[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
You seem to have javascript disabled. Please note that many of the page functionalities won't work as expected without javascript enabled.
 
 
Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Journals

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Article Types

Countries / Regions

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Search Results (1,010)

Search Parameters:
Keywords = prodrug

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
10 pages, 2134 KiB  
Article
Daylight Photodynamic Therapy: At-Home Delivery
by David Bajek, Andrea Lesar, Carol Goodman, Daniella Levins, Paul O’Mahoney, Marese O’Reilly, Susan Yule, Ewan Eadie and Sally Ibbotson
J. Clin. Med. 2024, 13(24), 7745; https://doi.org/10.3390/jcm13247745 - 18 Dec 2024
Viewed by 283
Abstract
This pilot study evaluated the design, usability, and practicality of the dPDT@home kit for treating actinic keratoses (AKs) on the face and scalp. The kit allowed patients to manage their treatment at home, reducing hospital visits and utilizing natural sunlight. While patients were [...] Read more.
This pilot study evaluated the design, usability, and practicality of the dPDT@home kit for treating actinic keratoses (AKs) on the face and scalp. The kit allowed patients to manage their treatment at home, reducing hospital visits and utilizing natural sunlight. While patients were very willing to use the kit again, further studies are required to evaluate outcomes and ascertain the need for additional improvements and support. Background/Objectives: Daylight photodynamic therapy (dPDT) is an established effective therapy for superficial mild-to-moderate actinic keratoses (AKs) on the face and scalp. In this project, we redesigned the delivery of dPDT using design principles and the concept of Realistic Medicine to create the dPDT@home kit. This user-friendly and environmentally conscious kit allows patients to manage their AKs at home, reducing the need for hospital visits and ensuring timely treatment to coincide with appropriate weather conditions and to prevent disease progression due to delays in diagnosis and treatment. The initial pilot phase of the study was to evaluate the usability and convenience of the practicalities of the dPDT@home kit. Methods: Patients were instructed to conduct two dPDT@home kit treatments approximately three weeks apart on suitable weather days. After a follow-up telephone consultation from the specialist PDT nurse following the first treatment, patients then completed an initial questionnaire (Questionnaire 1, Q1) to share their experience. A second questionnaire (Q2) was completed 3–6 months after their final treatment to assess treatment outcomes. Results: A total of 16 patients with AK on the face and/or scalp used the dPDT@home kit. Five patients formed an initial pilot group in 2020/21, whose feedback and involvement informed the final product for the larger group of eleven patients (2021/22). All patients reported no issues with receiving the kit or the pro-drug used in the treatment (Q1). Q2 had an 81.25% return rate, with an average willingness score of 8.9/10 to use dPDT@home again. However, patients expressed doubts about their confidence in the treatment’s efficacy, giving an average score of 6.9/10, with preferences leaning towards other treatments, such as hospital-based PDT or cryotherapy. Conclusions: The pilot deployment of the dPDT@home kit identified suitable patients and highlighted the need for comprehensive training and support for both patients and clinicians to deliver dPDT through this novel approach. The kit can reduce the number of hospital visits, but patients still require supervision, which can be provided remotely. The questionnaire outcomes emphasize the importance of setting patient expectations and taking a holistic approach to managing chronic field-change AK. Additionally, the kit’s recyclable components and reliance on natural sunlight promote sustainability and reduce patient travel. Further evaluation is required to determine cost-efficacy, safety, and the potential place of the dPDT@home kit in the therapeutic management of patients with this common and challenging condition. Full article
Show Figures

Figure 1

Figure 1
<p>Patient-driven storyboarding conceptualizing the PDT @home kit.</p>
Full article ">Figure 2
<p>The dPDT@home kit, interior and exterior.</p>
Full article ">Figure 3
<p>The contents of the dPDT@home kit.</p>
Full article ">Figure 4
<p>Step-by-step instructions for the dPDT@home kit.</p>
Full article ">
14 pages, 2097 KiB  
Article
Synthesis and Characterization of Novel Co(III)/Ru(II) Heterobimetallic Complexes as Hypoxia-Activated Iron-Sequestering Anticancer Prodrugs
by Tan Ba Tran, Éva Sipos, Attila Csaba Bényei, Sándor Nagy, István Lekli and Péter Buglyó
Molecules 2024, 29(24), 5967; https://doi.org/10.3390/molecules29245967 - 18 Dec 2024
Viewed by 250
Abstract
Heterobimetallic complexes of an ambidentate deferiprone derivative, 3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one (PyPropHpH), incorporating an octahedral [Co(4N)]3+ (4N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa)) and a half-sandwich type [(η6-p-cym)Ru]2+ (p-cym = p-cymene) entity have been synthesized and characterized [...] Read more.
Heterobimetallic complexes of an ambidentate deferiprone derivative, 3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one (PyPropHpH), incorporating an octahedral [Co(4N)]3+ (4N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa)) and a half-sandwich type [(η6-p-cym)Ru]2+ (p-cym = p-cymene) entity have been synthesized and characterized by various analytical techniques. The reaction between PyPropHpH and [Co(4N)Cl]Cl2 resulted in the exclusive (O,O) coordination of the ligand to Co(III) yielding [Co(tren)PyPropHp](PF6)2 (1) and [Co(tpa)PyPropHp](PF6)2 (2). This binding mode was further supported by the molecular structure of [Co(tpa)PyPropHp]2(ClO4)3(OH)·6H2O (5) and [Co(tren)PyPropHpH]Cl(PF6)2·2H2O·C2H5OH (6), respectively, obtained via the slow evaporation of the appropriate reaction mixtures and analyzed using X-ray crystallography. Subsequent treatment of 1 or 2 with [Ru(η6-p-cym)Cl2]2 in a one-pot reaction afforded the corresponding heterobimetallic complexes, [Co(tren)PyPropHp(η6-p-cym)RuCl](PF6)3 (3) and [Co(tpa)PyPropHp(η6-p-cym)RuCl](PF6)3 (4), in which the piano-stool Ru core is coordinated by the (N,N) chelating set of the ligand. Cyclic voltammetric measurements revealed that the tpa complexes can be reduced at less negative potentials, suggesting their capability to be bioreductively activated under hypoxia (1% O2). Hypoxia activation of 2 and 4 was demonstrated by cytotoxicity studies on the MCF-7 human breast cancer cell line. PyPropHpH was shown to be a typical iron-chelating anticancer agent, raising the mRNA levels of TfR1, Ndrg1 and p21. Further qRT-PCR studies provided unambiguous evidence for the bioreduction of 2 after 72 h incubation under hypoxia, in which the characteristic gene induction profile caused by the liberated iron-sequestering PyPropHpH was observed. Full article
(This article belongs to the Special Issue Exclusive Feature Papers in Inorganic Chemistry, 2nd Edition)
Show Figures

Figure 1

Figure 1
<p>Structural formulas of the studied and model ligands as well as the metal building blocks.</p>
Full article ">Figure 2
<p>Ortep view of the molecular structure of [Co(tren)(PyPropHpH)]<sup>3+</sup> (<b>top</b>) and [Co(tpa)(PyPropHp)]<sup>2+</sup> (<b>bottom</b>) cations. The anions and solvent molecules are omitted for clarity.</p>
Full article ">Figure 3
<p>(<b>A</b>) Cell viability after 72 h treatment of PyPropHpH under normoxia (black) and hypoxia (gray). (<b>B</b>) Cell viability after 72 h treatment with the complexes under normoxia (black) and hypoxia (gray). Data points are presented as mean (SD). Multiple paired <span class="html-italic">t</span> test and Holm–Šidák post hoc test were used to analyze the data. Significance level: ns: <span class="html-italic">p</span> &gt; 0.05, *: <span class="html-italic">p</span> ≤ 0.05, **: <span class="html-italic">p</span> ≤ 0.01, ***: <span class="html-italic">p</span> ≤ 0.001, ****: <span class="html-italic">p</span> ≤ 0.0001.</p>
Full article ">Figure 4
<p>Gene expression level changes calculated by 2<sup>40-ct</sup> method after (<b>A</b>) 24 h treatment with PyPropHpH, (<b>B</b>) 24 h treatment with PyPropHpH and <b>2</b> at 200 μM and (<b>C</b>) 72 h treatment with PyPropHpH and <b>2</b> at 100 μM under normoxia (black) and hypoxia (gray). Data points are presented as mean (SD). Two-way ANOVA for (<b>A</b>,<b>B</b>) and one-way ANOVA for (<b>C</b>) followed by Dunett’s post hoc test for (<b>A</b>) and Tukey’s post hoc test for (<b>B</b>,<b>C</b>) were used to analyze the data. Significance level: ns: <span class="html-italic">p</span> &gt; 0.05, *: <span class="html-italic">p</span> ≤ 0.05, **: <span class="html-italic">p</span> ≤ 0.01, ***: <span class="html-italic">p</span> ≤ 0.001, ****: <span class="html-italic">p</span> ≤ 0.0001.</p>
Full article ">Scheme 1
<p>Synthetic procedure of the Co(III) complexes and Co(III)/Ru(II) heterobimetallic complexes. The structures of Co(III)-based geometric isomers are shown. Stereogenic centers are denoted with *.</p>
Full article ">
21 pages, 8334 KiB  
Article
A Phosphatidyl Conjugated Telomerase-Dependent Telomere-Targeting Nucleoside Demonstrates Colorectal Cancer Direct Killing and Immune Signaling
by Merve Yilmaz, Sibel Goksen, Ilgen Mender, Gunes Esendagli, Sefik Evren Erdener, Alessandra Ahmed, Ates Kutay Tenekeci, Larisa L. Birichevskaya, Sergei M. Gryaznov, Jerry W. Shay and Z. Gunnur Dikmen
Biomolecules 2024, 14(12), 1616; https://doi.org/10.3390/biom14121616 - 18 Dec 2024
Viewed by 426
Abstract
Telomerase and telomeres are crucial in cancer cell immortalization, making them key targets for anticancer therapies. Currently, 6-thio-dG (THIO) combined with the anti-PD-1 inhibitor Cemiplimab is under phase II clinical investigation (NCT05208944) in NSCLC patients resistant to prior immunotherapies. This study presents the [...] Read more.
Telomerase and telomeres are crucial in cancer cell immortalization, making them key targets for anticancer therapies. Currently, 6-thio-dG (THIO) combined with the anti-PD-1 inhibitor Cemiplimab is under phase II clinical investigation (NCT05208944) in NSCLC patients resistant to prior immunotherapies. This study presents the design, synthesis, and evaluation of novel bimodular conjugate molecules combining telomere-targeting nucleoside analogs and phosphatidyl diglyceride groups. Among them, dihexanoyl-phosphatidyl-THIO (diC6-THIO) showed high anticancer activity with sub-µM EC50 values in vitro across various cancer cell lines. In mouse colorectal cancer models, diC6-THIO demonstrated strong anticancer effects alone and in combination with PD1/PD-L1 inhibitors. Administration of this compound resulted in the efficient formation of Telomere dysfunction Induced Foci (TIFs) in vitro, indicating an on-target, telomerase-mediated telomere-modifying mechanism of action for the molecule. Systemic treatment also activated CD4+ and CD8+ T cells while reducing regulatory T cells, indicating immune system enhancement. Notably, diC6-THIO exhibits an improved solubility profile while maintaining comparable anticancer properties, further supporting its potential as a promising therapeutic candidate. These findings highlight diC6-THIO as a promising telomere-targeting prodrug with dual effects on telomere modification and immune activation. Full article
(This article belongs to the Special Issue Novel Molecules for Cancer Treatment (3rd Edition))
Show Figures

