [...] Read more.
Theranostics is a growing field that matches diagnostics and therapeutics. In this approach, drugs and techniques are uniquely coupled to diagnose and treat medical conditions synergically or sequentially. By integrating diagnostic and treatment functions in a single platform, the aim of theranostics is to improve precision medicine by tailoring treatments based on real-time information. In this context, lipid-based nanocarriers have attracted great scientific attention due to their biodegradability, biocompatibility, and targeting capabilities. The present review highlights the latest research advances in the field of lipid-based nanocarriers for cancer theranostics, exploring several ways of improving in vivo performance and addressing associated challenges. These nanocarriers have significant potential to create new perspectives in the field of nanomedicine and offer promise for a significant step towards more personalized and precise medicine, reducing side effects and improving clinical outcomes for patients. This review also presents the actual barriers to and the possible challenges in the use of nanoparticles in the theranostic field, such as regulatory hurdles, high costs, and technological integration. Addressing these issues through a multidisciplinary and collaborative approach among institutions could be essential for advancing lipid nanocarriers in the theranostic field. Such collaborations can leverage diverse expertise and resources, fostering innovation and overcoming the complex challenges associated with clinical translation. This approach will be crucial for realizing the full potential of lipid-based nanocarriers in precision medicine. Full article
(This article belongs to the Topic Challenges and Opportunities in Drug Delivery Research)
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16 pages, 3069 KB  
Article
An Antibacterial-Loaded PLA 3D-Printed Model for Temporary Prosthesis in Arthroplasty Infections: Evaluation of the Impact of Layer Thickness on the Mechanical Strength of a Construct and Drug Release
by Carlos Tamarit-Martínez, Lucía Bernat-Just, Carlos Bueno-López, Adrián M. Alambiaga-Caravaca, Virginia Merino, Alicia López-Castellano and Vicent Rodilla
Pharmaceutics 2024, 16(9), 1151; https://doi.org/10.3390/pharmaceutics16091151 - 30 Aug 2024
Cited by 1 | Viewed by 1483
Abstract
Infections are one of the main complications in arthroplasties. These infections are difficult to treat because the bacteria responsible for them settle in the prosthesis and form a biofilm that does not allow antimicrobials to reach the infected area. This study is part [...] Read more.
Infections are one of the main complications in arthroplasties. These infections are difficult to treat because the bacteria responsible for them settle in the prosthesis and form a biofilm that does not allow antimicrobials to reach the infected area. This study is part of a research project aimed at developing 3D-printed spacers (temporary prostheses) capable of incorporating antibacterials for the personalized treatment of arthroplasty infections. The main objective of this research was to analyze the impact of the layer thickness of 3D-printed constructs based on polylactic acid (PLA) for improved treatment of infections in arthroplasty. The focus is on the following parameters: resistance, morphology, drug release, and the effect of antibacterials incorporated in the printed temporary prostheses. The resistance studies revealed that the design and layer thickness of a printed spacer have an influence on its resistance properties. The thickness of the layer used in printing affects the amount of methylene blue (used as a model drug) that is released. Increasing layer thickness leads to a greater release of the drug from the spacer, probably as a result of higher porosity. To evaluate antibacterial release, cloxacillin and vancomycin were incorporated into the constructs. When incorporated into the 3D construct, both antibacterials were released, as evidenced by the growth inhibition of Staphylococcus aureus. In conclusion, preliminary results indicate that the layer thickness during the three-dimensional (3D) printing process of the spacer plays a significant role in drug release. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of 3D Printing)
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27 pages, 9145 KB  
Article
Application of Hydrophilic Polymers to the Preparation of Prolonged-Release Minitablets with Bromhexine Hydrochloride and Bisoprolol Fumarate
by Agata Grzejdziak, Witold Brniak, Olaf Lengier, Justyna Anna Żarek, Dziyana Hliabovich and Aleksander Mendyk
Pharmaceutics 2024, 16(9), 1153; https://doi.org/10.3390/pharmaceutics16091153 - 30 Aug 2024
Cited by 2 | Viewed by 2162
Abstract
Minitablets have been extensively studied in recent years as a convenient pediatric form because they allow successful administration even in very young children. Their advantages include easy dose adjustment by multiplication of single units as well as the possibility of drug release modification [...] Read more.
