Anticancer Research Articles

Bilosomes and Niosomes for Enhanced Intestinal Absorption and In Vivo Efficacy of Cytarabine in Treatment of Acute Myeloid Leukemia

Cytarabine (CTR) is a hydrophilic anticancer drug used to treat leukemia. It suffers from poor permeability and intestinal metabolism, diminishing its oral bioavailability. Background/Objectives: The objective was to develop and evaluate niosomes and bilosomes for enhanced intestinal absorption; hence, oral bioavailability. Results: CTR-loaded niosomes and bilosomes with vesicle sizes of 152 and 204.3 nm were successfully prepared with acceptable properties. The presence of bile salts increased the zeta potential of bilosomes. The recorded entrapment efficiency of cytarabine was acceptable for such a hydrophilic drug. CTR-bilosomes showed a pH-dependent drug release pattern with preferred release in pH 6.8. Intestinal absorption behavior indicated a site-dependent CTR absorption pattern with unfavorable absorption in the distal intestine. Niosomal and bilosomal formulations enhanced intestinal absorption parameters with evidence for a predominant paracellular absorption mechanism that bypasses intestinal barriers. The investigation of the anti-leukemic effect of niosomal and bilosomal formulations indicated that both formulations ameliorated the blood parameters, reflecting significant improvement in leukemia treatment compared with the drug solution. Pathological examination of blood films revealed decreased blast cells in peripheral blood in groups treated with tested formulations. Methods: Tested formulations were prepared according to the pro-concentrate method and characterized for particle size, zeta potential, entrapment efficiency, and in vitro release. CTR-loaded niosomes and bilosomes were evaluated for enhanced intestinal absorption utilizing the single-pass in situ intestinal perfusion method in rabbits, and the anti-leukemic effect was assessed using the benzene-induced leukemia model in rats. Conclusions: This study introduced surfactant vesicles for enhanced oral bioavailability of CTR.

Idarubicin-loaded degradable hydrogel for TACE therapy enhances anti-tumor immunity in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common and deadly cancer, often diagnosed at advanced stages, limiting surgical options. Transcatheter arterial chemoembolization (TACE) is a primary treatment for inoperable and involves the use of drug-eluting microspheres to slowly release chemotherapy drugs. However, patient responses to TACE vary, with some experiencing tumor progression and recurrence. Traditional TACE uses agents like oil-based drug emulsions and polyvinyl alcohol particles, which can permanently block blood vessels and increase tumor hypoxia. Additionally, TACE can suppress the immune system by reducing immune cell numbers and function, contributing to poor treatment outcomes. New approaches, like TACE using degradable starch microspheres and hydrogel-based materials, offer the potential to create different tumor environments that could improve both safety and efficacy. In our research, we developed a composite hydrogel (IF@Gel) made of Poloxamer-407 gel and Fe3O4 nanoparticles, loaded with idarubicin, to use as an embolic material for TACE in a rat model of orthotopic HCC. We observed promising therapeutic effects and investigated the impact on the tumor immune microenvironment, focusing on the role of immunogenic cell death (ICD). The composite hydrogel demonstrated excellent potential as an embolic material for TACE, and IF@Gel-based TACE demonstrated significant efficacy in rat HCC. Furthermore, our findings highlight the potential synergistic effects of ICD with anti-PD-L1 therapy, providing new insights into HCC treatment strategies. This study aims to provide improved treatment options for HCC and to deepen our understanding of the mechanisms of TACE and tumor environment regulation.

Combinatorial MD/QM studies to develop novel ionic liquid-based anticancer drug delivery systems with aminium derived from carbohydrates as cationic components

