Pharmaceutics

26 pages, 2876 KiB

Open AccessArticle

Phytosynthesis of Silver Nanoparticles Using Mansoa alliacea (Lam.) A.H. Gentry (Bignoniaceae) Leaf Extract: Characterization and Their Biological Activities

by Johana Zuñiga-Miranda, Saskya E. Carrera-Pacheco, Rebeca Gonzalez-Pastor, Arianna Mayorga-Ramos, Cristina Rodríguez-Pólit, Jorge Heredia-Moya, Karla Vizuete, Alexis Debut, Carlos Barba-Ostria, Elena Coyago-Cruz and Linda P. Guamán

Pharmaceutics 2024, 16(10), 1247; https://doi.org/10.3390/pharmaceutics16101247 (registering DOI) - 25 Sep 2024

Abstract

Background. Mansoa alliacea is a native plant renowned for its medicinal properties in traditional healing in the Amazon Region. This plant is rich in polyphenols, flavonoids, anthocyanins, phenolic acids, tannins, ketones, triterpenes, as well as other bioactive compounds. Objectives. This study [...] Read more.

Background. Mansoa alliacea is a native plant renowned for its medicinal properties in traditional healing in the Amazon Region. This plant is rich in polyphenols, flavonoids, anthocyanins, phenolic acids, tannins, ketones, triterpenes, as well as other bioactive compounds. Objectives. This study aims to develop an innovative, eco-friendly method for synthesizing silver nanoparticles using an aqueous extract of M. alliacea (Ma-AgNPs), enhancing the biological activities of AgNPs by leveraging the therapeutic potential of the plant’s bioactive compounds. Methods. Silver nanoparticles were synthesized using the aqueous extract of M. alliacea. The biological activities of Ma-AgNPs were assessed, including antibacterial, anti-inflammatory, antioxidant, antitumor, and anti-biofilm effects, along with evaluating their hemolytic activity. Results. Quantitative analysis revealed that Ma-AgNPs exhibit potent antibacterial activity against multidrug and non-multidrug-resistant bacteria, with MIC values ranging from 1.3 to 10.0 µg/mL. The Ma-AgNPs significantly reduced NO production by 86.9% at 4 µg/mL, indicating strong anti-inflammatory effects. They demonstrated robust antioxidant activity with an IC50 of 5.54 ± 1.48 µg/mL and minimal hemolytic activity, with no hemolysis observed up to 20 µg/mL and only 4.5% at 40 µg/mL. Their antitumor properties were notable, with IC50 values between 2.9 and 5.4 µg/mL across various cell lines, and they achieved over 50% biofilm inhibition at concentrations of 30–40 µg/mL. Conclusions. These findings underscore the potential of Ma-AgNPs for biomedical applications, particularly in developing new antimicrobial agents and bioactive coatings with reduced toxicity. This research highlights a sustainable approach that not only preserves but also amplifies the inherent biological activities of plant extracts, paving the way for innovative therapeutic solutions. Full article

(This article belongs to the Special Issue Advances in Drug Delivery Systems of Plant Extracts for Antibacterial and Antioxidant Applications)

18 pages, 5942 KiB

Open AccessArticle

An Efficient Fabrication Approach for Multi-Cancer Responsive Chemoimmuno Co-Delivery Nanoparticles

by Jianxi Huang, Yu-Ting Chien, Qingxin Mu and Miqin Zhang

Pharmaceutics 2024, 16(10), 1246; https://doi.org/10.3390/pharmaceutics16101246 - 25 Sep 2024

Abstract

Background/Objectives: Cancer remains one of the leading causes of death, with breast, liver, and pancreatic cancers significantly contributing to this burden. Traditional treatments face issues including dose-limiting toxicity, drug resistance, and limited efficacy. Combining therapeutic agents can enhance effectiveness and reduce toxicity, but [...] Read more.

Background/Objectives: Cancer remains one of the leading causes of death, with breast, liver, and pancreatic cancers significantly contributing to this burden. Traditional treatments face issues including dose-limiting toxicity, drug resistance, and limited efficacy. Combining therapeutic agents can enhance effectiveness and reduce toxicity, but separate administration often leads to inefficiencies due to differing pharmacokinetics and biodistribution. Co-formulating hydrophobic chemotherapeutics such as paclitaxel (PTX) and hydrophilic immunologic agents such as polyinosinic-polycytidylic acid (Poly IC) is particularly challenging due to their distinct physicochemical properties. This study presents a novel and efficient approach for the co-delivery of PTX and Poly IC using chitosan-based nanoparticles. Method: Chitosan-PEG (CP) nanoparticles were developed to encapsulate both PTX and Poly IC, overcoming their differing physicochemical properties and enhancing therapeutic efficacy. Results: With an average size of ~100 nm, these nanoparticles facilitate efficient cellular uptake and stability. In vitro results showed that CP-PTX-Poly IC nanoparticles significantly reduced cancer cell viability in breast (4T1), liver (HepG2), and pancreatic (Pan02) cancer types, while also enhancing dendritic cell (DC) maturation. Conclusions: This dual-modal delivery system effectively combines chemotherapy and immunotherapy, offering a promising solution for more effective cancer treatment and improved outcomes. Full article

