Biology subjects

Scodeller, P.

Publications and source records attributed to Scodeller, P..

7 recordsLinked to original sources

bioRxiv2026

Disrupting Myeloid Persistence and Replenishment Enables Sustained Control of Esophageal Squamous Cell Carcinoma

Responses to macrophage-directed therapy can be transient because tumors preserve myeloid support through complementary persistence and replenishment. In esophageal squamous cell carcinoma (ESCC), CSF1R inhibition reduced established tumor-associated macrophages but was followed by expansion of Ly6C/CCR2-positive monocytic and Ly6G-positive granulocytic populations. Low-dose decitabine preferentially restricted recruited populations while sparing a LYVE1-associated macrophage state, exposing reciprocal pharmacologic blind spots. Combined treatment suppressed both arms and produced sustained control across patient-derived organoid xenograft, orthotopic, and immunocompetent models. Neutrophil depletion reproduced initial regression but not sustained control, indicating that the recruited escape arm extended beyond Ly6G-positive granulocytes. Single-cell profiling mapped these vulnerabilities onto a treatment-resolved myeloid architecture comprising a C1qa-positive TAM continuum, a C1qa-negative Ccr2/Ly6c2-high inflammatory monocytic-like compartment, and a LYVE1/MRC1-positive tissue-supportive macrophage state. Human ESCC contained corresponding macrophage programs and an adverse-outcome-associated LYVE1-rich niche. These findings identify state-aware coverage of complementary myeloid vulnerabilities as a strategy to overcome escape from macrophage-directed therapy.

cancer biology↗

bioRxiv2025

A neuroprotective tetrapeptide for treatment of acute traumatic brain injury

Traumatic brain injury (TBI) is a major clinical problem because of the high incidence and the severity of the subsequent sequelae. Despite extensive efforts, there are no therapeutic drugs clinically approved for treating acute TBI patients. To address this unmet need, we assessed the activity of the tetrapeptide, CAQK, in mice. When administered intravenously shortly after moderate or severe TBI, CAQK accumulates in the injured brain in mice and pigs. CAQK binds to an extracellular matrix glycoprotein complex that is upregulated in injured brain. Treatment of TBI mice with CAQK resulted in reduction in the size of the injury compared to control mice. There was reduced upregulation of the glycoprotein complex, less apoptosis, and lower expression of inflammatory markers in the injured area, indicating that CAQK alleviates neuroinflammation and the ensuing secondary injury. CAQK treatment also improved functional deficit in TBI mice, with no overt toxicity. Our findings suggest that CAQK may have therapeutic applications in TBI.

neuroscience↗

bioRxiv2024

A CYCLIC PEPTIDE TARGETS GLIOBLASTOMA BY BINDING TO ABERRANTLY EXPOSED SNAP25

Disease-specific changes in tumors and other diseased tissues are an important target of research because they provide clues on the pathophysiology of the disease as well as uncovering potentially useful markers for diagnosis and treatment. Here, we report a new cyclic peptide, CESPLLSEC (CES), that specifically accumulated (homed) in intracranial U87MG and the WT-GBM model of glioblastoma from intravenous (IV) injection, associating with the vasculature. Affinity chromatography of U87MG tumor extracts on insolubilized CES peptide identified Synaptosomal Associated Protein 25 (SNAP25) as a candidate target molecule (receptor) for CES. Several results supported the identification of SNAP25 as the CES receptor. IV-injected FAM-CES colocalized with SNAP25 in the tumors, and direct binding studies showed specific CES peptide binding to recombinant human SNAP25. A CES peptide-drug conjugate designed for photodynamic therapy showed selective cytotoxicity to SNAP25+ glioblastoma cell lines. Specific accumulation of systemically injected anti-SNAP25 antibody in U87MG glioblastoma, and labeling of intact U87MG cells with anti-SNAP in flow cytometry showed that SNAP25 is available from the circulation but not in normal tissues and that it is present at the cell surface. Using an array of ECM proteins and surface plasmon resonance revealed that SNAP25 binds moderately to collagen V and strongly to collagen VI. Modeling studies suggested that CES and collagen VI compete for the same binding site on SNAP25. Our results introduce CES as a valuable targeting peptide for drug delivery, and its receptor SNAP25 as a possible molecular marker of interest for glioblastoma.

cancer biology↗

bioRxiv2024

Therapeutic Tumor Macrophage Reprogramming in Breast Cancer Through a Peptide-Drug Conjugate

In triple negative breast cancer (TNBC), pro-tumoral macrophages promote metastasis and suppress the immune response. To target these cells, we engineered a previously identified CD206 (mannose receptor)-binding peptide, mUNO, to enhance its affinity and proteolytic stability. The new rationally designed peptide, MACTIDE, includes a trypsin inhibitor loop, from the Sunflower Trypsin Inhibitor-I. Binding studies to recombinant CD206 revealed a 15-fold lower KD for MACTIDE compared to parental mUNO. Additionally, mass spectrometry showed a 5-fold increase in half-life in tumor lysate for MACTIDE compared to mUNO. Homing studies in TNBC-bearing mice showed that fluorescein (FAM)-MACTIDE precisely targeted CD206+ tumor-associated macrophages (TAMs) upon intravenous, intraperitoneal and even oral administration, with no significant accumulation in liver. We coupled MACTIDE to the FDA-approved drug Verteporfin, an established photosensitizer for photodynamic therapy and inhibitor of the YAP/TAZ pathway, to generate a conjugate here referred to as MACTIDE-V. In the orthotopic 4T1 TNBC mouse model, non-irradiated MACTIDE-V-treated mice unexpectedly showed a similar anti-tumoral effect and fewer signs of toxicity as irradiated MACTIDE-V-treated mice, leading to subsequent studies on the laser-independent activity of this conjugate. In vitro studies using bone-marrow derived mouse macrophages showed that MACTIDE-V excluded YAP from the nucleus, increased the phagocytic activity and upregulated several genes associated with cytotoxic anti-tumoral macrophages. In mouse models of TNBC, MACTIDE-V slowed primary tumor growth, suppressed lung metastases, increased markers of phagocytosis and antigen presentation in TAMs and monocytes, increasing the tumor infiltration of several lymphocyte subsets. We therefore propose MACTIDE-V as a useful peptide-drug conjugate to modulate macrophage function in the context of breast tumor immunotherapy.