Minitablets have been extensively studied in recent years as a convenient pediatric form because they allow successful administration even in very young children. Their advantages include easy dose adjustment by multiplication of single units as well as the possibility of drug release modification by coating or forming matrix systems. The aim of this study was to demonstrate the possibility of the formulation of prolonged-release minitablets with bromhexine hydrochloride (BHX) and bisoprolol fumarate (BFM) dedicated to pediatric patients. Minitablets with 3 mm diameter and 15 mg mass, containing 1 mg of active substance in 1 unit, were prepared by direct compression with hydroxypropyl methylcellulose (HPMC) of different grades, methylcellulose, sodium alginate, or polyvinyl alcohol (PVA) as a sustained-release polymer. Different amounts of polymers and different compression forces were evaluated. Analysis of minitablets included their uniformity, hardness, and dissolution tests. The kinetics of drug substance release were analyzed with dedicated software. The prepared minitablets met the pharmacopeial requirements with respect to the uniformity of mass and content. The compressibility of BFM was significantly better than that of BHX, yet all minitablets had good mechanical properties. Dissolution studies showed a strong relationship between the type of polymer and its amount in the mass of a tablet and the dissolution rate. Prolonged release of up to 8 h was achieved when HPMC of 4000 cP viscosity was used in the amount of 30% to 80%. Sodium alginate in the amount of 50% was also effective in prolonging dissolution, but PVA was much less effective. Studies on the release kinetics showed that dissolution from prolonged-release minitablets with BHX fit the best to Hopfenberg or Hixson–Crowell models, while in the case of BFM, the best fit was found for Hopfenberg or Korsmeyer–Peppas models. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Excipients Used in Solid Dosage Forms)
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16 pages, 6332 KB  
Review
Recent Advances in Drug Delivery Strategies for High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer: A Brief Review from 2018 to 2024
by Feng Qu, Saloni Darji and David H. Thompson
Pharmaceutics 2024, 16(9), 1154; https://doi.org/10.3390/pharmaceutics16091154 - 30 Aug 2024
Cited by 13 | Viewed by 7085
Abstract
High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is a condition that is typically treated with Bacillus Calmette–Guérin (BCG) therapy. Unfortunately, NMIBC is characterized by high recurrence, with a significant percentage of BCG patients ultimately requiring radical cystectomy. As a consequence, the development of [...] Read more.
High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is a condition that is typically treated with Bacillus Calmette–Guérin (BCG) therapy. Unfortunately, NMIBC is characterized by high recurrence, with a significant percentage of BCG patients ultimately requiring radical cystectomy. As a consequence, the development of effective new therapies to avoid RC has become a rapidly evolving field to address this unmet clinical need. To date, three biologics—Keytruda, Adstiladrin, and Anktiva—have been approved by the FDA, and multiple drug modalities, particularly gene therapies, have shown promising results in clinical trials. Advances in drug delivery strategies, such as targeted delivery, sustained release, and permeabilization of protective layers, are critical in overcoming the challenges posed by therapeutic intervention in bladder cancer. This review focuses on high-risk BCG-unresponsive NMIBC therapies that have been or are currently being investigated in clinical trials, offering a broad overview of the delivery system designs and up-to-date clinical outcomes that have been reported as of July 2024. It aims to inform the development of future drug delivery systems for second-line therapies in high-risk BCG-unresponsive NMIBC. Full article
(This article belongs to the Special Issue Nanotechnology Applied in Prevention, Diagnosis and Treatment of Cancer)
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21 pages, 1480 KB  
Review
Drug Nanocrystals in Oral Absorption: Factors That Influence Pharmacokinetics
by Luiza de Oliveira Macedo, Jéssica Fagionato Masiero and Nádia Araci Bou-Chacra
Pharmaceutics 2024, 16(9), 1141; https://doi.org/10.3390/pharmaceutics16091141 - 29 Aug 2024
Cited by 11 | Viewed by 4144
Abstract
Despite the safety and convenience of oral administration, poorly water-soluble drugs compromise absorption and bioavailability. These drugs can exhibit low dissolution rates, variability between fed and fasted states, difficulty permeating the mucus layer, and P-glycoprotein efflux. Drug nanocrystals offer a promising strategy to [...] Read more.
Despite the safety and convenience of oral administration, poorly water-soluble drugs compromise absorption and bioavailability. These drugs can exhibit low dissolution rates, variability between fed and fasted states, difficulty permeating the mucus layer, and P-glycoprotein efflux. Drug nanocrystals offer a promising strategy to address these challenges. This review focuses on the opportunities to develop orally administered nanocrystals based on pharmacokinetic outcomes. The impacts of the drug particle size, morphology, dissolution rate, crystalline state on oral bioavailability are discussed. The potential of the improved dissolution rate to eliminate food effects during absorption is also addressed. This review also explores whether permeation or dissolution drives nanocrystal absorption. Additionally, it addresses the functional roles of stabilizers. Drug nanocrystals may result in prolonged concentrations in the bloodstream in some cases. Therefore, nanocrystals represent a promising strategy to overcome the challenges of poorly water-soluble drugs, thus encouraging further investigation into unclear mechanisms during oral administration. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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17 pages, 3399 KB  
Article
Lipid-Based Nanoparticles Fused with Natural Killer Cell Plasma Membrane Proteins for Triple-Negative Breast Cancer Therapy
by Eun-Jeong Won, Myungchul Lee, Eui-Kyung Lee, Seung-Hoon Baek and Tae-Jong Yoon
Pharmaceutics 2024, 16(9), 1142; https://doi.org/10.3390/pharmaceutics16091142 - 29 Aug 2024
Cited by 6 | Viewed by 2780
Abstract
Immunotherapy combined with chemicals and genetic engineering tools is emerging as a promising strategy to treat triple-negative breast cancer (TNBC), which is more aggressive with poorer progress than other breast cancer subtypes. In this study, lipid-based nanoparticles (LNPs) possessed an NK cell-like function [...] Read more.