(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)

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14 pages, 6702 KiB

Open AccessArticle

Antimicrobial Peptide Octoprohibitin-Encapsulated Chitosan Nanoparticles Enhanced Antibacterial Activity against Acinetobacter baumannii

by E. H. T. Thulshan Jayathilaka, Jinwook Han, Mahanama De Zoysa and Ilson Whang

Pharmaceutics 2024, 16(10), 1245; https://doi.org/10.3390/pharmaceutics16101245 - 25 Sep 2024

Abstract

Background: This study focused on evaluating the physiochemical characteristics and antibacterial activity of Octoprohibitin-encapsulated CNPs (Octoprohibitin-CNPs) against Acinetobacter baumannii. Methods: Octoprohibitin was encapsulated into CNPs via ionotropic gelation with carboxymethyl chitosan (CMC) and low molecular weight chitosan (CS). Octoprohibitin-CNPs were dispersed in [...] Read more.

Background: This study focused on evaluating the physiochemical characteristics and antibacterial activity of Octoprohibitin-encapsulated CNPs (Octoprohibitin-CNPs) against Acinetobacter baumannii. Methods: Octoprohibitin was encapsulated into CNPs via ionotropic gelation with carboxymethyl chitosan (CMC) and low molecular weight chitosan (CS). Octoprohibitin-CNPs were dispersed in phosphate-buffered saline and the release kinetic profile was determined. Then Octoprohibitin-CNPs were examined using field-emission transmission electron microscopy and physicochemical characterization was performed. Antibacterial activity of Octoprohibitin-CNPs against A. baumannii was evaluated. Biofilm inhibition and eradication assays were performed using the crystal violet (CV) staining-based method for biofilm quantification. Results: The average diameter, zeta potential, encapsulation efficiency, and loading capacity of Octoprohibitin-CNPs were 244.5 ± 21.97 nm, +48.57 ± 0.38 mV, and 85.7% and 34.2%, respectively. TEM analysis imaging revealed that Octoprohibitin-CNPs are irregularly shaped, with fewer aggregates than CNPs. Octoprohibitin-CNPs exhibited a biphasic release pattern, characterized by an initial rapid phase followed by a sustained release over time, extending up to 93.68 ± 6.48% total release until 96 h. In vitro, Octoprohibitin-CNPs showed lower cytotoxicity compared to Octoprohibitin alone. Time-kill kinetic and bacterial viability reduction assays showed Octoprohibitin-CNPs exhibited slightly higher antibacterial activity against A. baumannii than Octoprohibitin. Conclusions: Octoprohibitin-CNP-treated A. baumannii exhibited higher levels of morphological deviation, increased membrane permeability, and the production of reactive oxygen species, as well as antibiofilm activity with greater biofilm inhibition and eradication than Octoprohibitin. These findings show that Octoprohibitin-CNPs perform better against A. baumannii compared to Octoprohibitin alone. Full article

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

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15 pages, 22332 KiB

Open AccessArticle

Using Hybrid MnO₂-Au Nanoflowers to Accelerate ROS Scavenging and Wound Healing in Diabetes

by Ning Jiang, Xinwei Liu, Baiyan Sui, Jiale Wang, Xin Liu and Zun Zhang

Pharmaceutics 2024, 16(10), 1244; https://doi.org/10.3390/pharmaceutics16101244 - 25 Sep 2024

Abstract

Objectives: Excessive reactive oxygen species (ROS) in diabetic wounds are major contributors to chronic wounds and impaired healing, posing significant challenges in regenerative medicine. Developing innovative drug delivery systems is crucial to address these issues by modifying the adverse microenvironment and promoting effective [...] Read more.

Objectives: Excessive reactive oxygen species (ROS) in diabetic wounds are major contributors to chronic wounds and impaired healing, posing significant challenges in regenerative medicine. Developing innovative drug delivery systems is crucial to address these issues by modifying the adverse microenvironment and promoting effective wound healing. Methods: Herein, we designed a novel drug delivery platform using manganese dioxide nanoflower hybridized gold nanoparticle composites (MnO₂-Au) synthesized via a hydrothermal reaction, and investigated the potential of MnO₂-Au nanoflowers to relieve the high oxidative stress microenvironment and regulate diabetic wound tissue healing. Results: This hybrid material demonstrated superior catalytic activity compared to MnO₂ alone, enabling the rapid decomposition of hydrogen peroxide and a substantial reduction in ROS levels within dermal fibroblasts. The MnO₂-Au nanoflowers also facilitated enhanced dermal fibroblast migration and Col-I expression, which are critical for tissue regeneration. Additionally, a hydrogel-based wound dressing incorporating MnO₂-Au nanoflowers was developed, showing its potential as an intelligent drug delivery system. This dressing significantly reduced oxidative stress, accelerated wound closure, and improved the quality of neonatal epithelial tissue regeneration in a diabetic rat skin defect model. Conclusions: Our findings underscore the potential of MnO₂-Au nanoflower-based drug delivery systems as a promising therapeutic approach for chronic wound healing, particularly in regenerative medicine. Full article

