Search Results (225)

Talaporfin sodium (mono-L-aspartyl chlorin e6; NPe6), a second-generation photosensitizer, is clinically used in photodynamic therapy (PDT). It accumulates preferentially in tumors and exhibits deep tissue penetration, rapid systemic clearance, and minimal photosensitivity. However, treatment of deep-seated malignancies remains challenging. Here, we demonstrate that talaporfin sodium undergoes physicochemical reactions with X-rays to generate reactive oxygen species, a mechanism analogous to that of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX in radiodynamic therapy (RDT). To evaluate its therapeutic efficacy, we employed a pancreatic cancer xenograft model using MIA PaCa-2 cells in mice. Talaporfin sodium was administered intravenously 2 h before X-ray exposure, followed by fractionated X-ray irradiation (3 Gy daily for 3 consecutive days). Talaporfin-mediated RDT significantly inhibited tumor growth compared with radiation therapy alone. Furthermore, an exploratory RNA-seq analysis of xenografts revealed transcriptional signatures of stress and immune activation, suggesting that talaporfin-mediated RDT enhances oxidative and immunogenic responses within the tumor microenvironment. These findings highlight the potential of talaporfin sodium as a clinically translatable radiosensitizer for RDT, offering a promising strategy for the treatment of deep-seated cancers such as pancreatic carcinoma. Full article

A promising strategy for pancreatic cancer therapy involves developing nanocarriers capable of simultaneously delivering various antitumor substances with diverse physicochemical properties, often resulting in synergistic effects. In the present work, novel biocomposites were developed using amphiphilic N-vinylpyrrolidone polymer incorporating bortezomib (BTZ) and modified with either the DR5-selective TRAIL cytokine (DR5-B) or its fusion with the iRGD effector peptide (DR5-B-iRGD), resulting in AmphPVP-BTZ-DR5-B and AmphPVP-BTZ-DR5-B-iRGD formulations. The release of BTZ was most extensive at acidic pH 5.6, mimicking endolysosomal compartments, while at near-neutral pH 7.4 and alkaline pH 8.2 the release was slower and less complete, indicating a smart pH-responsive behavior suitable for triggered release in the tumor microenvironment. Both AmphPVP-BTZ-DR5-B and AmphPVP-BTZ-DR5-B-iRGD significantly inhibited the growth of pancreatic adenocarcinoma cell lines PANC-1, BxPC-3, and MIA PaCa-2 and induced more rapid internalization of the DR5 receptor in MIA PaCa-2 cells than unmodified particles and free DR5-B or DR5-B-iRGD. Importantly, AmphPVP-BTZ-DR5-B-iRGD exhibited a more pronounced DR5 internalization rate and cytotoxic effect than AmphPVP-BTZ-DR5-B owing to the presence of fusion protein with internalizing iRGD peptide. Both biocomposites induced cell death via the apoptotic pathway while exhibiting minimal cytotoxic effects on healthy cells. Therefore, biocomposites incorporating BTZ and functionalized with DR5-selective TRAIL variants DR5-B or DR5-B-iRGD represent a promising avenue for future studies in pancreatic cancer animal models. Full article

Background: The synthesis and biological investigation of pyrrolidine (L-gulo) iminosugars bearing an organic boron pharmacophore in ortho and meta positions of an N-benzyl group is reported. This paper completes the structure–activity relationship data for this novel family of boron-bearing iminosugars. These can establish reversible intramolecular interactions via dative bonding from nucleophilic amino acid side chains to the empty p-orbital of the boron atom. Methods: Inhibitory activities against two panels of glycosidases and cancer cell lines were investigated to ascertain structure–activity relationship profiles for these novel iminosugar drug leads. Results: These iminosugars display selective, moderate-to-weak inhibitions (IC₅₀s = 116–617 μM) of β-D-galactosidase (bovine liver), and indications of inhibition of β-D-glucosidases (almond, bovine liver) (IC₅₀s = 633 and 710 μM) and α-D-glucosidases (rice, yeast, rat intestinal maltase) (IC₅₀s = 106–784 μM). The boronic acid group emerges as a useful pharmacophore for management of lysosomal storage disorders via the chaperone-mediated therapy approach. The cancer assays revealed that the A2780 ovarian carcinoma cell line is selectively inhibited by all compounds screened and the MIA-Pa-Ca2 pancreatic carcinoma cell line is selectively inhibited by most compounds. Growth inhibition and GI₅₀ values were most potent for the meta 7 side-product. Conclusions: Beyond the cancer cell line inhibition and dose-response capabilities, the real therapeutic potential of these borylated drugs lies in their switch on/switch off activation under boron neutron capture therapy (BNCT) radiotherapeutic conditions, thus providing an important area of application for borylated monosaccharides. Full article