The main challenges in anticancer drug design include solubility in organic and aqueous phases, bioavailability, selective targeting of specific receptors, and low toxicity. Notably, solubility, bioavailability, and receptor-specific targeting are interconnected factors that significantly influence the therapeutic efficacy of anticancer drugs. The primary objective of this study is to design novel drug delivery systems based on ionic liquids. These systems incorporate structures such as N, N, N-trimethyl-2-(((2 S,3R,4 S,5 S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2 H-pyran-2-yl)oxy)ethan-1-aminium (GTA) and (2 S,3R,4 S,5 S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-N, N, N-trimethyltetrahydro-2 H-pyran-2-aminium (NTPA) derived from carbohydrates as cationic components, with anticancer drugs acting as anions. The goal is to investigate the effects of these novel pharmaceutical active ionic liquids on the interactions between the drugs and cell membranes. Additionally, this study examines changes in the solubility of anticancer drugs in both organic and aqueous phases after their conversion into ionic liquids. Molecular dynamics simulations (MD) and quantum mechanics calculations (QM) are employed to achieve these objectives. Known anticancer-candidate ionic liquid, such as 3-(2-((4-fluorophenyl)amino)-2-oxoethyl)-1-methyl-1 H-imidazol-3-ium-tetrafluoroborate, is considered as a reference point in our investigations. Furthermore, we aim to assess whether the direct attachment of the aminium group to the saccharide portion of the cations or the indirect attachment through a choline group significantly impacts the final properties of the designed anticancer ionic liquids. Another aim of this study is to demonstrate that QM studies need to be complemented by MD studies to provide insights into the behaviors of ionic liquids. Initially, we calculate the binding energies between cations and anions of all the ionic liquids at the B3LYP/6-311 + + G(d, p) level of theory. Subsequently, molecular dynamics simulations using GROMACS 5.2 are employed to obtain more precise information about these understudied ionic liquids. A combination of density functional theory (DFT) calculations and a solvation model based on density (SMD) is utilized to determine the solubility of free anticancer drugs and our active anticancer ionic liquids in various phases. We validate our findings by evaluating the interactions between the formulated ionic liquids and cell membranes using the DPPC model through combined MD simulations and docking procedures.

Effect of stem extract of Schisandra Chinensis on improving spermatogenesis disorder induced by Cisplatin in Vivo and in Vitro

BackgroundThe primary adverse effect of chemotherapy drugs is the induction of spermatogenic disorders. Schisandra chinensis (Turcz) Baill. have been preliminarily shown to have a significant ameliorative in spermatogenic disorders. Nevertheless, there are relatively few studies on non-medicinal parts such as stems of S. chinensis, which have good therapeutic potential for side effects caused by cisplatin. Up to now, a total of 238 compounds have been isolated and identified from the vine stem of S. chinensi. The main components are lignans, polysaccharides, volatile oils, and organic acids. Therefore, the development of S. chinensis stem as a source of a novel chemotherapy drug protector is of great significance. MethodsIn the present study, we explored the protective effect of the stem extract of S. chinensis (SCE) against cisplatin-induced spermatogenic disorders and its possible molecular mechanisms in vitro and in vivo. The network pharmacology was used to predict the targets that may act on spermatogenic disorders. Mice were injected intraperitoneally with cisplatin at 2 mg/kg for 7 days to induce spermatogenic disorders. SCE (75, 150, and 300 mg/kg) was administered to mice by gavage for 21 days. TM3 cells were treated with Schisandrol B (Sol B) (0.5, 1, and 2 µM) in the presence or absence of cisplatin (40 µM), and then cell viability, oxidative stress, apoptosis, and mitochondrial function were evaluated. Results16 constituents and target proteins were predicted to have possible effects on spermatogenic disorders by network pharmacology. Both in vivo and in vitro experiments showed a favorable protective effect of SCE against cisplatin-induced spermatogenic disorders. Sol B might as the major chemical component is responsibility for the protective effect. The mechanism may involve the regulation of Nrf2\\HO-1 protein, PI3K\\Akt, apoptosis, and MAPK signaling pathway to modulate 17βHSD, cycp450, Star and other crucial proteins in the testosterone synthesis pathway. Ultimately, this regulatory process aims to ameliorate the disruption of sex hormone secretion by cisplatin. ConclusionThese results indicated that the lignans in SCE could effectively improve the spermatogenesis barrier caused by cisplatin. These findings provided a theoretical basis for the development of non-medicinal parts of S. chinensis, and laid a foundation for improving spermatogenesis disorders caused by chemotherapy drugs.

Engineering Nano-Pills to Inhibit Ovarian Cancer Proliferation and Migration through a Combination of Chemical/Nucleic Acid Therapy.