(This article belongs to the Special Issue Innovative Drug Delivery Systems for Regenerative Medicine, 2nd Edition)

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17 pages, 4899 KiB

Open AccessArticle

Inhibition of Angiogenesis and Effect on Inflammatory Bowel Disease of Ginsenoside Rg3-Loaded Thermosensitive Hydrogel

by Yiqiong Xie, Ying Ma, Lu Xu, Hongwen Liu, Weihong Ge, Baojuan Wu, Hongjue Duan, Hongmei Zhang, Yuping Fu, Hang Xu, Yuxiang Sun, Zhou Han and Yun Zhu

Pharmaceutics 2024, 16(10), 1243; https://doi.org/10.3390/pharmaceutics16101243 - 25 Sep 2024

Abstract

Background: Inflammatory bowel disease (IBD), characterized by chronic inflammation of the digestive tract, involves angiogenesis as a key pathogenic mechanism. Ginsenoside Rg3, derived from the traditional Chinese herb ginseng, is recognized for its anti-angiogenic properties but is limited by low oral bioavailability. [...] Read more.

Background: Inflammatory bowel disease (IBD), characterized by chronic inflammation of the digestive tract, involves angiogenesis as a key pathogenic mechanism. Ginsenoside Rg3, derived from the traditional Chinese herb ginseng, is recognized for its anti-angiogenic properties but is limited by low oral bioavailability. This necessitates the development of an alternative delivery system to improve its therapeutic effectiveness. Methods: Pluronic F-127 (F127) and Pluronic F-68 (F68) were used to construct Rg3-loaded thermosensitive hydrogel Gel-Rg3. Meanwhile, a series of physicochemical properties were determined. Then the safety and pharmacological activity of Gel-Rg3 were evaluated in vitro and in vivo using human umbilical vein endothelial cells (HUVECs) and colitis mouse model, in order to initially validate the potential of Gel-Rg3 for the treatment of IBD. Results: We engineered a rectally administrable, thermosensitive Gel-Rg3 hydrogel using F127 and F68, which forms at body temperature, enhancing Rg3’s intestinal retention and slowly releasing the drug. In vitro, Gel-Rg3 demonstrated superior anti-angiogenic activity by inhibiting HUVEC proliferation, migration, and tube formation. It also proved safer and better suited for IBD’s delicate intestinal environment than unformulated Rg3. In vivo assessments confirmed increased intestinal adhesion and anti-angiogenic efficacy. Conclusions: The Gel-Rg3 hydrogel shows promise for IBD therapy by effectively inhibiting angiogenesis via rectal delivery, overcoming Rg3’s bioavailability limitations with improved safety and efficacy. This study provides new inspiration and data support for the design of treatment strategies for IBD. Full article

(This article belongs to the Special Issue Nanoformulations for Local Treatment of Cancer, Infections and Wounds)

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15 pages, 4688 KiB

Open AccessArticle

Development of Gastroretentive Floating Combination Tablets Containing Amoxicillin Trihydrate 500 mg and Levofloxacin 125 mg for Eradicating Resistant Helicobacter pylori

by Da Hun Kim, Sa-Won Lee, Jun Hak Lee, Jin Woo Park, Sung Mo Park, Han-Joo Maeng, Tae-Sung Koo and Kwan Hyung Cho

Pharmaceutics 2024, 16(10), 1242; https://doi.org/10.3390/pharmaceutics16101242 - 24 Sep 2024

Abstract

Background/Objectives: The aim of this work was to prepare and characterize gastroretentive floating combination tablets (GRCTs) containing 500 mg of amoxicillin trihydrate (AMX) and 125 mg of levofloxacin (LVX) that provide sustained drug release and stability at gastric pH levels for the eradication [...] Read more.

Background/Objectives: The aim of this work was to prepare and characterize gastroretentive floating combination tablets (GRCTs) containing 500 mg of amoxicillin trihydrate (AMX) and 125 mg of levofloxacin (LVX) that provide sustained drug release and stability at gastric pH levels for the eradication of resistant Helicobacter pylori. Method: GRCTs were prepared with low-density excipients and hydrophilic swellable polymers, including hydroxypropyl methylcellulose (HPMC) of various viscosities, polyethylene oxide (PEO), and carboxymethylcellulose (CMC), by the direct compression method. The prepared GRCTs were investigated and optimized in terms of pH stability, tablet hardness, floating lag time and total floating time, drug release rate, gel strength. Results: AMX and LVX in GRCT were stable at the HP eradication target pH above 4.0. The effervescent GRCT composition (AMX/LVX/HPMC [4000 cP]/CMC/microcrystalline cellulose/citric acid/sodium bicarbonate/calcium silicate/silicon dioxide/magnesium stearate = 500/125/50/50/125/40/60/30/10/10, w/w) yielded acceptable hardness (>6 kp), reduced floating lag time (<5 s), a long floating duration (>12 h), and sustained release rates of AMX and LVX (>90% until 12 h). This optimized GRCT had a gel strength of 107.33 ± 10.69 g and pH > 4.0, which maintained the tablets’ shape and AMX stability for 12 h. Conclusions: Collectively, the formulated effervescent GRCTs combining AMX and LVX represented a promising candidate dosage form for eradicating resistant H. pylori. Full article

