Pharmaceutics

17 pages, 2899 KiB

Open AccessArticle

Cyclodextrin-Based Nanosponges as Perse Antimicrobial Agents Increase the Activity of Natural Antimicrobial Peptide Nisin

by Yousef Khazaei Monfared, Mohammad Mahmoudian, Gjylije Hoti, Fabrizio Caldera, José Manuel López Nicolás, Parvin Zakeri-Milani, Adrián Matencio and Francesco Trotta

Pharmaceutics 2022, 14(3), 685; https://doi.org/10.3390/pharmaceutics14030685 - 21 Mar 2022

Cited by 8 | Viewed by 2461

Abstract

At present, antibiotic resistance is considered a real problem. Therefore, for decades scientists have been looking for novel strategies to treat bacterial infections. Nisin Z, an antimicrobial peptide (AMP), can be considered an option, but its usage is mainly limited by the poor [...] Read more.

At present, antibiotic resistance is considered a real problem. Therefore, for decades scientists have been looking for novel strategies to treat bacterial infections. Nisin Z, an antimicrobial peptide (AMP), can be considered an option, but its usage is mainly limited by the poor stability and short duration of its antimicrobial activity. In this context, cyclodextrin (CD)-based nanosponges (NSs), synthesized using carbonyldiimidazole (CDI) and pyromellitic dianhydride (PMDA), were chosen for nisin Z loading. To determine the minimum inhibitory of nisin Z loaded on CD-NS formulations, agar well diffusion plates were used. Then, the bactericide concentrations of nisin Z loaded on CD-NS formulations were determined against Gram-positive (Staphylococcus aureus) and -negative (Escherichia coli) bacteria, using microdilution brain heart infusion (BHI) and tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). The minimum and bactericide inhibitory values of the nisin complex with NSs were potentially decreased against both bacteria, compared with the nisin-free sample, while the nisin complex with β-CD showed lower antibacterial activity. The antimicrobial effect was also demonstrated by free NSs. Furthermore, the total viable counts (TVCs) antibacterial experiment indicated that the combination of nisin Z in both PMDA and CDI β-CD-based NSs, especially CDI, can provide a better conservative effect on cooked chicken meat. Generally, the present study outcomes suggest that the cross-linked β-CD-based NSs can present their own antimicrobial potency or serve as promising carriers to deliver and enhance the antibacterial action of nisin Z. Full article

(This article belongs to the Special Issue Novel Cyclodextrin Based Systems for Drug Delivery and Related Issues)

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12 pages, 2164 KiB

Open AccessArticle

Dapsone Azo-Linked with Two Mesalazine Moieties Is a “Me-Better” Alternative to Sulfasalazine

by Changyu Kang, Jaejeong Kim, Sanghyun Ju, Sohee Park, Jin-Wook Yoo, In-Soo Yoon, Min-Soo Kim and Yunjin Jung

Pharmaceutics 2022, 14(3), 684; https://doi.org/10.3390/pharmaceutics14030684 - 21 Mar 2022

Cited by 3 | Viewed by 1908

Abstract

Dapsone (DpS) is an antimicrobial and antiprotozoal agent, especially used to treat leprosy. The drug shares a similar mode of action with sulfonamides. Additionally, it possesses anti-inflammatory activity, useful for treating autoimmune diseases. Here, we developed a “me-better” alternative to sulfasalazine (SSZ), a [...] Read more.

Dapsone (DpS) is an antimicrobial and antiprotozoal agent, especially used to treat leprosy. The drug shares a similar mode of action with sulfonamides. Additionally, it possesses anti-inflammatory activity, useful for treating autoimmune diseases. Here, we developed a “me-better” alternative to sulfasalazine (SSZ), a colon-specific prodrug of mesalazine (5-ASA) used as an anti-inflammatory bowel diseases drug; DpS azo-linked with two molecules of 5-ASA (AS-DpS-AS) was designed and synthesized, and its colon specificity and anti-colitic activity were evaluated. AS-DpS-AS was converted to DpS and the two molecules of 5-ASA (up to approximately 87% conversion) within 24 h after incubation in the cecal contents. Compared to SSZ, AS-DpS-AS showed greater efficiency in colonic drug delivery following oral gavage. Simultaneously, AS-DpS-AS substantially limited the systemic absorption of DpS. In a dinitrobenzene sulfonic acid-induced rat colitis model, oral AS-DpS-AS elicited better efficacy against rat colitis than oral SSZ. Moreover, intracolonic treatment with DpS and/or 5-ASA clearly showed that combined treatment with DpS and 5-ASA was more effective against rat colitis than the single treatment with either DpS or 5-ASA. These results suggest that AS-DpS-AS may be a “me-better” drug of SSZ with higher therapeutic efficacy, owing to the combined anti-colitic effects of 5-ASA and DpS. Full article

(This article belongs to the Section Drug Targeting and Design)

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15 pages, 2867 KiB

Open AccessArticle

Study of Viral Photoinactivation by UV-C Light and Photosensitizer Using a Pseudotyped Model

by Mohammad Sadraeian, Fabio Francisco Pinto Junior, Marcela Miranda, Juliana Galinskas, Rafaela Sachetto Fernandes, Edgar Ferreira da Cruz, Libing Fu, Le Zhang, Ricardo Sobhie Diaz, Gustavo Cabral-Miranda and Francisco Eduardo Gontijo Guimarães

Pharmaceutics 2022, 14(3), 683; https://doi.org/10.3390/pharmaceutics14030683 - 21 Mar 2022

Cited by 10 | Viewed by 3398

Abstract

Different light-based strategies have been investigated to inactivate viruses. Herein, we developed an HIV-based pseudotyped model of SARS-CoV-2 (SC2) to study the mechanisms of virus inactivation by using two different strategies; photoinactivation (PI) by UV-C light and photodynamic inactivation (PDI) by Photodithazine photosensitizer [...] Read more.

Different light-based strategies have been investigated to inactivate viruses. Herein, we developed an HIV-based pseudotyped model of SARS-CoV-2 (SC2) to study the mechanisms of virus inactivation by using two different strategies; photoinactivation (PI) by UV-C light and photodynamic inactivation (PDI) by Photodithazine photosensitizer (PDZ). We used two pseudoviral particles harboring the Luciferase-IRES-ZsGreen reporter gene with either a SC2 spike on the membrane or without a spike as a naked control pseudovirus. The mechanism of viral inactivation by UV-C and PDZ-based PDI were studied via biochemical characterizations and quantitative PCR on four levels; free-cell viral damage; viral cell entry; DNA integration; and expression of reporter genes. Both UV-C and PDZ treatments could destroy single stranded RNA (ssRNA) and the spike protein of the virus, with different ratios. However, the virus was still capable of binding and entering into the HEK 293T cells expressing angiotensin-converting enzyme 2 (ACE-2). A dose-dependent manner of UV-C irradiation mostly damages the ssRNA, while PDZ-based PDI mostly destroys the spike and viral membrane in concentration and dose-dependent manners. We observed that the cells infected by the virus and treated with either UV-C or PDZ-based PDI could not express the luciferase reporter gene, signifying the viral inactivation, despite the presence of RNA and DNA intact genes. Full article

(This article belongs to the Special Issue Special Issue in Honor of Dr. Michael Weber’s 70th Birthday: Photodynamic Therapy: Rising Star in Pharmaceutical Applications)

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30 pages, 3889 KiB

Open AccessReview

Skin-on-a-Chip Technology: Microengineering Physiologically Relevant In Vitro Skin Models

by Patrícia Zoio and Abel Oliva

Pharmaceutics 2022, 14(3), 682; https://doi.org/10.3390/pharmaceutics14030682 - 21 Mar 2022

Cited by 16 | Viewed by 9041

Abstract

The increased demand for physiologically relevant in vitro human skin models for testing pharmaceutical drugs has led to significant advancements in skin engineering. One of the most promising approaches is the use of in vitro microfluidic systems to generate advanced skin models, commonly [...] Read more.