Immunotherapy combined with chemicals and genetic engineering tools is emerging as a promising strategy to treat triple-negative breast cancer (TNBC), which is more aggressive with poorer progress than other breast cancer subtypes. In this study, lipid-based nanoparticles (LNPs) possessed an NK cell-like function that could deliver tumor-specific therapeutics and inhibit tumor growth. LNPs fused with an NK cell membrane protein system (NK-LNP) have three main features: (i) hydrophilic plasmid DNA can inhibit TNBC metastasis when encapsulated within LNPs and delivered to cells; (ii) the lipid composition of LNPs, including C18 ceramide, exhibits anticancer effects; (iii) NK cell membrane proteins are immobilized on the LNP surface, enabling targeted delivery to TNBC cells. These particles facilitate the targeted delivery of HIC1 plasmid DNA and the modulation of immune cell functions. Delivered therapeutic genes can inhibit metastasis of TNBC and then induce apoptotic cell death while targeting macrophages to promote cytokine release. The anticancer effect is expected to be applied in treating various difficult-to-treat cancers with LNP fused with NK cell plasma membrane proteins, which can simultaneously deliver therapeutic chemicals and genes. Full article
(This article belongs to the Special Issue Recent Advances in Polymeric Nanoparticle-Based Drug Delivery System for Cancer Therapy)
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22 pages, 3650 KB  
Article
An Innovative Bio-Vehicle for Resveratrol and Tocopherol Based on Quinoa 11S Globulin—Nanocomplex Design and Characterization
by Alejandra J. Rubinstein, Guadalupe Garcia Liñares, Valeria Boeris and Oscar E. Pérez
Pharmaceutics 2024, 16(9), 1118; https://doi.org/10.3390/pharmaceutics16091118 - 24 Aug 2024
Cited by 3 | Viewed by 2133
Abstract
Nanocomplexes, which possess immense potential to function as nanovehicles, can link diverse ligand compounds. The objective of the present study was to design and characterize resveratrol (RSV)- and tocopherol (TOC)-loaded 11S quinoa seed protein nanocomplexes. Firstly, molecular docking was performed to describe the [...] Read more.
Nanocomplexes, which possess immense potential to function as nanovehicles, can link diverse ligand compounds. The objective of the present study was to design and characterize resveratrol (RSV)- and tocopherol (TOC)-loaded 11S quinoa seed protein nanocomplexes. Firstly, molecular docking was performed to describe the probable binding sites between protein and ligands, and binding energies of −5.6 and −6.2 kcal/mol were found for RSV and TOC, respectively. Isothermal titration calorimetry allowed us to obtain the thermodynamic parameters that described the molecular interactions between RSV or TOC with the protein, finding the complexation process to be exothermic and spontaneous. 11S globulin intrinsic fluorescence spectra showed quenching effects exerted by RSV and TOC, demonstrating protein–bioactive compound interactions. The application of Stern–Volmer, Scatchard, and Förster resonance energy transfer models confirmed static quenching and allowed us to obtain parameters that described the 11S-RSV and 11S-TOC complexation processes. RSV has a higher tendency to bind 11S globulin according to ITC and fluorescence analysis. Secondly, the protein aggregation induced by bioactive compound interactions was confirmed by dynamic light scattering and atomic force microscopy, with diameters <150 nm detected by both techniques. Finally, it was found that the antioxidant capacity of a single 11S globulin did not decrease; meanwhile, it was additive for 11S-RSV. These nanocomplexes could constitute a real platform for the design of nutraceutical products. Full article
(This article belongs to the Topic Applications of Polymers and Polymer Nanomaterials in Drug Delivery and Nanomedicine)
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18 pages, 2899 KB  
Article
The Development of a Chocolate-Based Chewable Tablet of Prednisolone—Enhancing the Palatability of Steroids for Pediatric Use
by Okhee Yoo, Edith Tang, Md Lokman Hossain, Britta S. von Ungern-Sternberg, David Sommerfield, Chloe Heath, Neil Hauser, R. Nazim Khan, Cornelia Locher, Minh Nguyen and Lee Yong Lim
Pharmaceutics 2024, 16(8), 1099; https://doi.org/10.3390/pharmaceutics16081099 - 21 Aug 2024
Cited by 2 | Viewed by 3519
Abstract
Oral liquid prednisolone medications have poor acceptance among paediatric patients due to ineffective masking of the bitterness taste of prednisolone. This study aimed to develop a child-friendly prednisolone tablet using a patented chewable chocolate-based delivery system (CDS) previously applied successfully to mask the [...] Read more.
Oral liquid prednisolone medications have poor acceptance among paediatric patients due to ineffective masking of the bitterness taste of prednisolone. This study aimed to develop a child-friendly prednisolone tablet using a patented chewable chocolate-based delivery system (CDS) previously applied successfully to mask the bitterness tastes of midazolam and tramadol. Prednisolone sodium phosphate (PSP) and prednisolone base (PB) CDS tablets were prepared, and the manufacturing process was optimised using a design of experiments (DoE) approach. Stability was assessed by quantifying residual drug content via a validated HPLC assay. A pilot randomised crossover taste study involving 25 young adult volunteers evaluated taste-masking effectiveness against Redipred™, a commercial oral PSP liquid medicine. The results showed that the PSP CDS tablet was chemically stable following storage for three months at ambient temperature, while the PB CDS tablet was unstable. The optimised PSP CDS tablet, manufactured at 50 °C with a stirring time of 26 h, was found to release over 80% of its drug load within 20 min in 0.1 M HCl and had a significantly better mean taste score compared to Redipred™ (7.08 ± 2.40 vs. 5.60 ± 2.33, p = 0.03). Fifty six percent of the participants preferred the PSP CDS tablet. In conclusion, compared to Redipred™, the CDS technology provided a more effective taste masking of PSP, potentially offering a child-friendly prednisolone formulation with improved compliance, dosing accuracy, and storage stability. Full article
(This article belongs to the Special Issue Advanced Pediatric Drug Formulation Strategies)
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12 pages, 1413 KB  
Article
Synthesis, Characterization, and Cytotoxicity Evaluation of Chlorambucil-Functionalized Mesoporous Silica Nanoparticles
by Juliana Camila Fischer Karnopp, Juliana Jorge, Jaqueline Rodrigues da Silva, Diego Boldo, Kristiane Fanti Del Pino Santos, Adriana Pereira Duarte, Gustavo Rocha de Castro, Ricardo Bentes de Azevedo, Ariadna Lafourcade Prada, Jesús Rafael Rodríguez Amado and Marco Antonio Utrera Martines
Pharmaceutics 2024, 16(8), 1086; https://doi.org/10.3390/pharmaceutics16081086 - 19 Aug 2024
Cited by 2 | Viewed by 2499
Abstract
This study describes the synthesis and characterization of chlorambucil (CLB)-functionalized mesoporous silica nanoparticles (MSNs) for potential application in cancer therapy. The nanoparticles were designed with a diameter between 20 and 50 nm to optimize cellular uptake and avoid rapid clearance from the bloodstream. [...] Read more.