(This article belongs to the Special Issue New Technology for Prolonged Drug Release, 2nd Edition)

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16 pages, 1903 KiB

Open AccessArticle

Rutin and Physalis peruviana Extract: Population Pharmacokinetics in New Zealand Rabbits

by Gina Paola Domínguez Moré, Diana P. Rey, Ivonne H. Valderrama, Luis F. Ospina and Diana Marcela Aragón

Pharmaceutics 2024, 16(10), 1241; https://doi.org/10.3390/pharmaceutics16101241 - 24 Sep 2024

Abstract

Background/Objectives: An extract of calyces from Physalis peruviana with hypoglycemic activity is being considered as a potential herbal medicine. Preclinical pharmacokinetics (PK) studies of the extract in rats, focusing on plasma concentrations of its main compound, rutin, and its metabolites, revealed PK interactions [...] Read more.

Background/Objectives: An extract of calyces from Physalis peruviana with hypoglycemic activity is being considered as a potential herbal medicine. Preclinical pharmacokinetics (PK) studies of the extract in rats, focusing on plasma concentrations of its main compound, rutin, and its metabolites, revealed PK interactions in the extract matrix that improved the absorption of rutin metabolites compared to the pure compound, among other PK effects. This research aimed to study the PK of rutin alone and in the extract and assess potential PK interactions in the extract matrix on the flavonoid and its metabolites in rabbits, a nonrodent species; Methods: Animals received pure rutin or extract orally and intravenously. The PK analysis used noncompartmental and population pharmacokinetics (popPK) methods, and simple allometry was applied to predict human PK parameters; Results: The rutin concentration–time profile fit a two-compartment model with first-order elimination, while its metabolites fit a double first-order absorption model. The extract matrix led to increased absorption, distribution, and elimination of rutin as well as increased bioavailability of its metabolites in rabbits; Conclusions: The popPK model defined the equations for PK parameters describing these findings, and the increased volume of distribution and clearance of rutin was maintained in human predictions. These results will support the development of a new herbal medicine. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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22 pages, 6892 KiB

Open AccessReview

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

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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33 pages, 1636 KiB

Open AccessReview

Combination Therapy and Phytochemical-Loaded Nanosytems for the Treatment of Neglected Tropical Diseases

by Jacqueline Soto-Sánchez and Gilberto Garza-Treviño

Pharmaceutics 2024, 16(10), 1239; https://doi.org/10.3390/pharmaceutics16101239 - 24 Sep 2024

Abstract

Background: Neglected tropical diseases (NTDs), including leishmaniasis, trypanosomiasis, and schistosomiasis, impose a significant public health burden, especially in developing countries. Despite control efforts, treatment remains challenging due to drug resistance and lack of effective therapies. Objective: This study aimed to synthesize the [...] Read more.

Background: Neglected tropical diseases (NTDs), including leishmaniasis, trypanosomiasis, and schistosomiasis, impose a significant public health burden, especially in developing countries. Despite control efforts, treatment remains challenging due to drug resistance and lack of effective therapies. Objective: This study aimed to synthesize the current research on the combination therapy and phytochemical-loaded nanosystems, which have emerged as promising strategies to enhance treatment efficacy and safety. Methods/Results: In the present review, we conducted a systematic search of the literature and identified several phytochemicals that have been employed in this way, with the notable efficacy of reducing the parasite load in the liver and spleen in cases of visceral leishmaniasis, as well as lesion size in cutaneous leishmaniasis. Furthermore, they have a synergistic effect against Trypanosoma brucei rhodesiense rhodesain; reduce inflammation, parasitic load in the myocardium, cardiac hypertrophy, and IL-15 production in Chagas disease; and affect both mature and immature stages of Schistosoma mansoni, resulting in improved outcomes compared to the administration of phytochemicals alone or with conventional drugs. Moreover, the majority of the combinations studied demonstrated enhanced solubility, efficacy, and selectivity, as well as increased immune response and reduced cytotoxicity. Conclusions: These formulations appear to offer significant therapeutic benefits, although further research is required to validate their clinical efficacy in humans and their potential to improve treatment outcomes in affected populations. Full article

(This article belongs to the Special Issue Novel Pharmaceuticals Development and Delivery Systems for the Treatment of Parasitic Diseases, 2nd Edition)