The increased demand for physiologically relevant in vitro human skin models for testing pharmaceutical drugs has led to significant advancements in skin engineering. One of the most promising approaches is the use of in vitro microfluidic systems to generate advanced skin models, commonly known as skin-on-a-chip (SoC) devices. These devices allow the simulation of key mechanical, functional and structural features of the human skin, better mimicking the native microenvironment. Importantly, contrary to conventional cell culture techniques, SoC devices can perfuse the skin tissue, either by the inclusion of perfusable lumens or by the use of microfluidic channels acting as engineered vasculature. Moreover, integrating sensors on the SoC device allows real-time, non-destructive monitoring of skin function and the effect of topically and systemically applied drugs. In this Review, the major challenges and key prerequisites for the creation of physiologically relevant SoC devices for drug testing are considered. Technical (e.g., SoC fabrication and sensor integration) and biological (e.g., cell sourcing and scaffold materials) aspects are discussed. Recent advancements in SoC devices are here presented, and their main achievements and drawbacks are compared and discussed. Finally, this review highlights the current challenges that need to be overcome for the clinical translation of SoC devices. Full article

(This article belongs to the Special Issue Tissue Engineering and Organ-on-Chip of Biological Barriers for Drug Absorption and Delivery Testing)

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14 pages, 3226 KiB

Open AccessArticle

A New Approach to Supramolecular Structure Determination in Pharmaceutical Preparation of Self-Assembling Peptides: A Case Study of Lanreotide Autogel

by Manuela Grimaldi, Angelo Santoro, Michela Buonocore, Claudio Crivaro, Nicola Funicello, Matilde Sublimi Saponetti, Cristina Ripoli, Manuela Rodriquez, Salvatore De Pasquale, Fabrizio Bobba, Lucia Ferrazzano, Walter Cabri, Anna Maria D’Ursi and Antonio Ricci

Pharmaceutics 2022, 14(3), 681; https://doi.org/10.3390/pharmaceutics14030681 - 20 Mar 2022

Cited by 3 | Viewed by 3132

Abstract

The supramolecular structure in peptides’ prolonged-released gel formulations is the most critical parameter for the determination of the pharmaceutical profile of the drug. Here, we report our investigation on lanreotide Autogel as a case study. For the first time, we describe the use [...] Read more.

The supramolecular structure in peptides’ prolonged-released gel formulations is the most critical parameter for the determination of the pharmaceutical profile of the drug. Here, we report our investigation on lanreotide Autogel as a case study. For the first time, we describe the use of the pulsed field gradient (PFG) diffusion-ordered spectroscopy (DOSY) magic-angle spinning NMR to characterize the supramolecular self-assembly and molecular mobility of different samples of lanreotide Autogel formulations prepared according to different formulation protocols. The diffusion coefficient was used to calculate the hydrodynamic radii of supramolecular assemblies and build relative molecular models. DOSY data were integrated with NMR imaging (MRI) measurements and atomic force microscopy (AFM) imaging. Full article

(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics)

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14 pages, 2632 KiB

Open AccessFeature PaperArticle

Formulation Development for Transdermal Delivery of Raloxifene, a Chemoprophylactic Agent against Breast Cancer

by Deepal Vora, Amruta Dandekar, Sonalika Bhattaccharjee, Onkar N. Singh, Vivek Agrahari, M. Melissa Peet, Gustavo F. Doncel and Ajay K. Banga

Pharmaceutics 2022, 14(3), 680; https://doi.org/10.3390/pharmaceutics14030680 - 20 Mar 2022

Cited by 9 | Viewed by 3239

Abstract

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator approved for the prevention of invasive breast cancer in women. Oral therapy of RLX requires daily intake and is associated with side effects that may lead to low adherence. We developed a weekly transdermal [...] Read more.

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator approved for the prevention of invasive breast cancer in women. Oral therapy of RLX requires daily intake and is associated with side effects that may lead to low adherence. We developed a weekly transdermal delivery system (TDS) for the sustained delivery of RLX to enhance the therapeutic effectiveness, increase adherence, and reduce side effects. We evaluated the weekly transdermal administration of RLX using passive permeation, chemical enhancers, physical enhancement techniques, and matrix- and reservoir-type systems, including polymeric gels. In vitro permeation studies were conducted using vertical Franz diffusion cells across dermatomed human skin or human epidermis. Oleic acid was selected as a chemical enhancer based on yielding the highest drug delivery amongst the various enhancers screened and was incorporated in the formulation of TDSs and polymeric gels. Based on in vitro results, both Eudragit- and colloidal silicon dioxide-based transdermal gels of RLX exceeded the target flux of 24 μg/cm²/day for 7 days. An infinite dose of these gels delivered 326.23 ± 107.58 µg/ cm² and 498.81 ± 14.26 µg/ cm² of RLX in 7 days, respectively, successfully exceeding the required target flux. These in vitro results confirm the potential of reservoir-based polymeric gels as a TDS for the weekly administration of RLX. Full article

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12 pages, 1831 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 6 | Viewed by 2435

Abstract

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

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

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

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25 pages, 11088 KiB

Open AccessArticle

Assessing the Dermal Penetration Efficacy of Chemical Compounds with the Ex-Vivo Porcine Ear Model

by Cornelia M. Keck, Ayat Abdelkader, Olga Pelikh, Sabrina Wiemann, Vasudha Kaushik, David Specht, Ralph W. Eckert, Reem M. Alnemari, Henriette Dietrich and Jana Brüßler

Pharmaceutics 2022, 14(3), 678; https://doi.org/10.3390/pharmaceutics14030678 - 19 Mar 2022

Cited by 14 | Viewed by 3270

Abstract

(1) Background: The ex vivo porcine ear model is often used for the determination of the dermal penetration efficacy of chemical compounds. This study investigated the influence of the post-slaughter storage time of porcine ears on the dermal penetration efficacy of chemical compounds. [...] Read more.

(1) Background: The ex vivo porcine ear model is often used for the determination of the dermal penetration efficacy of chemical compounds. This study investigated the influence of the post-slaughter storage time of porcine ears on the dermal penetration efficacy of chemical compounds. (2) Methods: Six different formulations (curcumin and different fluorescent dyes in different vehicles and/or nanocarriers) were tested on ears that were (i) freshly obtained, (ii) stored for 24 or 48 h at 4 °C after slaughter before use and (iii) freshly frozen and defrosted 12 h before use. (3) Results: Results showed that porcine ears undergo post-mortem changes. The changes can be linked to rigor mortis and all other well-described phenomena that occur with carcasses after slaughter. The post-mortem changes modify the skin properties of the ears and affect the penetration efficacy. The onset of rigor mortis causes a decrease in the water-holding capacity of the ears, which leads to reduced penetration of chemical compounds. The water-holding capacity increases once the rigor is released and results in an increased penetration efficacy for chemical compounds. Despite different absolute penetration values, no differences in the ranking of penetration efficacies between the different formulations were observed between the differently aged ears. (4) Conclusions: All different types of ears can be regarded to be suitable for dermal penetration testing of chemical compounds. The transepidermal water loss (TEWL) and/or skin hydration of the ears were not correlated with the ex vivo penetration efficacy because both an impaired skin barrier and rigor mortis cause elevated skin hydration and TEWL values but an opposite penetration efficacy. Other additional values (for example, pH and/or autofluorescence of the skin) should, therefore, be used to select suitable and non-suitable skin areas for ex vivo penetration testing. Finally, data from this study confirmed that smartFilms and nanostructured lipid carriers (NLC) represent superior formulation strategies for efficient dermal and transdermal delivery of curcumin. Full article

(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)

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20 pages, 9918 KiB

Open AccessArticle

Two Beats One: Osteosarcoma Therapy with Light-Activated and Chemo-Releasing Keratin Nanoformulation in a Preclinical Mouse Model

by Elisa Martella, Barbara Dozza, Claudia Ferroni, Clement Osuru Obeyok, Andrea Guerrini, Daniele Tedesco, Ilse Manet, Giovanna Sotgiu, Marta Columbaro, Marco Ballestri, Lucia Martini, Milena Fini, Enrico Lucarelli, Greta Varchi and Serena Duchi

Pharmaceutics 2022, 14(3), 677; https://doi.org/10.3390/pharmaceutics14030677 - 19 Mar 2022

Cited by 8 | Viewed by 2850

Abstract

Osteosarcoma treatment is moving towards more effective combination therapies. Nevertheless, these approaches present distinctive challenges that can complicate the clinical translation, such as increased toxicity and multi-drug resistance. Drug co-encapsulation within a nanoparticle formulation can overcome these challenges and improve the therapeutic index. [...] Read more.

