Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeted systemic dendrimer delivery of CSF-1R inhibitor to tumor-associated macrophages improves outcomes in orthotopic glioblastoma.

ABSTRACT: Glioblastoma is the most common and aggressive form of primary brain cancer, with median survival of 16-20 months and a 5-year survival rates of <5%. Recent advances in immunotherapies have shown that addressing the tumor immune profile by targeting the colony-stimulating factor 1 (CSF-1) signaling pathway of tumor-associated macrophages (TAMs) has the potential to improve glioblastoma therapy. However, such therapies have shown limited successes in clinical translation partially due to lack of specific cell targeting in solid tumors and systemic toxicity. In this study, we present a novel hydroxyl dendrimer-mediated immunotherapy to deliver CSF-1R inhibitor BLZ945 (D-BLZ) from systemic administration selectively to TAMs in glioblastoma brain tumors to repolarize the tumor immune environment in a localized manner. We show that conjugation of BLZ945 to dendrimers enables sustained release in intracellular and intratumor conditions. We demonstrate that a single systemic dose of D-BLZ targeted to TAMs decreases pro-tumor expression in TAMs and promotes cytotoxic T cell infiltration, resulting in prolonged survival and ameliorated disease burden compared to free BLZ945. Our results demonstrate that dendrimer-drug conjugates can facilitate specific, localized manipulation of tumor immune responses from systemic administration by delivering immunotherapies selectively to TAMs, thereby improving therapeutic efficacy while reducing off-target effects.

SUBMITTER: Liaw K

PROVIDER: S-EPMC8126814 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Systemic dendrimer delivery of triptolide to tumor-associated macrophages improves anti-tumor efficacy and reduces systemic toxicity in glioblastoma.

Project description:Novel delivery strategies are necessary to effectively address glioblastoma without systemic toxicities. Triptolide is a therapy derived from the thunder god vine that has shown potent anti-proliferative and immunosuppressive properties but exhibits significant adverse systemic effects. Dendrimer-based nanomedicines have shown great potential for clinical translation of systemic therapies targeting neuroinflammation and brain tumors. Here we present a novel dendrimer-triptolide conjugate that specifically targets tumor-associated macrophages (TAMs) in glioblastoma from systemic administration and exhibits triggered release under intracellular and intratumor conditions. This targeted delivery improves phenotype switching of TAMs from pro- towards anti-tumor expression in vitro. In an orthotopic model of glioblastoma, dendrimer-triptolide achieved significantly improved amelioration of tumor burden compared to free triptolide. Notably, the triggered release mechanism of dendrimer-mediated triptolide delivery significantly reduced triptolide-associated hepatic and cardiac toxicities. These results demonstrate that dendrimers are a promising targeted delivery platform to achieve effective glioblastoma treatment by improving efficacy while reducing systemic toxicities.

| S-EPMC7904646 | biostudies-literature

Delivery of CSF-1R to the lumen of macropinosomes promotes its destruction in macrophages.

Project description:Activation of the macrophage colony stimulating factor-1 receptor (CSF-1R) by CSF-1 stimulates pronounced macropinocytosis and drives proliferation of macrophages. Although the role of macropinocytosis in CSF-1R signaling remains unknown, we show here that, despite internalizing large quantities of plasma membrane, macropinosomes contribute little to the internalization of the CSF-1-CSF-1R complex. Rather, internalization of the CSF-1R in small endocytic vesicles that are sensitive to clathrin disruption, outcompetes macropinosomes for CSF-1R endocytosis. Following internalization, small vesicles carrying the CSF-1R underwent homotypic fusion and then trafficked to newly formed macropinosomes bearing Rab5. As these macropinosomes matured, acquiring Rab7, the CSF-1R was transported into their lumen and degraded. Inhibition of macropinocytosis delayed receptor degradation despite no disruption to CSF-1R endocytosis. These data indicate that CSF-1-stimulated macropinosomes are sites of multivesicular body formation and accelerate CSF-1R degradation. Furthermore, we demonstrate that macropinocytosis and cell growth have a matching dose dependence on CSF-1, suggesting that macropinosomes might be a central mechanism coupling CSF-1R signaling and macrophage growth.

| S-EPMC4265739 | biostudies-literature

EGFR-Targeted Adenovirus Dendrimer Coating for Improved Systemic Delivery of the Theranostic NIS Gene.