Figure 1

Figure 1
<p>Biologic activity of phosphatidyl nucleoside conjugates in different human and murine cancer cell lines. General chemical structure of nucleoside phosphatidyl diglycerides, where R′ = H, and R″ = C3–C17 fatty acid residues; for diC6-THIOmolecule, R′ = H, R″ = C5 (<b>Aa</b>). Chemical structures of 6-thio-dG (<b>Ab</b>). Cell viability of human colorectal HT29 (<b>B</b>), human cervical HeLa (<b>C</b>), human NSCLC A549 (<b>D</b>), murine colorectal CT26 (<b>E</b>) cancer cell lines, and human dermal fibroblast HDFa cells (<b>F</b>) treated with the indicated concentrations of compounds for 4 days. Cell viability was measured using the MTT Assay. Samples were analyzed in triplicate, and EC<sub>50</sub> values were calculated using GraphPad Prism.</p>
Full article ">Figure 2
<p>diC6-THIOinduces more TIFs compared to 6-thio-dG. Representative 2D images of TIF and DNA damage foci for diC6-THIO and 6-thio-dG in HT29 and CT26 cells with 1 μM treatment for 4 days. Green: Telomeric probe, red: gammaH2AX, yellow: TIFs, and blue: DAPI (<b>A</b>). Merged images with arrows show the representative pictures of TIFs (<b>A</b>); the quantitative measurements of TIF volumes (<b>B</b>); and global DNA damage (<b>C</b>) of HT29, HeLa, and CT26 cells treated with diC6-THIO (1 μM) and 6-thio-dG (1 μM) for 4 days. Data are shown as means ± SEM from two to three independent experiments. <span class="html-italic">p</span>-value was determined by two-way ANOVA followed by a post hoc test (Tukey’s). All TIF and global DNA damage volumes were scored by DiAna plugin (n ≈ 50 for HT29, HeLa, and CT26 cells. <span class="html-italic">p</span>-values for TIF between control vs. 6-thio-dG (**** <span class="html-italic">p</span> &lt; 0.0001) or control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001) or 6-thio-dG vs. diC6-THIO (* <span class="html-italic">p</span> = 0.0147) in HT29; control vs. 6-thio-dG (**** <span class="html-italic">p</span> &lt; 0.0001) or control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001) or 6-thio-dG vs. diC6-THIO (<span class="html-italic">p</span> = 0.9966) in HeLa; and control vs. 6-thio-dG (**** <span class="html-italic">p</span> &lt; 0.0001) or control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001) or 6-thio-dG vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001) in CT26. ns, not significant. <span class="html-italic">p</span>-values for global DNA damage between control vs. 6-thio-dG (**** <span class="html-italic">p</span> &lt; 0.0001) or control vs. diC6-THIO (*** <span class="html-italic">p</span> = 0.0001) or 6-thio-dG vs. diC6-THIO (<span class="html-italic">p</span> = 0.8267) in HT29; control vs. 6-thio-dG (*** <span class="html-italic">p</span> = 0.0004) or control vs. diC6-THIO (** <span class="html-italic">p</span> = 0.0014) or 6-thio-dG vs. diC6-THIO (<span class="html-italic">p</span> = 0.9314) in HeLa; and control vs. 6-thio-dG (** <span class="html-italic">p</span> = 0.0077) or control vs. diC6-THIO (*** <span class="html-italic">p</span> = 0.0003) or 6-thio-dG vs. diC6-THIO (<span class="html-italic">p</span> = 0.5879) in CT26. ns, not significant.</p>
Full article ">Figure 3
<p>diC6-THIO reduces tumor growth in xenograft and syngeneic mouse models. Xenograft model with HT29 cells. The mice were subjected to 3 mg/kg diC6-THIO treatment (total of 6 doses on days 0, 2, 4, 6, 8, and 10, with day 0 designated as the day of treatment start) and 6 mg/kg diC6-THIO treatment (total of 4 doses on days 0, 2, 4, and 6, with day 0 designated as the day of treatment start). Tumor volumes were scored by GraphPad Prism (n = 2 per each group for nude CD1 mice, 2 × 10<sup>6</sup> HT29 cells were injected). *** <span class="html-italic">p</span> = 0.0003 (control vs. 3 mg/kg diC6-THIO), **** <span class="html-italic">p</span> &lt; 0.0001 (control vs. 6 mg/kg diC6-THIO), and *** <span class="html-italic">p</span> = 0.0008 (3 mg/kg diC6-THIO vs. 6 mg/kg) in two-way ANOVA, (control; untreated) (<b>A</b>). The BALB/c mice tumor volume measurements. 2 × 10<sup>6</sup> murine CT26 cells were injected. BALB/c mice bearing CT26 tumors were treated with diC6-THIO (3 mg/kg, days 0, 2, 7, and 9, with day 0 designated as the day of treatment start). Data are shown as means ± SEM from two independent experiments. <span class="html-italic">p</span>-value was determined by two-way ANOVA by using GraphPad Prism. (n = 10 per each group, **** <span class="html-italic">p</span> &lt; 0.0001 control vs. diC6-THIO in two-way ANOVA, control; untreated) (<b>B</b>). Individual tumor growth of control and diC6-THIO treatment groups (<b>C</b>). Graph shows body weight changes of mice in percentage following diC6-THIO treatment. The weights were measured every 2 days (<b>D</b>).</p>
Full article ">Figure 4
<p>Therapeutic efficacy of diC6-THIO when sequentially combined with anti-PD-1 and anti-PD-L1 in MC38 and CT26 colon cancer models. Data are shown as means ± SEM. <span class="html-italic">p</span>-value was determined by two-way ANOVA by using GraphPad Prism. In MC38 mouse model treatment groups, the mice were administered with 6 mg/kg diC6-THIO (i.v.) or 6 mg/kg sdiC6-THIO (i.v.) on days 0, 1, 2, 7, 8, and 9 and/or 10 mg/kg anti-PD-1 (i.p.) on days 4 and 12 (n = 8 per group). There were statistically significant differences between control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001), control vs. diC6-THIO + anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), diC6-THIO + anti-PD-1 vs. anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), control vs. diC6-THIO + anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), anti-PD-1 vs. DIC6-THIO + anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), diC6-THIO vs. diC6-THIO + anti-PD-1 (**** <span class="html-italic">p</span> &lt; 0.0001), sdiC6-THIO vs. sdiC6-THIO + anti-PD-1 (** <span class="html-italic">p</span> = 0.0013), and diC6-THIO vs. sdiC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001). No significant differences (ns) were found between control vs. sdiC6-THIO (<span class="html-italic">p</span> = 0.9301), control vs. anti-PD-1 (<span class="html-italic">p</span> = 0.1357), control vs. sdiC6-THIO + anti-PD-1 (<span class="html-italic">p</span> = 0.0756), and anti-PD-1 vs. sdiC6-THIO + anti-PD-1 (<span class="html-italic">p</span> = 0.9995). For statistical calculations, the final measurements from the euthanized mice are included until the completion of each group, which is determined by the endpoint reached when all mice in that group die. When comparing two groups, the statistical calculations consider the endpoint of the earlier group as reference (<b>A</b>). The body weight changes in percentage from MC38 control, diC6-THIO, sdiC6-THIO, diC6-THIO+ anti-PD-1, sdiC6-THIO + anti-PD-1, and anti-PD-1 groups (<b>B</b>). Individual MC38 tumor growth curves from control and treatment groups (<b>C</b>). In the CT26 mouse model, the mice were administered with 3 mg/kg diC6-THIO (i.p.) on days 0, 2, 7, 9 and/or 10 mg/kg anti-PD-L1 (i.p.) on days 4, 11. there was statistically significant difference between control vs. diC6-THIO (**** <span class="html-italic">p</span> &lt; 0.0001), control vs. diC6-THIO + anti-PD-L1 (**** <span class="html-italic">p</span> &lt; 0.0001), diC6-THIO vs. anti-PD-L1 (*** <span class="html-italic">p</span> = 0.0009), and diC6-THIO + anti-PD-L1 vs. anti-PD-L1 (*** <span class="html-italic">p</span> = 0.0003). No significant differences were found between diC6-THIO vs. diC6-THIO + anti-PD-L1 (<span class="html-italic">p</span> = 0.3222) and control vs. anti-PD-L1 (<span class="html-italic">p</span> = 0.4222). For statistical purposes only, the final measurements from the euthanized mice were included up to the completion of each group, which occurred on day 19 (<b>D</b>). The body weight changes of mice in percentage from CT26 control, diC6-THIO, diC6-THIO + anti-PD-L1, and anti-PD-L1 groups (<b>E</b>). Individual CT26 tumor growth curves from control and treatment groups (<b>F</b>).</p>
Full article ">Figure 5
<p>Immunophenotyping of CT26 bearing mice after diC6-THIO treatment. Total leukocyte (<b>A</b>) subpopulations. Myeloid subpopulations (<b>B</b>–<b>D</b>), lymphocyte subpopulations (<b>E</b>–<b>I</b>), and cytotoxic T cells/T regulatory cells ratio (<b>J</b>) in tumor tissue (number of cells in tumor tissue(#)/mg). Data are shown as means ± SEM. <span class="html-italic">p</span>-values were determined by unpaired Student’s <span class="html-italic">t</span>-test by using GraphPad Prism. Despite the lack of statistical significance among the groups for CD8<sup>+</sup>, CD8<sup>+</sup> CD62L<sup>−</sup>, CD8<sup>+</sup> CD4<sup>+</sup> FoxP3<sup>+</sup>, and CD4<sup>+</sup> FoxP3<sup>+</sup> panels (<span class="html-italic">p</span> &gt; 0.05), the trend for T helper and cytotoxic T cells were indicated that diC6-THIO has potential to induce activated T cell infiltration (<b>E</b>,<b>F</b>,<b>H</b>,<b>I</b>). Opposite, in the treatment group, T regulatory cell numbers decreased (<b>G</b>). Following diC6-THIO treatment cytotoxic T cells: T regulatory cells ratio increased (<b>J</b>).</p>
