41 research outputs found
Nanoparticles as multimodal photon transducers of ionizing radiation
In biomedical imaging, nanoparticles combined with radionuclides that generate Cerenkov luminescence are used in diagnostic imaging, photon-induced therapies, and as activatable probes. In these applications, the nanoparticle is often viewed as a carrier inert to ionizing radiation from the radionuclide. However, certain phenomena such as enhanced nanoparticle luminescence and generation of reactive oxygen species cannot be explained by only Cerenkov luminescence interactions with nanoparticles. Herein, we report methods to examine the mechanisms of nanoparticle excitation by radionuclides, including interactions with Cerenkov luminescence, β particles, and γ radiation. We demonstrate that β scintillation contributes appreciably to excitation and reactivity in certain nanoparticle systems and that excitation of nanoparticles composed of large atomic number atoms by radionuclides generates X-rays, enabling multiplexed imaging through single photon emission computed tomography. These findings demonstrate practical optical imaging and therapy using radionuclides with emission energies below the Cerenkov threshold, thereby expanding the list of applicable radionuclides
Long-term Correction of Very Long-chain Acyl-CoA Dehydrogenase Deficiency in Mice Using AAV9 Gene Therapy
Very long-chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD-deficient mice and patients clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD-deficient mice were treated systemically with 1 × 1012 vector genomes of recombinant adeno-associated virus 9 (rAAV9)-VLCAD. Biochemical correction was observed in vector-treated mice beginning 2 weeks postinjection, as characterized by a significant drop in long-chain fatty acyl accumulates in whole blood after an overnight fast. Changes persisted through the termination point around 20 weeks postinjection. Magnetic resonance spectroscopy (MRS) and tandem mass spectrometry (MS/MS) revealed normalization of intramuscular lipids in treated animals. Correction was not observed in liver tissue extracts, but cardiac muscle extracts showed significant reduction of long-chain metabolites. Disease-specific phenotypes were characterized, including thermoregulation and maintenance of euglycemia after a fasting cold challenge. Internal body temperatures of untreated VLCAD−/− mice dropped below 20 °C and the mice became lethargic, requiring euthanasia. In contrast, all rAAV9-treated VLCAD−/− mice and the wild-type controls maintained body temperatures. rAAV9-treated VLCAD−/− mice maintained euglycemia, whereas untreated VLCAD−/− mice suffered hypoglycemia following a fasting cold challenge. These promising results suggest rAAV9 gene therapy as a potential treatment for VLCAD deficiency in humans
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
Activated Peyer's patch B cells sample antigen directly from M cells in the subepithelial dome
Environment-responsive nanophores for therapy and treatment monitoring via molecular MRI quenching
The effective delivery of therapeutics to disease sites significantly contributes to drug efficacy, toxicity and clearance. Here we demonstrate that clinically approved iron oxide nanoparticles (Ferumoxytol) can be utilized to carry one or multiple drugs. These so called \u27nanophores\u27 retain their cargo within their polymeric coating through weak electrostatic interactions and release it in slightly acidic conditions (pH 6.8 and below). The loading of drugs increases the nanophores\u27 transverse T2 and longitudinal T1 nuclear magnetic resonance (NMR) proton relaxation times, which is proportional to amount of carried cargo. Chemotherapy with translational nanophores is more effective than the free drug in vitro and in vivo, without subjecting the drugs or the carrier nanoparticle to any chemical modification. Evaluation of cargo incorporation and payload levels in vitro and in vivo can be assessed via benchtop magnetic relaxometers, common NMR instruments or magnetic resonance imaging scanners
Near-Infrared Quantum Dot and <sup>89</sup>Zr Dual-Labeled Nanoparticles for <i>in Vivo</i> Cerenkov Imaging
Cerenkov
luminescence (CL) is an emerging imaging modality that
utilizes the light generated during the radioactive decay of many
clinical used isotopes. Although it is increasingly used for background-free
imaging and deep tissue photodynamic therapy, <i>in vivo</i> applications of CL suffer from limited tissue penetration. Here,
we propose to use quantum dots (QDs) as spectral converters that can
transfer the CL UV-blue emissions to near-infrared light that is less
scattered or absorbed <i>in vivo</i>. Experiments on tissue
phantoms showed enhanced penetration depth and increased transmitted
intensity for CL in the presence of near-infrared (NIR) QDs. To realize
this concept for <i>in vivo</i> imaging applications, we
developed three types of NIR QDs and <sup>89</sup>Zr dual-labeled
nanoparticles based on lipid micelles, nanoemulsions, and polymeric
nanoplatforms, which enable codelivery of the radionuclide and the
QDs for maximized spectral conversion efficiency. We finally demonstrated
the application of these self-illuminating nanoparticles for imaging
of lymph nodes and tumors in a prostate cancer mouse model
Viral Delivery of CAR Targets to Solid Tumors Enables Effective Cell Therapy
Chimeric antigen receptor (CAR) T cell therapy has had limited efficacy for solid tumors, largely due to a lack of selectively and highly expressed surface antigens. To avoid reliance on a tumor's endogenous antigens, here we describe a method of tumor-selective delivery of surface antigens using an oncolytic virus to enable a generalizable CAR T cell therapy. Using CD19 as our proof of concept, we engineered a thymidine kinase-disrupted vaccinia virus to selectively deliver CD19 to malignant cells, and thus demonstrated potentiation of CD19 CAR T cell activity against two tumor types in vitro. In an immunocompetent model of B16 melanoma, this combination markedly delayed tumor growth and improved median survival compared with antigen-mismatched combinations. We also found that CD19 delivery could improve CAR T cell activity against tumor cells that express low levels of cognate antigen, suggesting a potential application in counteracting antigen-low escape. This approach highlights the potential of engineering tumors for effective adoptive cell therapy
Stable Radiolabeling of Sulfur-Functionalized Silica Nanoparticles with Copper-64
Nanoparticles
labeled with radiometals enable whole-body nuclear imaging and therapy.
Though chelating agents are commonly used to radiolabel biomolecules,
nanoparticles offer the advantage of attaching a radiometal directly
to the nanoparticle itself without the need of such agents. We previously
demonstrated that direct radiolabeling of silica nanoparticles with
hard, oxophilic ions, such as the positron emitters zirconium-89 and
gallium-68, is remarkably efficient. However, softer radiometals,
such as the widely employed copper-64, do not stably bind to the silica
matrix and quickly dissociate under physiological conditions. Here,
we overcome this limitation through the use of silica nanoparticles
functionalized with a soft electron-donating thiol group to allow
stable attachment of copper-64. This approach significantly improves
the stability of copper-64 labeled thiol-functionalized silica nanoparticles
relative to native silica nanoparticles, thereby enabling in vivo
PET imaging, and may be translated to other softer radiometals with
affinity for sulfur. The presented approach expands the application
of silica nanoparticles as a platform for facile radiolabeling with
both hard and soft radiometal ions