Search Results (120)

Graphene oxide (GO)-based nanomaterials functionalized with targeting ligands are promising platforms for selective cancer drug delivery. Among relevant targets, integrin α_Vβ₃ is a highly overexpressed receptor in several solid tumors and is commonly targeted using cyclic Arg-Gly-Asp (cRGD) peptides. However, the molecular details governing the interaction between cRGD-functionalized GO dots and integrins remain poorly understood. In this work, all-atom molecular dynamics simulations are employed to investigate the interaction between integrin α_Vβ₃ and a nanocarrier composed of a GO dot coated with polyethylene glycol (PEG) and functionalized with cRGD ligands. Multiple 1 μs simulation replicas are used to characterize both specific ligand recognition and non-specific nanocarrier/receptor interactions. The simulations show that cRGD binding within the integrin-binding pocket is stable, indicating that the nanocarrier does not impair receptor recognition. Beyond cRGD-mediated binding, both PEG-cRGD chains and GO itself establish additional contacts with the protein, whose nature and distribution are modulated by the relative orientation of the GO plane. Overall, the structural dynamics of integrin α_Vβ₃ remains preserved upon nanocarrier binding. These findings provide atomistic insights into the interplay between ligand-mediated and multivalent surface-mediated interactions of GO-based nanocarriers with integrins for the rational design of selective nanocarriers for cancer therapy. Full article

Background: Malignant prostate cancer (PrC) remains challenging to treat due to tumor heterogeneity and the limited availability of ligands that target disease-associated surface markers with properties appropriate for targeted drug delivery systems. To overcome this hurdle, we used an unbiased but stringent selection strategy to discover a series of phage-displayed peptides that internalize specifically into PrC tumors. Methods: Here we report the characteristics, properties and function of one of these peptides, Pr10, and validate its ability to specifically deliver cytotoxic drugs into PrC cells and kill them, both in vitro and in xenograft models. Results: Biochemical and proteomic studies identified the receptor for Pr10 as Desmocollin-3 (DSC3). This finding was confirmed by demonstrating the expression of the DSC-3 protein on PrC cells; by siRNA knockdown of DSC3 expression, which abrogated Pr10 function; and by in silico docking experiments. Conclusions: Together, these findings identify DSC3 as a novel, functional receptor on malignant prostate cancer cells and establish Pr10 as an effective and PrC-selective ligand for drug delivery PrC cells. More broadly, this work highlights the ability of unbiased screening approaches to identify and isolate novel target receptors with properties appropriate for use in effective target drug delivery systems for cancer therapy. Full article

Advanced gastric (GAC) or gastroesophageal junction (GEJAC) adenocarcinoma continues to carry a poor prognosis. Understanding GAC/GEJAC at the molecular level has provided a new understanding and the basis for individualized approaches to treatment. The current biomarker-driven therapy focuses on four areas: microsatellite instability (MSI), human epidermal growth factor receptor-2 (HER2), programmed death ligand-1 (PD-L1) combined positive score, and claudin 18.2 (CLDN18.2). However, because of improving technology, the focus has shifted to cancer cell-surface proteins and peptides. Each of these GAC/GEJAC subgroups provides a different treatment pathway. The agents utilized to treat advanced GAC/GEJAC include immune checkpoint inhibitors (ICIs), chemotherapy, monoclonal antibodies (mAbs), and antibody–drug conjugate (ADC) therapy, as well as bispecific antibodies (BsAbs), but they are certainly not limited to the above. Drug development has shifted in recent years to establish different mechanisms that are attempting more sophisticated and targeted approaches, such as BsAbs and ADCs. Meanwhile, the development of cytotoxics has tapered off. Along with these developments in drug therapy, more therapies directed at CLDN18.2, HER2, MSI, EGFR, HER3 and trophoblast cell-surface antigen 2 (TROP2) are underway. Here we review future areas in advanced GAC, including zanidatamab’s potential role in HER2-positive advanced GAC and deciphering the abundance of anti-CLDN18.2, extending beyond investigative therapies. Full article