Full article ">
15 pages, 1440 KiB  
Article
Monophosphate Derivatives of Luteolin and Apigenin as Efficient Precursors with Improved Oral Bioavailability in Rats
by Sydney Wu, Shang-Ta Wang, Guan-Yuan Chen, Chen Hsu, Yi-Hsin Chen, Hsin-Ya Tsai, Te-I Weng, Chien-Li Chen, Yi-Fang Wu and Nan-Wei Su
Antioxidants 2024, 13(12), 1530; https://doi.org/10.3390/antiox13121530 - 13 Dec 2024
Viewed by 394
Abstract
Luteolin (Lut) and apigenin (Apn), flavones present in various edible plants, exhibit diverse antioxidant and pharmacological activities but have limited in vivo efficacy due to low water solubility and poor bioavailability. Here, we generated luteolin and apigenin monophosphate derivatives (LutPs and ApnPs) individually [...] Read more.
Luteolin (Lut) and apigenin (Apn), flavones present in various edible plants, exhibit diverse antioxidant and pharmacological activities but have limited in vivo efficacy due to low water solubility and poor bioavailability. Here, we generated luteolin and apigenin monophosphate derivatives (LutPs and ApnPs) individually via microbial biotransformation. We then characterized their physicochemical properties and evaluated their in vitro and in vivo pharmacokinetics and bioavailability. Both LutPs and ApnPs showed enhanced solubility and dissolution and remained stable in simulated gastrointestinal conditions. Additionally, they efficiently reverted to parental forms via alkaline phosphatase in Caco-2 cells. Following oral administration in rats, LutPs and ApnPs exhibited higher plasma exposure to both aglycone and conjugated forms compared to Lut and Apn. Notably, the in vivo biotransformation of Apn to Lut was observed in all apigenin-related groups. Our study suggests that flavone monophosphates are effective alternatives with enhanced bioavailability, providing insights for the potential application of emerging bioactive nutraceuticals. Full article
Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>HPLC chromatograms of (<b>A</b>) LutPs, with Lut3′P at a content of 665.0 mg/g, Lut4′P at 191.3 mg/g, and Lut7P at 54.7 mg/g, and (<b>B</b>) ApnPs, with Apn7P at 642.2 mg/g and Apn4′P at 272.9 mg/g, obtained through the flash chromatography process. Lut4′P, luteolin 4′-<span class="html-italic">O</span>-phosphate; Lut3′P, luteolin 3′-<span class="html-italic">O</span>-phosphate; Apn4′P, apigenin 4′-<span class="html-italic">O</span>-phosphate; and Apn7′P, apigenin 7′-<span class="html-italic">O</span>-phosphate.</p>
Full article ">Figure 2
<p>The physiological digestive stability of Lut, LutPs, Apn, and ApnPs at a concentration of 125 mg/L in (<b>A</b>) simulated gastric fluid and (<b>B</b>) simulated intestinal fluid, with an incubation period of 240 min, and dissolution profiles of Lut, LutPs, Apn, and ApnPs in (<b>C</b>) a pH of 6.8 in phosphate buffer alone and in (<b>D</b>) bile salt solution. Data are the mean ± SD (<span class="html-italic">n</span> = 3). Lut, luteolin; Lut4′P, luteolin 4′-<span class="html-italic">O</span>-phosphate; Lut3′P, luteolin 3′-<span class="html-italic">O</span>-phosphate; Lut7P, luteolin 7-<span class="html-italic">O</span>-phosphate; Apn, apigenin; Apn4′P, apigenin 4′-<span class="html-italic">O</span>-phosphate; and Apn7′P, apigenin 7′-<span class="html-italic">O</span>-phosphate.</p>
Full article ">Figure 3
<p>The elimination half-life (T<sub>1/2</sub>) of tested compounds at an initial concentration of 20 μM by apical membrane-associated alkaline phosphatase with 120 min of incubation. Data are the mean ± SD (<span class="html-italic">n</span> = 3). The elimination half-life was calculated as T<sub>1/2</sub> = −0.693/k. Values with different letters are significantly different by one-way ANOVA followed by Tukey’s multiple comparison test (<span class="html-italic">p</span> &lt; 0.05). LutPs, luteolin phosphate derivatives; Lut4′P, luteolin 4′-<span class="html-italic">O</span>-phosphate; Lut3′P, luteolin 3′-<span class="html-italic">O</span>-phosphate; Lut7P, luteolin 7-<span class="html-italic">O</span>-phosphate; Apn4′P, apigenin 4′-<span class="html-italic">O</span>-phosphate; and Apn7′P, apigenin 7′-<span class="html-italic">O</span>-phosphate.</p>
Full article ">Figure 4
<p>Mean plasma concentration–time profiles of (<b>A</b>) aglyconic Lut, (<b>B</b>) Lut conjugates, and (<b>C</b>) sum of Lut and its conjugates in rats after the oral administration of Lut, Lut7G suspension, and LutPs solution at 174.67 μmol/kg B.W. Data are the mean ± SE (<span class="html-italic">n</span> = 3). Lut, luteolin; LutPs, luteolin phosphate derivatives; and Lut7G, luteolin 7-<span class="html-italic">O</span>-glucoside.</p>
Full article ">Figure 5
<p>Mean plasma concentration–time profiles of (<b>A</b>) aglyconic Apn, (<b>B</b>) Apn conjugates, and (<b>C</b>) sum of Apn and its conjugates in rats after the oral administration of Apn, Apn7G suspension, and ApnPs solution at 185.02 μmol/kg B.W. Data are the mean ± SE (<span class="html-italic">n</span> = 3–4). Apn, apigenin; ApnPs, apigenin phosphate derivatives; and Apn7G, apigenin 7-<span class="html-italic">O</span>-glucoside.</p>
Full article ">Figure 6
<p>MRM chromatograms of (<b>A</b>) standards (200 ng/mL) for Apn (<b>top</b>) and Lut (<b>bottom</b>) and (<b>B</b>) overlay of MRM chromatograms for Apn (<span class="html-italic">m</span>/<span class="html-italic">z</span> 269) and its metabolite Lut (<span class="html-italic">m</span>/<span class="html-italic">z</span> 285) in plasma. (<b>C</b>) UPLC-MS/MS spectrum of the Lut qualifier ion (<span class="html-italic">m</span>/<span class="html-italic">z</span> 133) from rat plasma. Mean plasma concentration–time profiles of (<b>D</b>) aglyconic Lut, (<b>E</b>) Lut conjugates, and (<b>F</b>) total Lut (Lut and its conjugates) in rats following the oral administration of Apn, Apn7G suspension, and ApnPs solution at 185.02 μmol/kg B.W. Data are the mean ± SE (<span class="html-italic">n</span> = 3−4). Lut, luteolin; Apn, apigenin; ApnPs, apigenin phosphate derivatives; and Apn7G, apigenin 7-<span class="html-italic">O</span>-glucoside.</p>
Full article ">
4 pages, 355 KiB  
Proceeding Paper
Synthesis of New 1Z,5Z-Dienoic Macrodiolides with Benzenyl and Naphthyl Moieties
by Ilgam Gaisin and Ilgiz Islamov
Chem. Proc. 2024, 16(1), 30; https://doi.org/10.3390/ecsoc-28-20111 - 12 Dec 2024
Viewed by 196
Abstract
Macrocycles represent an important class of compounds that are widespread in nature. Of particular interest to researchers are aromatic macrocyclic compounds, which, due to their rigid structure and unique physicochemical properties, can find application in many areas of science, industry and medicine. Previously, [...] Read more.
Macrocycles represent an important class of compounds that are widespread in nature. Of particular interest to researchers are aromatic macrocyclic compounds, which, due to their rigid structure and unique physicochemical properties, can find application in many areas of science, industry and medicine. Previously, we synthesized polyether aromatic macrodiolides, which showed intriguing antitumor properties. In the work, Peyrottes S. and co-authors showed that the introduction of biphenyl or naphthyl rings, as well as triple bonds, into the structure of the compounds they synthesized, not only helps to reduce the molecular flexibility of the molecule, but also increases the bioavailability after oral administration of the corresponding neutral prodrugs. Studies in mice have shown that the presence of two aromatic groups is well tolerated and has resulted in compounds with valuable properties in vitro and in vivo. Based on these results, in continuation of our research on the synthesis of biologically active macrodiolides, in the framework of this work, new aromatic macrocycles were synthesized, the structure of which, along with the 1Z,5Z-diene fragment, contains phenyl or naphthyl rings. The target polyester macrodiolides were obtained by Hf-catalyzed intermolecular cyclocondensation of 1,14-tetradeca-5Z,9Z-dienedioic acid with diols synthesized from dihydroxybenzenes and naphthalenediols. Full article
Show Figures

