Imaging of surface-enhanced Raman scattering (SERS) nanoparticles (NPs) has been intensively studied for cancer detection due to its high sensitivity, unconstrained low signal-to-noise ratios, and multiplexing detection capability. Furthermore, conjugating SERS NPs with various biomarkers is straightforward, resulting in numerous successful studies on cancer detection and diagnosis. However, Raman spectroscopy only provides spectral data from an imaging area without co-registered anatomic context. This is not practical and suitable for clinical applications. Here, we propose a custom-made Raman spectrometer with computer-vision-based positional tracking and monocular depth estimation using deep learning (DL) for the visualization of 2D and 3D SERS NPs imaging, respectively. In addition, the SERS NPs used in this study (hyaluronic acid-conjugated SERS NPs) showed clear tumor targeting capabilities (target CD44 typically overexpressed in tumors) by anex vivoexperiment and immunohistochemistry. The combination of Raman spectroscopy, image processing, and SERS molecular imaging, therefore, offers a robust and feasible potential for clinical applications.
more »
« less
Anti-KIT DNA aptamer-conjugated porous silicon nanoparticles for the targeted detection of gastrointestinal stromal tumors
Evaluation of Gastrointestinal Stromal Tumors (GIST) during initial clinical staging, surgical intervention, and postoperative management can be challenging. Current imaging modalities ( e.g. , PET and CT scans) lack sensitivity and specificity. Therefore, advanced clinical imaging modalities that can provide clinically relevant images with high resolution would improve diagnosis. KIT is a tyrosine kinase receptor overexpressed on GIST. Here, the application of a specific DNA aptamer targeting KIT, decorated onto a fluorescently labeled porous silicon nanoparticle (pSiNP), is used for the in vitro & in vivo imaging of GIST. This nanoparticle platform provides high-fidelity GIST imaging with minimal cellular toxicity. An in vitro analysis shows greater than 15-fold specific KIT protein targeting compared to the free KIT aptamer, while in vivo analyses of GIST-burdened mice that had been injected intravenously (IV) with aptamer-conjugated pSiNPs show extensive nanoparticle-to-tumor signal co-localization (>90% co-localization) compared to control particles. This provides an effective platform for which aptamer-conjugated pSiNP constructs can be used for the imaging of KIT-expressing cancers or for the targeted delivery of therapeutics.
more »
« less
- Award ID(s):
- 2011924
- PAR ID:
- 10413533
- Date Published:
- Journal Name:
- Nanoscale
- Volume:
- 14
- Issue:
- 47
- ISSN:
- 2040-3364
- Page Range / eLocation ID:
- 17700 to 17713
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Peptides are an emerging class of biologics for cancer immunotherapy; however, their clinical translation is hindered by poor binding kinetics, bioavailability, and short plasma half‐life compared to their corresponding antibodies. Nanoparticles present potential solutions but face scale‐up difficulties due to complexity. Here, a translatable, modular nanoparticle scaffold is presented for peptide‐based immune checkpoint inhibitors (ICIs). This platform is based on a simple structure of generation 7 (G7) poly(amidoamine) (PAMAM) dendrimers conjugated with engineered peptides (dendrimer‐peptide conjugates, DPCs). DPCs functionalized with multiple copies of a programmed death‐ligand 1 (PD‐L1)‐binding peptide exhibited significantly enhanced avidity‐based binding kinetics and in vitro specificity, in addition to the substantially prolonged plasma half‐life in vivo. Notably, a series of in vivo experiments revealed that DPCs displayed selective tumor accumulation and high efficacy, without apparent toxicity, when applied to a syngeneic mouse model bearing mouse oral carcinoma (MOC1) tumors. The results indicate that the DPC platform significantly improves the antagonistic effect and in vivo behaviors of the PD‐L1‐binding peptides, which can be potentially applied to virtually any peptide‐based ICIs. The DPC platform's simplicity and modular nature will likely increase the potential of its clinical translation and ultimately enable precision/personalized cancer immunotherapy.more » « less
-
Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics. To enhance the quality of MR images, contrast agents (CAs) are used, which account for nearly 40% of MRI exams in the clinic globally. The most used CAs are gadolinium-based CAs (GBCAs) but the use of GBCAs has been linked with metal-deposition in vital organs. Gadolinium deposition has been shown to be correlated with nephrogenic systemic fibrosis, a fibrosis of the skin and internal organs. Therefore, there is an unmet need for a new CA alternative to GBCAs for T 1 -weighted Ce-MRI. Herein, we designed paramagnetic ferric iron( iii ) ion-chelated poly(lactic- co -glycolic)acid nanoparticle formulation and routinely examined their application in Ce-MRI using clinical and ultra-high-field MRI scanners. Nanoparticles were monodispersed and highly stable at physiological pH over time with the hydrodynamic size of 130 ± 12 nm and polydispersity index of 0.231 ± 0.026. The T 1 -contrast efficacy of the nanoparticles was compared with commercial agent gadopentetate dimeglumine, called Magnevist®, in aqueous phantoms in vitro and then validated in vivo by visualizing an angiographic map in a clinical MRI scanner. Relaxivities of the nanoparticles in an aqueous environment were r 1 = 10.59 ± 0.32 mmol −1 s −1 and r 1 = 3.02 ± 0.14 mmol −1 s −1 at 3.0 T and 14.1 T measured at room temperature and pH 7.4, respectively. The clinically relevant magnetic field relaxivity is three times higher compared to the Magnevist®, a clinical GBCA, signifying its potential applicability in clinical settings. Moreover, iron is an endogenous metal with known metabolic safety, and the polymer and phospholipids used in the nanoconstruct are biodegradable and biocompatible components. These properties further put the proposed T 1 agent in a promising position in contrast-enhanced MRI of patients with any disease conditions.more » « less
-
Abstract Many new technologies, such as cancer microenvironment‐induced nanoparticle targeting and multivalent ligand approach for cell surface receptors, are developed for active targeting in cancer therapy. While the principle of each technology is well illustrated, most systems suffer from low targeting specificity and sensitivity. To fill the gap, this work demonstrates a successful attempt to combine both technologies to simultaneously improve cancer cell targeting sensitivity and specificity. Specifically, the main component is a targeting ligand conjugated self‐assembling monomer precursor (SAM‐P), which, at the tumor site, undergoes tumor‐triggered cleavage to release the active form of self‐assembling monomer capable of forming supramolecular nanostructures. Biophysical characterization confirms the chemical and physical transformation of SAM‐P from unimers or oligomers with low ligand valency to supramolecular assemblies with high ligand valency under a tumor‐mimicking reductive microenvironment. The in vitro fluorescence assay shows the importance of supramolecular morphology in mediating ligand–receptor interactions and targeting sensitivity. Enhanced targeting specificity and sensitivity can be achieved via tumor‐triggered supramolecular assembly and induces multivalent ligand presentation toward cell surface receptors, respectively. The results support this combined tumor microenvironment‐induced cell targeting and multivalent ligand display approach, and have great potential for use as cell‐specific molecular imaging and therapeutic agents with high sensitivity and specificity.more » « less
-
Abstract The programmed cell death protein 1 (PD‐1) signaling pathway is a major source of dampened T cell activity in the tumor microenvironment. While clinical approaches to inhibiting the PD‐1 pathway using antibody blockade have been broadly successful, these approaches lead to widespread PD‐1 suppression, increasing the risk of autoimmune reactions. This study reports the development of an ionizable lipid nanoparticle (LNP) platform for simultaneous therapeutic gene expression and RNA interference (RNAi)‐mediated transient gene knockdown in T cells. In developing this platform, interesting interactions are observed between the two RNA cargoes when co‐encapsulated, leading to improved expression and knockdown characteristics compared to delivering either cargo alone. This messenger RNA (mRNA)/small interfering RNA (siRNA) co‐delivery platform is adopted to deliver chimeric antigen receptor (CAR) mRNA and siRNA targeting PD‐1 to primary human T cells ex vivo and strong CAR expression and PD‐1 knockdown are observed without apparent changes to overall T cell activation state. This delivery platform shows great promise for transient immune gene modulation for a number of immunoengineering applications, including the development of improved cancer immunotherapies.more » « less
An official website of the United States government