The adhesion G protein-coupled receptor F5 (ADGRF5) has been implicated in modulating immune responses in cancer; however, its role in inflammatory bowel diseases (IBDs), particularly colitis, remains largely unexplored. In this study, we aimed to design and characterize novel peptide agonists derived from the ADGRF5 Stachel sequence, as well as to evaluate their therapeutic potential in preclinical colitis models. In silico analysis and single amino acid substitutions within the ADGRF5 tethered agonist sequence, combined with functional assays in ADGRF5-overexpressing cells, including calcium mobilization and inositol phosphate production, were employed to assess the activity of novel ADGRF5 agonists. Western blot technique and murine model of colitis were used to evaluate downstream signaling pathways and immunomodulatory effects of ADGRF5 ligands. We identified a series of peptides exhibiting significantly enhanced ADGRF5 agonist activity, achieving up to a 6-fold increase in potency over the wild-type version. We identified critical substitutions within the Stachel sequence, namely S11N and D13S, as essential for improving agonistic activity. Finally, using these novel ADGRF5 agonists, we demonstrated their potent anti-inflammatory effects in vivo, showing that ADGRF5 activation ameliorates experimental colitis, as evidenced by reduced macroscopic damage scores and improved colon architecture. These findings establish ADGRF5 as a potential therapeutic target for colitis and highlight the promise of Stachel-derived peptide agonists for the development of novel anti-inflammatory therapies. Full article

Photodynamic therapy (PDT) is a technique based on the use of photosensitizers activated by light to destroy cancer cells in the presence of oxygen. This enables localized cancer treatment and, in some settings, fluorescence-guided visualization. However, the efficacy and clinical translation of PDT have been limited by the low specificity of traditional photosensitizers. The aim of the study is to create a ligand-guided PDT approach for pancreatic ductal adenocarcinoma (PDAC) using a peptide-conjugated photosensitizer binding to integrin αvβ6, which is a receptor linked to tumor growth and prevalent in PDAC cells. Current treatment options for this tumor are limited, with surgical resection and chemotherapy only effective when the tumor is detected early. Given the limited treatment options for PDAC, PDT via αvβ6 offers a new pathway for precision treatment. The cyclic peptide cyclo[FRGDLAFp(NMe)K], recognized for its high affinity to αvβ6, was chosen to guide a phthalocyanine-class photosensitizer toward αvβ6-expressing PDAC models. The PDT approach was further refined by developing 3D spheroid models and in vivo BxPc3 xenograft models in NOD/SCID mice, where its therapeutic efficacy was assessed. In the absence of a non-targeted control photosensitizer, a contribution from non-specific accumulation and EPR effects in the in vivo setting cannot be fully ruled out. This study highlights the potential of a peptide-guided photosensitizer, demonstrating uptake and photodynamic activity in spheroids, with moderate in vivo results addressing tumor microenvironment challenges. Optimization of PDT dosing, laser precision, and preclinical models, such as patient-derived xenografts, are crucial to enhance clinical translation. Full article

Headache disorders, including migraine, tension-type headache, trigeminal autonomic cephalalgias, post-traumatic headache and medication overuse headache, represent a major global health burden and remain difficult to treat despite therapeutic advances. The endocannabinoid system (ECS) has emerged as a key regulator of neural, vascular, and immune processes central to headache pathophysiology. Through coordinated actions of CB1 and CB2 receptors, the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes, the ECS modulates trigeminovascular activity, descending pain control, cortical excitability, and neuroimmune sensitization. Preclinical studies demonstrate that ECS activation suppresses trigeminal firing, reduces calcitonin gene-related peptide (CGRP) release, attenuates neurogenic inflammation, stabilizes cortical susceptibility to spreading depression, and limits glial activation following traumatic brain injury. Conversely, ECS dysregulation contributes to central sensitization and impaired descending inhibition underlying medication overuse headache and other headache disorders. Pharmacological strategies targeting endocannabinoid degradation, such as inhibition of FAAH, MAGL, and COX-2, enhance endogenous cannabinoid tone and consistently reduce headache-like behaviors across diverse models. Importantly, sex differences shape ECS function, with females exhibiting distinct hormonal regulation, receptor expression, and glial activation that influence responsiveness to ECS-targeted interventions. Collectively, mechanistic and translational evidence highlights the ECS as a promising therapeutic target across primary and secondary headache disorders. Future clinical studies should incorporate sex-informed designs, integrate biomarkers of trigeminovascular and neuroimmune activity, and evaluate peripherally restricted ECS modulators and cannabinoid-based formulations as candidates for individualized headache therapy. Full article