Scheme 1

Scheme 1
<p>Synthesis of aromatic polyether macrodiolides.</p>
Full article ">
16 pages, 6034 KiB  
Article
Precisely Tailoring Molecular Structure of Doxorubicin Prodrugs to Enable Stable Nanoassembly, Rapid Activation, and Potent Antitumor Effect
by Chengcheng Feng, Yuting Wang, Jiaxu Xu, Yanzi Zheng, Wenhu Zhou, Yuequan Wang and Cong Luo
Pharmaceutics 2024, 16(12), 1582; https://doi.org/10.3390/pharmaceutics16121582 - 11 Dec 2024
Viewed by 445
Abstract
Background: Achieving a balance between stable drug loading/delivery and on-demand drug activation/release at the target sites remains a significant challenge for nanomedicines. Carrier-free prodrug nanoassemblies, which rely on the design of prodrug molecules, offer a promising strategy to optimize both drug delivery efficiency [...] Read more.
Background: Achieving a balance between stable drug loading/delivery and on-demand drug activation/release at the target sites remains a significant challenge for nanomedicines. Carrier-free prodrug nanoassemblies, which rely on the design of prodrug molecules, offer a promising strategy to optimize both drug delivery efficiency and controlled drug release profiles. Methods: A library of doxorubicin (DOX) prodrugs was created by linking DOX to fatty alcohols of varying chain lengths via a tumor-responsive disulfide bond. In vitro studies assessed the stability and drug release kinetics of the nanoassemblies. In vivo studies evaluated their drug delivery efficiency, tumor accumulation, and antitumor activity in mouse models. Results: In vitro results demonstrated that longer fatty alcohol chains improved the stability of the nanoassemblies but slowed down the disassembly and drug release process. DSSC16 NAs (hexadecanol-modified DOX prodrug) significantly prolonged blood circulation time and enhanced tumor accumulation, with AUC values 14.2-fold higher than DiR Sol. In 4T1 tumor-bearing mouse models, DSSC16 NAs exhibited notably stronger antitumor activity, resulting in a final mean tumor volume of 144.39 ± 36.77 mm3, significantly smaller than that of all other groups (p < 0.05 by ANOVA at a 95% confidence interval). Conclusions: These findings underscore the critical role of prodrug molecule design in the development of effective prodrug nanoassemblies. The balance between stability and drug release is pivotal for optimizing drug delivery and maximizing therapeutic efficacy. Full article
(This article belongs to the Special Issue ROS-Mediated Nano Drug Delivery for Antitumor Therapy)
Show Figures

Figure 1

Figure 1
<p>Preparation and characterization of fatty alcohol-DOX prodrug nanoassemblies. (<b>A</b>) Schematic diagram of prodrug nanoassemblies; Photographs and particle size distribution profiles of (<b>B</b>) DSSC8 NAs, (<b>C</b>) DSSC12 NAs, (<b>D</b>) DSSC16 Nas, and (<b>E</b>) DSSC20 NAs; (<b>F</b>) Molecular docking simulation of prodrug nanoassemblies pink and light blue: Carbon atom, red: Oxygen atom, yellow: Sulfur atom, blue: Nitrogen atom; (<b>G</b>) The size change curves of prodrug nanoassemblies (n = 3); Colloidal stability of prodrug nanoassemblies incubated in (<b>H</b>) PBS (pH 7.4) and (<b>I</b>) PBS (pH 7.4) containing 10% FBS (n = 3); and (<b>J</b>) Long-term colloidal stability of prodrug nanoassemblies at 4 °C (n = 3).</p>
Full article ">Figure 2
<p>DTT-triggered prodrug activation and mechanism. The in vitro drug release of the active intermediate (DOX-SH) at 5 mM DTT from DSSC8 NAs (<b>A</b>), DSSC12 NAs (<b>B</b>), DSSC16 NAs (<b>C</b>), and DSSC20 NAs (<b>D</b>) (n = 3). The proportion of remaining prodrug in 1 mM (<b>E</b>) and 0 mM (<b>F</b>) (n = 3); (<b>G</b>) DTT-triggered drug release mechanism of DSSC8 NAs, DSSC12 NAs, DSSC16 Nas, and DSSC20 NAs.</p>
Full article ">Figure 3
<p>Cellular uptake and MTT assay. (<b>A</b>) CLSM images of 4T1 cells incubated with C6 Sol or C6-labeled prodrug-nanoassemblies for 0.5 h and 2 h (scale bar = 10 μm); Flow cytometric analyses of 4T1 cells incubated with C6 sol or C6-labeled prodrug-nanoassemblies for (<b>B</b>) 0.5 and (<b>C</b>) 2 h (n = 3) * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, n.s. no significant; Cell viability after treated with various concentrations of DOX Sol and prodrug nanoassemblies for 48 h in (<b>D</b>) 4T1 cells, (<b>E</b>) RM-1 cells, and (<b>F</b>) CT26 cells (n = 3).</p>
Full article ">Figure 4
<p>Pharmacokinetic and in vivo biodistribution. (<b>A</b>) Pharmacokinetic profiles of DiR Sol and DiR-labeled prodrug-nanoassemblies following a single intravenous administration of 2 mg/kg (DiR equivalent) (n = 5); (<b>B</b>) Living images of 4T1 tumor-bearing BALB/c mice treated with DiR Sol and DiR-labeled prodrug-nanoassemblies at a DiR equivalent dose of 1.5 mg/kg; (<b>C</b>) Quantitative analysis of excised tissues treated with various formulations at the time when tumor accumulation was brightest (n = 3). ** <span class="html-italic">p</span> &lt; 0.01.</p>
Full article ">Figure 5
<p>In vivo antitumor efficacy of prodrug nanoassemblies. (<b>A</b>) Treatment schedule; (<b>B</b>) Digital images of excised tumors from 4T1 tumor-bearing BALB/c mice following various treatments (× represents the death of the mice); (<b>C</b>) Tumor growth curves post-treatment; (<b>D</b>) Tumor burden following different treatments; (<b>E</b>) Hepatic and renal function assessments post-treatment, including alanine aminotransferase (ALT, U/L), aspartate aminotransferase (AST, U/L), creatinine (CREA, μmol/L), and blood urea nitrogen (BUN, mg/dL) (n = 3). (<b>F</b>) Body weight changes during treatment; (<b>G</b>) H&amp;E and TUNEL staining of tumor tissues after treatment (Scale bar = 100 μm). * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01.</p>
Full article ">Scheme 1
<p>Precisely Programming Prodrug Molecular Structure to Enable Stable Nanoassembly and Rapid Activation.</p>
Full article ">
11 pages, 3161 KiB  
Article
Compared Inhibitory Activities of Tamoxifen and Avenanthramide B on Liver Esterase and Correlation Based on the Superimposed Structure Between Porcine and Human Liver Esterase
by Hakseong Lim, Sungbo Hwang, Seung-Hak Cho, Young-Seok Bak, Woong-Suk Yang, Daeui Park and Cheorl-Ho Kim
Int. J. Mol. Sci. 2024, 25(24), 13291; https://doi.org/10.3390/ijms252413291 - 11 Dec 2024
Viewed by 416
Abstract
Exposure to tamoxifen can exert effects on the human liver, and esterases process prodrugs such as antibiotics and convert them to less toxic metabolites. In this study, the porcine liver esterase (PLE)-inhibitory activity of tamoxifen has been investigated. PLE showed inhibition of a [...] Read more.
Exposure to tamoxifen can exert effects on the human liver, and esterases process prodrugs such as antibiotics and convert them to less toxic metabolites. In this study, the porcine liver esterase (PLE)-inhibitory activity of tamoxifen has been investigated. PLE showed inhibition of a PLE isoenzyme (PLE5). In addition, avenanthramides, which have a similar structure to that of tamoxifen, have been used to determine the PLE-inhibitory effect. Among the avenanthramide derivatives, avenanthramide B has been shown to inhibit PLE. Avenanthramide B interacts with Lys284 of PLE, whereas avenanthramide A and C counteract with Lys284. Avenanthramide B has shown a similar inhibitory effect to that of tamoxifen. Given that avenanthramide B can modulate the action of PLE, it can be used in pharmaceutical and industrial applications for modulating the effects of PLE. Based on superimposed structures between PLE and human liver esterase, the impact of tamoxifen use in humans is discussed. In addition, this study can serve as a fundamental basis for future investigations regarding the potential risk of tamoxifen and other drugs. Thus, this study presents an insight into the comparison of structurally similar tamoxifen and avenanthramides on liver esterases, which can have implications for the pharmaceutical and agricultural industries. Full article
(This article belongs to the Section Molecular Biology)
Show Figures

