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An Engineered Prussian Blue Nanoparticles-based Nanoimmunotherapy Elicits Robust and Persistent Immunological Memory in a TH-MYCN Neuroblastoma Model.

ABSTRACT: A combination therapy using Prussian blue nanoparticles (PBNP) as photothermal therapy (PTT) agents coated with CpG oligodeoxynucleotides, an immunologic adjuvant, as a nanoimmunotherapy (CpG-PBNP-PTT) for neuroblastoma (NB) is described. NB driven by MYCN amplification confers high risk and correlates with a dismal prognosis, accounting for the majority of NB-related mortality. The efficacy of the CpG-PBNP-PTT nanoimmunotherapy in a clinically relevant, TH-MYCN murine NB model (9464D) overexpressing MYCN is tested. When administered to 9464D NB cells in vitro, CpG-PBNP-PTT triggers thermal dose-dependent immunogenic cell death and tumor cell priming for immune recognition in vitro, measured by the expression of specific costimulatory and antigen-presenting molecules. In vivo, intratumorally administered CpG-PBNP-PTT generates complete tumor regression and significantly higher long-term survival compared to controls. Furthermore, CpG-PBNP-PTT-treated mice reject tumor rechallenge. Ex vivo studies confirm these therapeutic responses result from the generation of robust T cell-mediated immunological memory. Consequently, in a synchronous 9464D tumor model, CpG-PBNP-PTT induces complete tumor regression on the treated flank and significantly slows tumor progression on the untreated flank, improving animal survival. These findings demonstrate that localized administration of the CpG-PBNP-PTT nanoimmunotherapy drives potent systemic T cell responses in solid tumors such as NB and therefore has therapeutic implications for NB.

SUBMITTER: Shukla A

PROVIDER: S-EPMC8382205 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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An Engineered Prussian Blue Nanoparticles-based Nanoimmunotherapy Elicits Robust and Persistent Immunological Memory in a TH-MYCN Neuroblastoma Model.

Shukla Anshi A Cano-Mejia Juliana J Andricovich Jaclyn J Burga Rachel A RA Sweeney Elizabeth E EE Fernandes Rohan R

Advanced nanobiomed research 20210313 8

A combination therapy using Prussian blue nanoparticles (PBNP) as photothermal therapy (PTT) agents coated with CpG oligodeoxynucleotides, an immunologic adjuvant, as a nanoimmunotherapy (CpG-PBNP-PTT) for neuroblastoma (NB) is described. NB driven by MYCN amplification confers high risk and correlates with a dismal prognosis, accounting for the majority of NB-related mortality. The efficacy of the CpG-PBNP-PTT nanoimmunotherapy in a clinically relevant, TH-MYCN murine NB model (9464D) overexpre ...[more]

PMID: 34435194

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Project description:The elucidation of the ideal coordination environment of a catalytic site has been at the heart of catalytic applications. Herein, we show that the water oxidation activities of catalytic cobalt sites in a Prussian blue (PB) structure could be tuned systematically by decorating its coordination sphere with a combination of cyanide and bidentate pyridyl groups.  K0.1[Co(bpy)]2.9[Fe(CN)6]2 ([Cobpy-Fe]), K0.2[Co(phen)]2.8[Fe(CN)6]2 ([Cophen-Fe]), {[Co(bpy)2]3[Fe(CN)6]2}[Fe(CN)6]1/3 ([Cobpy2-Fe]), and {[Co(phen)2]3[Fe(CN)6]2}[Fe(CN)6]1/3 Cl0.11 ([Cophen2-Fe]) were prepared by introducing bidentate pyridyl groups (phen: 1,10-phenanthroline, bpy: 2,2'-bipyridine) to the common synthetic protocol of Co-Fe Prussian blue analogues. Characterization studies indicate that [Cobpy2-Fe] and [Cophen2-Fe] adopt a pentanuclear molecular structure, while [Cobpy-Fe] and [Cophen-Fe] could be described as cyanide-based coordination polymers with lower-dimensionality and less crystalline nature compared to the regular Co-Fe Prussian blue analogue (PBA), K0.1Co2.9[Fe(CN)6]2 ([Co-Fe]). Photocatalytic studies reveal that the activities of [Cobpy-Fe] and [Cophen-Fe] are significantly enhanced compared to those of [Co-Fe], while molecular [Cobpy2-Fe] and [Cophen2-Fe] are inactive toward water oxidation. [Cobpy-Fe] and [Cophen-Fe] exhibit upper-bound turnover frequencies (TOFs) of 1.3 and 0.7 s-1, respectively, which are ∼50 times higher than that of [Co-Fe] (1.8 × 10-2 s-1). The complete inactivity of [Cobpy2-Fe] and [Cophen2-Fe] confirms the critical role of aqua coordination to the catalytic cobalt sites for oxygen evolution reaction (OER). Computational studies show that bidentate pyridyl groups enhance the susceptibility of the rate-determining Co(IV)-oxo species to the nucleophilic water attack during the critical O-O bond formation. This study opens a new route toward increasing the intrinsic water oxidation activity of the catalytic sites in PB coordination polymers.