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21 pages, 3719 KiB

Open AccessArticle

Cyclin-Dependent Kinase 8 Represents a Positive Regulator of Cytomegalovirus Replication and a Novel Host Target for Antiviral Strategies

by Debora Obergfäll, Markus Wild, Mona Sommerer, Malena Barillas Dahm, Jintawee Kicuntod, Julia Tillmanns, Melanie Kögler, Josephine Lösing, Kishore Dhotre, Regina Müller, Christina Wangen, Sabrina Wagner, Quang V. Phan, Lüder Wiebusch, Katarína Briestenská, Jela Mistríková, Lauren Kerr-Jones, Richard J. Stanton, Sebastian Voigt, Friedrich Hahn and Manfred Marschall Show full author list Hide full author list

Pharmaceutics 2024, 16(9), 1238; https://doi.org/10.3390/pharmaceutics16091238 - 23 Sep 2024

Abstract

Background. Cyclin-dependent kinase 8 (CDK8) is a multifaceted regulator and represents a catalytic component of the transcriptional Mediator complex. CDK8 activity, on the one hand, increases transcriptional elongation by the recruitment of Mediator/super elongation complexes, but, on the other hand, negatively regulates [...] Read more.

Background. Cyclin-dependent kinase 8 (CDK8) is a multifaceted regulator and represents a catalytic component of the transcriptional Mediator complex. CDK8 activity, on the one hand, increases transcriptional elongation by the recruitment of Mediator/super elongation complexes, but, on the other hand, negatively regulates CDK7-controlled transcriptional initiation through inactivating cyclin H phosphorylation. Recently, these combined properties of CDK8 have also suggested its rate-limiting importance for herpesviral replication. Objectives. In this paper, we focused on human cytomegalovirus (HCMV) and addressed the question of whether the pharmacological inhibition or knock-down of CDK8 may affect viral replication efficiency in cell culture models. Methods. A number of human and animal herpesviruses, as well as non-herpesviruses, were used to analyze the importance of CDK8 for viral replication in cell culture models, and to assess the antiviral efficacy of CDK8 inhibitors. Results. Using clinically relevant CDK8 inhibitors (CCT-251921, MSC-2530818, and BI-1347), HCMV replication was found strongly reduced even at nanomolar drug concentrations. The EC₅₀ values were consistent for three different HCMV strains (i.e., AD169, TB40, and Merlin) analyzed in two human cell types (i.e., primary fibroblasts and astrocytoma cells), and the drugs comprised a low level of cytotoxicity. The findings highlighted the following: (i) the pronounced in vitro SI values of anti-HCMV activity obtained with CDK8 inhibitors; (ii) a confirmation of the anti-HCMV efficacy by CDK8–siRNA knock-down; (iii) a CDK8-dependent reduction in viral immediate early, early, and late protein levels; (iv) a main importance of CDK8 for viral late-stage replication; (v) several mechanistic aspects, which point to a strong impact on viral progeny production and release, but a lack of CDK8 relevance for viral entry or nuclear egress; (vi) a significant anti-HCMV drug synergy for combinations of inhibitors against host CDK8 and the viral kinase vCDK/pUL97 (maribavir); (vii) finally, a broad-spectrum antiviral activity, as seen for the comparison of selected α-, β-, γ-, and non-herpesviruses. Conclusions. In summary, these novel data provide evidence for the importance of CDK8 as a positive regulator of herpesviral replication efficiency, and moreover, suggest its exploitability as an antiviral target for novel strategies of host-directed drug development. Full article

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28 pages, 1603 KiB

Open AccessReview

Alternative Cancer Therapeutics: Unpatentable Compounds and Their Potential in Oncology

by Dmitriy Ovcharenko, Dmitry Mukhin and Galina Ovcharenko

Pharmaceutics 2024, 16(9), 1237; https://doi.org/10.3390/pharmaceutics16091237 - 23 Sep 2024

Abstract

Cancer remains a leading cause of death globally. Cancer patients often seek alternative therapies in addition to, or instead of, conventional treatments like chemotherapy, radiation, and surgery. The progress in medical advancements and early detection provides more treatment options; however, the development of [...] Read more.

Cancer remains a leading cause of death globally. Cancer patients often seek alternative therapies in addition to, or instead of, conventional treatments like chemotherapy, radiation, and surgery. The progress in medical advancements and early detection provides more treatment options; however, the development of cancer drugs requires a significant amount of time, demands substantial investments, and results in an overall low percent of regulatory approval. The complex relationship between patent protection and pharmaceutical innovation complicates cancer drug development and contributes to high mortality rates. Adjusting patent criteria for alternative cancer therapeutics could stimulate innovation, enhance treatment options, and ultimately improve outcomes for cancer patients. This article explores the potential of alternative cancer therapeutics, chemopreventive agents, natural products, off-patent drugs, generic unpatentable chemicals, and repurposed drugs in cancer treatment, emphasizing the mechanisms and therapeutic potential of these unconventional compounds as combinatorial cancer therapies. The biological pathways, therapeutic effects, and potential to enhance existing therapies are reviewed, demonstrating their cost-effective and accessible options as adjuvant cancer therapies. Full article