Figure 1

Figure 1
<p>Structure of three different selective estrogen receptor modulators (tamoxifen, toremifene, and raloxifene) and avenanthramides. Tamoxifen and toremifene contain triphenylethylene, whereas raloxifene has a benzothiophene structure.</p>
Full article ">Figure 2
<p>The superimposed structure between PLE and HLE (<b>A</b>) and the esterase inhibition by tamoxifen (<b>B</b>). The white structure represents tamoxifen. The tan and cyan structures represent HLE and PLE, respectively. The pink structure represents the crystal structure of tamoxifen. The salmon and green structures represent the best binding pose of tamoxifen in HLE and PLE. Tamoxifen is shown to inhibit the activity of porcine liver esterase dose-dependently.</p>
Full article ">Figure 3
<p>The selected binding poses of avenanthramide derivatives using molecular docking simulation. (<b>a</b>) All avenanthramide derivatives, with the orange surface representing the PLE. Each avenanthramide derivative was generated by molecular docking. (<b>b</b>) Avenanthramide A is represented by the blue structure, (<b>c</b>) avenanthramide B is represented by the yellow structure, and (<b>d</b>) avenanthramide C is represented by the pink structure. The orange surface represents the PLE. None of the binding poses of the avenanthramide derivatives could be located in the active site of PLE; instead, they were located outside of the active site because Phe286 was blocking the entrance to the active site of PLE. The green surface represents Phe286 in PLE.</p>
Full article ">Figure 4
<p>The PIE measures. (<b>a</b>) The PIE of the attractive common residue. (<b>b</b>) The PIE of the repulsive common residue. The red lines represent the minimum absolute PIE value (4 kcal/mol) for selection as a common residue.</p>
Full article ">Figure 5
<p>The interaction difference between (<b>a</b>) avenanthramide B and (<b>b</b>) avenanthramide A and C. The difference between (<b>a</b>) avenanthramide B and (<b>b</b>) avenanthramide A and C. The significant interactions between avenanthramide B and the other avenanthramide derivatives are represented by the red dashed line.</p>
Full article ">Figure 6
<p>The comparison of the PLE-inhibitory activity of tamoxifen and avenanthramide A, B, and C. (<b>A</b>) Inhibition of porcine liver esterase activity by avenanthramide A, B, and C. (<b>B</b>) Comparison of porcine liver esterase-inhibitory activity of tamoxifen and avenanthramide A, B, and C. The statistically significant inhibition of PLE activity was induced by tamoxifen and avenanthramide B, but not avenanthramide A and C. The results shown are the mean ± SEM and represent three independent tests. * <span class="html-italic">p</span> &lt; 0.05 = significant differences.</p>
Full article ">
16 pages, 1740 KiB  
Article
Novel Lipid-Based Carriers of Provitamin D3: Synthesis and Spectroscopic Characterization of Acylglycerol Conjugated with 7-Dehydrocholesterol Residue and Its Glycerophospholipid Analogue
by Witold Gładkowski, Susanna Ortlieb, Natalia Niezgoda, Anna Chojnacka, Paulina Fortuna and Paweł Wiercik
Molecules 2024, 29(23), 5805; https://doi.org/10.3390/molecules29235805 - 9 Dec 2024
Viewed by 438
Abstract
The aim of this research was to design and synthesize new lipid conjugates of 7-DHC that could serve as a new storage form of esterified provitamin D3, increasing the reservoir of this biomolecule in the epidermis and enabling controlled production of [...] Read more.
The aim of this research was to design and synthesize new lipid conjugates of 7-DHC that could serve as a new storage form of esterified provitamin D3, increasing the reservoir of this biomolecule in the epidermis and enabling controlled production of vitamin D3 even during periods of sunlight deficiency. Acylglycerol and glycerophospholipid containing succinate-linked provitamin D3 at the sn-2 position of the glycerol backbone were synthesized from dihydroxyacetone (DHA) and sn-glycerophosphocholine (GPC), respectively. The three-step synthesis of 1,3-dipalmitoyl-2-(7-dehydrocholesterylsuccinoyl)glycerol involved the esterification of DHA with palmitic acid, reduction of the carbonyl group, and conjugation of the resulting 1,3-dipalmitoylglycerol with 7-dehydrocholesterol hemisuccinate (7-DHC HS). The use of NaBH3CN as a reducing agent was crucial to avoid acyl migration and achieve the final product with 100% regioisomeric purity. For the preparation of 1-palmitoyl-2-(7-dehydrocholesterylsuccinoyl)-sn-glycero-3-phosphocholine, a two-step process was applied, involving the esterification of GPC at the sn-1 position with palmitic acid, followed by the conjugation of 1-palmitoyl-sn-glycero-3-phosphocholine with 7-DHC HS. Alongside the main product, a small amount of its regioisomer with provitamin D3 linked at the sn-1 position and palmitic acid at the sn-2 position was detected, indicating acyl migration from the sn-1 to the sn-2 position in the intermediate 1-palmitoyl-sn-glycerophosphocholine. The synthesized novel lipids were fully characterized using spectroscopic methods. They can find applications as novel lipid-based prodrugs as additives to sunscreen creams. Full article
(This article belongs to the Section Bioactive Lipids)
Show Figures

Figure 1

Figure 1
<p>Fragment of <sup>1</sup>H NMR (<b>A</b>) and <sup>13</sup>C NMR (<b>B</b>) spectrum of acylglycerol <b>4</b>.</p>
Full article ">Figure 1 Cont.
<p>Fragment of <sup>1</sup>H NMR (<b>A</b>) and <sup>13</sup>C NMR (<b>B</b>) spectrum of acylglycerol <b>4</b>.</p>
Full article ">Figure 2
<p>Fragment of <sup>1</sup>H NMR (<b>A</b>) and <sup>13</sup>C NMR (<b>B</b>) spectrum of phospholipid <b>7</b>.</p>
Full article ">Scheme 1
<p>Synthesis of acylglycerol <b>4</b> containing succinyl-linked 7-DHC at the sn-2 position. Reagents and conditions: (i) succinic anhydride, DMAP, anhydrous pyridine, 60 °C, 24 h (ii) palmitic acid, DCC, DMAP, CHCl<sub>3</sub>, r.t., 24 h (iii) NaBH<sub>3</sub>CN, THF, glacial MeCOOH, r.t., 40 min. (iv) DCC, DMAP, CHCl<sub>3</sub>, r.t., 24 h.</p>
Full article ">Scheme 2
<p>Synthesis of glycerophospholipid <b>7</b> containing succinyl-linked 7-DHC at the sn-2 position. Reagents and conditions: (i) DBTO, <sup>i</sup>PrOH, reflux, 1 h; then TEA, palmitoyl chloride, r.t., 0.5 h; (ii) DCC, DMAP, CH<sub>2</sub>Cl<sub>2</sub>, 4 °C, 96 h.</p>
Full article ">
15 pages, 4730 KiB  
Article
The Interactions of Anti-HIV Pronucleotides with a Model Phospholipid Membrane
by Monika Rojewska, Joanna Romanowska, Adam Kraszewski, Michał Sobkowski and Krystyna Prochaska
Molecules 2024, 29(23), 5787; https://doi.org/10.3390/molecules29235787 - 7 Dec 2024
Viewed by 452
Abstract
Pronucleotides, after entering the cell, undergo chemical or enzymatic conversion into nucleotides with a free phosphate residue, and the released nucleoside 5′-monophosphate is then phosphorylated to the biologically active form, namely nucleoside 5′-triphosphate. The active form can inhibit HIV virus replication. For the [...] Read more.
Pronucleotides, after entering the cell, undergo chemical or enzymatic conversion into nucleotides with a free phosphate residue, and the released nucleoside 5′-monophosphate is then phosphorylated to the biologically active form, namely nucleoside 5′-triphosphate. The active form can inhibit HIV virus replication. For the most effective therapy, it is necessary to improve the transport of prodrugs into organelles. The introduction of new functional groups into their structure increases lipophilicity and, as a result, facilitates the interaction of pronucleotide molecules with components of biological membranes. Studies of these interactions were performed using the Langmuir technique. The prototype of the biological membrane was a thin monolayer composed of phospholipid molecules, DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine). The pronucleotides were 3′-azido-3′-deoxythymidine (AZT) analogs, formed by the phosphorylation of AZT to monophosphate (AZTMP) and containing various masking moieties that could increase their lipophilicity. Our results show the influence of the pronucleotide’s chemical structure on the fluidization of the model biomembrane. Changes in monolayer morphology in the presence of prodrugs were investigated by BAM microscopy. It was found that the incorporation of new groups into the structure of the drug as well as the concentration of AZT derivatives have a significant impact on the surface properties of the formed DPPC monolayer. Full article
(This article belongs to the Section Bioactive Lipids)
Show Figures