Project description:We recently demonstrated tumor-selective iodide uptake and therapeutic efficacy of combined radiovirotherapy after systemic delivery of the theranostic sodium iodide symporter (NIS) gene using a dendrimer-coated adenovirus. To further improve shielding and targeting we physically coated replication-selective adenoviruses carrying the hNIS gene with a conjugate consisting of cationic poly(amidoamine) (PAMAM) dendrimer linked to the peptidic, epidermal growth factor receptor (EGFR)-specific ligand GE11. In vitro experiments demonstrated coxsackie-adenovirus receptor-independent but EGFR-specific transduction efficiency. Systemic injection of the uncoated adenovirus in a liver cancer xenograft mouse model led to high levels of NIS expression in the liver due to hepatic sequestration, which were significantly reduced after coating as demonstrated by (123)I-scintigraphy. Reduction of adenovirus liver pooling resulted in decreased hepatotoxicity and increased transduction efficiency in peripheral xenograft tumors. (124)I-PET-imaging confirmed EGFR-specificity by significantly lower tumoral radioiodine accumulation after pretreatment with the EGFR-specific antibody cetuximab. A significantly enhanced oncolytic effect was observed following systemic application of dendrimer-coated adenovirus that was further increased by additional treatment with a therapeutic dose of (131)I. These results demonstrate restricted virus tropism and tumor-selective retargeting after systemic application of coated, EGFR-targeted adenoviruses therefore representing a promising strategy for improved systemic adenoviral NIS gene therapy.Molecular Therapy-Nucleic Acids (2013) 2, e131; doi:10.1038/mtna.2013.58; published online 5 November 2013.

| S-EPMC3889187 | biostudies-literature

Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival.

Project description:Most current cancer therapies focus on killing malignant cells, but these cells are often genetically unstable and can become resistant to chemotherapy. Tumor-associated macrophages (TAMs) facilitate disease progression by promoting angiogenesis and tumor cell growth, as well as by suppressing the adaptive immune response. TAMs are therefore potential targets for adjuvant anticancer therapies. However, resident macrophages are critical to host defense, and preferential ablation of TAMs remains challenging. Macrophage activation is broadly categorized as classically activated, or M1, and alternatively activated, or M2, and TAMs in the tumor microenvironment have been shown to adopt the anti-inflammatory, M2-like phenotype. To date, there are no methods for specific molecular targeting of TAMs. In this work, we report the discovery of a unique peptide sequence, M2pep, identified using a subtractive phage biopanning strategy against whole cells. The peptide preferentially binds to murine M2 cells, including TAMs, with low affinity for other leukocytes. Confocal imaging demonstrates the accumulation of M2pep in TAMs in vivo after tail vein injection. Finally, tail vein injection of an M2pep fusion peptide with a proapoptotic peptide delays mortality and selectively reduces the M2-like TAM population. This work therefore describes a molecularly targeted construct for murine TAMs and provides proof of concept of this approach as an anticancer treatment. In addition, M2pep is a useful tool for murine M2 macrophage identification and for modulating M2 macrophages in other murine models of disease involving M2 cells.

| S-EPMC3791765 | biostudies-literature

High Expression of CSF-1R Predicts Poor Prognosis and CSF-1R<sup>high</sup> Tumor-Associated Macrophages Inhibit Anti-Tumor Immunity in Colon Adenocarcinoma.