Osteosarcoma treatment is moving towards more effective combination therapies. Nevertheless, these approaches present distinctive challenges that can complicate the clinical translation, such as increased toxicity and multi-drug resistance. Drug co-encapsulation within a nanoparticle formulation can overcome these challenges and improve the therapeutic index. We previously synthetized keratin nanoparticles functionalized with Chlorin-e6 (Ce6) and paclitaxel (PTX) to combine photo (PDT) and chemotherapy (PTX) regimens, and the inhibition of osteosarcoma cells growth in vitro was demonstrated. In the current study, we generated an orthotopic osteosarcoma murine model for the preclinical evaluation of our combination therapy. To achieve maximum reproducibility, we systematically established key parameters, such as the number of cells to generate the tumor, the nanoparticles dose, the design of the light-delivery device, the treatment schedule, and the irradiation settings. A 60% engrafting rate was obtained using 10 million OS cells inoculated intratibial, with the tumor model recapitulating the histological hallmarks of the human counterpart. By scheduling the treatment as two cycles of injections, a 32% tumor reduction was obtained with PTX mono-therapy and a 78% reduction with the combined PTX-PDT therapy. Our findings provide the in vivo proof of concept for the subsequent clinical development of a combination therapy to fight osteosarcoma. Full article

(This article belongs to the Special Issue Drug Delivery in Photodynamic Therapy (PDT))

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13 pages, 3537 KiB

Open AccessEditor’s ChoiceArticle

Molecular Tuning of IR-786 for Improved Tumor Imaging and Photothermal Therapy

by Wonbong Lim, Jae Yong Byun, Gayoung Jo, Eun Jeong Kim, Min Ho Park and Hoon Hyun

Pharmaceutics 2022, 14(3), 676; https://doi.org/10.3390/pharmaceutics14030676 - 19 Mar 2022

Cited by 10 | Viewed by 2179

Abstract

A tumor-targeted near-infrared (NIR) fluorophore CA800Cl was developed based on commercially available IR-786 by modulating its physicochemical properties. IR-786, a hydrophobic cationic heptamethine cyanine fluorophore, was previously recognized as a mitochondria-targeting NIR agent with excellent optical properties. Owing to the poor tumor specificity [...] Read more.

A tumor-targeted near-infrared (NIR) fluorophore CA800Cl was developed based on commercially available IR-786 by modulating its physicochemical properties. IR-786, a hydrophobic cationic heptamethine cyanine fluorophore, was previously recognized as a mitochondria-targeting NIR agent with excellent optical properties. Owing to the poor tumor specificity of IR-786 itself, in vivo studies on tumor-targeted imaging have not yet been investigated. A chloro-cyclohexene ring and indolium side groups on the heptamethine chain are key structural features that improve tumor targetability, owing to better biodistribution and clearance. Thus, IR-786 should be designed to be more soluble in aqueous solutions so that it can preferentially accumulate in the tumor based on the structure-inherent targeting strategy. In this study, we developed a bifunctional NIR fluorophore CA800Cl by incorporating carboxylate moieties in the basic structure of IR-786. This improved its tumor targetability and water solubility, thereby enabling the use of CA800Cl for enhanced photothermal cancer therapy. Full article

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

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12 pages, 8836 KiB

Open AccessEditor’s ChoiceArticle

PLA₂-Triggered Activation of Cyclosporine-Phospholipid Prodrug as a Drug Targeting Approach in Inflammatory Bowel Disease Therapy

by Milica Markovic, Shimon Ben-Shabat, Jagadeesh Nagendra Manda, Karina Abramov-Harpaz, Clil Regev, Yifat Miller, Aaron Aponick, Ellen M. Zimmermann and Arik Dahan

Pharmaceutics 2022, 14(3), 675; https://doi.org/10.3390/pharmaceutics14030675 - 18 Mar 2022

Cited by 5 | Viewed by 2462

Abstract

Oral medication with activity specifically at the inflamed sites throughout the gastrointestinal tract and limited systemic exposure would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). For this purpose, we have designed a prodrug by linking active drug [...] Read more.

Oral medication with activity specifically at the inflamed sites throughout the gastrointestinal tract and limited systemic exposure would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). For this purpose, we have designed a prodrug by linking active drug moiety to phospholipid (PL), the substrate of phospholipase A₂ (PLA₂). PLA₂ expression and activity is significantly elevated in the inflamed intestinal tissues of IBD patients. Since PLA₂ enzyme specifically hydrolyses the sn-2 bond within PLs, in our PL-based prodrug approach, the sn-2 positioned FA is replaced with cyclosporine, so that PLA₂ may be exploited as the prodrug-activating enzyme, releasing the free drug from the PL-complex. Owing to the enzyme overexpression, this may effectively target free cyclosporine to the sites of inflammation. Four PL-cyclosporine prodrugs were synthesized, differing by their linker length between the PL and the drug moiety. To study the prodrug activation, a novel enzymatically enriched model was developed, the colonic brush border membrane vesicles (cBBMVs); in this model, tissue vesicles were produced from colitis-induced (vs. healthy) rat colons. PLA₂ overexpression (3.4-fold) was demonstrated in diseased vs. healthy cBBMVs. Indeed, while healthy cBBMVs induced only marginal activation, substantial prodrug activation was evident by colitis-derived cBBMVs. Together with the PLA₂ overexpression, these data validate our drug targeting strategy. In the diseased cBBMVs, quick and complete activation of the entire dose was obtained for the 12-carbon linker prodrug, while slow and marginal activation was obtained for the 6/8-carbon linkers. The potential to target the actual sites of inflammation and treat any localizations throughout the GIT, together with the extended therapeutic index, makes this orally delivered prodrug approach an exciting new therapeutic strategy for IBD treatment. Full article

(This article belongs to the Special Issue Prospects of the Prodrug Approach: From Initial Design to Clinical Application)

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19 pages, 2151 KiB

Open AccessArticle

Physicochemical Profile of Antiandrogen Drug Bicalutamide: Solubility, Distribution, Permeability

by Tatyana V. Volkova, Olga R. Simonova and German L. Perlovich

Pharmaceutics 2022, 14(3), 674; https://doi.org/10.3390/pharmaceutics14030674 - 18 Mar 2022

Cited by 4 | Viewed by 2032

Abstract

The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous solution, 1-octanol, n-hexane, and ethanol was measured by the shake flask method in the temperature range of 293.15–313.15 K. The compound was [...] Read more.