Figure 1

Figure 1
<p>The general mode of action of pronucleotides.</p>
Full article ">Figure 2
<p>(<b>a</b>) π-A isotherms for DPPC, AZTMP and tested pronucleotides ((<b>1</b>)–(<b>3</b>)) at a concentration of 5 mg/L; (<b>b</b>) compression modulus-surface pressure (C<sub>s</sub><sup>−1</sup>–π) graphs.</p>
Full article ">Figure 3
<p>Relaxation curves for AZTMP and derivatives (<b>1</b>)–(<b>3</b>) (c = 5 mg/L) pumped underneath the DPPC monolayer.</p>
Full article ">Figure 4
<p>Surface pressure–area per molecule (π–A) isotherms and compression modulus–surface pressure (C<sub>s</sub><sup>−1</sup>–π) insert graphs for the analyzed systems: (<b>a</b>) AZTMP, (<b>b</b>) derivative (<b>2</b>), and (<b>c</b>) derivative (<b>3</b>) at different concentrations: 5, 30, and 60 mg/L.</p>
Full article ">Figure 5
<p>BAM images for mixed monolayers DPPC and DPPC/pronucleotides forming during compression. The size of the image is 3.6 × 4.0 mm.</p>
Full article ">Figure 6
<p>Impact of derivative concentrations on DPPC monolayer relaxation: (<b>a</b>) AZTMP, (<b>b</b>) derivative (<b>2</b>), and (<b>c</b>) derivative (<b>3</b>).</p>
Full article ">
15 pages, 980 KiB  
Review
Buccal Absorption of Biopharmaceutics Classification System III Drugs: Formulation Approaches and Mechanistic Insights
by Rayan Sabra, Daniel Kirby, Vikram Chouk, Kleta Malgorzata and Afzal R. Mohammed
Pharmaceutics 2024, 16(12), 1563; https://doi.org/10.3390/pharmaceutics16121563 - 6 Dec 2024
Viewed by 828
Abstract
Buccal drug delivery emerges as a promising strategy to enhance the absorption of drugs classified under the Biopharmaceutics Classification System (BCS) Class III, characterized by high solubility and low permeability. However, addressing the absorption challenges of BCS Class III drugs necessitates innovative formulation [...] Read more.
Buccal drug delivery emerges as a promising strategy to enhance the absorption of drugs classified under the Biopharmaceutics Classification System (BCS) Class III, characterized by high solubility and low permeability. However, addressing the absorption challenges of BCS Class III drugs necessitates innovative formulation strategies. This review delves into optimizing buccal drug delivery for BCS III drugs, focusing on various formulation approaches to improve absorption. Strategies such as permeation enhancers, mucoadhesive polymers, pH modifiers, ion pairing, and prodrugs are systematically explored for their potential to overcome challenges associated with BCS Class III drugs. The mechanistic insight into how these strategies influence drug absorption is discussed, providing a detailed understanding of their applicability. Furthermore, the review advocates for integrating conventional buccal dosage forms with these formulation approaches as a potential strategy to enhance absorption. By emphasizing bioavailability enhancement, this review contributes to a holistic understanding of optimizing buccal absorption for BCS Class III drugs, presenting a unified approach to overcome inherent limitations in their delivery. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
Show Figures

Figure 1

Figure 1
<p>Mechanism of mucoadhesion.</p>
Full article ">Figure 2
<p>Summary depicting the key advantages and limitations for each strategy.</p>
Full article ">
23 pages, 869 KiB  
Article
Synthesis of Enantiostructured Triacylglycerols Possessing a Saturated Fatty Acid, a Polyunsaturated Fatty Acid and an Active Drug Intended as Novel Prodrugs
by Lena Rós Jónsdóttir and Gudmundur G. Haraldsson
Molecules 2024, 29(23), 5745; https://doi.org/10.3390/molecules29235745 - 5 Dec 2024
Viewed by 409
Abstract
This report describes the asymmetric synthesis of a focused library of enantiopure structured triacylglycerols (TAGs) comprised of a single saturated fatty acid (C6, C8, C10, C12, C14 or C16), a pure bioactive n-3 polyunsaturated fatty acid (EPA or DHA) and a potent drug [...] Read more.
This report describes the asymmetric synthesis of a focused library of enantiopure structured triacylglycerols (TAGs) comprised of a single saturated fatty acid (C6, C8, C10, C12, C14 or C16), a pure bioactive n-3 polyunsaturated fatty acid (EPA or DHA) and a potent drug (ibuprofen or naproxen) intended as a novel type of prodrug. One of the terminal sn-1 or sn-3 positions of the glycerol backbone is occupied with a saturated fatty, the remaining one with a PUFA, and the drug entity is present in the sn-2 position. This was accomplished by a six-step chemoenzymatic approach starting from enantiopure (R)- and (S)-solketals. The highly regioselective immobilized Candida antarctica lipase (CAL-B) played a crucial role in the regiocontrol of the synthesis. All combinations, a total of 48 such prodrug TAGs, were prepared, isolated and fully characterized, along with 60 acylglycerol intermediates, obtained in very high to excellent yields. Full article
(This article belongs to the Section Organic Chemistry)
Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>The structure of TAG prodrugs <b>1</b> and <b>2</b> belong to the first category prodrugs, and TAG products <b>3</b> and <b>4</b> belong to the second category prodrugs.</p>
Full article ">Figure 2
<p>Chemoenzymatic synthesis of the first category TAG prodrug diastereomer series (<span class="html-italic">S</span>,<span class="html-italic">S′</span>)-<b>10a</b>–<b>f</b>–<b>13a</b>–<b>f</b>, starting from 1-<span class="html-italic">O</span>-benzyl-<span class="html-italic">sn</span>-glycerol. In the scheme, SFA-CO-, PUFA-CO- and Drug-CO- refer to the corresponding saturated fatty acyl, polyunsaturated fatty acyl and drug acyl group substituents, respectively. In box: (<span class="html-italic">S′</span>)-ibuprofen and (<span class="html-italic">S′</span>)-naproxen attached as esters to acylglycerols (AG).</p>
Full article ">Figure 3
<p>Chemoenzymatic synthesis of the first category TAG prodrug diastereomer series (<span class="html-italic">R</span>,<span class="html-italic">S′</span>)-<b>10a</b>–<b>f</b>–<b>13a</b>–<b>f</b>, starting from 3-<span class="html-italic">O</span>-benzyl-<span class="html-italic">sn</span>-glycerol. In the scheme, SFA-CO-, PUFA-CO- and Drug-CO- refer to the corresponding saturated fatty acyl, polyunsaturated fatty acyl and drug acyl group substituents, respectively. In box: (<span class="html-italic">S′</span>)-ibuprofen and (<span class="html-italic">S′</span>)-naproxen attached as esters to acylglycerols (AG).</p>
Full article ">
20 pages, 6644 KiB  
Article
Host–Guest Complexation of Olmesartan Medoxomil by Heptakis(2,6-di-O-methyl)-β-cyclodextrin: Compatibility Study with Excipients
by Dana Emilia Man, Ema-Teodora Nițu, Claudia Temereancă, Laura Sbârcea, Adriana Ledeți, Denisa Ivan, Amalia Ridichie, Minodora Andor, Alex-Robert Jîjie, Paul Barvinschi, Gerlinde Rusu, Renata-Maria Văruţ and Ionuț Ledeți
Pharmaceutics 2024, 16(12), 1557; https://doi.org/10.3390/pharmaceutics16121557 - 4 Dec 2024
Viewed by 544
Abstract
Background: Olmesartan medoxomil (OLM) is the prodrug of olmesartan, an angiotensin II type 1 receptor blocker that has antihypertensive and antioxidant activities and renal protective properties. It exhibits low water solubility, which leads to poor bioavailability and limits its clinical potential. To improve [...] Read more.
Background: Olmesartan medoxomil (OLM) is the prodrug of olmesartan, an angiotensin II type 1 receptor blocker that has antihypertensive and antioxidant activities and renal protective properties. It exhibits low water solubility, which leads to poor bioavailability and limits its clinical potential. To improve the solubility of OLM, a host–guest inclusion complex (IC) between heptakis(2,6-di-O-methyl)-β-cyclodextrin (DMβCD) and the drug substance was obtained. Along with active substances, excipients play a crucial role in the quality, safety, and efficacy of pharmaceutical formulations. Therefore, the compatibility of OLM/DMβCD IC with several pharmaceutical excipients was evaluated. Methods: IC was characterized in both solid and liquid states, employing thermoanalytical techniques, universal-attenuated total reflectance Fourier-transform infrared spectroscopy, powder X-ray diffractometry, UV spectroscopy, and saturation solubility studies. Compatibility studies were carried out using thermal and spectroscopic methods to assess potential physical and chemical interactions. Results: The 1:1 OLM:DMβCD stoichiometry ratio and the value of the apparent stability constant were determined by means of the phase solubility method that revealed an AL-type diagram. The binary system showed different physicochemical characteristics from those of the parent entities, supporting IC formation. The geometry of the IC was thoroughly investigated using molecular modeling. Compatibility studies revealed a lack of interaction between the IC and all studied excipients at ambient conditions and the thermally induced incompatibility of IC with magnesium stearate and α-lactose monohydrate. Conclusions: The results of this study emphasize that OLM/DMβCD IC stands out as a valuable candidate for future research in the development of new pharmaceutical formulations, in which precautions should be considered in choosing magnesium stearate and α-lactose monohydrate as excipients if the manufacture stage requires temperatures above 100 °C. Full article
Show Figures