This study describes the synthesis and characterization of chlorambucil (CLB)-functionalized mesoporous silica nanoparticles (MSNs) for potential application in cancer therapy. The nanoparticles were designed with a diameter between 20 and 50 nm to optimize cellular uptake and avoid rapid clearance from the bloodstream. The synthesis method involved modifying a previously reported technique to reduce particle size. Successful functionalization with CLB was confirmed through various techniques, including Fourier transform infrared spectroscopy (FTIR) and elemental analysis. The cytotoxicity of the CLB-functionalized nanoparticles (MSN@NH2-CLB) was evaluated against human lung adenocarcinoma cells (A549) and colon carcinoma cells (CT26WT). The results suggest significantly higher cytotoxicity of MSN@NH2-CLB compared to unbound CLB, with improved selectivity towards cancer cells over normal cells. This suggests that MSN@NH2-CLB holds promise as a drug delivery system for targeted cancer therapy. Full article
(This article belongs to the Special Issue Advances in Nanotechnology-Based Drug Delivery Systems)
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24 pages, 4412 KB  
Article
Unlocking the Potential of Camel Milk-Derived Exosomes as Novel Delivery Systems: Enhanced Bioavailability of ARV-825 PROTAC for Cancer Therapy
by Aakash Nathani, Mounika Aare, Li Sun, Arvind Bagde, Yan Li, Arun Rishi and Mandip Singh
Pharmaceutics 2024, 16(8), 1070; https://doi.org/10.3390/pharmaceutics16081070 - 15 Aug 2024
Cited by 14 | Viewed by 3997
Abstract
This study investigates the use of camel milk-derived exosomes (CMEs) as carriers for ARV-825, an anticancer agent targeting bromodomain-containing protein 4 (BRD4), in oral chemotherapy. CMEs were isolated and characterized, and ARV-825-loaded CME formulations were prepared and evaluated through various in vitro and [...] Read more.
This study investigates the use of camel milk-derived exosomes (CMEs) as carriers for ARV-825, an anticancer agent targeting bromodomain-containing protein 4 (BRD4), in oral chemotherapy. CMEs were isolated and characterized, and ARV-825-loaded CME formulations were prepared and evaluated through various in vitro and in vivo tests. The ARV-825-CME formulation exhibited an entrapment efficiency of 42.75 ± 5.05%, a particle size of 136.8 ± 1.94 nm, and a zeta potential of −32.75 ± 0.70 mV, ensuring stability and sustained drug release. In vitro studies showed a 5.4-fold enhancement in drug release kinetics compared to the free ARV-825 solution. Permeability studies indicated a 3.2-fold increase in apparent permeability, suggesting improved cellular uptake. Cytotoxicity assays demonstrated potent anticancer activity, with IC50 values decreasing by 1.5 to 2-fold in cancer cell lines SF8628 DIPG and H1975R (resistant to Osimertinib). In vivo pharmacokinetic studies in Sprague-Dawley rats revealed superior systemic absorption and bioavailability of ARV-825 from CMEs, with a 2.55-fold increase in plasma concentration and a 5.56-fold increase in AUC. Distribution studies confirmed absorption through the ileum. This research highlights the potential of CMEs as a promising delivery platform for ARV-825, enhancing its therapeutic efficacy and offering a novel approach to cancer treatment. Full article
(This article belongs to the Special Issue Exosomes as Drug Carriers for Cancer Therapy)
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22 pages, 4036 KB  
Article
Development and Evaluation of Different Electrospun Cysteamine-Loaded Nanofibrous Webs: A Promising Option for Treating a Rare Lysosomal Storage Disorder
by Safaa Omer, Nándor Nagy, Balázs Pinke, László Mészáros, Adrienn Kazsoki and Romána Zelkó
Pharmaceutics 2024, 16(8), 1052; https://doi.org/10.3390/pharmaceutics16081052 - 9 Aug 2024
Cited by 3 | Viewed by 2381
Abstract
Nanofibers can be utilized to overcome the challenges faced by conventional ophthalmic formulations. This study aimed to develop and characterize cysteamine (Cys)-loaded nanofiber-based ophthalmic inserts (OIs) as a potential candidate for the treatment of ophthalmic cystinosis using water-soluble polyvinyl alcohol (PVA)/poloxamer 407 (PO-407) [...] Read more.