Glioblastoma (GB) is one of the most aggressive and invasive cancers. Current treatment protocols for GB include surgical resection, radiotherapy, and chemotherapy with temozolomide. However, despite these treatments, physicians still struggle to effectively image, diagnose, and treat GB. As such, patients frequently experience recurrence of GB, demanding innovative strategies for early detection and effective therapy. Bioconjugated quantum dots (QDs) have emerged as powerful nanoplatforms for precision imaging and targeted drug delivery due to their unique optical properties, tunable size, and surface versatility. Due to their extremely small size, QDs can cross the blood–brain barrier and be used for precision imaging of GB. This review explores the integration of QDs with click chemistry for robust bioconjugation, focusing on artificial intelligence (AI) to advance GB therapy, mechanistic insights into cellular uptake and signaling, and strategies for mitigating toxicity. Click chemistry enables site-specific and stable conjugation of targeting ligands, peptides, and therapeutic agents to QDs, enhancing selectivity and functionalization. Algorithms driven by AI may facilitate predictive modeling, image reconstruction, and personalized treatment planning, optimizing QD design and therapeutic outcomes. We discuss molecular mechanisms underlying interactions of QDs with GB, including receptor-mediated endocytosis and intracellular trafficking, which influence biodistribution and therapeutic efficacy. Use of QDs in photodynamic therapy, which uses reactive oxygen species to induce apoptotic cell death in GB cells, is an innovative therapy that is covered in this review. Finally, this review addresses concerns associated with the toxicity of metal-based QDs and highlights how QDs can be coupled with AI to develop new methods for precision imaging for detecting and treating GB for induction of apoptosis. By converging nanotechnology and computational intelligence, bioconjugated QDs represent a transformative platform for paving a safer path to smarter and more effective clinical interventions of GB. Full article

Therapeutic peptides have rapidly evolved into multifunctional tools for precision oncology, offering molecular specificity and biocompatibility. Their roles in cancer therapy, however, are inherently overlapping. The same peptide can function as a targeting ligand, a cell-penetrating motif, a therapeutic effector, or a structural component of peptide–drug conjugates (PDCs), nanoparticle (NP) systems, and radionuclide constructs. This functional convergence makes rigid classification challenging. In this review, we therefore organize peptide modalities according to their dominant therapeutic function while acknowledging the fluid boundaries between categories. Firstly, we outline the main functional classes of therapeutic peptides, covering their use as targeting ligands and their roles as active agents (i.e., receptor agonists/antagonists, intracellular protein–protein interaction modulators, etc.). Additionally, we summarize their application in peptide–drug conjugates (PDCs), peptide-guided radionuclides, and cancer vaccines, integrating key mechanistic principles and clinical evidence. Finally, we discuss the major translational barriers to clinical use and how they might be overcome. The developments in peptide engineering position them as adaptable, multifunctional platforms capable of improving precision, reducing toxicity, and advancing personalized cancer care. Full article

Calcins represent a class of novel peptide ligands for ryanodine receptors (RyRs), demonstrating therapeutic potential against Ca²⁺ dysregulation-related cardiac diseases. Nevertheless, their biological effects beyond RyR modulation and underlying mechanisms remain unexplored. This study employed Opicalcin1 (OpiCa1), the most bioactive calcin member, revealing that while it reduced cytosolic Ca²⁺ in H9c2 cardiomyocytes, it concurrently diminished cell viability and promoted apoptosis. Transcriptomics and Western blot analyses identified suppression of the negatively regulatory PI3K/Akt pathway as the mechanistic basis. In acute/chronic in vivo studies, high-dose OpiCa1 (≥50 mg/kg i.v.) exhibited minimal impact on body weight, histopathology, and organ indices, while accompanied with subtle alterations in serum indicators, including slight elevations in AST, ALT, and LDH, alongside mild reductions in CK-MB and TBIL-Z. These findings unveil OpiCa1’s modulation on cardiomyocyte viability through PI3K/Akt inhibition with minimal systemic impact, providing new insights into non-RyR-mediated actions of calcins and critical toxicological support for developing calcin-based therapies targeting Ca²⁺-dysregulated cardiac pathologies. Full article