The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous solution, 1-octanol, n-hexane, and ethanol was measured by the shake flask method in the temperature range of 293.15–313.15 K. The compound was shown to be poorly soluble in aqueous medium and n-hexane; at the same time, an essentially higher solubility in the alcohols was revealed. The following order of molar solubility was determined: ethanol > 1-octanol > water ≈ n-hexane. The solubility was correlated with the Van’t Hoff and Apelblat equations. Evaluation of the Hansen solubility parameters and the atomic group contribution approach of Hoftyzer and Van Krevelen demonstrated consistency with the experimental data and good potential adsorption of bicalutamide. The temperature dependences of the distribution coefficients in the 1-octanol/water and n-hexane/water two-phase systems were measured and discussed in the framework of the thermodynamic approach. The ∆logD parameter determined from the distribution experiment clearly demonstrated the preference of the lipophilic delivery pathways for the compound in the biological media. The overall thermodynamic analysis based on the solubility and distribution results of the present study and the sublimation characteristics published previously has been performed. To this end, the thermodynamic parameters of the dissolution, solvation, and transfer processes were calculated and discussed in view of the solute-solvent interactions. The permeation rate of BCL through the PermeaPad barrier was measured and compared with PAMPA permeability. Full article

(This article belongs to the Special Issue Physico Chemical Profiling Pharmaceutics: Solubility and Permeability)

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32 pages, 4515 KiB

Open AccessEditor’s ChoiceReview

Finite Element Analysis and Modeling in Pharmaceutical Tableting

by Ioannis Partheniadis, Vasiliki Terzi and Ioannis Nikolakakis

Pharmaceutics 2022, 14(3), 673; https://doi.org/10.3390/pharmaceutics14030673 - 18 Mar 2022

Cited by 5 | Viewed by 2732

Abstract

Finite element analysis (FEA) is a computational method providing numerical solutions and mathematical modeling of complex physical phenomena that evolve during compression tableting of pharmaceutical powders. Since the early 2000s, FEA has been utilized together with various constitutive material models in a quest [...] Read more.

Finite element analysis (FEA) is a computational method providing numerical solutions and mathematical modeling of complex physical phenomena that evolve during compression tableting of pharmaceutical powders. Since the early 2000s, FEA has been utilized together with various constitutive material models in a quest for a deeper understanding and unraveling of the complex mechanisms that govern powder compression. The objective of the present review paper is to highlight the potential and feasibility of FEA for implementation in pharmaceutical tableting in order to elucidate important aspects of the process, namely: stress and density distributions, temperature evolution, effect of punch shape on tablet formation, effect of friction, and failure of the tablet under stress. The constitutive models and theoretical background governing the above aspects of tablet compression and tablet fracture under diametral loading are also presented. In the last sections, applications of FEA in pharmaceutical tableting are demonstrated by many examples that prove its utilization and point out further potential applications. Full article

(This article belongs to the Special Issue Preformulation and Formulation during Drug Development)

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14 pages, 1876 KiB

Open AccessReview

Strategies for Targeted Delivery of Exosomes to the Brain: Advantages and Challenges

by Hojun Choi, Kyungsun Choi, Dae-Hwan Kim, Byung-Koo Oh, Hwayoung Yim, Soojin Jo and Chulhee Choi

Pharmaceutics 2022, 14(3), 672; https://doi.org/10.3390/pharmaceutics14030672 - 18 Mar 2022

Cited by 34 | Viewed by 6983

Abstract

Delivering therapeutics to the central nervous system (CNS) is difficult because of the blood–brain barrier (BBB). Therapeutic delivery across the tight junctions of the BBB can be achieved through various endogenous transportation mechanisms. Receptor-mediated transcytosis (RMT) is one of the most widely investigated [...] Read more.

Delivering therapeutics to the central nervous system (CNS) is difficult because of the blood–brain barrier (BBB). Therapeutic delivery across the tight junctions of the BBB can be achieved through various endogenous transportation mechanisms. Receptor-mediated transcytosis (RMT) is one of the most widely investigated and used methods. Drugs can hijack RMT by expressing specific ligands that bind to receptors mediating transcytosis, such as the transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (INSR). Cell-penetrating peptides and viral components originating from neurotropic viruses can also be utilized for the efficient BBB crossing of therapeutics. Exosomes, or small extracellular vesicles, have gained attention as natural nanoparticles for treating CNS diseases, owing to their potential for natural BBB crossing and broad surface engineering capability. RMT-mediated transport of exosomes expressing ligands such as LDLR-targeting apolipoprotein B has shown promising results. Although surface-modified exosomes possessing brain targetability have shown enhanced CNS delivery in preclinical studies, the successful development of clinically approved exosome therapeutics for CNS diseases requires the establishment of quantitative and qualitative methods for monitoring exosomal delivery to the brain parenchyma in vivo as well as elucidation of the mechanisms underlying the BBB crossing of surface-modified exosomes. Full article

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

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19 pages, 2492 KiB

Open AccessArticle

Aggregates Associated with Instability of Antibodies during Aerosolization Induce Adverse Immunological Effects

by Thomas Sécher, Elsa Bodier-Montagutelli, Christelle Parent, Laura Bouvart, Mélanie Cortes, Marion Ferreira, Ronan MacLoughlin, Guy Ilango, Otmar Schmid, Renaud Respaud and Nathalie Heuzé-Vourc’h

Pharmaceutics 2022, 14(3), 671; https://doi.org/10.3390/pharmaceutics14030671 - 18 Mar 2022

Cited by 13 | Viewed by 2574

Abstract

Background: Immunogenicity refers to the inherent ability of a molecule to stimulate an immune response. Aggregates are one of the major risk factors for the undesired immunogenicity of therapeutic antibodies (Ab) and may ultimately result in immune-mediated adverse effects. For Ab delivered by [...] Read more.

Background: Immunogenicity refers to the inherent ability of a molecule to stimulate an immune response. Aggregates are one of the major risk factors for the undesired immunogenicity of therapeutic antibodies (Ab) and may ultimately result in immune-mediated adverse effects. For Ab delivered by inhalation, it is necessary to consider the interaction between aggregates resulting from the instability of the Ab during aerosolization and the lung mucosa. The aim of this study was to determine the impact of aggregates produced during aerosolization of therapeutic Ab on the immune system. Methods: Human and murine immunoglobulin G (IgG) were aerosolized using a clinically-relevant nebulizer and their immunogenic potency was assessed, both in vitro using a standard human monocyte-derived dendritic cell (MoDC) reporter assay and in vivo in immune cells in the airway compartment, lung parenchyma and spleen of healthy C57BL/6 mice after pulmonary administration. Results: IgG aggregates, produced during nebulization, induced a dose-dependent activation of MoDC characterized by the enhanced production of cytokines and expression of co-stimulatory markers. Interestingly, in vivo administration of high amounts of nebulization-mediated IgG aggregates resulted in a profound and sustained local and systemic depletion of immune cells, which was attributable to cell death. This cytotoxic effect was observed when nebulized IgG was administered locally in the airways as compared to a systemic administration but was mitigated by improving IgG stability during nebulization, through the addition of polysorbates to the formulation. Conclusion: Although inhalation delivery represents an attractive alternative route for delivering Ab to treat respiratory infections, our findings indicate that it is critical to prevent IgG aggregation during the nebulization process to avoid pro-inflammatory and cytotoxic effects. The optimization of Ab formulation can mitigate adverse effects induced by nebulization. Full article

(This article belongs to the Special Issue Inhaled Treatment of Respiratory Infections)

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12 pages, 3013 KiB

Open AccessArticle

Effect of Pregabalin Combined with Duloxetine and Tramadol on Allodynia in Chronic Postischemic Pain and Spinal Nerve Ligation Mouse Models

by Jie Quan, Jin Young Lee, Hoon Choi, Young Chan Kim, Sungwon Yang, Jongmin Jeong and Hue Jung Park

Pharmaceutics 2022, 14(3), 670; https://doi.org/10.3390/pharmaceutics14030670 - 18 Mar 2022

Cited by 1 | Viewed by 2612

Abstract

Although there are various drugs for Neuropathic pain (NP), the effects of single drugs are often not very satisfactory. The analgesic effects of different combinations of pregabalin, duloxetine, and tramadol or the combination of all three are still unclear. Mixtures of two or [...] Read more.