Ovarian cancer (OC) is the most fatal of all gynecological malignancies, presenting a significant threat to women's health. Its treatment is complicated by severe dose-dependent chemotherapy toxicity, drug resistance, and tumor migration. Herein, an intelligent combination strategy of chemotherapy and nucleic acid therapy, named ApMEmiR&D is developed. This integrated system consists of three parts: the nano-pill, the protective membrane, and the navigation element. Nano-pills are nanospheres assembled from miRNA and doxorubicin (DOX) with the help of ferrous ions (Fe2+). The protective membrane is derived from tumor-associated macrophages (TAMs membrane) originating from the primary tumor microenvironment (TME). The navigation element is the cholesterol-conjugated AS1411 aptamer. The resulting ApMEmiR&D nanoparticles exhibit uniform size, a well-defined nanosphere structure, robust serum stability, and ultra-high drug loading efficiency and capacity. The system can efficiently accumulate in the tumor, allowing for the synergistic inhibition of tumor growth and metastasis without apparent systemic toxicity. The results demonstrate the homing effect of tumor microenvironment-derived macrophage cell membrane and the targeting effect of aptamer, leading to precise drug targeting and immune compatibility, thereby enhancing therapeutic efficacy. The success of this strategy paves the way for metastasis inhibition and targeted cancer therapy.

Zuogui pills ameliorate chemotherapy-induced ovarian aging by improving stemness, regulating cell cycle and reducing apoptosis of oogonial stem cells via the Notch1/Nrf2 pathway

Ethnopharmacological relevanceZuogui Pills (ZGP) is a classic traditional Chinese herbal formula originating from the Ming Dynasty. It has been widely used in the treatment of kidney deficiency-related diseases, including ovarian aging. Aim of the studyTo investigate the effects and potential mechanisms of ZGP on ovarian aging induced by the chemotherapeutic agent cyclophosphamide (CTX), as well as its impact on the therapeutic target, oogonial stem cells (OSCs), involving the Notch1/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Materials and methodsThis study utilized High-Performance Liquid Chromatography (HPLC) to analyze the active components of Zuogui Pills (ZGP). In vivo experiments involved the establishment of an ovarian aging model in female rats through intraperitoneal injection of CTX, followed by an 8-week treatment with ZGP and dehydroepiandrosterone (DHEA). The Notch pathway inhibitor DAPT was administered via intraperitoneal injection, followed by ZGP intervention to validate its therapeutic effects. Transcriptomic sequencing was used to analyze the differential genes before and after ZGP treatment of CTX-induced ovarian aging, and KEGG and GO analyses were applied to assess the changes in relevant signaling pathways and biological processes. In vitro experiments included the extraction, separation, and purification of ovarian germ stem cells, followed by transfection with a Notch1 overexpression plasmid. The CTX active component 4-Hydroxycyclophosphamide (4HC) was used for model intervention, and ZGP, DHEA-containing serum, and DAPT were applied to intervene with the oogonial stem cells. The effects of CTX modeling, the therapeutic efficacy of ZGP, and the general condition of the rats were observed. H&E staining was employed to assess ovarian morphology and follicle counting at various stages. Serum hormone levels were measured using ELISA, while qPCR, Western blot, flow cytometry, immunofluorescence, and IHC were utilized to analyze the expression of the Notch1/Nrf2 pathway, cell cycle proteins, and stemness-related indicators. Flow cytometry, TUNEL fluorescence, and CCK8 assays were conducted to evaluate changes in cell cycle composition, apoptosis, and proliferation. Finally, ChIP-qPCR was employed to validate the transcriptional regulation of the target gene NFE2L2 by Notch1. ResultsZGP improved serum sex hormones in ovarian aging rats, enhanced ovarian index, and optimized ovarian and uterine morphology, as well as follicle quantity composition. After transcriptome sequencing, KEGG analysis enriched the Notch signaling pathway and cell cycle, while GO analysis highlighted enrichment in the Notch pathway and stem cell population maintenance. Various experiments validated that ZGP significantly improved the expression of cell cycle-related proteins Cyclin D1 (CCND1), Cyclin E1 (CCNE1), cyclin-dependent kinase inhibitor 1a (CDKN1A), stemness markers Mouse Vasa Homolog (MVH), Octamer-binding Transcription Factor 4 (Oct4), Fragilis, 5-Bromo-2′-deoxyuridine (BrdU), as well as Notch1 and Nrf2 in aging ovarian tissues and OSCs. Additionally, ZGP promoted the proliferation of 4HC-damaged OSCs, optimized OSCs cell cycle composition, reduced G0/G1 phase arrest, and decreased early and late apoptosis. ZGP could reverse the detrimental effects on stemness and cell cycle of OSCs caused by blocking the Notch pathway. Furthermore, ZGP may activate the regulation of its target gene NFE2L2 by upregulating Notch1 expression in OSCs, thereby exerting therapeutic effects. ConclusionZGP protects ovarian function in CTX-induced ovarian aging rats by regulating the Notch1/Nrf2 pathway. It restores serum sex hormone levels, maintains normal follicle development, promotes the proliferation of aged OSCs, optimizes the cell cycle, reduces apoptosis, and preserves stemness, thereby alleviating ovarian aging.