Prostate-specific membrane antigen (PSMA) targeting agents have been the cornerstone of advanced prostate cancer (PCa) management in theranostics due to their high sensitivity for detecting and treating metastatic disease. However, approximately one-third of metastatic castration-resistant PCa (mCRPC) lesions may exhibit low or absent PSMA expression due to tumor heterogeneity, prior androgen deprivation therapy, or loss of androgen receptor expression, subsequently altering their response to PSMA-targeted therapy. The molecular and biological mechanisms underlying PSMA downregulation remain elusive but may include neuroendocrine differentiation or epithelial-to-mesenchymal transition (EMT). This review addresses this knowledge gap by examining recent preclinical and clinical evidence on novel radiotracers with the potential to provide alternative strategies beyond PSMA for imaging and treating PCa. The diagnostic performance and therapeutic potential of three emerging radiotracer classes are discussed, including gastrin-releasing peptide receptor (GRPR) ligands, androgen receptor (AR) ligands, and amino acid analogs. This article further highlights the complementary roles of these radiotracers along with their utility in specific patient populations, such as those with low prostate-specific antigen (PSA), biochemical recurrence (BCR), or confirmed PSMA-negative disease. For instance, GRPR-targeted radiotracers have achieved sensitivity of up to 88% and specificity of up to 90% for detecting primary tumors in PCa. The radiolabeled androgen agonist, fluorine-18 (¹⁸F)-fluoro-5α-dihydrotestosterone (FDHT), has demonstrated 98% true-positive rate in predicting lesions on positron emission tomography (PET) scans of mCRPC patients. On the other hand, the synthetic amino acid analog ¹⁸F-fluciclovine demonstrated a lesion detection rate of 84% for PSA levels at or above 5, and 62.5% for PSA levels ranging from 0.7 to less than 1. This review concludes with future directions on the paradigm of multi-tracer and dual-targeting strategies, which can effectively address challenges associated with PCa tumor heterogeneity and facilitate personalized approaches in theranostics. Full article

The novel data show that the Hsp70 protein is a potent activator of the immune system. Using limited trypsinolisis, we have identified the epitopes of Hsp70 responsible for TREM-1-dependent and TREM-1-independent cytotoxicity. The 11aa N9 peptide (AMTKDNNLLGR) contains nine amino acids that correspond to the amino acid sequence of the known TKD peptide. Also, like TKD, this peptide does not interact with the TREM-1 receptor but activates CD94+ NK cells that kill tumor cells by secreting granzymes and inducing apoptosis. The 16aa peptide N7 (SDNQPGVLIQVYEGEK) interacts with the TREM-1 receptor and induces the activation of NK cells and cytotoxic T lymphocytes at different time points. T-lymphocytes activated by this peptide induce two alternative processes of cell death in HLA-negative tumor cells, apoptosis and necroptosis, through the interaction of the FasL lymphocyte with the Fas receptor of the tumor cell. A shortened fragment of this peptide, N7.1 (SDNQPGVL), has been identified that inhibits the interaction of TREM-1 with its ligands. This peptide has shown protective effects in the development of sepsis in mice. The results obtained can be used in antitumor and anti-inflammation therapy. Full article

Triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant forms. TNBC is an aggressive and therapeutically resistant subtype of breast cancer, marked by the absence of estrogen, progesterone, and HER2 receptors. The lack of defined molecular targets significantly limits treatment options and contributes to high recurrence rates. Among the key pathways involved in TNBC progression and resistance, the CXCR4/CXCL12 chemokine axis has emerged as a critical player. CXCR4, a G-protein-coupled receptor, binds specifically to its ligand CXCL12, promoting tumour cell proliferation, metastasis, immune evasion, and stromal remodelling. Its overexpression is frequently associated with poor prognosis, disease progression, and resistance to conventional therapies in TNBC. This review explores how the chemokine receptor type 4 (CXCR4/CXCL12) axis facilitates drug resistance through mechanisms such as epithelial–mesenchymal transition (EMT), cancer stemness, and microenvironmental interactions. Notably, CXCR4 antagonists like plerixafor, balixafortide, and POL5551 have shown encouraging preclinical and clinical results, particularly when combined with chemotherapy or immunotherapy. Additionally, innovative strategies, including radiopharmaceuticals, peptide inhibitors, and nanotechnology-based delivery platforms, offer expanded therapeutic avenues. Despite persistent challenges such as tumour heterogeneity and potential toxicity, growing clinical evidence supports the translational relevance of this axis. This manuscript provides an in-depth analysis of CXCR4/CXCL12-mediated drug resistance in TNBC and evaluates current and emerging therapeutic interventions. Full article