Although there are various drugs for Neuropathic pain (NP), the effects of single drugs are often not very satisfactory. The analgesic effects of different combinations of pregabalin, duloxetine, and tramadol or the combination of all three are still unclear. Mixtures of two or three drugs at low and high concentrations (7.5, 10, 15, and 20 mg/kg pregabalin; 7.5, 10, 15, and 30 mg/kg duloxetine; 5 and 10 mg/kg tramadol) were administered to chronic postischemic pain (CPIP) and spinal nerve ligation (SNL) model mice. The effects of these combinations of drugs on mechanical allodynia were investigated. The expression of the glial fibrillary acidic protein (GFAP) in the spinal cord and dorsal root ganglia (DRGs) was measured. The combination of pregabalin, duloxetine, and tramadol significantly alleviated mechanical hyperalgesia in mice with CPIP and SNL. After the administration of this drug combination, the expression of GFAP in the spinal cord and DRGs was lower in the CPIP and SNL model mice than in control mice. This result suggests that the combination of these three drugs may be advantageous for the treatment of NP because it can reduce side effects by preventing the overuse of a single drug class and exert increased analgesic effects via synergism. Full article

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

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18 pages, 8055 KiB

Open AccessArticle

Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease

by Chuhan Zhang, Yu Hang, Weimin Tang, Diptesh Sil, Heather C. Jensen-Smith, Robert G. Bennett, Benita L. McVicker and David Oupický

Pharmaceutics 2022, 14(3), 669; https://doi.org/10.3390/pharmaceutics14030669 - 18 Mar 2022

Cited by 6 | Viewed by 2331

Abstract

Alcohol-associated liver disease (AALD) is a major cause of liver disorders worldwide. Current treatment options are limited, especially for AALD-associated fibrosis. Promising approaches include RNA interference for miR-155 overexpression in Kupffer cells (KCs), as well as the use of CXCR4 antagonists that inhibit [...] Read more.

Alcohol-associated liver disease (AALD) is a major cause of liver disorders worldwide. Current treatment options are limited, especially for AALD-associated fibrosis. Promising approaches include RNA interference for miR-155 overexpression in Kupffer cells (KCs), as well as the use of CXCR4 antagonists that inhibit the activation of hepatic stellate cells (HSCs) through the CXCL12/CXCR4 axis. The development of dual-functioning nanoparticles for the effective delivery of antifibrotic RNA together with a CXCR4 inhibitor thus promises to improve the treatment of AALD fibrosis. In this study, cholesterol-modified polymeric CXCR4 inhibitor (Chol-PCX) was synthesized and used to encapsulate anti-miR-155 or non-coding (NC) miRNA in the form of Chol-PCX/miRNA nanoparticles. The results indicate that the nanoparticles induce a significant miR-155 silencing effect both in vitro and in vivo. Treatment with the Chol-PCX/anti-miR-155 particles in a model of moderate alcohol consumption with secondary liver insult resulted in a significant reduction in aminotransferase enzymes as well as collagen content in the liver parenchyma. Overall, our data support the use of Chol-PCX as a carrier for anti-miR-155 for the combined therapeutic inhibition of CXCR4 and miR-155 expression as a way to improve fibrotic damage in the liver. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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16 pages, 3516 KiB

Open AccessArticle

High-Resolution Ultrasound Spectroscopy for the Determination of Phospholipid Transitions in Liposomal Dispersions

by Diego Romano Perinelli, Marco Cespi, Giovanni Filippo Palmieri, Annalisa Aluigi and Giulia Bonacucina

Pharmaceutics 2022, 14(3), 668; https://doi.org/10.3390/pharmaceutics14030668 - 18 Mar 2022

Cited by 5 | Viewed by 1792

Abstract

High-resolution ultrasound spectroscopy (HR-US) is a spectroscopic technique using ultrasound waves at high frequencies to investigate the structural properties of dispersed materials. This technique is able to monitor the variation of ultrasound parameters (sound speed and attenuation) due to the interaction of ultrasound [...] Read more.

High-resolution ultrasound spectroscopy (HR-US) is a spectroscopic technique using ultrasound waves at high frequencies to investigate the structural properties of dispersed materials. This technique is able to monitor the variation of ultrasound parameters (sound speed and attenuation) due to the interaction of ultrasound waves with samples as a function of temperature and concentration. Despite being employed for the characterization of several colloidal systems, there is a lack in the literature regarding the comparison between the potential of HR-US for the determination of phospholipid thermal transitions and that of other common techniques both for loaded or unloaded liposomes. Thermal transitions of liposomes composed of pure phospholipids (dimyristoylphosphatidylcholine, DMPC; dipalmitoylphosphatidylcholine, DPPC and distearoylphosphatidylcholine, DSPC), cholesterol and their mixtures were investigated by HR-US in comparison to the most commonly employed microcalorimetry (mDSC) and dynamic light scattering (DLS). Moreover, tramadol hydrochloride, caffeine or miconazole nitrate as model drugs were loaded in DPPC liposomes to study the effect of their incorporation on thermal properties of a phospholipid bilayer. HR-US provided the determination of phospholipid sol-gel transition temperatures from both attenuation and sound speed that are comparable to those calculated by mDSC and DLS techniques for all analysed liposomal dispersions, both loaded and unloaded. Therefore, HR-US is proposed here as an alternative technique to determine the transition temperature of phospholipid membrane in liposomes. Full article

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13 pages, 2212 KiB

Open AccessArticle

Image-Based Quantification of Gold Nanoparticle Uptake and Localization in 3D Tumor Models to Inform Radiosensitization Schedule

by Ljubica Z. Petrovic, Michael Oumano, Justin Hanlon, Mark Arnoldussen, Igor Koruga, Sayeda Yasmin-Karim, Wilfred Ngwa and Jonathan Celli

Pharmaceutics 2022, 14(3), 667; https://doi.org/10.3390/pharmaceutics14030667 - 18 Mar 2022

Cited by 2 | Viewed by 2054

Abstract

Gold nanoparticles (GNPs) have shown particular promise as radiosensitizing agents and as complementary drug delivery agents to improve therapeutic index in cancer treatment. Optimal implementation, however, depends critically on the localization of GNPs at the time of irradiation, which, in turn, depends on [...] Read more.

Gold nanoparticles (GNPs) have shown particular promise as radiosensitizing agents and as complementary drug delivery agents to improve therapeutic index in cancer treatment. Optimal implementation, however, depends critically on the localization of GNPs at the time of irradiation, which, in turn, depends on their size, shape, and chemical functionalization, as well as organism-level pharmacokinetics and interactions with the tumor microenvironment. Here, we use in vitro 3D cultures of A549 lung carcinoma cells, which recapitulate interaction with extracellular matrix (ECM) components, combined with quantitative fluorescence imaging to study how time-dependent localization of ultrasmall GNPs in tumors and ECM impacts the degree of damage enhancement to tumor cells. Confocal imaging of fluorescence-labeled GNPs in 3D culture reveals that nanoparticles are initially embedded in ECM and only gradually accumulate in cancer cells over multiple days. Furthermore, the timing of GNP redistribution from ECM to cellular compartments directly impacts efficacy, with major damage enhancement when irradiation is performed after GNPs have accumulated significantly in 3D tumor nodules. These results underscore the importance of the timing and scheduling in treatment planning to ensure optimal radiosensitization, as well as the necessity of studying these effects in model systems that recapitulate elements of tumor microenvironment interaction. Full article

(This article belongs to the Special Issue Nanoparticle Delivery to Tumors: Challenges and Advances)

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19 pages, 2596 KiB

Open AccessArticle

Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCK₂R Cancer Theranostic Agents: A Preclinical Study

by Berthold A. Nock, Panagiotis Kanellopoulos, Oleg G. Chepurny, Maritina Rouchota, George Loudos, George G. Holz, Eric P. Krenning and Theodosia Maina

Pharmaceutics 2022, 14(3), 666; https://doi.org/10.3390/pharmaceutics14030666 - 18 Mar 2022

Cited by 4 | Viewed by 1963

Abstract

(1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCK₂R)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCK₂R-radioligands instead, we herein present three analogs of the nonpeptidic CCK₂R-antagonist Z360, GAS1/2/3. Each [...] Read more.

