Shortwave-Infrared-Emitting Nanoprobes for CD8 Targeting and In Vivo Imaging of Cytotoxic T Cells in Breast Cancer.

Checkpoint immunotherapy has made great strides in the treatment of solid tumors, but many patients do not respond to immune checkpoint inhibitors. Identification of tumor-infiltrating cytotoxic T cells (CTLs) has the potential to stratify patients and monitor immunotherapy responses. In this study, the design of cluster of differentiation (CD8) T cell-targeted nanoprobes that emit shortwave infrared (SWIR) light in the second tissue-transparent window for noninvasive, real-time imaging of CTLs in murine models of breast cancer is presented.

Early Detection of Myeloid-Derived Suppressor Cells in the Lung Pre-Metastatic Niche by Shortwave Infrared Nanoprobes.

Metastatic breast cancer remains a significant source of mortality amongst breast cancer patients and is generally considered incurable in part due to the difficulty in detection of early micro-metastases. The pre-metastatic niche (PMN) is a tissue microenvironment that has undergone changes to support the colonization and growth of circulating tumor cells, a key component of which is the myeloid-derived suppressor cell (MDSC). Therefore, the MDSC has been identified as a potential biomarker for PMN formation, the detection of which would enable clinicians to proactively treat metastases.

Extracellular Vesicle Molecular Signatures Characterize Metastatic Dynamicity in Ovarian Cancer.

Background: Late-stage diagnosis of ovarian cancer, a disease that originates in the ovaries and spreads to the peritoneal cavity, lowers 5-year survival rate from 90% to 30%. Early screening tools that can: i) detect with high specificity and sensitivity before conventional tools such as transvaginal ultrasound and CA-125, ii) use non-invasive sampling methods and iii) longitudinally significantly increase survival rates in ovarian cancer are needed. Studies that employ blood-based screening tools using circulating tumor-cells, -DNA, and most recently tumor-derived small extracellular vesicles (sEVs) have shown promise in non-invasive detection of cancer before standard of care.

Short-Wave Infrared Emitting Nanocomposites for Fluorescence-Guided Surgery.

Fluorescence-guided surgery (FGS) is an emerging technique for tissue visualization during surgical procedures. Structures of interest are labeled with exogenous probes whose fluorescent emissions are acquired and viewed in real-time with optical imaging systems. This study investigated rare-earth-doped albumin-encapsulated nanocomposites (REANCs) as short-wave infrared emitting contrast agents for FGS.

A single NGS-based assay covering the entire genomic sequence of the DMD gene facilitates diagnostic and newborn screening confirmatory testing.

Molecular diagnosis for Duchenne and Becker muscular dystrophies (DMD/BMD) involves a two-tiered approach for detection of deletions/duplications using MLPA or array CGH, followed by sequencing of coding and flanking intronic regions to detect sequence variants, which is time-consuming and expensive. We have developed a comprehensive next-generation sequencing (NGS)-based single-step assay to sequence the entire 2.2 Mb of the DMD gene to detect all copy number and sequence variants in both index males and carrier females.

Shortwave infrared emitting multicolored nanoprobes for biomarker-specific cancer imaging in vivo.

Background: The ability to detect tumor-specific biomarkers in real-time using optical imaging plays a critical role in preclinical studies aimed at evaluating drug safety and treatment response. In this study, we engineered an imaging platform capable of targeting different tumor biomarkers using a multi-colored library of nanoprobes. These probes contain rare-earth elements that emit light in the short-wave infrared (SWIR) wavelength region (900-1700 nm), which exhibits reduced absorption and scattering compared to visible and NIR, and are rendered biocompatible by encapsulation in human serum albumin.

Shortwave Infrared-Emitting Theranostics for Breast Cancer Therapy Response Monitoring.

Therapeutic drug monitoring (TDM) in cancer, while imperative, has been challenging due to inter-patient variability in drug pharmacokinetics. Additionally, most pharmacokinetic monitoring is done by assessments of the drugs in plasma, which is not an accurate gauge for drug concentrations in target tumor tissue. There exists a critical need for therapy monitoring tools that can provide real-time feedback on drug efficacy at target site to enable alteration in treatment regimens early during cancer therapy.

Engineering Tumor-Targeting Nanoparticles as Vehicles for Precision Nanomedicine.

As a nascent and emerging field that holds great potential for precision oncology, nanotechnology has been envisioned to improve drug delivery and imaging capabilities through precise and efficient tumor targeting, safely sparing healthy normal tissue. In the clinic, nanoparticle formulations such as the first-generation Abraxane® in breast cancer, Doxil® for sarcoma, and Onivyde® for metastatic pancreatic cancer, have shown advancement in drug delivery while improving safety profiles. However, effective accumulation of nanoparticles at the tumor site is sub-optimal due to biological barriers that must be overcome.

Surface-Modified Shortwave-Infrared-Emitting Nanophotonic Reporters for Gene-Therapy Applications.

Gene therapy is emerging as the next generation of therapeutic modality with United States Food and Drug Administration approved gene-engineered therapy for cancer and a rare eye-related disorder, but the challenge of real-time monitoring of on-target therapy response remains. In this study, we have designed a theranostic nanoparticle composed of shortwave-infrared-emitting rare-earth-doped nanoparticles (RENPs) capable of delivering genetic cargo and of real-time response monitoring. We showed that the cationic coating of RENPs with branched polyethylenimine (PEI) does not have a significant impact on cellular toxicity, which can be further reduced by selectively modifying the surface characteristics of the PEI coating using counter-ions and expanding their potential applications in photothermal therapy.