Nanofibers can be utilized to overcome the challenges faced by conventional ophthalmic formulations. This study aimed to develop and characterize cysteamine (Cys)-loaded nanofiber-based ophthalmic inserts (OIs) as a potential candidate for the treatment of ophthalmic cystinosis using water-soluble polyvinyl alcohol (PVA)/poloxamer 407 (PO-407) and water-insoluble tetraethoxysilane (TEOS)/PVA nanofibers. Plain and Cys-loaded fibers in different proportions were prepared by the electrospinning method and studied for their morphological, physicochemical, release study, cytocompatibility effects, and stability study. The fiber formation was confirmed by scanning electron microscopy, while Fourier transform infrared spectra showed the most critical peaks for the Cys and the excipients. The release of the Cys was fast from the two polymeric matrices (≤20 min). The release from TEOS/PVA nanofibers is characterized by Case II transport (0.75 < β < 1), while the release from PVA/PO-407 nanofibers follows Fickian diffusion (β < 0.75). The cytocompatibility of compositions was confirmed by hen eggs tested on the chorioallantoic membrane (HET-CAM) of chick embryos. All formulations remained stable under stress conditions (40 ± 2 °C, 75 ± 5% relative humidity) regarding morphology and physicochemical characteristics. The developed nanofibrous mats could be an excellent alternative to available Cys drops, with better stability and convenience of self-administration as OIs. Full article
(This article belongs to the Topic Applications of Polymers and Polymer Nanomaterials in Drug Delivery and Nanomedicine)
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20 pages, 2134 KB  
Article
Dopamine and Citicoline-Co-Loaded Solid Lipid Nanoparticles as Multifunctional Nanomedicines for Parkinson’s Disease Treatment by Intranasal Administration
by Stefano Castellani, Giorgia Natalia Iaconisi, Francesca Tripaldi, Vito Porcelli, Adriana Trapani, Eugenia Messina, Lorenzo Guerra, Cinzia Di Franco, Giuseppe Maruccio, Anna Grazia Monteduro, Filomena Corbo, Sante Di Gioia, Giuseppe Trapani and Massimo Conese
Pharmaceutics 2024, 16(8), 1048; https://doi.org/10.3390/pharmaceutics16081048 - 7 Aug 2024
Cited by 11 | Viewed by 4163
Abstract
This work aimed to evaluate the potential of the nanosystems constituted by dopamine (DA) and the antioxidant Citicoline (CIT) co-loaded in solid lipid nanoparticles (SLNs) for intranasal administration in the treatment of Parkinson disease (PD). Such nanosystems, denoted as DA-CIT-SLNs, were designed according [...] Read more.
This work aimed to evaluate the potential of the nanosystems constituted by dopamine (DA) and the antioxidant Citicoline (CIT) co-loaded in solid lipid nanoparticles (SLNs) for intranasal administration in the treatment of Parkinson disease (PD). Such nanosystems, denoted as DA-CIT-SLNs, were designed according to the concept of multifunctional nanomedicine where multiple biological roles are combined into a single nanocarrier and prepared by the melt emulsification method employing the self-emulsifying Gelucire® 50/13 as lipid matrix. The resulting DA-CIT-SLNs were characterized regarding particle size, surface charge, encapsulation efficiency, morphology, and physical stability. Differential scanning calorimetry, FT-IR, and X ray diffraction studies were carried out to gain information on solid-state features, and in vitro release tests in simulated nasal fluid (SNF) were performed. Monitoring the particle size at two temperatures (4 °C and 37 °C), the size enlargement observed over the time at 37 °C was lower than that observed at 4 °C, even though at higher temperature, color changes occurred, indicative of possible neurotransmitter decomposition. Solid-state studies indicated a reduction in the crystallinity when DA and CIT are co-encapsulated in DA-CIT-SLNs. Interestingly, in vitro release studies in SNF indicated a sustained release of DA. Furthermore, DA-CIT SLNs displayed high cytocompatibility with both human nasal RPMI 2650 and neuronal SH-SY5Y cells. Furthermore, OxyBlot assay demonstrated considerable potential to assess the protective effect of antioxidant agents against oxidative cellular damage. Thus, such protective effect was shown by DA-CIT-SLNs, which constitute a promising formulation for PD application. Full article
(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application, 2nd Edition)
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57 pages, 3841 KB  
Review
Functionalized Polymeric Micelles for Targeted Cancer Therapy: Steps from Conceptualization to Clinical Trials
by Ana Serras, Célia Faustino and Lídia Pinheiro
Pharmaceutics 2024, 16(8), 1047; https://doi.org/10.3390/pharmaceutics16081047 - 6 Aug 2024
Cited by 12 | Viewed by 4797
Abstract
Cancer is still ranked among the top three causes of death in the 30- to 69-year-old age group in most countries and carries considerable societal and macroeconomic costs that differ depending on the cancer type, geography, and patient gender. Despite advances in several [...] Read more.