(1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCK₂R)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCK₂R-radioligands instead, we herein present three analogs of the nonpeptidic CCK₂R-antagonist Z360, GAS1/2/3. Each was conjugated to a different chelator (DOTA, NODAGA or DOTAGA) for labeling with medically relevant trivalent radiometals (e.g., Ga-68, In-111, Lu-177) for potential use as anti-CCK₂R cancer agents; (2) Methods: The in vitro properties of the thee analogs were compared in stably transfected HEK293-CCK₂R cells. Biodistribution profiles were compared in SCID mice bearing twin HEK293-CCK₂R and wtHEK293 tumors; (3) Results: The GAS1/2/3 analogs displayed high CCK₂R-affinity (lower nM-range). The radioligands were fairly stable in vivo and selectively targeted the HEK293-CCK₂R, but not the CCK₂R-negative wtHEK293 tumors in mice. Their overall pharmacokinetic profile was found strongly dependent on the radiometal-chelate. Results could be visualized by SPECT/CT for the [¹¹¹In]In-analogs; (4) Conclusions: The present study highlighted the high impact of the radiometal-chelate on the end-pharmacokinetics of a new series of Z360-based radioligands, revealing candidates with promising properties for clinical translation. It also provided the impetus for the development of a new class of nonpeptidic radioligands for CCK₂R-targeted theranostics of human cancer. Full article

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

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19 pages, 8741 KiB

Open AccessArticle

Computational Design and Biological Evaluation of Analogs of Lupin Peptide P5 Endowed with Dual PCSK9/HMG-CoAR Inhibiting Activity

by Carmen Lammi, Enrico M. A. Fassi, Jianqiang Li, Martina Bartolomei, Giulia Benigno, Gabriella Roda, Anna Arnoldi and Giovanni Grazioso

Pharmaceutics 2022, 14(3), 665; https://doi.org/10.3390/pharmaceutics14030665 - 18 Mar 2022

Cited by 12 | Viewed by 2274

Abstract

(1) Background: Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible for the degradation of the hepatic low-density lipoprotein receptor (LDLR), which regulates the circulating cholesterol level. In this field, we discovered natural peptides derived from lupin that showed PCSK9 inhibitory activity. Among these, the [...] Read more.

(1) Background: Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible for the degradation of the hepatic low-density lipoprotein receptor (LDLR), which regulates the circulating cholesterol level. In this field, we discovered natural peptides derived from lupin that showed PCSK9 inhibitory activity. Among these, the most active peptide, known as P5 (LILPHKSDAD), reduced the protein-protein interaction between PCSK9 and LDLR with an IC₅₀ equals to 1.6 µM and showed a dual hypocholesterolemic activity, since it shows complementary inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR). (2) Methods: In this study, by a computational approach, the P5 primary structure was optimized to obtain new analogs with improved affinity to PCSK9. Then, biological assays were carried out for fully characterizing the dual cholesterol-lowering activity of the P5 analogs by using both biochemical and cellular techniques. (3) Results: A new peptide, P5-Best (LYLPKHSDRD) displayed improved PCSK9 (IC₅₀ 0.7 µM) and HMG-CoAR (IC₅₀ 88.9 µM) inhibitory activities. Moreover, in vitro biological assays on cells demonstrated that, not only P5-Best, but all tested peptides maintained the dual PCSK9/HMG-CoAR inhibitory activity and remarkably P5-Best exerted the strongest hypocholesterolemic effect. In fact, in the presence of this peptide, the ability of HepG2 cells to absorb extracellular LDL was improved by up to 254%. (4) Conclusions: the atomistic details of the P5-Best/PCSK9 and P5-Best/HMG-CoAR interactions represent a reliable starting point for the design of new promising molecular entities endowed with hypocholesterolemic activity. Full article

(This article belongs to the Special Issue Proteins and Peptides as a Treatment for Cardiovascular Disease: From Bacteria to Human)

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27 pages, 3810 KiB

Open AccessReview

Gold Nanorods for Drug and Gene Delivery: An Overview of Recent Advancements

by Atieh Jahangiri-Manesh, Marziyeh Mousazadeh, Shirinsadat Taji, Abbas Bahmani, Atefeh Zarepour, Ali Zarrabi, Esmaeel Sharifi and Mostafa Azimzadeh

Pharmaceutics 2022, 14(3), 664; https://doi.org/10.3390/pharmaceutics14030664 - 17 Mar 2022

Cited by 14 | Viewed by 3341

Abstract

Over the past few decades, gold nanomaterials have shown great promise in the field of nanotechnology, especially in medical and biological applications. They have become the most used nanomaterials in those fields due to their several advantageous. However, rod-shaped gold nanoparticles, or gold [...] Read more.

Over the past few decades, gold nanomaterials have shown great promise in the field of nanotechnology, especially in medical and biological applications. They have become the most used nanomaterials in those fields due to their several advantageous. However, rod-shaped gold nanoparticles, or gold nanorods (GNRs), have some more unique physical, optical, and chemical properties, making them proper candidates for biomedical applications including drug/gene delivery, photothermal/photodynamic therapy, and theranostics. Most of their therapeutic applications are based on their ability for tunable heat generation upon exposure to near-infrared (NIR) radiation, which is helpful in both NIR-responsive cargo delivery and photothermal/photodynamic therapies. In this review, a comprehensive insight into the properties, synthesis methods and toxicity of gold nanorods are overviewed first. For the main body of the review, the therapeutic applications of GNRs are provided in four main sections: (i) drug delivery, (ii) gene delivery, (iii) photothermal/photodynamic therapy, and (iv) theranostics applications. Finally, the challenges and future perspectives of their therapeutic application are discussed. Full article

(This article belongs to the Special Issue Recent Advances in Metallic Nanoparticles as Theranostics Platforms)

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13 pages, 9660 KiB

Open AccessArticle

3,4-Dihydroxyphenylethanol (DPE or Hydroxytyrosol) Counteracts ERK1/2 and mTOR Activation, Pro-Inflammatory Cytokine Release, Autophagy and Mitophagy Reduction Mediated by Benzo[a]pyrene in Primary Human Colonic Epithelial Cells

by Roberta Santarelli, Chiara Pompili, Maria Saveria Gilardini Montani, Lorenzo Evangelista, Roberta Gonnella and Mara Cirone

Pharmaceutics 2022, 14(3), 663; https://doi.org/10.3390/pharmaceutics14030663 - 17 Mar 2022

Cited by 7 | Viewed by 2223

Abstract

Understanding the effects induced by carcinogens on primary colonic epithelial cells and how to counteract them might help to prevent colon cancer, which is one of the most frequent and aggressive cancers. In this study, we exposed primary human colonic epithelial cells (HCoEpC) [...] Read more.

Understanding the effects induced by carcinogens on primary colonic epithelial cells and how to counteract them might help to prevent colon cancer, which is one of the most frequent and aggressive cancers. In this study, we exposed primary human colonic epithelial cells (HCoEpC) to Benzo[a]pyrene (B[a]P) and found that it led to an increased production of pro-inflammatory cytokines and activated ERK1/2 and mTOR. These pathways are known to be involved in inflammatory bowel disease (IBD), which represents a colon cancer risk factor. Moreover, B[a]P reduced autophagy and mitophagy, processes whose dysregulation has been clearly demonstrated to predispose to cancer either by in vitro or in vivo studies. Interestingly, all the effects induced by B[a]P could be counteracted by 3,4-Dihydroxyphenylethanol (DPE or Hydroxytyrosol, H), the most powerful anti-inflammatory and antioxidant compound contained in olive oil. This study sheds light on the mechanisms that could be involved in colon carcinogenesis induced by a chemical carcinogen and identifies a safe natural product that may help to prevent them. Full article

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

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8 pages, 231 KiB

Open AccessArticle

Absorption of Direct Oral Anticoagulants in Cancer Patients after Gastrectomy

by Hannah C. Puhr, Aysegül Ilhan-Mutlu, Matthias Preusser, Peter Quehenberger, Paul A. Kyrle, Sabine Eichinger and Lisbeth Eischer

Pharmaceutics 2022, 14(3), 662; https://doi.org/10.3390/pharmaceutics14030662 - 17 Mar 2022

Cited by 3 | Viewed by 2676

Abstract

Direct oral anticoagulants (DOACs) are safe and effective in cancer patients treated for venous thromboembolism (VTE) or atrial fibrillation (AF). Gastrectomy is the treatment of choice in patients with localized upper gastrointestinal cancer. DOACs are absorbed in the upper gastrointestinal tract, but to [...] Read more.