cancer biology↗

bioRxiv2021

Depletion of CD206+ Tumour Macrophages via a Peptide-Targeted Star-Shaped Polyglutamate Inhibits Tumourigenesis and Metastatic Dissemination in Mouse Breast Cancer Models

Although many studies have explored the depletion of tumour-associated macrophages (TAMs) as a therapeutic strategy for solid tumours, currently available compounds suffer from poor efficacy and dose-limiting side effects. Here, we developed a novel TAM-depleting agent ("OximUNO") that specifically targets CD206+ TAMs and demonstrated efficacy in triple negative breast cancer (TNBC) mouse models. OximUNO comprises a star-shaped polyglutamate (St-PGA) decorated with the CD206-targeting peptide mUNO that carries the chemotherapeutic drug doxorubicin (DOX). In TNBC models, a fluorescently labelled mUNO-decorated St-PGA homed to CD206+ TAMs within primary lesions and metastases. OximUNO exhibited no acute liver or kidney toxicity in vivo. Treatment with OximUNO reduced the progression of primary tumour lesions and pulmonary metastases, significantly diminished the number of CD206+ TAMs and increased the CD8/FOXP3 expression ratio (demonstrating immunostimulation). Our findings suggest the potential benefit of OximUNO as a TAM-depleting agent for TNBC treatment. Importantly, our studies also represent the first report of a peptide-targeted St-PGA as a targeted therapeutic nanoconjugate.

cancer biology↗

bioRxiv2017

Detection of small breast tumors using tumor penetrating-polymersomes engineered to target p32 protein

Triple negative breast cancer (TNBC) is the deadliest form of breast cancer and its successful treatment critically depends on early diagnosis and therapy. The multi-compartment protein p32 is overexpressed and present at cell surfaces in a variety of tumors, including TNBC, specifically in the malignant cells and endothelial cells, and in macrophages localized in hypoxic areas of the tumor. Herein we used polyethylene glycol-polycaprolactone polymersomes that were affinity targeted with the p32-binding tumor penetrating peptide LinTT1 (AKRGARSTA) for imaging of TNBC lesions. A tyrosine residue was added to the peptide to allow for 124I labeling and PET imaging. In a TNBC model in mice, systemic LinTT1-targeted polymersomes accumulated in early tumor lesions more than twice as efficiently as untargeted polymersomes with up to 20% ID/cc at 24 h after administration. The PET-imaging was very sensitive, allowing detection of tumors as small as [~]20mm3. Confocal imaging of tumor tissue sections revealed a high degree of vascular exit and stromal penetration of LinTT1-targeted polymersomes and co-localization with tumor-associated macrophages. Our studies show that systemic LinTT1-targeted polymersomes can be potentially used for precision-guided tumor imaging and treatment of TNBC.

cancer biology↗

bioRxiv2017

Competition of Charge-Mediated and Specific Binding by Peptide-Tagged Cationic Liposome-DNA Nanoparticles In Vitro and In Vivo

Cationic liposome-nucleic acid (CL-NA) complexes, which form spontaneously, are a highly modular gene delivery system. These complexes can be sterically stabilized via PEGylation [PEG: poly(ethylene glycol)] into nanoparticles (NPs) and targeted to specific tissues and cell types via the conjugation of an affinity ligand. However, there are currently no guidelines on how to effectively navigate the large space of compositional parameters that modulate the specific and nonspecific binding interactions of peptide-targeted NPs with cells. Such guidelines are desirable to accelerate the optimization of formulations with novel peptides. Using PEG-lipids functionalized with a library of prototypical tumor-homing peptides, we varied the peptide density and other parameters (binding motif, peptide charge, CL/DNA charge ratio) to study their effect on the binding and uptake of the corresponding NPs. We used flow cytometry to quantitatively assess binding as well as internalization of NPs by cultured cancer cells. Surprisingly, full peptide coverage resulted in less binding and internalization than intermediate coverage, with the optimum coverage varying between cell lines. In, addition, our data revealed that great care must be taken to prevent nonspecific electrostatic interactions from interfering with the desired specific binding and internalization. Importantly, such considerations must take into account the charge of the peptide ligand as well as the membrane charge density and the CL/DNA charge ratio. To test our guidelines, we evaluated the in vivo tumor selectivity of selected NP formulations in a mouse model of peritoneally disseminated human gastric cancer. Intraperitoneally administered peptide-tagged CL-DNA NPs showed tumor binding, minimal accumulation in healthy control tissues, and preferential penetration of smaller tumor nodules, a highly clinically relevant target known to drive recurrence of the peritoneal cancer.\n\nGraphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biophysics↗