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19 pages, 4062 KiB

Open AccessArticle

Molded Round Window Niche Implant as a Dexamethasone Delivery System in a Cochlear Implant-Trauma Animal Model

by Chunjiang Wei, Ziwen Gao, Robert Mau, Thomas Eickner, Gabor Jüttner, Nicklas Fiedler, Hermann Seitz, Thomas Lenarz and Verena Scheper

Pharmaceutics 2024, 16(9), 1236; https://doi.org/10.3390/pharmaceutics16091236 - 23 Sep 2024

Abstract

Background: Preserving residual hearing after cochlear implant (CI) surgery remains a crucial challenge. The application of dexamethasone (DEX) has been proven to positively affect residual hearing. To deliver DEX in a localized and controlled way, a round window niche implant (RNI), allowing drug [...] Read more.

Background: Preserving residual hearing after cochlear implant (CI) surgery remains a crucial challenge. The application of dexamethasone (DEX) has been proven to positively affect residual hearing. To deliver DEX in a localized and controlled way, a round window niche implant (RNI), allowing drug diffusion via the round window membrane into the cochlea, may be used. To prove this concept, an RNI for guinea pigs as a CI-trauma model was manufactured by molding and tested for its drug release in vitro and biological effects in vivo. Methods: The RNIs were molded using silicone containing 10% DEX. Release was analyzed over time using high-performance liquid chromatography (HPLC). Fourteen adult guinea pigs were randomly assigned to two groups (CI or CI + RNI group). All animals received a unilateral CI electrode insertion trauma followed by CI insertion. The CI + RNI group was additionally implanted with an RNI containing 10% DEX. Animals were followed up for 4 weeks. Acoustically evoked auditory brainstem response and impedance measurement, micro-computed tomography (µCT) imaging, and histology were performed for evaluation. Results: DEX was released for more than 250 days in vitro, with an initial burst followed by a slower release over time. Comparing the hearing threshold shift (from day 0 to day 28) of the CI and CI + RNI groups, significant differences were observed at 32 and 40 kHz. The impedance shift at basal contacts was lower in the CI + RNI group than in the CI group. Moreover, the fibrosis in the lower basal turn was reduced in the CI + RNI group in contrast to the CI group. Conclusions: The RNI containing 10% DEX has anti-inflammatory potential concerning fibrosis inhibition and has beneficial effects on hearing preservation at high frequencies. Full article

(This article belongs to the Special Issue Site-Specific Drug Delivery: Formulation Strategies and Regulatory Challenges)

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12 pages, 1289 KiB

Open AccessArticle

Analysis of Lipophilicity and Pharmacokinetic Parameters of Dipyridothiazine Dimers with Anticancer Potency

by Emilia Martula, Beata Morak-Młodawska, Małgorzata Jeleń and Patrick Nwabueze Okechukwu

Pharmaceutics 2024, 16(9), 1235; https://doi.org/10.3390/pharmaceutics16091235 - 23 Sep 2024

Abstract

Lipophilicity is an essential parameter of a compound that determines the solubility and pharmacokinetic properties that determine the transport of the drug to the molecular target. Dimers of dipyridothiazines are diazaphenothiazine derivatives exhibiting diverse anticancer potential in vitro, which is related to their [...] Read more.

Lipophilicity is an essential parameter of a compound that determines the solubility and pharmacokinetic properties that determine the transport of the drug to the molecular target. Dimers of dipyridothiazines are diazaphenothiazine derivatives exhibiting diverse anticancer potential in vitro, which is related to their affinity for histone deacetylase. In this study, the lipophilicity of 16 isomeric dipyridothiazine dimers was investigated theoretically and experimentally by reversed-phase thin-layer chromatography (RP-TLC) in an acetone–TRIS buffer (pH = 7.4). The relative lipophilicity parameter R_M0 and specific hydrophobic surface area b were significantly intercorrelated, showing congeneric classes of dimers. The parameter R_M0 was transformed into parameter logP_TLC by use of the calibration curve. Molecular descriptors, ADMET parameters and probable molecular targets were determined in silico for analysis of the pharmacokinetic profile of the tested compounds showing anticancer activity. The analyzed compounds were tested in the context of Lipinski’s rule of five, Ghose’s rule and Veber’s rule, confirming their bioavailability. Full article

(This article belongs to the Special Issue Role of Pharmacokinetics in Drug Development and Evaluation)

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14 pages, 2300 KiB

Open AccessArticle

Glioblastoma Multiforme: Sensitivity to Antimicrobial Peptides LL-37 and PG-1, and Their Combination with Chemotherapy for Predicting the Overall Survival of Patients

by Alexander N. Chernov, Sofia S. Skliar, Alexander V. Kim, Anna Tsapieva, Sarng S. Pyurveev, Tatiana A. Filatenkova, Marina V. Matsko, Sergey D. Ivanov, Olga V. Shamova and Alexander N. Suvorov

Pharmaceutics 2024, 16(9), 1234; https://doi.org/10.3390/pharmaceutics16091234 - 22 Sep 2024

Abstract

Background/Objectives: Glioblastomas (GBMs) are the most malignant and intractable of all cancers, with an unfavorable clinical prognosis for affected patients. The objective was to analyze the sensitivity of GBM cells to the antimicrobial peptides (AMPs) cathelicidin (LL-37) and protegrin-1 (PG-1), both alone and [...] Read more.