Background/Objectives: Dendritic cell (DC)-based immunotherapies offer a promising strategy for cancer treatment but are limited by inefficient activation of cytotoxic T cells and, in turn, the host immune system. This report demonstrated that CD34⁺ hematopoietic stem cell (HSC)-derived allogeneic DCs engineered by an optimized lentiviral vector (LVV) expressing CD93, CD40-ligand (CD40L), and Chemokine (C-X-C motif) ligand-13 (CXCL13) significantly enhanced the host immune system, activated tumor-specific cytotoxic T cells, and led to complete regression of both primary and metastatic pancreatic tumors in humanized mouse models. This LVV shows comparable pre-clinical efficacy compared to the first-generation vector, in addition to being compliant for clinical use, which allows further pre-clinical development towards the human trials. Methods: This 2nd generation (Gen) LVV incorporates codon-optimized transgenes (CD40L, CD93, and CXCL13) with rearranged sequence to enhance expression, driven by a strong EF1α promoter. CD34⁺ HSCs were transduced with this modified 2nd Gen LVV and differentiated to Engineered DCs. Therapeutic efficacy of the DC therapy with the modified vector was tested on humanized mouse models of pancreatic tumors. This was accomplished by establishing an early-stage disease model (using MIA PaCa-2 (MP2)-tumors) and late-stage metastatic disease model of the pancreatic tumors to mimic the clinical setting using luciferase-expressing MP2-(Luc)-pancreatic tumor-bearing humanized mice. Results: The modified lentiviral construct had 6-fold greater expression of CD40L, 2% less toxicity, 4.5-fold greater CD40L, and 2.2-fold greater CXCL13 secretion than its predecessor. In vitro, Engineered DCs induced robust T cell proliferation in up to 20% of T cells, up to 4-fold greater interferon-gamma (IFN-γ) secretion than controls, and showcased antigen-specific cytotoxicity by CD8⁺ T cells. In vivo, two intradermal doses of the 2nd Gen DCs led to complete regression of primary pancreatic tumors and metastases. Treated mice exhibited prolonged survival, indicating the induction of durable anti-tumor immunity. Conclusions: Vector optimization retained the efficacy of DC-based therapy, achieving curative responses in pancreatic tumor models. These findings support the clinical development of this 2nd Gen DC immunotherapy for pancreatic and potentially other tumors. Full article

Pancreatic cancer is an extremely deadly disease with few effective treatment options and the lowest survival rate among all types of cancer. As a result, there is an urgent need for the development of new and more effective treatment strategies. Natural products have long been a vital source of drug discovery, offering unique bioactive compounds, and representing a promising source for new, effective, and less toxic treatments. In the present study, we aimed to investigate the effects of Apteranthes europaea (Guss.) Murb (A. europaea) root extract on the growth of pancreatic cancer cells. The proliferation assay (XTT) and real-time analysis using the IncuCyte Live-Cell Analysis System, following treatment of PL45 and Mia PaCa-2 pancreatic cancer cells with escalating concentrations (50–200 µL) to A. europaea root extract, demonstrated the progression of apoptosis. Apoptosis induction was confirmed through cell cycle analysis and Annexin V/PI double staining assays. Western blot analysis revealed the distinct activation of caspase-8, accompanied by the cleavage of caspase-3 and Poly (ADP-ribose) polymerase (PARP). Interestingly, no activation of caspase-9 was observed, suggesting the involvement of the extrinsic apoptotic pathway. Our findings suggest that A. europaea extract may be a potential novel strategy for treating pancreatic cancer. Full article