Project description:BackgroundColony stimulating factor 1 receptor (CSF-1R) is a single channel III transmembrane receptor tyrosine kinase (RTK) and plays an important role in immune regulation and the development of various cancer types. The expression of CSF-1R in colon adenocarcinoma (COAD) and its prognostic value remain incompletely understood. Therefore, we aim to explore the prognostic value of CSF-1R in COAD and its relationship with tumor immunity.MethodsCSF-1R expression in a COAD cohort containing 103 patients was examined using immunohistochemistry (IHC). The relationship between CSF-1R expression and clinicopathological parameters and prognosis was evaluated. Dual immunofluorescence staining was conducted to determine the localization of CSF-1R in COAD tissues. Univariate and multivariate Cox regression analysis were performed to evaluate independent prognostic factors. Transcriptomic profiles of CSF-1Rhigh and CSF-1Rlow tumor-associated macrophages (TAMs) were investigated. Gene enrichment analysis was used to explore the signal pathways related to CSF-1R. In addition, the relationship between CSF-1R in tumor microenvironment (TME) and tumor immunity was also studied.ResultsIHC analysis showed that CSF-1R was overexpressed in COAD, and higher expression was associated with shorter overall survival (OS). Immunofluorescence staining showed that CSF-1R was co-localized with macrophage marker CD68. Univariate and multivariate Cox regression analysis showed that CSF-1R was an independent prognostic factor for COAD. The results of gene enrichment analysis showed that CSF-1R was involved in tumor immune response and regulation of TME. In addition, CSF-1R was significantly correlated with TME, immune cell infiltration, TMB, MSI, Neoantigen, and immune checkpoint molecules.ConclusionCSF-1R can serve as an independent prognostic factor of COAD and promising immunotherapeutic target of COAD.

| S-EPMC9014714 | biostudies-literature

Peptide-Functionalized Dendrimer Nanocarriers for Targeted Microdystrophin Gene Delivery.

Project description:Gene therapy is a good alternative for determined congenital disorders; however, there are numerous limitations for gene delivery in vivo including targeted cellular uptake, intracellular trafficking, and transport through the nuclear membrane. Here, a modified G5 polyamidoamine (G5 PAMAM) dendrimer-DNA complex was developed, which will allow cell-specific targeting to skeletal muscle cells and transport the DNA through the intracellular machinery and the nuclear membrane. The G5 PAMAM nanocarrier was modified with a skeletal muscle-targeting peptide (SMTP), a DLC8-binding peptide (DBP) for intracellular transport, and a nuclear localization signaling peptide (NLS) for nuclear uptake, and polyplexed with plasmid DNA containing the GFP-tagged microdystrophin (µDys) gene. The delivery of µDys has been considered as a therapeutic modality for patients suffering from a debilitating Duchenne muscular dystrophy (DMD) disorder. The nanocarrier-peptide-DNA polyplexes were prepared with different charge ratios and characterized for stability, size, surface charge, and cytotoxicity. Using the optimized nanocarrier polyplexes, the transfection efficiency in vitro was determined by demonstrating the expression of the GFP and the µDys protein using fluorescence and Western blotting studies, respectively. Protein expression in vivo was determined by injecting an optimal nanocarrier polyplex formulation to Duchenne model mice, mdx4Cv. Ultimately, these nanocarrier polyplexes will allow targeted delivery of the microdystrophin gene to skeletal muscle cells and result in improved muscle function in Duchenne muscular dystrophy patients.

| S-EPMC8708248 | biostudies-literature

Fibrotic Response to anti-CSF-1R Treatment Potentiates Glioblastoma Recurrence

Project description:Treatment of glioblastoma with anti-CSF-1R immunotherapy, radiotherapy, or surgical tumor resection were found to all induce a fibrotic response to treatment, which was highly associated with tumor recurrence. To investigate the drivers of fibrotic treatment response we performed multi-omic analysis of the glioblastoma microenvironment following treatment with anti-CSF-1R immunotherapy. Studies consisted of mass spectrometry proteomic analysis, single cell transcriptomics, and high-dimensional spatial analysis. These data identified a protective spatial niche that supported tumor cell survival following treatment, ultimately leading to tumor recurrence. Therapeutic inhibition of fibrotic treatment response blocked the formation of this niche, and significantly improved survival in anti-CSF-1R preclinical trials

2024-08-12 | PXD041689 | Pride

Synthetically controlling dendrimer flexibility improves delivery of large plasmid DNA.