Multiscale optical imaging of rare-earth-doped nanocomposites in a small animal model.

Rare-earth-doped nanocomposites have appealing optical properties for use as biomedical contrast agents, but few systems exist for imaging these materials. We describe the design and characterization of (i) a preclinical system for whole animal in vivo imaging and (ii) an integrated optical coherence tomography/confocal microscopy system for high-resolution imaging of ex vivo tissues. We demonstrate these systems by administering erbium-doped nanocomposites to a murine model of metastatic breast cancer.

Surveillance nanotechnology for multi-organ cancer metastases.

The identification and molecular profiling of early metastases remains a major challenge in cancer diagnostics and therapy. Most in vivo imaging methods fail to detect small cancerous lesions, a problem that is compounded by the distinct physical and biological barriers associated with different metastatic niches. Here, we show that intravenously injected rare-earth-doped albumin-encapsulated nanoparticles emitting short-wave infrared light (SWIR) can detect targeted metastatic lesions in vivo, allowing for the longitudinal tracking of multi-organ metastases.

Line-scanning confocal microscopy for high-resolution imaging of upconverting rare-earth-based contrast agents.

Rare-earth (RE) doped nanocomposites emit visible luminescence when illuminated with continuous wave near-infrared light, making them appealing candidates for use as contrast agents in biomedical imaging. However, the emission lifetime of these materials is much longer than the pixel dwell times used in scanning intravital microscopy. To overcome this limitation, we have developed a line-scanning confocal microscope for high-resolution, optically sectioned imaging of samples labeled with RE-based nanomaterials.

CXCR-4 Targeted, Short Wave Infrared (SWIR) Emitting Nanoprobes for Enhanced Deep Tissue Imaging and Micrometastatic Cancer Lesion Detection.

Realizing the promise of precision medicine in cancer therapy depends on identifying and tracking cancerous growths to maximize treatment options and improve patient outcomes. This goal of early detection remains unfulfilled by current clinical imaging techniques that fail to detect lesions due to their small size and suborgan localization. With proper probes, optical imaging techniques can overcome this by identifying the molecular phenotype of tumors at both macroscopic and microscopic scales.

Targeting tumor metastases: Drug delivery mechanisms and technologies.

Primary sites of tumor are the focal triggers of cancers, yet it is the subsequent metastasis events that cause the majority of the morbidity and mortality. Metastatic tumor cells exhibit a phenotype that differs from that of the parent cells, as they represent a resistant, invasive subpopulation of the original tumor, may have acquired additional genetic or epigenetic alterations under exposure to prior chemotherapeutic or radiotherapeutic treatments, and reside in a microenvironment differing from that of its origin. This combination of resistant phenotype and distal location make tracking and treating metastases particularly challenging.

Luminal breast cancer metastasis is dependent on estrogen signaling.

Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains.

Targeting the Transforming Growth Factor-beta pathway inhibits human basal-like breast cancer metastasis.

Background: Transforming Growth Factor beta (TGF-beta) plays an important role in tumor invasion and metastasis. We set out to investigate the possible clinical utility of TGF-beta antagonists in a human metastatic basal-like breast cancer model. We examined the effects of two types of the TGF-beta pathway antagonists (1D11, a mouse monoclonal pan-TGF-beta neutralizing antibody and LY2109761, a chemical inhibitor of TGF-beta type I and II receptor kinases) on sublines of basal cell-like MDA-MB-231 human breast carcinoma cells that preferentially metastasize to lungs (4175TR, 4173) or bones (SCP2TR, SCP25TR, 2860TR, 3847TR).

TGFbeta prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest.

TGFbeta mediates cell cycle arrest in late G(1) phase of the cell cycle with a simultaneous peak in the levels of the cyclin-dependent kinase inhibitor, p27(kip1) (p27). In this report, we show that whereas p27 resides in the cytoplasm in the endometrial carcinoma (ECA) cell line HEC-1A, TGFbeta increases the total levels and translocation of p27 into the nucleus. Concomitantly, TGFbeta activates the transcription factors Smad2 and Smad3, inhibits proliferation, and blocks Cdk2 activity; all these events are blocked by an inhibitor of TbetaRI serine kinase activity (SD208).

Alternative splicing and caspase-mediated cleavage generate antagonistic variants of the stress oncoprotein LEDGF/p75.

There is increasing evidence that an augmented state of cellular oxidative stress modulates the expression of stress genes implicated in diseases associated with health disparities such as certain cancers and diabetes. Lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 autoantigen, is emerging as a survival oncoprotein that promotes resistance to oxidative stress-induced cell death and chemotherapy. We previously showed that LEDGF/p75 is targeted by autoantibodies in prostate cancer patients and is overexpressed in prostate tumors, and that its stress survival activity is abrogated during apoptosis.

LEDGF/p75: a novel nuclear autoantigen at the crossroads of cell survival and apoptosis.

Intracellular autoantigens recognized by autoantibodies in systemic autoimmune and other chronic inflammatory disorders often undergo proteolytic cleavage during apoptosis. Cleaved autoantigens may display altered functions and higher immunogenicity, and could potentially elicit autoantibody responses under a pro-inflammatory environment. LEDGF/p75 (lens epithelium derived growth factor p75) is a ubiquitous nuclear autoantigen targeted by autoantibodies in subsets of patients with atopic disorders, mainly atopic dermatitis, and other inflammatory conditions involving dysregulated apoptosis.