The tumor suppressor SALL2 opposes chemotherapeutic resistance in breast cancer.

Chemotherapy continues to be the primary treatment for certain types of breast cancer. However, despite an initial positive response to chemotherapeutic agents, the development of resistance is inevitable. The exact molecular mechanisms underlying this phenomenon remain unclear. In this research, a significant downregulation of SALL2 expression was observed in chemo-resistant breast cancer, which was attributed to promoter methylation. Decreased SALL2 expression correlated significantly with poorer relapse-free survival in chemotherapy-treated patients with breast cancer. Functionally, SALL2 silencing induced a stem cell-like phenotype in breast cancer cells, fostering resistance to cisplatin both in vitro and in vivo. This resistance was mediated, at least in part, through the transcriptional regulation of BTG2, a negative regulator of stemness, achieved by direct binding to its promoter regions. These findings underscore the critical role of SALL2 in modulating cisplatin response and propose SALL2 as a potential prognostic biomarker for chemotherapy response in breast cancer.

Mesenchymal stem cells - the secret agents of cancer immunotherapy: Promises, challenges, and surprising twists.

Mesenchymal stem cells (MSCs) are recognized for their immunomodulatory capabilities, tumor-homing abilities, and capacity to serve as carriers for therapeutic agents. This review delves into the role of adoptively transferred MSCs in tumor progression, their interactions with the tumor microenvironment, and their use in delivering anti-cancer drugs, oncolytic viruses, and genetic material. It also addresses the challenges and limitations associated with MSC therapy, such as variability in MSC preparations and potential tumorigenic effects emphasizing the need for advanced genetic engineering and personalized approaches to enhance therapeutic efficacy. The review concludes with an optimistic outlook on the future of MSC-based therapies, underscoring their promise to develop effective and personalized cancer treatments.

Synthesis of novel imino-coumarin and acrylonitile 2-benzazole hybrids as potent anticancer agents targeting tubulin

Building on previous research indicating the robust biological effects of coumarins, we focused on exploring imino-coumarin 2-benzazole conjugates. Compounds were tested for antiproliferative activity in vitro, with the most active ones further examined to determine the mechanism of biological action.Five derivatives exhibited significant antiproliferative activity against all tested cancer cells (IC50 ranging from 0.04 to 8.5 μM), falling within the low micromolar/submicromolar range of inhibitory concentrations. Three compounds had remarkable antiproliferative effects against Capan-1 (IC50 0.04–0.05 μM) and DND-41 (IC50 0.06–0.07 μM). Promising compounds were further investigated, confirming their mechanism of action through tubulin polymerization inhibition.Computational docking and molecular dynamics simulations confirmed the high affinity of potent derivatives for the tubulin colchicine site and justified the suitability of the employed skeleton by identifying crucial protein–ligand interactions promoting binding. This insight highlights a strategy for further potency improvements through substituents that can donate hydrogen bonds or bear a positive charge, allowing such ligands to more optimally adapt to the identified anionic binding site environment.

Molecular Design of Phthalocyanine-Based Drug Coassembly with Tailored Function.