Figure 1

Figure 1
<p>Chemical structures of OLM (<b>a</b>) and DMβCD (<b>b</b>).</p>
Full article ">Figure 2
<p>Phase solubility diagram of OLM with DMβCD in 0.1 M phosphate buffer, pH 7.4.</p>
Full article ">Figure 3
<p>OLM/DMβCD IC simulation for 1:1 molar ratio. Images (<b>a</b>,<b>b</b>) show the supramolecular entity from the secondary face of the DMβCD cavity. OLM is represented as sticks colored by element, and DMβCD is represented by red/green/white dots (<b>a</b>); OLM is shown as spheres colored by element, and DMβCD is shown as sticks in red/green/white (<b>b</b>). Polar/hydrophobic contacts between OLM and DMβCD, where OLM is represented as sticks colored by element, and DMβCD is represented as lines (<b>c</b>). H-bond surface interaction of OLM/DMβCD (<b>d</b>).</p>
Full article ">Figure 4
<p>TG/DTG/DSC thermoanalytical curves of OLM (<b>a</b>); DMβCD (<b>b</b>); OLM/DMβCD PM (<b>c</b>); and KP (<b>d</b>) in air atmosphere.</p>
Full article ">Figure 5
<p>FTIR spectra of OLM, DMβCD, OLM/DMβCD PM, and KP.</p>
Full article ">Figure 6
<p>Diffraction profiles of OLM, DMβCD, and OLM/DMβCD binary systems PM and KP.</p>
Full article ">Figure 7
<p>UV spectra of DMβCD 150.0 µg mL<sup>−1</sup> and OLM 27.0 µg mL<sup>−1</sup> in 0.1 M phosphate buffer, pH 7.4, at 25 °C.</p>
Full article ">Figure 8
<p>TG (<b>a</b>,<b>b</b>), DTG (<b>c</b>,<b>d</b>), and DSC (<b>e</b>,<b>f</b>) curves of OLM/DMβCD IC and its mixture with pharmaceutical excipients TA and STA (<b>a</b>,<b>c</b>,<b>e</b>), and Mg STR and LA (<b>b</b>,<b>d</b>,<b>f</b>) in synthetic air atmosphere.</p>
Full article ">Figure 9
<p>UATR-FTIR spectra of (<b>a</b>) OLM/DMβCD IC, TA, STA, and the physical mixture of IC with TA and STA; (<b>b</b>) OLM/DMβCD IC, MgSTR, LA, and the mixture of IC with MgSTR and LA, recorded at ambient temperature.</p>
Full article ">Figure 10
<p>PXRD diffraction patterns of (<b>a</b>) OLM/DMβCD IC, TA, and their corresponding physical mixtures—main image; OLM/DMβCD KP + TA with 2θ values of diffraction peaks corresponding to KP—inset image; and OLM/DMβCD KP, excipients, and their mixture. (<b>b</b>) STA. (<b>c</b>) MgSTR. (<b>d</b>) LA.</p>
Full article ">Figure 10 Cont.
<p>PXRD diffraction patterns of (<b>a</b>) OLM/DMβCD IC, TA, and their corresponding physical mixtures—main image; OLM/DMβCD KP + TA with 2θ values of diffraction peaks corresponding to KP—inset image; and OLM/DMβCD KP, excipients, and their mixture. (<b>b</b>) STA. (<b>c</b>) MgSTR. (<b>d</b>) LA.</p>
Full article ">
17 pages, 7070 KiB  
Article
Colon-Targeted Poly(ADP-ribose) Polymerase Inhibitors Synergize Therapeutic Effects of Mesalazine Against Rat Colitis Induced by 2,4-Dinitrobenzenesulfonic Acid
by Changyu Kang, Jaejeong Kim, Yeonhee Jeong, Jin-Wook Yoo and Yunjin Jung
Pharmaceutics 2024, 16(12), 1546; https://doi.org/10.3390/pharmaceutics16121546 - 2 Dec 2024
Viewed by 524
Abstract
Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) [...] Read more.
Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. Results: The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Conclusions: Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA. Full article
Show Figures

Figure 1

Figure 1
<p><b>Synthetic scheme and colonic activation of derivatives of PARP inhibitors.</b> (<b>A</b>) Synthetic scheme of derivatives of PARP inhibitors. 3-AB: 3-aminobenzamide, 5-AIQ: 5-aminoisoquinoline, ABSA: 3-AB azo-linked with SA, AQSA: 5-AIQ azo-linked with SA, ACN: acetonitrile, CDI: 1,1′-carbonydiimidazole, AQSA-Asp: <span class="html-italic">L</span>-aspartic acid-conjugated AQSA, AQSA-Glu: <span class="html-italic">L</span>-glutamic acid-conjugated AQSA. (<b>B</b>) Colonic activation of derivatives of PARP inhibitors. 5-ASA: 5-aminosalicylic acid.</p>
Full article ">Figure 2
<p><b>Derivatives of PARP inhibitors are colon-specific.</b> (<b>A</b>) AQSA, AQSA-Glu, and AQSA-Asp (1 mM) were incubated with 10% cecal contents suspended in PBS (pH 6.8) under nitrogen. The concentrations of 5-AIQ were analyzed using HPLC at appropriate time intervals. (<b>B</b>) The same experiment was conducted using ABSA (1 mM). (<b>C</b>) 5-AIQ, AQSA, AQSA-Glu, and AQSA-Asp (500 µM, 2 mL) dissolved in DMEM medium without phenol red were added to the apical compartment of the Caco-2 cell monolayer. At appropriate time intervals, the concentrations of each drug were determined in the basolateral compartment filled with the medium (3 mL) using HPLC. (<b>D</b>) The same experiment was conducted using 3-AB and ABSA (500 µM, 2 mL). (<b>E</b>,<b>F</b>) 5-AIQ (10.0 mg/kg) or AQSA-Glu (29.3 mg/kg, equivalent to 10 mg/kg of 5-AIQ) suspended in PBS (1 mL) was administered orally to rats. The rats were killed 2, 4, and 8 h after oral administration (<b>E</b>). The same experiment was conducted using 3-AB (17 mg/kg) and ABSA (36 mg/kg, equivalent to 17 mg/kg of 3-AB) (<b>F</b>). The concentrations of 5-AIQ and 3-AB in the cecum were analyzed using HPLC. The data in (<b>A</b>–<b>F</b>) are presented as mean ± SD (n = 3).</p>
Full article ">Figure 3
<p><b>AQSA-Glu potentiates the anticolitic activity of 5-AIQ.</b> Three days after colitis induction by DNBS, 5-AIQ (5 mg/kg) and AQSA-Glu [7.5 mg/kg, equivalent to 2.5 mg/kg of 5-AIQ (L) and 15 mg/kg, equivalent to 5 mg/kg of 5-AIQ (H)] were administered orally to rats once per day, and the rats were euthanized 24 h after the sixth treatment. (<b>A</b>) Left panel: photos of the distal colons of rats in which serosal and luminal sides are shown separately. Right panel: overall colonic damage was scored for each group and presented as colonic damage score (CDS). * α &lt; 0.05 vs. DNBS control. (<b>B</b>) H &amp; E staining was performed with the colonic tissue sections of rats subjected to various treatments. Upper panel: representative images of 100× magnification. Lower panel: representative images of 200× magnification for the dotted boxes in the upper panel. In the inflamed distal colons (4.0 cm), (<b>C</b>) myeloperoxidase (MPO) activity was measured in addition to determining the levels of (<b>D</b>) CINC-3 and (<b>E</b>) iNOS and COX-2 using an Elisa kit and Western blotting. A loading control (α-Tubulin) was used for Western blot analysis of COX-2 and iNOS. NM: not measurable. The data are represented as mean ± SD (n = 5). * <span class="html-italic">p</span> &lt; 0.05 vs. DNBS control <sup>#</sup> <span class="html-italic">p</span> &lt; 0.05.</p>
Full article ">Figure 4
<p><b>Colon-targeted PARP inhibitors synergize the anticolitic effects of mesalazine.</b> (<b>A</b>) RAW264.7 cells pretreated with 5-ASA (20 mM), 3-AB (1 mM), and 5-AIQ (10 μM) for 1 h were challenged with LPS for 24 h. The levels of iNOS and COX-2 proteins were analyzed using Western blotting. (<b>B</b>) SSZ (50 mg/kg) and ABSA (36 mg/kg, equimolar to 50 mg/kg of SSZ) suspended in PBS (1 mL) were administered orally to rats. The rats were killed 2, 4, and 8 h after oral administration. The concentrations of 5-ASA in the cecum were analyzed using HPLC. (<b>C</b>) Three days after colitis induction by DNBS, SSZ (50 mg/kg), AQSA-Glu (15 mg/kg), a mixture of AQSA-Glu (15 mg/kg) + olsalazine (OSZ, 19 mg/kg, half-equimolar to 50 mg/kg of SSZ), and ABSA (36 mg/kg, equimolar to 50 mg/kg of SSZ) were administered orally to rats once per day, and the rats were euthanized 24 h after the sixth treatment. (<b>C</b>) Left panel: photos of the distal colons of rats where serosal and luminal sides are shown separately. Right panel: overall colonic damage was scored for each group and presented as colonic damage score (CDS). * α &lt; 0.05 vs. DNBS control. (<b>D</b>) H &amp; E staining was performed with the colonic tissue sections of rats subjected to various treatments. Upper panel: representative images of 100× magnification. Lower panel: representative images of 200× magnification for the dotted boxes in the upper panel. In the inflamed distal colons (4.0 cm), (<b>E</b>) myeloperoxidase (MPO) activity was measured in addition to determining the levels of (<b>F</b>) CINC-3 and (<b>G</b>) iNOS and COX-2 using an Elisa kit and Western blotting. A loading control (α-Tubulin) was used for Western blot analysis of COX-2 and iNOS. NM: not measurable. The data are represented as mean ± SD (n = 5). * <span class="html-italic">p</span> &lt; 0.05 vs. DNBS control <sup>#</sup> <span class="html-italic">p</span> &lt; 0.05.</p>
Full article ">Figure 4 Cont.
<p><b>Colon-targeted PARP inhibitors synergize the anticolitic effects of mesalazine.</b> (<b>A</b>) RAW264.7 cells pretreated with 5-ASA (20 mM), 3-AB (1 mM), and 5-AIQ (10 μM) for 1 h were challenged with LPS for 24 h. The levels of iNOS and COX-2 proteins were analyzed using Western blotting. (<b>B</b>) SSZ (50 mg/kg) and ABSA (36 mg/kg, equimolar to 50 mg/kg of SSZ) suspended in PBS (1 mL) were administered orally to rats. The rats were killed 2, 4, and 8 h after oral administration. The concentrations of 5-ASA in the cecum were analyzed using HPLC. (<b>C</b>) Three days after colitis induction by DNBS, SSZ (50 mg/kg), AQSA-Glu (15 mg/kg), a mixture of AQSA-Glu (15 mg/kg) + olsalazine (OSZ, 19 mg/kg, half-equimolar to 50 mg/kg of SSZ), and ABSA (36 mg/kg, equimolar to 50 mg/kg of SSZ) were administered orally to rats once per day, and the rats were euthanized 24 h after the sixth treatment. (<b>C</b>) Left panel: photos of the distal colons of rats where serosal and luminal sides are shown separately. Right panel: overall colonic damage was scored for each group and presented as colonic damage score (CDS). * α &lt; 0.05 vs. DNBS control. (<b>D</b>) H &amp; E staining was performed with the colonic tissue sections of rats subjected to various treatments. Upper panel: representative images of 100× magnification. Lower panel: representative images of 200× magnification for the dotted boxes in the upper panel. In the inflamed distal colons (4.0 cm), (<b>E</b>) myeloperoxidase (MPO) activity was measured in addition to determining the levels of (<b>F</b>) CINC-3 and (<b>G</b>) iNOS and COX-2 using an Elisa kit and Western blotting. A loading control (α-Tubulin) was used for Western blot analysis of COX-2 and iNOS. NM: not measurable. The data are represented as mean ± SD (n = 5). * <span class="html-italic">p</span> &lt; 0.05 vs. DNBS control <sup>#</sup> <span class="html-italic">p</span> &lt; 0.05.</p>
Full article ">Figure 5
<p><b>Colon-targeted PARP inhibitors reduce the risk of systemic side effects of PARP inhibitors.</b> (<b>A</b>) ABSA (36 mg/kg, equivalent to 17 mg/kg of 3-AB) and 3-AB (17 mg/kg) suspended in PBS (1 mL) were administered orally to rats. The rats were killed 2, 4, and 8 h after oral administration. The concentrations of 3-AB in the blood were analyzed using HPLC. (<b>B</b>) The same experiment was conducted with 5-AIQ (10 mg/kg) and AQSA-Glu (30 mg/kg, equivalent to 10 mg/kg of 5-AIQ). The data in A and B are presented as mean ± SD (n = 3).</p>
Full article ">
16 pages, 1006 KiB  
Review
Lipid-Based Niclosamide Delivery: Comparative Efficacy, Bioavailability, and Potential as a Cancer Drug
by Jihoo Woo, Russell W. Wiggins and Shizue Mito
Lipidology 2024, 1(2), 134-149; https://doi.org/10.3390/lipidology1020010 - 1 Dec 2024
Viewed by 429
Abstract
Niclosamide, an FDA-approved anti-parasitic drug, has demonstrated significant potential as a repurposed anti-cancer agent due to its ability to interfere with multiple oncogenic pathways. However, its clinical application has been hindered by poor solubility and bioavailability. Lipid-based nanocarrier systems such as liposomes, solid [...] Read more.
Niclosamide, an FDA-approved anti-parasitic drug, has demonstrated significant potential as a repurposed anti-cancer agent due to its ability to interfere with multiple oncogenic pathways. However, its clinical application has been hindered by poor solubility and bioavailability. Lipid-based nanocarrier systems such as liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid nanoemulsions (LNE), along with lipid prodrugs, have successfully been employed by researchers to overcome these limitations and improve niclosamide’s pharmacokinetic profile. Lipids are the core organic compounds which serve as the foundation of these advanced drug delivery methods and in turn play a critical role in enhancing niclosamide’s therapeutic efficacy through improving drug solubility and bioavailability. Lipid-based nanoparticles encapsulate niclosamide, protect it from degradation, facilitate drug delivery and release, and may facilitate targeted delivery in the future. While niclosamide holds significant potential as an anticancer agent due to its multi-pathway inhibitory effects, the challenges associated with its poor bioavailability and rapid clearance underscore the need for innovative delivery methods and chemical modifications to unlock its full therapeutic potential. This review aims to present the latest instances of lipid-based delivery of niclosamide and to compile successful strategies which may be employed when aiming to develop effective anticancer therapies. Full article
Show Figures