Background/Objectives: Glioblastomas (GBMs) are the most malignant and intractable of all cancers, with an unfavorable clinical prognosis for affected patients. The objective was to analyze the sensitivity of GBM cells to the antimicrobial peptides (AMPs) cathelicidin (LL-37) and protegrin-1 (PG-1), both alone and in combination with chemotherapy, to predict overall survival (OS) in the patients. Methods: The study was conducted on 27 GBM patients treated in the neurosurgical department of the Almazov Medical Research Centre (Saint Petersburg, Russia) from 2021 to 2024. The cytotoxic effects of chemotherapy, AMPs, and their combinations on brain tumor cells were assessed by an MTT assay using a 50% inhibitory concentration (IC₅₀). Results: In GBM cells from the patients, LL-37 and PG-1 exhibited strong anticancer effects, surpassing those of chemotherapy drugs. These LL-37 and PG-1 anticancer effects were associated with a statistically significant increase in life expectancy and OS in GBM patients. These findings were confirmed by experiments on rats with C6 glioma, where the intranasal administration of LL-37 (300 μM) and PG-1 (600 μM) increased the life expectancy of the animals to 69 and 55 days, respectively, compared to 24 days in the control group (HR = 4.139, p = 0.0005; HR = 2.542, p = 0.0759). Conclusions: Additionally, the combination of LL-37 and PG-1 with chemotherapy drugs showed that a high IC₅₀ of LL-37 with cisplatin (cutoff > 800 μM) in GBM cells was associated with increased life expectancy (19 vs. 5 months, HR = 4.708, p = 0.0101) and OS in GBM patients. These combinations could be used in future GBM treatments. Full article

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23 pages, 4533 KiB

Open AccessArticle

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

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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49 pages, 2873 KiB

Open AccessReview

Unlocking the Potential of Silver Nanoparticles: From Synthesis to Versatile Bio-Applications

by Ahmad Almatroudi

Pharmaceutics 2024, 16(9), 1232; https://doi.org/10.3390/pharmaceutics16091232 - 21 Sep 2024

Abstract

Silver nanoparticles (AgNPs) are leading the way in nanotechnological innovation, combining the captivating properties of silver with the accuracy of nanoscale engineering, thus revolutionizing material science. Three main techniques arise within the alchemical domains of AgNP genesis: chemical, physical, and biological synthesis. Each [...] Read more.

Silver nanoparticles (AgNPs) are leading the way in nanotechnological innovation, combining the captivating properties of silver with the accuracy of nanoscale engineering, thus revolutionizing material science. Three main techniques arise within the alchemical domains of AgNP genesis: chemical, physical, and biological synthesis. Each possesses its distinct form of magic for controlling size, shape, and scalability—key factors necessary for achieving expertise in the practical application of nanoparticles. The story unravels, describing the careful coordination of chemical reduction, the environmentally sensitive charm of green synthesis utilizing plant extracts, and the precise accuracy of physical techniques. AgNPs are highly praised in the field of healthcare for their powerful antibacterial characteristics. These little warriors display a wide-ranging attack against bacteria, fungi, parasites, and viruses. Their critical significance in combating hospital-acquired and surgical site infections is highly praised, serving as a beacon of hope in the fight against the challenging problem of antibiotic resistance. In addition to their ability to kill bacteria, AgNPs are also known to promote tissue regeneration and facilitate wound healing. The field of cancer has also observed the adaptability of AgNPs. The review documents their role as innovative carriers of drugs, specifically designed to target cancer cells with accuracy, minimizing harm to healthy tissues. Additionally, it explores their potential as cancer therapy or anticancer agents capable of disrupting the growth of tumors. In the food business, AgNPs are utilized to enhance the durability of packing materials and coatings by infusing them with their bactericidal properties. This results in improved food safety measures and a significant increase in the duration that products can be stored, thereby tackling the crucial issue of food preservation. This academic analysis recognizes the many difficulties that come with the creation and incorporation of AgNPs. This statement pertains to the evaluation of environmental factors and the effort to enhance synthetic processes. The review predicts future academic pursuits, envisioning progress that will enhance the usefulness of AgNPs and increase their importance from being new to becoming essential within the realms of science and industry. Besides, AgNPs are not only a subject of scholarly interest but also a crucial component in the continuous effort to tackle some of the most urgent health and conservation concerns of contemporary society. This review aims to explore the complex process of AgNP synthesis and highlight their numerous uses, with a special focus on their growing importance in the healthcare and food business sectors. This review invites the scientific community to explore the extensive possibilities of AgNPs in order to fully understand and utilize their potential. Full article