Direct oral anticoagulants (DOACs) are safe and effective in cancer patients treated for venous thromboembolism (VTE) or atrial fibrillation (AF). Gastrectomy is the treatment of choice in patients with localized upper gastrointestinal cancer. DOACs are absorbed in the upper gastrointestinal tract, but to what extent is unclear. In a retrospective analysis, hospital data were searched for adult patients who underwent gastrectomy for gastroesophageal or pancreatic cancer, and DOAC therapy for VTE or AF after gastrectomy. DOAC blood levels were determined by chromogenic assays before and after administration, and thromboembolic and bleeding complications were recorded. Eleven patients (median age 76 years) received a factor Xa inhibitor (FXaI; apixaban (3), edoxaban (3), rivaroxaban (4)) or the factor IIa inhibitor dabigatran (1) for VTE (7) or AF (4) after gastrectomy. Eight patients on FXaI had anti-Xa (aXa) trough levels within the expected range (ER). In all of them, aXa levels increased upon DOAC administration. Two patients on 30 mg edoxaban had low aXa trough levels. Administration of 20 mg of rivaroxaban resulted in trough levels in the ER in one of them. None of the FXaI patients had thromboembolism, while two experienced bleeding (arterial puncture site, gastrointestinal). One dabigatran AF patient with trough and peak concentrations below the ER had strokes during 110 mg and 150 mg dabigatran administration. While on apixaban, aXa levels were in the ER, and no clinical complications occurred. DOACs, particularly FXaI, were adequately absorbed in cancer patients after gastrectomy. Our observation of recurrent thromboembolic events in a patient treated with dabigatran warrants cautious use in this specific patient population. Full article

(This article belongs to the Section Clinical Pharmaceutics)

15 pages, 4093 KiB

Open AccessArticle

Smart Injectable Chitosan Hydrogels Loaded with 5-Fluorouracil for the Treatment of Breast Cancer

by Ahmed A. H. Abdellatif, Ahmed M. Mohammed, Imran Saleem, Mansour Alsharidah, Osamah Al Rugaie, Fatma Ahmed and Shaaban K. Osman

Pharmaceutics 2022, 14(3), 661; https://doi.org/10.3390/pharmaceutics14030661 - 17 Mar 2022

Cited by 19 | Viewed by 2723

Abstract

The treatment of breast cancer requires long chemotherapy management, which is accompanied by severe side effects. Localized delivery of anticancer drugs helps to increase the drug concentration at the site of action and overcome such a problem. In the present study, chitosan hydrogel [...] Read more.

The treatment of breast cancer requires long chemotherapy management, which is accompanied by severe side effects. Localized delivery of anticancer drugs helps to increase the drug concentration at the site of action and overcome such a problem. In the present study, chitosan hydrogel was prepared for local delivery of 5-Fluorouracil. The in vitro release behavior was investigated and the anticancer activity was evaluated against MCF-7 cells using MTT assay. The in vivo studies were investigated via intra-tumoral injection of a 5-FU loaded hydrogel into breast cancer of female rats. The results indicated that the modified hydrogel has excellent physicochemical properties with a sustained in vitro release profile matching a zero-order kinetic for one month. In addition, the hydrogel showed superior inhibition of cell viability compared with the untreated control group. Moreover, the in vivo studies resulted in antitumor activity with minor side effects. The tumor volume and level of tumor markers in blood were inhibited significantly by applying the hydrogel compared with the untreated control group. In conclusion, the designed injectable hydrogels are potential drug delivery systems for the treatment of breast cancer with a controlled drug release profile, which could be suitable for decreasing the side effects of chemotherapy agents. Full article

(This article belongs to the Special Issue Biomolecule-Based Supramolecular Hydrogels for Biomedical Applications: The Current Trends)

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17 pages, 3273 KiB

Open AccessReview

PLGA-Gold Nanocomposite: Preparation and Biomedical Applications

by Alaaldin M. Alkilany, Ousama Rachid, Mahmoud Y. Alkawareek, Nashiru Billa, Anis Daou and Catherine J. Murphy

Pharmaceutics 2022, 14(3), 660; https://doi.org/10.3390/pharmaceutics14030660 - 17 Mar 2022

Cited by 8 | Viewed by 3006

Abstract

A composite system consisting of both organic and inorganic nanoparticles is an approach to prepare a new material exhibiting “the best of both worlds”. In this review, we highlight the recent advances in the preparation and applications of poly(lactic-co-glycolic acid)-gold nanoparticles (PLGA-GNP). With [...] Read more.

A composite system consisting of both organic and inorganic nanoparticles is an approach to prepare a new material exhibiting “the best of both worlds”. In this review, we highlight the recent advances in the preparation and applications of poly(lactic-co-glycolic acid)-gold nanoparticles (PLGA-GNP). With its current clinically use, PLGA-based nanocarriers have promising pharmaceutical applications and can “extract and utilize” the fascinating optical and photothermal properties of encapsulated GNP. The resulting “golden polymeric nanocarrier” can be tracked, analyzed, and visualized using the encapsulated gold nanoprobes which facilitate a better understanding of the hosting nanocarrier’s pharmacokinetics and biological fate. In addition, the “golden polymeric nanocarrier” can reveal superior nanotherapeutics that combine both the photothermal effect of the encapsulated gold nanoparticles and co-loaded chemotherapeutics. To help stimulate more research on the development of nanomaterials with hybrid and exceptional properties, functionalities, and applications, this review provides recent examples with a focus on the available chemistries and the rationale behind encapsulating GNP into PLGA nanocarriers that has the potential to be translated into innovative, clinically applicable nanomedicine. Full article

(This article belongs to the Special Issue Polymer-Based Micro- and Nanocarriers for Drug Delivery and Targeting)

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17 pages, 3218 KiB

Open AccessEditor’s ChoiceArticle

Nanoforming Hyaluronan-Based Thermoresponsive Hydrogels: Optimized and Tunable Functionality in Osteoarthritis Management

by Alexandre Porcello, Paula Gonzalez-Fernandez, Olivier Jordan and Eric Allémann

Pharmaceutics 2022, 14(3), 659; https://doi.org/10.3390/pharmaceutics14030659 - 17 Mar 2022

Cited by 8 | Viewed by 2454

Abstract

Hyaluronic acid (HA) constitutes a versatile chemical framework for the development of osteoarthritis pain treatment by means of injection in the joints, so-called viscosupplementation. Without appropriate physico-chemical tuning, such preparations are inherently hindered by prompt in vivo degradation, mediated by hyaluronidases and oxidative [...] Read more.