Background/Objectives: This study aimed to synthesize a novel, high-molecular-weight acyclic heterocyclic compound, compound 5, via a one-pot reaction between Trichloroisocyanuric acid (TCCA) and ethanolamine, and evaluate its anticancer, antioxidant, and antifungal activities. Methods: Its complex tetrameric structure, assembled through N-N linkages, was unequivocally confirmed by a full suite of spectroscopic techniques including IR, ¹H & ¹³C NMR, ²D-NMR, and high-resolution mass spectrometry (LC/Q-TOF/MS). The MTT assay was used to assess the anticancer activity of compound 5 against four different human cancer cell lines. Results: The findings indicate that human colon (HT29) and ovarian (OVCAR3) cancer cells were sensitive to the treatment, whereas brain (glioblastoma) (T98G) cancer cells were resistant. The most pronounced cytotoxic effect was observed in pancreatic (MiaPaCa2) cancer cells. Notably, compound 5 exhibited potent antifungal properties, achieving 100% inhibition of the pathogenic water mould Saprolegnia parasitica zoospores at 100 µM after 10 min. Molecular docking studies corroborated the biological data, revealing a high binding affinity for key cancer and fungal targets (Thymidylate Synthase and CYP51), providing a strong mechanistic basis for its observed activities. Conclusions: These findings establish compound 5 as a promising dual-action agent with significant potential as both a targeted anticancer lead and an eco-friendly antifungal for applications in aquaculture. Full article

Mastic gum from Pistacia lentiscus L. has long been valued in Mediterranean medicine and food preservation, yet its bioactive potential remains underexplored in specific geographic contexts. In Morocco, the resin—locally known as Meska Horra—is abundant but insufficiently characterized. This study compared three extraction methods—cold maceration (CM), Soxhlet extraction (SE), and ultrasound-assisted extraction (UAE)—using sequential acetone and 70% ethanol to recover complementary phenolic compounds from defatted resin. Targeted UHPLC–ESI–MS/MS profiling identified and quantified 30 phenolics, mainly flavonoids and phenolic acids, providing the first systematic dataset for Moroccan mastic gum. UAE–EtOH extract displayed the strongest antioxidant activity (DPPH IC₅₀ = 0.029 mg/mL; ABTS•⁺ IC₅₀ = 0.026 mg/mL). SE–acetone and SE–EtOH extracts showed potent antifungal activity, particularly against Geotrichum candidum, Rhodotorula glutinis, and Aspergillus niger (MBC = 1.7%). The SE–acetone extract exhibited cytotoxicity toward MIA PaCa-2 pancreatic cancer cells (IC₅₀ = 19 µg/mL). These findings demonstrate that extraction method and solvent choice strongly influence phenolic recovery and associated bioactivities, supporting the valorization of Moroccan mastic gum as a promising source for nutraceutical and pharmaceutical applications. Full article

Cancer treatments are limited by poor tumor specificity and toxicity. We tested a radiosensitizing approach using PEG/RGD-functionalized gold nanoparticles (GNPs), a lipid-nanoparticle–encapsulated docetaxel prodrug (LNP_DTX–P), and external-beam radiotherapy (RT). In MIA PaCa-2 xenografts, intravenous GNPs (2 mg/kg) and LNP_DTX–P (6 mg/kg) were given before 5 Gy RT. Both LNP_DTX–P + RT and GNPs + LNP_DTX–P + RT reduced tumor volume by ~40% and significantly prolonged survival versus RT alone (p < 0.001). Adding GNPs did not enhance efficacy, indicating LNP_DTX–P was the main driver under this regimen. These results demonstrate nanocarrier-enabled radiosensitization in vivo and support further studies toward clinical translation. Full article

Background: Gemcitabine (GEM) remains a cornerstone in the treatment of pancreatic cancer. Upon exposure to GEM, pancreatic cancer cells (PCCs) tend to adapt quickly to outcompete drug-induced cytotoxicity, thereby contributing to treatment failure. Thus, understanding GEM-induced molecular changes in PCCs is important. Methods: Three primary PCC lines (PCC-1, PCC-2, PCC-7) and Mia PaCa-2 cultured for 40 passages (p) in the absence (control) or presence of GEM (GemR) were assessed for phenotypic changes. Proteome profiles for all PCCs at p10, p20, p25, p30, p35, and p40 were obtained using mass spectrometry (MS). Protein expression was determined using immunoblotting. Differentially abundant proteins (DAPs) were evaluated for enrichment of functional and biological attributes and protein–protein interactions. Results: GEM sensitivity and growth were both reduced in GemR versus paired controls for all four PCC lines. MS mapped > 7000 proteins in each PCC line, and the abundance of 70–83% of these was found to be significantly altered when comparing all sample groups. Proteomic changes in GemR versus paired controls differed remarkably among the PCCs and were affected by passaging and treatment duration. DAPs at p40 were mostly related to metabolic pathways, including nucleotide metabolism and diverse cell growth processes. Several closely related DAPs and multiple hub proteins in each PCC line were identified. Conclusions: Overall, this study revealed cell-line-specific, heterogeneous changes in proteome profiles of PCCs following their long-term exposure to GEM, and these were likely affected by treatment duration, dosage, and passaging. Full article