Coassemblies with tailored functions, such as drug loading, tissue targeting and releasing, therapeutic and/or imaging purposes, and so on, have been widely studied and applied in biomedicine. De novo design of these coassemblies hinges on an integrated approach involving synergy between various design strategies, ranging from structure screening of combinations of "phthalocyanine-chemotherapeutic drug" molecules for molecular scaffolds, exploration of related fabrication principles to verification of intended activity of specific designs. Here, we propose an integrated approach combining computation and experiments to design from scratch coassembled nanoparticles. This nanocoassembly, termed NanoPC here, consists of phthalocyanine-based scaffolds hosting chemotherapeutic drugs, aimed at hypersensitive chemotherapy guided by photoimaging for targeting tumors. Our design starts from the selection of phthalocyanine derivatives that are not aggregation-prone, followed by computational screening of coassembled molecules covering various categories of chemotherapy drugs. To facilitate an efficient and accurate assessment of coassembly capabilities, we utilize small systems as surrogates to enable free-energy calculations at all-atom levels facilitated with enhanced sampling and statistical mechanics for efficient and accurate evaluation of coassembly ability. The final top NanoPC candidate, comprised of phthalocyanine PcL and cytarabine (CYT), can greatly increase the fluorescence intensity ratio of tumor/liver by 21.5 times and achieve higher antitumor efficiency in a pH-dependent manner. Therefore, the designing approach proposed here has a potential pattern, which can provide ideas and references for the design and development of coassembled nanodrugs with tailored functions and applications in biomedicine.

Ivermectin inhibits the growth of ESCC by activating the ATF4-mediated endoplasmic reticulum stress-autophagy pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most common forms of malignancy worldwide. However, there is currently a lack of effective chemotherapeutic drugs for ESCC. Ivermectin is a broad-spectrum antiparasitic drug with notable antitumor activity. However, the cellular and molecular mechanisms by which ivermectin inhibits cancer growth remain unclear. In this study, we elucidate the role of ivermectin in ESCC suppression by activating the endoplasmic reticulum (ER) stress and autophagy pathways. In transcriptome analyses, we find that activating transcription factor 4 (ATF4) and DNA damage inducible transcript 3 (DDIT3) are involved in the activation of ER stress by ivermectin. Moreover, ivermectin treatment suppresses the growth of ESCC xenograft tumors in nude mice. Taken together, our results establish the antitumor molecular role of ivermectin in targeting the ER stress-autophagy pathway and suggest that ivermectin is a potential drug candidate for the treatment of ESCC.

Rhaponticin suppresses the stemness phenotype of gastric cancer stem-like cells CD133+/CD166 + by inhibiting programmed death-ligand 1

BackgroundGastric cancer stem cells (GCSCs) are key contributors to tumorigenesis, recurrence and metastasis, complicating gastric cancer (GC) treatment. Rhaponticin (RA), a potential novel anticancer drug, has unexplored effects on GCSCs.MethodsGCSCs were isolated using CD133 and CD166 markers with magnetic bead separation method and then evaluated their response to the IC50 concentrations of RA (16.90 µg/mL for BGC-823 and 22.18 µg/mL for SGC-7901), and effects on cell proliferation, migration, invasion, and stemness were measured. We analyzed the GCSC-related microarray dataset GSE111556 and explored RA’s role in restoring programmed cell death ligand 1 (PD-L1) function in CD133+/CD166 + cells post-PD-L1 knockdown. RA’s impact on tumour growth and immune microenvironment was assessed in a xenograft mouse model.ResultsThe CD133+/CD166 + subpopulation exhibited stem-like characteristics, with the highest proportion in BGC-823 (38.85%) and SGC-7901 (43.81%) cells. These cells formed tumour spheres and had increased expression of stemness markers Sox2 and Oct-4 (compared to the parental cell line, P < 0.001). RA treatment showed no toxicity to normal GES-1 cells but reduced the viability of CD133+/CD166 + cells in a dose-dependent manner, with IC50 values of 16.90 µg/ml for BGC-823 and 22.18 µg/ml for SGC-7901. RA also decreased the proportion of CD133+/CD166 + cells and their stem-like properties (P < 0.001). Analysis of the GEO database identified PD-L1 as a key target gene of RA, with high expression in GC tissues. Knocking down PD-L1 in CD133+/CD166 + cells and introducing RA did not significantly change PD-L1 expression (P>0.05), suggesting RA’s effect may be PD-L1 dependent. In a xenograft mouse model, the tumour size in the RA treatment group was approximately one-sixth that of the CD133+/CD166 + group (P < 0.001). Post-RA treatment, there was an elevation in the expression levels of CD4 and CD8, alongside a reduction in PD-L1 expression (P < 0.001).ConclusionsRA suppresses GCSC stem - like phenotype by inhibiting PD - L1 and enhancing T cell tumour infiltration in the studied models. These findings suggest that RA may have potential for further exploration as a candidate for GC treatment, but extensive preclinical and clinical studies are required to determine its true therapeutic value.