Cancer is still ranked among the top three causes of death in the 30- to 69-year-old age group in most countries and carries considerable societal and macroeconomic costs that differ depending on the cancer type, geography, and patient gender. Despite advances in several pharmacological approaches, the lack of stability and specificity, dose-related toxicity, and limited bioavailability of chemotherapy (standard therapy) pose major obstacles in cancer treatment, with multidrug resistance being a driving factor in chemotherapy failure. The past three decades have been the stage for intense research activity on the topic of nanomedicine, which has resulted in many nanotherapeutics with reduced toxicity, increased bioavailability, and improved pharmacokinetics and therapeutic efficacy employing smart drug delivery systems (SDDSs). Polymeric micelles (PMs) have become an auspicious DDS for medicinal compounds, being used to encapsulate hydrophobic drugs that also exhibit substantial toxicity. Through preclinical animal testing, PMs improved pharmacokinetic profiles and increased efficacy, resulting in a higher safety profile for therapeutic drugs. This review focuses on PMs that are already in clinical trials, traveling the pathways from preclinical to clinical studies until introduction to the market. Full article
(This article belongs to the Special Issue Supramolecular Systems for Gene and Drug Delivery, 2nd Edition)
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13 pages, 12577 KB  
Article
Melanoma Brain Metastases Patient-Derived Organoids: An In Vitro Platform for Drug Screening
by Saif-Eldin Abedellatif, Racha Hosni, Andreas Waha, Gerrit H. Gielen, Mohammed Banat, Motaz Hamed, Erdem Güresir, Anne Fröhlich, Judith Sirokay, Anna-Lena Wulf, Glen Kristiansen, Torsten Pietsch, Hartmut Vatter, Michael Hölzel, Matthias Schneider and Marieta Ioana Toma
Pharmaceutics 2024, 16(8), 1042; https://doi.org/10.3390/pharmaceutics16081042 - 5 Aug 2024
Cited by 5 | Viewed by 3141
Abstract
Background and aims: Brain metastases are prevalent in the late stages of malignant melanoma. Multimodal therapy remains challenging. Patient-derived organoids (PDOs) represent a valuable pre-clinical model, faithfully recapitulating key aspects of the original tumor, including the heterogeneity and the mutational status. This study [...] Read more.
Background and aims: Brain metastases are prevalent in the late stages of malignant melanoma. Multimodal therapy remains challenging. Patient-derived organoids (PDOs) represent a valuable pre-clinical model, faithfully recapitulating key aspects of the original tumor, including the heterogeneity and the mutational status. This study aimed to establish PDOs from melanoma brain metastases (MBM-PDOs) and to test the feasibility of using them as a model for in vitro targeted-therapy drug testing. Methods: Surgical resection samples from eight patients with melanoma brain metastases were used to establish MBM-PDOs. The samples were enzymatically dissociated followed by seeding into low-attachment plates to generate floating organoids. The MBM-PDOs were characterized genetically, histologically, and immunohistologically and compared with the parental tissue. The MBM-PDO cultures were exposed to dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) followed by a cell viability assessment. Results: Seven out of eight cases were successfully cultivated, maintaining the histological, immunohistological phenotype, and the mutational status of the parental tumors. Five out of seven cases harbored BRAF V600E mutations and were responsive to BRAF and MEK inhibitors in vitro. Two out of seven cases were BRAF wild type: one case harboring an NRAS mutation and the other harboring a KIT mutation, and both were resistant to BRAF and MEK inhibitor therapy. Conclusions: We successfully established PDOs from melanoma brain metastases surgical specimens, which exhibited a consistent histological and mutational profile with the parental tissue. Using FDA-approved BRAF and MEK inhibitors, our data demonstrate the feasibility of employing MBM-PDOs for targeted-therapy in vitro testing. Full article
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18 pages, 3175 KB  
Article
Application of a Novel Dissolution Medium with Lipids for In Vitro Simulation of the Postprandial Gastric Content
by Tjaša Felicijan, Iva Rakoše, Manca Prislan, Igor Locatelli, Marija Bogataj and Jurij Trontelj
Pharmaceutics 2024, 16(8), 1040; https://doi.org/10.3390/pharmaceutics16081040 - 3 Aug 2024
Viewed by 2155
Abstract
Food can change various physiological parameters along the gastrointestinal tract, potentially impacting postprandial drug absorption. It is thus important to consider different in vivo conditions during in vitro studies. Therefore, a novel dissolution medium simulating variable postprandial pH values and lipid concentrations was [...] Read more.
Food can change various physiological parameters along the gastrointestinal tract, potentially impacting postprandial drug absorption. It is thus important to consider different in vivo conditions during in vitro studies. Therefore, a novel dissolution medium simulating variable postprandial pH values and lipid concentrations was developed and used in this study. Additionally, by establishing and validating a suitable analytical method, the effects of these parameters on the dissolution of a model drug, cinnarizine, and on its distribution between the lipid and aqueous phases of the medium were studied. Both parameters, pH value and lipid concentration, were shown to influence cinnarizine behavior in the in vitro dissolution studies. The amount of dissolved drug decreased with increasing pH due to cinnarizine’s decreasing solubility. At pH values 5 and 7, the higher concentration of lipids in the medium increased drug dissolution, and most of the dissolved drug was distributed in the lipid phase. In all media with a lower pH of 3, dissolution was fast and complete, with a significant amount of drug distributed in the lipid phase. These results are in accordance with the in vivo observed positive food effect on cinnarizine bioavailability described in the literature. The developed medium, with its ability to easily adjust the pH level and lipid concentration, thus offers a promising tool for assessing the effect of co-ingested food on the dissolution kinetics of poorly soluble drugs. Full article
(This article belongs to the Special Issue Recent Advances in Pharmaceutical Dosage Forms)
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23 pages, 4946 KB  
Article
Next-Generation Contraceptive Intravaginal Ring: Comparison of Etonogestrel and Ethinyl Estradiol In Vitro and In Vivo Release from 3D-Printed Intravaginal Ring and NuvaRing
by Isabella C. Young, Allison L. Thorson, Mackenzie L. Cottrell, Craig Sykes, Amanda P. Schauer, Rani S. Sellers, Rima Janusziewicz, Kathleen L. Vincent and Soumya Rahima Benhabbour
Pharmaceutics 2024, 16(8), 1030; https://doi.org/10.3390/pharmaceutics16081030 - 2 Aug 2024
Cited by 5 | Viewed by 4676
Abstract
Intravaginal rings (IVRs) represent a well-established, woman-controlled and sustained vaginal drug delivery system suitable for a wide range of applications. Here, we sought to investigate the differences in etonogestrel (ENG) and ethinyl estradiol (EE) release from a 3D-printed IVR utilizing continuous liquid interface [...] Read more.