Figure 1

Figure 1
<p>Structures which have been employed in lipid-based niclosamide delivery. Niclosamide represented as a payload in five different lipid-based drug delivery systems: (<b>a</b>) LNE (lipid nanoemulsions): niclosamide solubilized within lipid droplets in an aqueous phase, (<b>b</b>) NLC (nanostructured lipid carriers): niclosamide enclosed in a hybrid core of solid and liquid lipids, (<b>c</b>) SLN (solid lipid nanoparticles): niclosamide encapsulated in a solid lipid core with a lipid bilayer, (<b>d</b>) liposome: niclosamide encapsulated in a spherical vesicle with a lipid bilayer, and (<b>e</b>) SMEDDS (self-microemulsifying drug delivery system): niclosamide in a solid molecular dispersion of oil, surfactants, and cosurfactants [<a href="#B17-lipidology-01-00010" class="html-bibr">17</a>,<a href="#B18-lipidology-01-00010" class="html-bibr">18</a>,<a href="#B19-lipidology-01-00010" class="html-bibr">19</a>,<a href="#B21-lipidology-01-00010" class="html-bibr">21</a>]. Created in BioRender.</p>
Full article ">Figure 2
<p>Schematic representation of a niclosamide loaded with SMEDDS formation, based on Liu et al. [<a href="#B76-lipidology-01-00010" class="html-bibr">76</a>]. Created using BioRender.</p>
Full article ">
13 pages, 3932 KiB  
Article
Zero-Order Kinetics Release of Lamivudine from Layer-by-Layer Coated Macromolecular Prodrug Particles
by Tomasz Urbaniak, Yauheni Milasheuski and Witold Musiał
Int. J. Mol. Sci. 2024, 25(23), 12921; https://doi.org/10.3390/ijms252312921 - 1 Dec 2024
Viewed by 535
Abstract
To reduce the risk of side effects and enhance therapeutic efficiency, drug delivery systems that offer precise control over active ingredient release while minimizing burst effects are considered advantageous. In this study, a novel approach for the controlled release of lamivudine (LV) was [...] Read more.
To reduce the risk of side effects and enhance therapeutic efficiency, drug delivery systems that offer precise control over active ingredient release while minimizing burst effects are considered advantageous. In this study, a novel approach for the controlled release of lamivudine (LV) was explored through the fabrication of polyelectrolyte-coated microparticles. LV was covalently attached to poly(ε-caprolactone) via ring-opening polymerization, resulting in a macromolecular prodrug (LV-PCL) with a hydrolytic release mechanism. The LV-PCL particles were subsequently coated using the layer-by-layer (LbL) technique, with polyelectrolyte multilayers assembled to potentially modify the carrier’s properties. The LbL assembly process was comprehensively analyzed, including assessments of shell thickness, changes in ζ-potential, and thermodynamic properties, to provide insights into the multilayer structure and interactions. The sustained LV release over 7 weeks was observed, following zero-order kinetics (R2 > 0.99), indicating a controlled and predictable release mechanism. Carriers coated with polyethylene imine/heparin and chitosan/heparin tetralayers exhibited a distinct increase in the release rate after 6 weeks and 10 weeks, respectively, suggesting that this coating can facilitate the autocatalytic degradation of the polyester microparticles. These findings indicate the potential of this system for long-term, localized drug delivery applications, requiring sustained release with minimal burst effects. Full article
Show Figures

Figure 1

Figure 1
<p>Chemical structure of lamivudine employed as ring-opening polymerization initiator.</p>
Full article ">Figure 2
<p>Scheme of ring-opening polymerization reaction initiated by lamivudine.</p>
Full article ">Figure 3
<p>Mass spectra of LV-initiated ring-opening polymerization product with ionic distributions subset attributed to LV-PCL macromolecular prodrug molecules (marked in red).</p>
Full article ">Figure 4
<p>GPC chromatogram of LV-initiated ring-opening polymerization product.</p>
Full article ">Figure 5
<p>ITC titration curves reflecting interaction of polyanion HEP with polycations CHIT (<b>A</b>) and PEI (<b>B</b>) in LbL shell assembly conditions.</p>
Full article ">Figure 6
<p>ITC titration curves reflecting interaction of LV-PVL particles with polycations CHIT (<b>A</b>) and PEI (<b>B</b>) in LbL shell assembly conditions.</p>
Full article ">Figure 7
<p>Changes in particle electrokinetic potential and hydrodynamic diameters during the assembly of (PEI/HEP)<sub>2</sub> shells (<b>A</b>,<b>C</b>) and (CHIT/HEP)<sub>2</sub> shells (<b>B</b>,<b>D</b>) on LV-PCL microparticles. Error bars represent standard deviations calculated from three independent measurements.</p>
Full article ">Figure 8
<p>SEM micrographs of LV-PCL microparticles (<b>A</b>) and their modified variants with (CHI/HEP)<sub>2</sub> shells (<b>B</b>) and (PEI/HEP)<sub>2</sub> shells (<b>C</b>).</p>
Full article ">Figure 9
<p>Release profiles of lamivudine (LV) from non-modified LV-PCL microparticles (black squares), (CHIT/HEP)<sub>2</sub>-coated LV-PCL cores (blue triangles), and (PEI/HEP)<sub>2</sub>-coated LV-PCL cores (red circles), along with fitted linear functions (dashed lines). The y-axis represents the mass of released LV per mg of microparticles.</p>
Full article ">
Back to TopTop