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies due to late diagnosis, poor drug penetration, and intrinsic chemoresistance. Targeted delivery strategies are urgently needed to enhance therapeutic precision while minimizing systemic toxicity. Here, we developed an AS1411 aptamer-functionalized liposomal platform encapsulating siRNA against metastasis-associated protein 2 (MTA2), a chromatin remodeling factor that suppresses the tumor suppressor PTEN and activates PI3K/AKT signaling. The AS1411 aptamer, which binds nucleolin overexpressed on PDAC cells, was conjugated to cationic liposomes via copper-free click chemistry. The resulting AS1411-Lipm[siRNA] exhibited high siRNA encapsulation efficiency, selective uptake by nucleolin-positive PDAC cells, and enhanced endosomal escape. Treatment of MIA PaCa-2 cells with AS1411-Lipm[siRNA] significantly reduced MTA2 expression by ~60%, substantially restored PTEN, and inhibited AKT phosphorylation by ~50%, leading to decreased cell viability, impaired migration by ~75%, and increased apoptosis by ~35%, while sparing nucleolin-negative cells. These findings highlight AS1411-Lipm[siRNA] as a promising platform for selective siRNA delivery and potent molecular inhibition in PDAC therapy. Full article

Background: Podocalyxin (PODXL) has been identified as a promising therapeutic target and a potential diagnostic biomarker in various tumors. Despite the therapeutic potential of anti-PODXL monoclonal antibodies (mAbs), their further development has been limited by concerns regarding potential on-target off-tumor toxicities. To minimize adverse effects on normal tissues, developing a cancer-specific mAb (CasMab) against PODXL is essential. Methods: Our group established a cancer-specific anti-PODXL mAb, PcMab-60 (IgM, κ), through the screening of over one hundred hybridoma clones. In this study, PcMab-60 was engineered into a humanized IgG₁-type mAb (humPcMab-60), and its antitumor activity was examined using mouse xenograft models of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer. Results: HumPcMab-60 retains cancer-specific reactivity; humPcMab-60 reacted to PDAC cell lines (PK-45H and MIA PaCa-2) and the colorectal cancer cell line (Caco-2), but not to a normal lymphatic endothelial cell line in flow cytometry. Furthermore, humPcMab-60 exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against PODXL-expressing cell lines and showed antitumor effects against the tumor xenografts. Conclusions: A humanized anti-PODXL CasMab, humPcMab-60, could be a promising mAb-based tumor therapy. Full article

Background/Purpose: The only potentially curative procedure for pancreatic cancer is R0 resection, which is difficult to achieve due to poorly defined tumor margins. In the present study, we used an anti-CA19-9 antibody conjugated to a near-infrared fluorophore in orthotopic mouse models to target and visualize pancreatic cancer. Methods: Orthotopic models of the human pancreatic cancer cell lines SW1990 and BxPC3 were established by implanting tumor fragments into the pancreas of athymic nude mice. Anti-CA19-9 and control IgG were conjugated with IRDye800CW. Mice received 50 µg of CA19-9–IRDye800CW or IgG-IRDye800CW via tail-vein injection and were imaged after 72 h. MIA PaCa-2, a CA19-9-negative cell line, was used in subcutaneous models to assess targeting specificity. Results: Using the LI-COR Pearl imaging system in the SW1990 model, the tumor-to-pancreas ratio (TPR) was 4.51 (±0.74), and the tumor to the liver ratio (TLR) was 3.05 (±0.60) with CA19-9-IRDye800CW, while the TPR was 1.67 (±0.16) and the TLR was 0.95 (±0.05) for the non-specific control IgG–IRDye800CW. Using a clinically available fluorescence laparoscope, CA19-9-1RDye800CW demonstrated a TPR of 2.34 (±0.44) and a TLR of 2.23 (±0.49), compared to 1.11 (±0.13) and 0.69 (±0.07), respectively, for IgG-IRDye800CW in the SW1990 orthotopic model. In the BxPC3 models, the TPR was 3.82 (±0.55) and the TLR was 4.13 (±0.77) for CA19-9-IRDye800CW compared to 2.40 (±0.31) and 1.49 (±0.23), respectively, for IgG-IRDye800CW. Conclusions: CA19-9-IRDye800CW provided specific in vivo targeting of two human pancreatic cancer cell lines in orthotopic nude mouse models with superior TPRs and TLRs compared to IgG-IRDye800CW. This tumor-specific fluorescent CA19-9 antibody is a promising clinical tool for improved visualization of pancreatic cancer. Full article