(This article belongs to the Special Issue Novel Micro/Nanomaterials Based Drug Delivery Systems for Theranostic Applications)

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11 pages, 922 KiB

Open AccessArticle

Automated Production of [⁶⁸Ga]Ga-Desferrioxamine B on Two Different Synthesis Platforms

by Martin Kraihammer, Miloš Petřík, Christine Rangger, Michael Gabriel, Hubertus Haas, Bernhard Nilica, Irene Virgolini and Clemens Decristoforo

Pharmaceutics 2024, 16(9), 1231; https://doi.org/10.3390/pharmaceutics16091231 - 21 Sep 2024

Abstract

Background/Objectives: PET imaging of bacterial infection could potentially provide added benefits for patient care through non-invasive means. [⁶⁸Ga]Ga-desferrioxamine B—a radiolabelled siderophore—shows specific uptake by human-pathogenic bacteria like Staphylococcus aureus or Pseudomonas aeruginosa and sufficient serum stability for clinical application. In this [...] Read more.

Background/Objectives: PET imaging of bacterial infection could potentially provide added benefits for patient care through non-invasive means. [⁶⁸Ga]Ga-desferrioxamine B—a radiolabelled siderophore—shows specific uptake by human-pathogenic bacteria like Staphylococcus aureus or Pseudomonas aeruginosa and sufficient serum stability for clinical application. In this report, we present data for automated production of [⁶⁸Ga]Ga-desferrioxamine B on two different cassette-based synthesis modules (Modular-Lab PharmTracer and GRP 3V) utilising commercially obtainable cassettes together with a licensed ⁶⁸Ge/⁶⁸Ga radionuclide generator. Methods: Quality control, including the determination of radiochemical purity, as well as a system suitability test, was set up via RP-HPLC on a C18 column. The two described production processes use an acetic acid/acetate buffer system with ascorbic acid as a radical scavenger for radiolabelling, yielding ready-to-use formulations with sufficient activity yield. Results: Batch data analysis demonstrated radiochemical purity of >95% by RP-HPLC combined with ITLC and excellent stability up to 2 h after synthesis. Specifications for routine production were set up and validated with four masterbatches for each synthesis module. Conclusions: Based on this study, an academic clinical trial for imaging of bacterial infection was initiated. Both described synthesis methods enable automated production of [⁶⁸Ga]Ga-desferrioxamine B in-house with high reproducibility for clinical application. Full article

(This article belongs to the Special Issue Advances in Radiopharmaceuticals for Disease Diagnoses and Therapy)

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17 pages, 8494 KiB

Open AccessArticle

Enhancing Radiotherapy Sensitivity in Prostate Cancer with Lentinan-Functionalized Selenium Nanoparticles: Mechanistic Insights and Therapeutic Potential

by Yani Zou, Helin Xu, Xiu Wu, Xuesong Liu and Jianfu Zhao

Pharmaceutics 2024, 16(9), 1230; https://doi.org/10.3390/pharmaceutics16091230 - 21 Sep 2024

Abstract

Radiation therapy is a cornerstone of prostate cancer (PCa) treatment. However, its limited tumor sensitivity and severe side effects restrict its clinical utility. Lentinan-functionalized selenium nanoparticles (LET-SeNPs) have shown promise in enhancing radiotherapy sensitivity and exhibiting antitumor activity. In this study, we investigated [...] Read more.

Radiation therapy is a cornerstone of prostate cancer (PCa) treatment. However, its limited tumor sensitivity and severe side effects restrict its clinical utility. Lentinan-functionalized selenium nanoparticles (LET-SeNPs) have shown promise in enhancing radiotherapy sensitivity and exhibiting antitumor activity. In this study, we investigated the radiotherapy sensitization mechanism of LET-SeNPs in PCa. Our results demonstrate that the combination of LET-SeNPs and X-ray therapy (4 Gy) significantly inhibited the growth and colony formation of PCa cells by inducing apoptosis, surpassing the effects of individual treatments. This combined approach modulated DNA damage through the p53, MAPK (mitogen-activated protein kinase), and AKT pathways. Furthermore, LET-SeNPs increased PC3 cell sensitivity to X-ray-induced apoptosis by downregulating TrxR (Thioredoxin reductase) expression and inducing reactive oxygen species (ROS) overproduction, thereby activating mitochondria-mediated apoptosis signaling pathways. Additionally, LET-SeNPs regulated PARP (poly (ADP-ribose) polymerase) to prevent DNA damage repair. In vivo studies confirmed that the combination treatment inhibited PCa growth by synergistically activating the p53 pathway to induce cell apoptosis. These findings highlight LET-SeNPs’ potential as a radiotherapy sensitizer and suggest that combining LET-SeNPs with X-ray therapy could be a promising strategy for clinical application, leveraging selenium-modified nanoparticles’ antitumor effects. Full article

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15 pages, 2077 KiB

Open AccessArticle

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

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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