Project description:BackgroundThe TH-MYCN transgenic neuroblastoma model, with targeted MYCN expression to the developing neural crest, has been used to study neuroblastoma development and evaluate novel targeted tumor therapies.MethodsWe followed tumor development in 395 TH-MYCN (129X1/SvJ) mice (125 negative, 206 hemizygous and 64 homozygous mice) by abdominal palpations up to 40 weeks of age. DNA sequencing of MYCN in the original plasmid construct and mouse genomic DNA was done to verify the accuracy. Copy number analysis with Affymetrix® Mouse Diversity Genotyping Arrays was used to characterize acquired genetic aberrations.ResultsDNA sequencing confirmed presence of human MYCN cDNA in genomic TH-MYCN DNA corresponding to the original plasmid construct. Tumor incidence and growth correlated significantly to transgene status with event-free survival for hemizygous mice at 50%, and 0% for homozygous mice. Hemizygous mice developed tumors at 5.6-19 weeks (median 9.1) and homozygous mice at 4.0-6.9 weeks (5.4). The mean treatment window, time from palpable tumor to sacrifice, for hemizygous and homozygous mice was 15 and 5.2 days, respectively. Hemizygous mice developing tumors as early as homozygous mice had a longer treatment window. Age at tumor development did not influence treatment window for hemizygous mice, whereas treatment window in homozygous mice decreased significantly with increasing age. Seven out of 10 analysed tumors had a flat DNA profile with neither segmental nor numerical chromosomal aberrations. Only three tumors from hemizygous mice showed acquired genetic features with one or more numerical aberrations. Of these, one event corresponded to gain on the mouse equivalent of human chromosome 17.ConclusionHemizygous and homozygous TH-MYCN mice have significantly different neuroblastoma incidence, tumor growth characteristics and treatment windows but overlap in age at tumor development making correct early genotyping essential to evaluate therapeutic interventions. Contrasting previous studies, our data show that TH-MYCN tumors have few genetic aberrations.

Project description:In neuroblastoma, amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN is the defining prognosticator of high-risk disease, occurs in one-third of neuroblastoma, and drastically reduces overall survival rates. As a proto-oncogene, targeted MYCN overexpression in peripheral neural crest is sufficient to initiate disease in mouse models. In MYCN amplified neuroblastoma, elevated expression of the factor is crucial to maintain tumor stemness and is associated with increased proliferation and aberrant cell cycle progression, as these tumors lack the ability to arrest in G1 in response to irradiation. MYCN down-regulation broadly reverses these oncogenic phenotypes in a variety of neuroblastoma models and recent thereapeutic strategies to indirectly target MYCN production or protein stability have reduced tumor growth in vivo. These observations motivate an investigation of MYCN binding in MYCN amplified tumors as it remains fundamentally unclear how elevated levels of the factor occupy the genome and alter transcriptional programs in neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of direct MYCN perturbation in neuroblastoma. We find that at oncogenic levels, MYCN associates with E-box (CANNTG) binding motifs in an affinity dependent manner across most active cis-regulatory promoters and enhancers. MYCN shutdown globally reduces histone acetylation and transcription, consistent with prior descriptions of MYC proteins as non-linear amplifiers of gene expression. We establish that MYCN load at the promoter and proximal enhancers predicts transcriptional responsiveness to MYCN shutdown and that MYCN enhancer binding occurs prominently at the most strongly occupied and down-regulated genes, suggesting a role for these tissue specific elements in predicating MYCN responsive “target” genes. At these invaded enhancers, we identify the lineage specific bHLH TWIST1 as a key collaborator and dependency of oncogenic MYCN. These data suggest that MYCN enhancer invasion helps shape transcriptional amplification of the neuroblastoma gene expression program to promote tumorigenesis.

Dataset Information

An Engineered Prussian Blue Nanoparticles-based Nanoimmunotherapy Elicits Robust and Persistent Immunological Memory in a TH-MYCN Neuroblastoma Model.

Publications

An Engineered Prussian Blue Nanoparticles-based Nanoimmunotherapy Elicits Robust and Persistent Immunological Memory in a TH-MYCN Neuroblastoma Model.

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