Hydrazidomethyl starch as a pH-sensitive coating for magnetic core in tailored magnetic nanoparticles with selective doxorubicin release

The work aimed to use and modify starch as a biodegradable and biocompatible polysaccharide to create a modern pH-sensitive anticancer drug carrier based on a hydrazone bond. The multi-step reaction created a material that can bind to the carbonyl group of anticancer drugs. Additionally, polysaccharide was used to coat magnetic nanoparticles to increase the applicability of the carrier system. At each synthesis stage, the material was characterized in detail by performing FTIR-ATR spectra, thermal analysis, XRD, and SEM photos. In the next step, doxorubicin was loaded with a maximum of 19 % drug loading to the carrier via hydrazone bond. In the last research stage, the carrier-hydrazone bond-drug system was tested in solutions with different pH values, imitating the environments of a cancer cell, a healthy cell, and their subcellular elements regarding drug release from the carrier. The obtained release results indicate a >4-fold increase in the amount of drug released from the carrier in conditions of a slightly lower pH environment (70 %), compared to neutral pH (15 %). This represents a promising potential for using the material as an intelligent drug delivery system (DDS).

Green hydrothermal synthesis of gallic acid carbon dots: characterization and cytotoxic effects on colorectal cancer cell line

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide, necessitating the development of novel therapeutic approaches. Carbon dots (CDs) have emerged as promising nanoparticles for biomedical applications due to their unique properties. Gallic acid (GA), an anticancer agent, is effective against various tumor types. This study explores the potential of gallic acid-derived carbon dots (GA-CDs) as an innovative anticancer agent against HCT-116 CRC cells, focusing on apoptosis signaling pathways. GA-CDs were synthesized using a one-pot hydrothermal method. Characterization was conducted using transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, and ultraviolet-visible (UV-vis) absorption spectroscopy. The cytotoxicity of GA and GA-CDs on HCT-116 cells was evaluated using the MTT assay at various concentrations over 24 and 48 h. Cellular uptake was assessed via fluorescence microscopy, and apoptosis was analyzed using acridine orange/propidium iodide (AO/PI) staining. Total RNA extraction followed by complementary DNA (cDNA) synthesis via reverse transcription-PCR was performed, and real time-PCR (Q-PCR) was conducted to examine the expression of apoptosis-related genes includingCaspase-3,Bax, andBcl-2. Characterization confirmed the successful synthesis of spherical GA-CDs. GA-CDs exhibited dose- and time-dependent cytotoxicity, with IC50 values of 88.55 μg ml-1for GA-CDs and 192.2 μg ml-1for GA after 24 h. Fluorescence microscopy confirmed the efficient uptake of GA-CDs by HCT-116 cells. AO/PI staining showed a significant increase in apoptotic cell numbers after treatment with GA-CDs. Q-PCR analysis revealed overexpression ofCaspase-3 andBaxgenes in GA-CD-treated cells, though no significant changes were observed in the expression ofBcl-2 or theBax/Bcl-2 ratio. GA-CDs demonstrated potent anticancer properties by inducing apoptosis and reducing cell viability in HCT-116 cells. These findings suggest the potential of GA-CDs as a novel therapeutic agent for CRC treatment, warranting further investigation into their mechanism of action andin vivoefficacy.

Dynamics of Amphiphilic Poly(ε-Caprolactone) Micelles with Doxorubicin and Transition Temperature Predictions Using All-Atom Molecular Dynamics Simulation.