Intravaginal rings (IVRs) represent a well-established, woman-controlled and sustained vaginal drug delivery system suitable for a wide range of applications. Here, we sought to investigate the differences in etonogestrel (ENG) and ethinyl estradiol (EE) release from a 3D-printed IVR utilizing continuous liquid interface production (CLIP™) (referred to as CLIPLOW for low drug loading and CLIPHIGH IVRs for high drug loading) and NuvaRing, a commercially available injection molded IVR. We conducted in vitro release studies in simulated vaginal fluid to compare the release of ENG and EE from CLIPLOW IVRs and NuvaRing. CLIPLOW IVRs had a similar hormone dose to NuvaRing and exhibited slightly slower ENG release and greater EE release in vitro compared to NuvaRing. When administered to female sheep, NuvaRing demonstrated greater ENG/EE levels in plasma, vaginal tissue and vaginal fluids compared to CLIPLOW IVR despite similar drug loadings. Leveraging observed hormones levels in sheep from NuvaRing as an effective contraceptive benchmark, we developed a long-acting CLIPHIGH IVR with increased ENG and EE doses that demonstrated systemic and local hormone levels greater than the NuvaRing for 90 days in sheep. No signs of toxicity were noted regarding general health, colposcopy, or histological analysis in sheep after CLIPHIGH IVR administration. Our results provided (1) a comparison of ENG and EE release between a 3D-printed IVR and NuvaRing in vitro and in vivo, (2) a preclinical pharmacokinetic benchmark for vaginally delivered ENG and EE and (3) the generation of a 90-day CLIP IVR that will be utilized in future work to support the development of a long-acting ENG/EE IVR combined with an antiretroviral for the prevention of HIV and unplanned pregnancy. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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16 pages, 3117 KB  
Article
Optimization of Sodium Iodide-Based Root Filling Material for Clinical Applications: Enhancing Physicochemical Properties
by Hye-Shin Park, Yu-Jin Kim, Soo-Jin Chang, Hae-Hyoung Lee, Mi-Ran Han, Joon-Haeng Lee, Jong-Soo Kim, Jong-Bin Kim, Ji-Sun Shin and Jung-Hwan Lee
Pharmaceutics 2024, 16(8), 1031; https://doi.org/10.3390/pharmaceutics16081031 - 2 Aug 2024
Cited by 3 | Viewed by 2854
Abstract
Premature loss of root canal-treated primary teeth has long been a concern in dentistry. To address this, researchers developed a sodium iodide-based root canal-filling material as an alternative to traditional iodoform-based materials. The goal of this study was to improve the physicochemical properties [...] Read more.
Premature loss of root canal-treated primary teeth has long been a concern in dentistry. To address this, researchers developed a sodium iodide-based root canal-filling material as an alternative to traditional iodoform-based materials. The goal of this study was to improve the physicochemical properties of the sodium iodide-based material to meet clinical use standards. To resolve high solubility issues in the initial formulation, researchers adjusted component ratios and added new ingredients, resulting in a new paste called L5. This study compared L5 with L0 (identical composition minus lanolin) and Vitapex as controls, conducting physicochemical and antibacterial tests. Results showed that L5 met all ISO 6876 standards, demonstrated easier injection and irrigation properties than Vitapex, and exhibited comparable antibacterial efficacy to Vitapex, which is currently used clinically. The researchers conclude that if biological stability is further verified, L5 could potentially be presented as a new option for root canal-filling materials in primary teeth. Full article
(This article belongs to the Special Issue Advances in Scaffolds for Dental and Periodontal Tissue Regeneration)
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13 pages, 3288 KB  
Article
Identification of the Biotransformation Pathways of a Potential Oral Male Contraceptive, 11β-Methyl-19-Nortestosterone (11β-MNT) and Its Prodrugs: An In Vitro Study Highlights the Contribution of Polymorphic Intestinal UGT2B17
by Namrata Bachhav, Dilip Kumar Singh, Diana L. Blithe, Min S. Lee and Bhagwat Prasad
Pharmaceutics 2024, 16(8), 1032; https://doi.org/10.3390/pharmaceutics16081032 - 2 Aug 2024
Cited by 1 | Viewed by 2260
Abstract
11β-Methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) is a prodrug of 11β-MNT and is being considered as a promising male oral contraceptive candidate in clinical development. However, the oral administration of 11β-MNTDC exhibits an ~200-fold lower serum concentration of 11β-MNT compared to 11β-MNTDC, resulting in the poor [...] Read more.