Stereotactic body radiation therapy (SBRT) for lung tumors near the chest wall often causes significant chest wall pain (CWP), negatively impacting patients’ quality of life. The mechanisms behind SBRT-induced CWP remain unclear and may involve multiple factors. We investigated crosstalk between radiation-activated osteoclasts and sensory neurons, focusing on osteoclast-derived factors in CWP. Using murine pre-osteoclast cell line Raw264.7, we induced differentiation with Receptor Activator of Nuclear Factor kappa-beta Ligand (RANKL), followed by 10 Gy gamma-irradiation. Conditioned media (C.M) from irradiated osteoclasts was used to treat sensory neuronal cultures from mouse dorsal root ganglia. Neuronal cultures were also exposed to 10 Gy radiation, with and without osteoclast co-culture. Osteoclast markers and pain-associated neuropeptides were analyzed using RT-qPCR and histochemical staining. Osteoclasts differentiation and activity were inhibited using osteoprotegerin (OPG) and risedronate. High-dose radiation significantly increased the size of tartrate-resistant-acid-phosphatase (TRAP)-positive osteoclasts (1.36-fold) and activity biomarkers (Ctsk, 1.35-fold, Mmp9, 1.76-fold). Neurons treated with C.M from irradiated osteoclasts showed ~1.5-fold increase in Calca (calcitonin gene-related peptide) and Tac1 (substance P) expression, which was mitigated by osteoclast inhibitors. These findings suggest that radiation enhances osteoclast activity and promotes pain signaling. Osteoclast inhibitors may represent a therapeutic strategy to reduce CWP and improve quality of life. Full article

MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produces injection-site reactions in most patients and is used experimentally to probe MRGPRX2 function in skin tests. While reported to be G-protein-biased, it is unknown how skin MCs respond to icatibant, although these are the primary target cells during therapy. We therefore compared responses to icatibant with those induced by the balanced agonist substance P (SP) in skin MCs. Degranulation and desensitization were assessed via β-hexosaminidase release, receptor internalization by flow cytometry, and downstream signaling by immunoblotting. Skin MCs degranulated in response to SP and icatibant, relying on Gi proteins and calcium channels; Gq and PI3K (Phosphoinositide 3-kinase) contributed more strongly to exocytosis following icatibant, while JNK (c-Jun n-terminal kinase) was more relevant for SP. Both agonists activated ERK, PI3K/AKT, and (weakly) p38. Surprisingly, and in contrast to the LAD2 (Laboratory of Allergic Diseases 2 mast cell line) MC line, icatibant was at least as potent as SP in eliciting MRGPRX2 internalization and (cross-)desensitization in skin MCs. These findings suggest that icatibant functions differently in primary versus transformed MCs, acting as a fully balanced ligand in the former by triggering not only degranulation but also receptor internalization and desensitization. Therefore, not only the ligand but also the MRGPRX2-expressing cell plays a decisive role in whether a ligand is balanced or biased. These findings are relevant to our understanding of icatibant’s clinical effects on edema and itch. Full article

Head and neck squamous cell carcinomas (HNSCCs) are the seventh most common form of cancer worldwide, typically characterized by high mortality and significant morbidity, including pain and speech and swallowing disorders. Complete tumor tissue resection, the common first line of therapy, remains a surgical challenge with room for improvements. Because tumor cells express highly specific surface molecules serving as receptors for ligands, specific targeting ligands can be conjugated to fluorescent molecules in order to better visualize tumor borders. Targeted fluorescence-guided surgery (T-FGS) as well as tumor-targeted and near-infrared (NIR) fluorescence imaging are emerging techniques for real-time intraoperative cancer imaging. Targeting agents include nanodots or fluorophores, which have been conjugated to specific ligands like antibodies, peptides, or other synthetic moieties. This article surveys tumor-targeted ligands in recent and current preclinical studies and clinical trials related to HNSCC, highlighting common NIRF dyes used for molecular imaging and their physical properties, working concentrations, and associated risks. Smaller ligands, nanodots, dual-modality NIR dyes, and activatable agents can enhance tumor-targeting processes, resulting in faster, more penetrable, and clearer imaging, which could lead to improved clinical applications and better tumor removal rates in the future. Full article