Despite the advent of novel therapeutics, the efficient delivery of antineoplastic drugs remains a challenge. Biodegradable polymeric micelles represent a promising frontier by offering enhanced drug solubility, tumor targeting, and controlled release profiles. However, the underlying dynamics governing the drug encapsulation and solvation within these micellar structures is still vague and poorly understood. In this study, we used amphiphilic poly(γ-benzyloxy-ε-caprolactone)-b-poly(γ-2-[2-(2-methoxy ethoxy)ethoxy]ethoxy-ε-caprolactone) as a model copolymer with doxorubicin as a model drug and performed all-atom molecular dynamics simulations to understand the regulating mechanism of the encapsulation process. The results are in good agreement with the experimental results. In addition, we interpreted the dynamic behavior of the polymeric micelles and vital intermolecular interactions that play a key role in drug encapsulation. Our study provides a theoretical approach to obtain insights for designing and enhancing novel anticancer drug carriers for therapeutics.

Genomic profiling and expanded use of targeted anticancer drugs in solid cancers with exhausted evidence-based treatment options (PRECODE): study protocol of a prospective, non-randomized, cohort study

BackgroundGenomic profiling of advanced solid cancer in patients with no further evidence based standard treatment options is a novel approach to identify potential experimental treatment options based on specific genomic alterations. Due to the expected short survival of these patients timely assessment of potential druggable targets is critical to minimize the risk of deterioration during the analysis.The primary objective of this prospective study is to evaluate the turnaround time for genomic profiling and the clinical investigational procedures. The secondary objectives are to investigate how often genomic alterations in tumor tissue gives rise to a matched treatment offer and evaluate the clinical outcome.MethodsThe PRECODE study is a prospective, non-randomized, single-center cohort study conducted at Departments of Oncology and Pathology, Odense University Hospital, Denmark. Enrollment between March 1, 2019 and December 31, 2024. Eligibility criteria are age ≥ 18 years, written informed consent, advanced solid tumors, exhausted treatment options, ECOG performance status 0–2, adequate organ function and life expectancy ≥ 3 months. A core needle biopsy is analyzed by next generation sequencing using a pan-cancer comprehensive panel. Results are discussed weekly at institutional/local and national multidisciplinary tumor boards.DiscussionStrategies and methods for genomic profiling of advanced solid cancers differ. Rapid analysis and interpretation of sequencing data are key to avoiding delays in initiation potential experimental treatments, as these late-stage patients may quickly deteriorate.Although a highly optimized setup with fast-track clinical evaluation and genomic profiling has been established a subset will not be offered a targeted treatment due to deterioration. Local and national multidisciplinary teams have been established to optimize individualized treatment decisions. After genomic profiling a subset of patients will take part in clinical trials, which will constrain the reporting of overall survival or progression free survival.Trial registrationDanish Ethics Committee, Projekt-ID: S-2018014, date of approval: 27- FEB- 2019) Danish Data Protection Agency (Journal no: 18/58329, date of approval: 23-NOV-2018).ClinicalTrials.gov Identifier: NCT05385081 (retrospectively registered).

Design and Synthesis of Triazine-Based Hydrogel for Combined Targeted Doxorubicin Delivery and PI3K Inhibition.

Melanoma, an aggressive skin cancer originating from melanocytes, presents substantial challenges due to its high metastatic potential and resistance to conventional therapies. Hydrogels, three-dimensional networks of hydrophilic polymers with high water-retention capacities, offer significant promise for controlled drug delivery applications. In this study, we report the synthesis and characterization of hydrogelators based on the triazine molecular scaffold, which self-assemble into fibrous networks conducive to hydrogel formation. Rheological analysis confirmed their hydrogelation properties, while microscopic techniques including FE-SEM and FEG-TEM provided insights into their morphological networks. The drug delivery capability of these hydrogelators was evaluated using doxorubicin, a widely employed anticancer agent, demonstrating enhanced biocompatibility and reduced side effects compared to free doxorubicin. Additionally, the hydrogelators exhibited inhibitory activity against phosphoinositide 3-kinase (PI3K), a key enzyme frequently mutated in cancer, and also involved in melanoma progression. The dual functionality of this delivery system - controlled drug release and PI3K inhibition - highlights the potential of triazine-based hydrogelators as innovative therapeutic platforms for melanoma treatment.