11β-Methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) is a prodrug of 11β-MNT and is being considered as a promising male oral contraceptive candidate in clinical development. However, the oral administration of 11β-MNTDC exhibits an ~200-fold lower serum concentration of 11β-MNT compared to 11β-MNTDC, resulting in the poor bioavailability of 11β-MNT. To elucidate the role of the first-pass metabolism of 11β-MNT in its poor bioavailability, we determined the biotransformation products of 11β-MNT and its prodrugs in human in vitro models. 11β-MNT and its two prodrugs 11β-MNTDC and 11β-MNT undecanoate (11β-MNTU) were incubated in cryopreserved human hepatocytes (HHs) and subjected to liquid chromatography–high resolution tandem mass spectrometry analysis, which identified ten 11β-MNT biotransformation products with dehydrogenated and glucuronidation (11β-MNTG) metabolites being the major metabolites. However, 11β-MNTG formation is highly variable and prevalent in human intestinal S9 fractions. A reaction phenotyping study of 11β-MNT using thirteen recombinant UDP-glucuronosyltransferase (UGT) enzymes confirmed the major role of UGT2B17 in 11β-MNTG formation. This was further supported by a strong correlation (R2 > 0.78) between 11β-MNTG and UGT2B17 abundance in human intestinal microsomes, human liver microsomes, and HH systems. These results suggest that 11β-MNT and its prodrugs are rapidly metabolized to 11β-MNTG by the highly polymorphic intestinal UGT2B17, which may explain the poor and variable bioavailability of the drug. Full article
(This article belongs to the Special Issue Advances in ADME for Drug Discovery)
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10 pages, 5741 KB  
Article
Quenched Zwitterionic Cyclic Arg-Gly-Asp-Containing Pentapeptide Probe for Real-Time Brain Tumor Imaging
by Hyunjin Kim, Maixian Liu and Yongdoo Choi
Pharmaceutics 2024, 16(8), 1034; https://doi.org/10.3390/pharmaceutics16081034 - 2 Aug 2024
Cited by 2 | Viewed by 1541
Abstract
The efficacy of glioblastoma treatment is closely associated with complete tumor resection. However, conventional surgical techniques often result in incomplete removal, leading to poor prognosis. A major challenge is the accurate delineation of tumor margins from healthy tissues. Imaging-guided surgery, particularly using fluorescent [...] Read more.
The efficacy of glioblastoma treatment is closely associated with complete tumor resection. However, conventional surgical techniques often result in incomplete removal, leading to poor prognosis. A major challenge is the accurate delineation of tumor margins from healthy tissues. Imaging-guided surgery, particularly using fluorescent probes, is a promising solution for intraoperative guidance. The recently developed ‘always-on’ types of targeted fluorescence probes generate signals irrespective of their presence in tumor cells or in blood circulation, hampering their effectiveness. Here, we propose a novel activatable fluorescence imaging probe, Q-cRGD, that targets glioma cells via the specific binding of the cyclic Arg-Gly Asp-containing pentapeptide (cRGD) to integrins. The Q-cRGD probe was synthesized by conjugating a near-infrared (NIR) dye to a tryptophan quencher via a disulfide linkage, including a cRGD-targeting ligand. This activatable probe remained inactive until the redox-responsive cleavage of the disulfide linkage occurred within the target cell. The zwitterionic nature of NIR dyes minimizes nonspecific interactions with serum proteins, thereby enhancing the tumor-to-background signal ratio (TBR). An in vivo fluorescence imaging study demonstrated a TBR value of 2.65 within 3 h of the intravenous injection of Q-cRGD, confirming its potential utility in imaging-guided brain cancer surgery. Full article
(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)
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16 pages, 3332 KB  
Article
Pulmonary Inhalation of Biotherapeutics: A Systematic Approach to Understanding the Effects of Atomisation Gas Flow Rate on Particle Physiochemical Properties and Retained Bioactivity
by Laura Foley, Ahmad Ziaee, Gavin Walker and Emmet O’Reilly
Pharmaceutics 2024, 16(8), 1020; https://doi.org/10.3390/pharmaceutics16081020 - 1 Aug 2024
Cited by 2 | Viewed by 1463
Abstract
The identification of spray-drying processing parameters capable of producing particles suitable for pulmonary inhalation with retained bioactivity underpins the development of inhalable biotherapeutics. Effective delivery of biopharmaceuticals via pulmonary delivery routes such as dry powder inhalation (DPI) requires developing techniques that engineer particles [...] Read more.
The identification of spray-drying processing parameters capable of producing particles suitable for pulmonary inhalation with retained bioactivity underpins the development of inhalable biotherapeutics. Effective delivery of biopharmaceuticals via pulmonary delivery routes such as dry powder inhalation (DPI) requires developing techniques that engineer particles to well-defined target profiles while simultaneously minimising protein denaturation. This study examines the simultaneous effects of atomisation gas flow rate on particle properties and retained bioactivity for the model biopharmaceutical lysozyme. The results show that optimising the interplay between atomisation gas flow rate and excipient concentration enables the production of free-flowing powder with retained bioactivity approaching 100%, moisture content below 4%, and D50 < 4 µm, at yields exceeding 50%. The developed methodologies inform the future design of protein-specific spray-drying parameters for inhalable biotherapeutics. Full article
(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)
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