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PPRX-1701, a nanoparticle formulation of 6'-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models.

ABSTRACT: Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6'-bromoindirubin-3'-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway in tumor cells. BiA blocks interferon-γ (IFNγ)-induced IDO1 protein expression in vitro and enhances T cell-mediated tumor cell killing in GBM stem-like cell co-culture models. PPRX-1701 reaches intracranial murine GBM and significantly improves survival in immunocompetent GBM models in vivo. Our results indicate that BiA improves survival in murine GBM models via effects on important immunotherapeutic targets in GBM and that it can be delivered efficiently via PPRX-1701, a nanoparticle injectable formulation of BiA.

SUBMITTER: Zdioruk M

PROVIDER: S-EPMC10213750 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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PPRX-1701, a nanoparticle formulation of 6'-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models.

Zdioruk Mykola M Jimenez-Macias Jorge-Luis JL Nowicki Michal Oskar MO Manz Katherine E KE Pennell Kurt D KD Koch Marilin S MS Finkelberg Tomer T Wu Bin B Boucher Paul P Takeda Yuji Y Li Weiyi W Piranlioglu Raziye R Ling Alexander L AL Ling Alexander L AL Chiocca E Antonio EA Lawler Sean E SE

Cell reports. Medicine 20230414 5

Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6'-bromoindirubin-3'-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), ...[more]

PMID: 37060903

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Project description:Rationale: Developing novel pre-operative and intraoperative imaging approaches for glioblastoma multiforme (GBM) could aid therapeutic intervention while sparing healthy normal brain, which remains a significant clinical challenge. 5-aminolevulinic acid (5-ALA) is the only intraoperative imaging agent approved to aid the resection of GBM. Matrix metalloproteinase 14 (MMP14), which is overexpressed in GBM, is an attractive target for preoperative and intraoperative imaging of GBM. Prior studies have shown the feasibility of near-infrared fluorescence (NIRF) imaging and positron emission tomography (PET) imaging of GBM xenografts in mice using MMP-14 targeted peptide probes. The present studies assessed the tumor-specific localization and contrast of these MMP-14 targeted peptides relative to 5-ALA in GBM models. Methods: Fluorescence and PET imaging was performed after i.v. injection of 5-ALA and the MMP-14 targeted peptide probes (non-labeled or radiolabeled with 64Cu) in mice bearing human GBM orthotopic xenografts (U87, D54). Imaging signals were correlated to MMP-14 expression determined by immunofluorescence. Tumor-to-normal brain ratio (TBR) and Dice similarity coefficient (DSC) relative to tumor defined by ex vivo pathology or in vivo magnetic resonance imaging were determined for each imaging agent. Results: NIRF signals from the MMP-14 targeted peptide probes showed comparable TBR (p < 0.05) but significantly higher DSC (p < 0.05) relative to 5-ALA. NIRF signals from the peptide probes significantly correlated with MMP-14 expression (p < 0.05). MMP-14 binding peptide labeled with 64Cu showed moderate DSC (0.45) while PET signals significantly correlated (p < 0.05) with NIRF signals from a co-injected MMP-14 substrate peptide. NIRF and PET signals localized in residual tumor regions in the resection cavity during in situ resection. Conclusions: MMP-14 targeted peptides showed favorable TBR and higher tumor localization than 5-ALA in GBM orthotopic models. Further development of MMP-14 targeted peptide probes could lead to improved pre-operative and intraoperative management of GBM.

Dataset Information

PPRX-1701, a nanoparticle formulation of 6'-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models.

Publications

PPRX-1701, a nanoparticle formulation of 6'-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models.

Similar Datasets

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