Discovering the inhibition of YAP/TEAD Hippo signaling pathway via new pyrazolone derivatives: synthesis, molecular docking and biological investigations

Heterocyclic compounds play a crucial role in the drug discovery process and development due to their significant presence and importance. Here, we report a comprehensive analysis of new pyrazolone derivatives, prepared according to a clear-cut, uncomplicated procedure. The pyrazolone derivatives were thoroughly characterized using various methods, such as elemental analysis, NMR, and FT-IR. The molecular docking interactions between the new pyrazolone derivatives and YAP/TEAD target protein observed that compound 4 had the top-ranked binding energy towards YAP/TEAD with a value equal to − 9.670 kcal/mol and this theoretically proves its inhibitory efficacy against YAP/TEAD Hippo signaling pathway. Besides, compound 4 showed the best IC50 against HCT-116, HepG-2, and MCF-7 (in-vitro) with IC50 7.67 ± 0.5, 5.85 ± 0.4, and 6.97 ± 0.5 μM, respectively which confirmed our results towards suppressing YAP/TEAD protein (in-silico) compared with the IC50 of Sorafenib (SOR) reference chemotherapeutic drug 5.47 ± 0.3, 9.18 ± 0.6 and 7.26 ± 0.3 μM, respectively. Also, compound 4 showed no cytotoxic effects against human lung fibroblast normal cell line (WI-38) and its pharmacokinetics were elucidated theoretically using ADMET compared with SOR which observed highly toxic effects on normal cells with IC50 equal to 20.27 ± 0.45 μM. Additionally, compound 4 clarified a powerful antioxidant scavenging activity against DPPH free radicals (in-vitro). Conclusively, newly synthesized pyrazolone derivative 4 could be used as anticancer candidate via inhibiting the YAP/TEAD mediated Hippo signaling pathway.

Comparative efficacy and safety of eribulin versus paclitaxel in breast cancer: a systematic review and meta-analysis.

We conducted a meta-analysis of published randomized controlled trials to compare the effectiveness and safety of eribulin versus paclitaxel for patients with breast cancer. We systematically searched multiple databases including Cochrane, PubMed, Medline, and Embase. The primary outcomes analyzed were overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), and adverse events (AEs). These outcomes were evaluated using RevMan5.3 software. A total of 5 studies were included in the analysis. Compared to paclitaxel plus other chemotherapy drugs, eribulin plus other chemotherapy drugs not only extended the overall survival of patients but also improved the disease control rate (DCR) [risk ratio (RR) 0.98, (95% confidence intervals (CI): 0.70, 1.38), p = 0.92]. Hematological system diseases [RR 1.18 (95% CI: 1.07, 1.31), p = 0.002] were the most frequently observed adverse event with eribulin, while paclitaxel was more likely to cause nervous system lesion [RR 0.66 (95% CI: 0.54, 0.80), p < 0.0001]. Compared with paclitaxel plus other chemotherapy drugs, eribulin plus other chemotherapy drugs can also prolong the PFS and OS of BC patients. Our recommendation is to use eribulin plus other chemotherapy drugs to treat advanced BC and to continuously monitor and manage the drug-related adverse events.

Incidence and impact of food aversions among patients with cancer receiving outpatient chemotherapy: a one-year prospective survey

PurposeTo determine the current incidence and impact of chemotherapy-associated food aversions in a variety of cancer types.MethodsCancer patients aged 18 years and older who received chemotherapy infusions at the outpatient chemotherapy unit of a university hospital between May 2022 and April 2023 were included in the study (n = 243). To monitor the occurrence of food aversions, participants were asked to complete a food preference questionnaire each time they visited the outpatient chemotherapy unit.ResultsDuring the one-year survey period, one in four cancer patients receiving outpatient chemotherapy developed food aversions, and one in four of them complained of interference with daily life due to eating problems at the same time or later. The median time to the onset of food aversion was 46 (interquartile range 36–77) days after the start of chemotherapy. The incidence of food aversions was significantly higher in patients who were women, had a digestive, gynecologic, or breast cancer, and received more cytotoxic agents in chemotherapy. Patients who developed food aversions tended to lose more body weight than those who did not.ConclusionFood aversions were still common among cancer patients undergoing chemotherapy. Even an aversion to a single food may have affected the patient’s nutritional status. Healthcare professionals should closely monitor the occurrence of food aversions, especially in the early days of chemotherapy induction, to detect an increasing risk of malnutrition.Trial registrationNot applicable.