Hyaluronic acid (HA) constitutes a versatile chemical framework for the development of osteoarthritis pain treatment by means of injection in the joints, so-called viscosupplementation. Without appropriate physico-chemical tuning, such preparations are inherently hindered by prompt in vivo degradation, mediated by hyaluronidases and oxidative stress. To prolong hydrogel residence time and confer optimized product functionality, novel thermoresponsive nanoforming HA derivatives were proposed and characterized. Combined use of sulfo-dibenzocyclooctyne-PEG4-amine linkers and poly(N-isopropylacrylamide) in green chemistry process enabled the synthesis of HA-based polymers, with in situ obtention of appropriate viscoelastic properties. Spontaneous and reversible thermoformation of nanoparticles above 30 °C was experimentally confirmed. Lead formulations were compared to a commercially available HA-based product and shown significantly better in vitro resistance to enzymatic and oxidative degradation, required half the injection force with optimal viscoelastic hydrogel properties in equine synovial fluids. Results highlighted the vast potential of appropriately engineered HA-based systems as next-generation long-acting viscosupplementation products for osteoarthritic patients. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Switzerland)

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12 pages, 2471 KiB

Open AccessArticle

Tailoring Rational Manufacturing of Extemporaneous Compounding Oral Dosage Formulations with a Low Dose of Minoxidil

by Carlos Torrado-Salmeron, Almudena Laguna, Alicia Guillén, Miguel G. Saro, Antonio Matji, Juan J. Torrado and Dolores R. Serrano

Pharmaceutics 2022, 14(3), 658; https://doi.org/10.3390/pharmaceutics14030658 - 17 Mar 2022

Cited by 1 | Viewed by 2823

Abstract

Low amounts of minoxidil in oral dosage forms are commonly prescribed as anti-alopecic pharmacological treatments. Side effects are usually related to individual susceptibility. However, poor drug content and mass uniformity can lead to a potential risk of overdosing, and higher chances to experience [...] Read more.

Low amounts of minoxidil in oral dosage forms are commonly prescribed as anti-alopecic pharmacological treatments. Side effects are usually related to individual susceptibility. However, poor drug content and mass uniformity can lead to a potential risk of overdosing, and higher chances to experience side effects. The impacts of four formulation variables on drug content and mass pharmaceutical quality attributes were studied with an experimental design at two levels. The first variable (A) was the particle size of the direct compression microcrystalline cellulose (MCC) used as a diluent (Avicel^® PH 101 vs. LP 200). The second variable (B) was the type of production process (direct filling vs. wet granulation). The third variable (C) was the particle size of riboflavin added as a color mixture indicator agent (granular vs. milled). The fourth variable (D) was the type of oral solid dosage form (capsule vs. tablet). In half of the formulations, the mean minoxidil content and minoxidil uniformity were out of the specification limits of the Pharmacopoeia, demonstrating the importance of carefully selecting the excipients as well as the utilized process when manufacturing low oral dosage minoxidil formulations. The best minoxidil content uniformity was achieved when using MCC LP 200, wet granulation, granular riboflavin, and capsules. However, tablets are the recommended dosage form when utilizing Avicel^® PH 101 or direct filling. Meeting these criteria, the content and mass uniformity are more likely to meet the specification limits of the Pharmacopeia. Techniques such as NIR spectroscopy should be implemented to control the quality of extemporaneous compounding formulations with a low dose of active ingredient. Full article

(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)

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18 pages, 7856 KiB

Open AccessArticle

Hepatoprotective Effect of Carob Pulp Flour (Ceratonia siliqua L.) Extract Obtained by Optimized Microwave-Assisted Extraction

by Nikola Martić, Jana Zahorec, Nebojša Stilinović, Bojana Andrejić-Višnjić, Branimir Pavlić, Nebojša Kladar, Dragana Šoronja-Simović, Zita Šereš, Miodrag Vujčić, Olga Horvat and Aleksandar Rašković

Pharmaceutics 2022, 14(3), 657; https://doi.org/10.3390/pharmaceutics14030657 - 17 Mar 2022

Cited by 14 | Viewed by 2753

Abstract

To examine antioxidant capacity and the hepatoprotective effect of carob pulp flour, microwave-assisted extraction was performed. The influence of ethanol concentration (0–40% w/w), extraction time (5–25 min) and irradiation power (400–800 W) on DPPH, FRAP and ABTS antioxidant activity of [...] Read more.

To examine antioxidant capacity and the hepatoprotective effect of carob pulp flour, microwave-assisted extraction was performed. The influence of ethanol concentration (0–40% w/w), extraction time (5–25 min) and irradiation power (400–800 W) on DPPH, FRAP and ABTS antioxidant activity of carob pulp flour extract was evaluated. The strongest influence was that of the ethanol concentration, followed by extraction time. Optimal process parameters for maximizing total antioxidant activity were determined, using response surface methodology: ethanol concentration 40%, time 25 min and power 800 W. Carob extract obtained at optimal conditions (CE) was analyzed in vivo using a paracetamol-induced hepatotoxicity model in mice. Treatment with CE attenuated the parameters of liver injury, especially aspartate and alanine aminotransferase activity, and prevented paracetamol-induced increase in malondialdehyde levels. Pretreatment with CE reversed the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase enzymes after the high dose of paracetamol in the liver. Hepatotoxicity induced using a toxic dose of paracetamol was also seen through histopathological alterations, which were significantly reduced in the groups treated with CE prior to paracetamol. Still, the number of Kupffer cells and macrophages did not differ among groups. Finally, pretreatment of mice with CE and paracetamol significantly decreased the expression of cytochrome P450 2E1 (CYP2E1) in hepatocytes. Full article

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

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22 pages, 3657 KiB

Open AccessArticle

Thymoquinone-Enriched Naringenin-Loaded Nanostructured Lipid Carrier for Brain Delivery via Nasal Route: In Vitro Prospect and In Vivo Therapeutic Efficacy for the Treatment of Depression

by Farheen Fatima Qizilbash, Muhammad Usama Ashhar, Ameeduzzafar Zafar, Zufika Qamar, Annu, Javed Ali, Sanjula Baboota, Mohammed M. Ghoneim, Sultan Alshehri and Asgar Ali

Pharmaceutics 2022, 14(3), 656; https://doi.org/10.3390/pharmaceutics14030656 - 16 Mar 2022

Cited by 20 | Viewed by 3647

Abstract

In the current research, a thymoquinone-enriched naringenin (NGN)-loaded nanostructured lipid carrier (NLC) was developed and delivered via the nasal route for depression. Thymoquinone (TQ) oil was used as the liquid lipid and provided synergistic effects. A TQ- and NGN-enriched NLC was developed via [...] Read more.

In the current research, a thymoquinone-enriched naringenin (NGN)-loaded nanostructured lipid carrier (NLC) was developed and delivered via the nasal route for depression. Thymoquinone (TQ) oil was used as the liquid lipid and provided synergistic effects. A TQ- and NGN-enriched NLC was developed via the ultrasonication technique and optimized using a central composite rotatable design (CCRD). The optimized NLC exhibited the following properties: droplet size, 84.17 to 86.71 nm; PDI, 0.258 to 0.271; zeta potential, −8.15 to −8.21 mV; and % EE, 87.58 to 88.21%. The in vitro drug release profile showed the supremacy of the TQ-NGN-NLC in comparison to the NGN suspension, with a cumulative drug release of 82.42 ± 1.88% from the NLC and 38.20 ± 0.82% from the drug suspension. Ex vivo permeation study displayed a 2.21-fold increase in nasal permeation of NGN from the NLC compared to the NGN suspension. DPPH study showed the better antioxidant potential of the TQ-NGN-NLC in comparison to NGN alone due to the synergistic effect of NGN and TQ oil. CLSM images revealed deeper permeation of the NGN-NLC (39.9 µm) through the nasal mucosa in comparison to the NGN suspension (20 µm). Pharmacodynamic studies, such as the forced swim test and the locomotor activity test, were assessed in the depressed rat model, which revealed the remarkable antidepressant effect of the TQ-NGN-NLC in comparison to the NGN suspension and the marketed formulation. The results signify the potential of the TQ-enriched NGN-NLC in enhancing brain delivery and the therapeutic effect of NGN for depression treatment. Full article

(This article belongs to the Special Issue Brain-Targeted Drug Delivery)

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Pharmaceutics, Volume 14, Issue 3 (March 2022) – 216 articles

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