Project description:Tools for editing the genome and epigenome have revolutionised the field of molecular biology and represent a new frontier in targeted therapeutic intervention. Although efficiencies and specificities of genome editing technologies have improved with the development of TALEs and CRISPR platforms, intracellular delivery of these larger constructs still remains a challenge using existing delivery agents. Viral vectors, including lentiviruses and adeno-associated viruses, as well as some non-viral strategies, such as cationic polymers and liposomes, are limited by packaging capacity, poor delivery, toxicity, and immunogenicity. We report a highly controlled synthetic strategy to engineer a flexible dendritic polymer using click chemistry to overcome the aforementioned delivery challenges associated with genome engineering technologies. Using a systematic approach, we demonstrate that high transfection efficiencies and packaging capacity can be achieved using this non-viral delivery methodology to deliver zinc fingers, TALEs and CRISPR/dCas9 platforms.

| S-EPMC5376716 | biostudies-literature

Local Targeting of Lung-Tumor-Associated Macrophages with Pulmonary Delivery of a CSF-1R Inhibitor for the Treatment of Breast Cancer Lung Metastases.

Project description:The lungs are major sites of metastases for several cancer types, including breast cancer (BC). Prognosis and quality of life of BC patients that develop pulmonary metastases are negatively impacted. The development of strategies to slow the growth and relieve the symptoms of BC lung metastases (BCLM) is thus an important goal in the management of BC. However, systemically administered first line small molecule chemotherapeutics have poor pharmacokinetic profiles and biodistribution to the lungs and significant off-target toxicity, severely compromising their effectiveness. In this work, we propose the local delivery of add-on immunotherapy to the lungs to support first line chemotherapy treatment of advanced BC. In a syngeneic murine model of BCLM, we show that local pulmonary administration (p.a.) of PLX-3397 (PLX), a colony-stimulating factor 1 receptor inhibitor (CSF-1Ri), is capable of overcoming physiological barriers of the lung epithelium, penetrating the tumor microenvironment (TME), and decreasing phosphorylation of CSF-1 receptors, as shown by the Western blot of lung tumor nodules. That inhibition is accompanied by an overall decrease in the abundance of protumorigenic (M2-like) macrophages in the TME, with a concomitant increase in the amount of antitumor (M1-like) macrophages when compared to the vehicle-treated control. These effects with PLX (p.a.) were achieved using a much smaller dose (1 mg/kg, every other day) compared to the systemic doses typically used in preclinical studies (40-800 mg/kg/day). As an additive in combination with intravenous (i.v.) administration of paclitaxel (PTX), PLX (p.a.) leads to a decrease in tumor burden without additional toxicity. These results suggested that the proposed immunochemotherapy, with regional pulmonary delivery of PLX along with the i.v. standard of care chemotherapy, may lead to new opportunities to improve treatment, quality of life, and survival of patients with BCLM.

| S-EPMC8060921 | biostudies-literature

Synthesis, Formulation and Characterization of Immunotherapeutic Glycosylated Dendrimer/cGAMP Complexes for CD206 Targeted Delivery to M2 Macrophages in Cold Tumors.

Project description:Anti-tumor responses can be achieved via the stimulation of the immune system, a therapeutic approach called cancer immunotherapy. Many solid tumor types are characterized by the presence of immune-suppressive tumor-associated macrophage (TAMs) cells within the tumor microenvironment (TME). Moreover, TAM infiltration is strongly associated with poor survival in solid cancer patients and hence a low responsiveness to cancer immunotherapy. Therefore, 2'3' Cyclic GMP-AMP (2'3' cGAMP) was employed for its ability to shift macrophages from pro-tumoral M2-like macrophages (TAM) to anti-tumoral M1. However, cGAMP transfection within macrophages is limited by the molecule's negative charge, poor stability and lack of targeting. To circumvent these barriers, we designed nanocarriers based on poly(amidoamine) dendrimers (PAMAM) grafted with D-glucuronic acid (Glu) for M2 mannose-mediated endocytosis. Two carriers were synthesized based on different dendrimers and complexed with cGAMP at different ratios. Orthogonal techniques were employed for synthesis (NMR, ninhydrin, and gravimetry), size (DLS, NTA, and AF4-DLS), charge (DLS and NTA), complexation (HPLC-UV and AF4-UV) and biocompatibility and toxicity (primary cells and hen egg chorioallantoic membrane model) evaluations in order to evaluate the best cGAMP carrier. The best formulation was selected for its low toxicity, biocompatibility, monodispersed distribution, affinity towards CD206 and ability to increase M1 (STAT1 and NOS2) and decrease M2 marker (MRC1) expression in macrophages.

| S-EPMC9503622 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data