Pancreatic cancer (PC) is an aggressive malignancy with a poor prognosis, requiring innovative approaches to evaluate new therapies. Considering the high activity of unsymmetrical bisacridines (UAs) in PC monolayer cultures, we employed multicellular tumor spheroids (MCTS) to assess whether UAs retain pro-apoptotic activity under more physiologically relevant conditions. Ultra-low attachment plates were used to form spheroids from three PC cell lines (Panc-1, MIA PaCa-2, and AsPC-1) with different genotypes and phenotypes. The effects of UA derivatives (C-2028, C-2045, and C-2053) were evaluated using microscopy and flow cytometry (7-AAD for viability and annexin V-FITC/PI for membrane integrity). UAs altered the morphology of the spheroids and reduced their growth. Notably, Panc-1 spheroids exhibited compromised integrity. The increase in 7-AAD⁺ cells confirmed diminished cell viability, and annexin V-FITC assays showed apoptosis as the dominant death pathway. Interestingly, the exact derivative was most active against a given cell line regardless of culture conditions. These results confirm that UAs maintain anticancer activity in 3D cultures and induce apoptosis, with varying efficacy across different cell lines. This underscores the value of diverse cellular models in compound evaluation and supports UAs as promising candidates for pancreatic cancer therapy. Full article

Pancreatic cancer is among the deadliest malignancies, with limited treatment options and poor prognosis. Novel strategies are therefore urgently needed. Sotorasib, a KRAS G12C-specific inhibitor, offers targeted treatment for a small subset of patients with this mutation. Electrochemotherapy (ECT), which enhances the cytotoxicity of chemotherapeutic agents through electroporation-induced membrane permeabilization, has shown promise in various tumor types, including deep-seated malignancies such as pancreatic cancer. Combining ECT with sotorasib may potentiate antitumor effects in KRAS G12C-mutated pancreatic cancer; however, preclinical data on such combinations are lacking. This proof-of-concept study evaluated the cytotoxic effects of ECT using bleomycin (BLM) or cisplatin (CDDP) in combination with sotorasib in KRAS G12C-mutated MIA PaCa-2 and KRAS G12D-mutated PANC-1 pancreatic cancer cell lines. ECT alone significantly reduced cell viability, particularly in MIA PaCa-2 cells, where electric pulses induced approximately 75% cell death. Combining ECT with sotorasib resulted in an additive effect on KRAS G12C-mutated MIA PaCa-2 cells, though no synergy was observed, likely due to the high intrinsic sensitivity to electric pulses. These results support the potential of combining physical and molecular therapies in a subset of pancreatic cancer patients and lay the groundwork for further in vivo studies to optimize treatment parameters and explore clinical translatability. Full article

A novel ruthenium(II) complex, [RuCl₂(η⁶-p-cymene)(bph-κN)] (1), was synthesized and structurally characterized using FTIR and NMR spectroscopy. Density functional theory (DFT) calculations supported the proposed geometry and allowed for comparative analysis of experimental and theoretical spectroscopic data. The interaction of complex 1 with human serum albumin (HSA) and calf thymus DNA was investigated through fluorescence quenching experiments, revealing spontaneous binding driven primarily by hydrophobic interactions. The thermodynamic parameters indicated mixed quenching mechanisms in both protein and DNA systems. Ethidium bromide displacement assays and molecular docking simulations confirmed DNA intercalation as the dominant binding mode, with a Gibbs free binding energy of −34.1 kJ mol⁻¹. Antioxidant activity, assessed by EPR spectroscopy, demonstrated effective scavenging of hydroxyl and ascorbyl radicals. In vitro cytotoxicity assays against A375, MDA-MB-231, MIA PaCa-2, and SW480 cancer cell lines revealed selective activity, with pancreatic and colorectal cells showing the highest sensitivity. QTAIM analysis provided insight into metal–ligand bonding characteristics and intramolecular stabilization. These findings highlight the potential of 1 as a promising candidate for further development as an anticancer agent, particularly against multidrug-resistant tumors. Full article