Concise review: Nanoparticles and cellular carriers-allies in cancer imaging and cellular gene therapy?

Ineffective treatment and poor patient management continue to plague the arena of clinical oncology. The crucial issues include inadequate treatment efficacy due to ineffective targeting of cancer deposits, systemic toxicities, suboptimal cancer detection and disease monitoring. This has led to the quest for clinically relevant, innovative multifaceted solutions such as development of targeted and traceable therapies. Mesenchymal stem cells (MSCs) have the intrinsic ability to “home” to growing tumors and are hypoimmunogenic. Therefore, these can be used as (a) “Trojan Horses” to deliver gene therapy directly into the tumors and (b) carriers of nanoparticles to allow cell tracking and simultaneous cancer detection. The camouflage of MSC carriers can potentially tackle the issues of safety, vector, and/or transgene immunogenicity as well as nanoparticle clearance and toxicity. The versatility of the nanotechnology platform could allow cellular tracking using single or multimodal imaging modalities. Toward that end, noninvasive magnetic resonance imaging (MRI) is fast becoming a clinical favorite, though there is scope for improvement in its accuracy and sensitivity. In that, use of superparamagnetic iron-oxide nanoparticles (SPION) as MRI contrast enhancers may be the best option for tracking therapeutic MSC. The prospects and consequences of synergistic approaches using MSC carriers, gene therapy, and SPION in developing cancer diagnostics and therapeutics are discussed. STEM CELLS 2010; 28:1686–1702

Characterization of an Orthotopic Rat Model of Glioblastoma Using Multiparametric Magnetic Resonance Imaging and Bioluminescence Imaging

Glioblastoma multiforme (GBM) is a lethal and incurable disease. The C6 rat model of GBM shares several similarities to human GBM and longitudinal non-invasive imaging may allow tumour features to be studied. In this thesis, a multimodality imaging framework, consisting of bioluminescence imaging (BLI) and multiparametric magnetic resonance imaging (mpMRI), was applied to the C6 rat model to characterize the growth of orthotopic tumours. BLI signal, a measure of cell viability, tended to increase and then decrease in the majority of animals, whereas tumour volume (from MRI) continually increased. Cellular viability and tumour volume did not correlate across all days, highlighting the value of using complimentary imaging modalities. Apparent diffusion coefficient maps and immunohistochemistry suggests decreases in BLI signal are in part due to decreased tumour cellularity (i.e. necrosis). This is the first use of BLI and mpMRI to characterize this model, and highlights the inter-subject variability in tumour growth

Iron Labeling and Pre-Clinical MRI Visualization of Therapeutic Human Neural Stem Cells in a Murine Glioma Model

Treatment strategies for the highly invasive brain tumor, glioblastoma multiforme, require that cells which have invaded into the surrounding brain be specifically targeted. The inherent tumor-tropism of neural stem cells (NSCs) to primary and invasive tumor foci can be exploited to deliver therapeutics to invasive brain tumor cells in humans. Use of the strategy of converting prodrug to drug via therapeutic transgenes delivered by immortalized therapeutic NSC lines have shown efficacy in animal models. Thus therapeutic NSCs are being proposed for use in human brain tumor clinical trials. In the context of NSC-based therapies, MRI can be used both to non-invasively follow dynamic spatio-temporal patterns of the NSC tumor targeting allowing for the optimization of treatment strategies and to assess efficacy of the therapy. Iron-labeling of cells allows their presence to be visualized and tracked by MRI. Thus we aimed to iron-label therapeutic NSCs without affecting their cellular physiology using a method likely to gain United States Federal Drug Administration (FDA) approval.For human use, the characteristics of therapeutic Neural Stem Cells must be clearly defined with any pertubation to the cell including iron labeling requiring reanalysis of cellular physiology. Here, we studied the effect of iron-loading of the therapeutic NSCs, with ferumoxide-protamine sulfate complex (FE-Pro) on viability, proliferation, migratory properties and transgene expression, when compared to non-labeled cells. FE-Pro labeled NSCs were imaged by MRI at tumor sites, after intracranial administration into the hemisphere contralateral to the tumor, in an orthotopic human glioma xenograft mouse model.FE-Pro labeled NSCs retain their proliferative status, tumor tropism, and maintain stem cell character, while allowing in vivo cellular MRI tracking at 7 Tesla, to monitor their real-time migration and distribution at brain tumor sites. Of significance, this work directly supports the use of FE-Pro-labeled NSCs for real-time tracking in the clinical trial under development: "A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically modified Neural Stem Cells Expressing Escherichia coli Cytosine Deaminase for Treatment of Recurrent High-Grade Gliomas"

Exploring Brain-Derived Progenitor Cells as a therapeutic delivery system to Glioblastoma

Glioblastoma (GBM) is a devastating incurable malignant brain cancer in need of new treatments. We have begun to investigate the feasibility of a primary adult cell type (Brain-Derived Progenitor Cells, BDPCs) as a novel therapeutic delivery system to GBM. Our objective was to track the viability of BDPCs after intratumoral infusion into syngeneic orthotopic rat GBM tumours using non-invasive bioluminescence imaging (BLI). We hypothesize rat BDPCs will survive greater than 1 week following infusion into orthotopic F98 GBM tumors. BDPCs harvested from the cortex of adult Fischer rats were expanded in culture then engineered to co-express firefly Luciferase for BLI as well as the fluorescence protein tdTomato. In vitro assays displayed consistent lentiviral engineering of transgenes as well as statistically significant GBM-homing by BDPCs (p \u3c 0.01). All animals showed in vivo BLI signal until the study’s endpoint, confirming viable BDPCs were still present. Histological examination revealed small numbers of fluorescent BDPCs at the tumours’ invading edges in frozen coronal sections

Diffuse Intrinsic Pontine Glioma

Diffuse intrinsic pontine glioma (DIPG) is a leading cause of brain cancer-related death in children. These aggressive high-grade gliomas cannot be effectively treated and are associated with dismal prognosis. Whilst radiation therapy (RT) prolongs survival, it is a palliative therapy, as half of children with DIPG die within 1 year of diagnosis and almost all are dead by 2 years. These statistics have not changed for decades, despite a multitude of clinical trials. No chemotherapeutic regimen has been shown to improve survival, emphasizing the need to find novel and effective treatments. One of the principal reasons for this poor outcome was our limited knowledge of the biology of DIPG’s. Due to their location in brainstem, surgical resection is not feasible and up until recently, even performing a limited biopsy was considered too dangerous. In the last decade, DIPG tumor tissue has become available through autopsies and biopsies. This combined with the genome revolution has resulted in a transformation in our understanding of the underlying biology of this disease. Moreover, viable DIPG cells can now be grown in the laboratory which have allowed development of in-vitro (neurospheres) and in-vivo models (allograft and xenograft). This chapter summarizes recent advances in DIPG and potential novel therapies

Accomplishments and challenges in stem cell imaging in vivo.

Stem cell therapies have demonstrated promising preclinical results, but very few applications have reached the clinic owing to safety and efficacy concerns. Translation would benefit greatly if stem cell survival, distribution and function could be assessed in vivo post-transplantation, particularly in patients. Advances in molecular imaging have led to extraordinary progress, with several strategies being deployed to understand the fate of stem cells in vivo using magnetic resonance, scintigraphy, PET, ultrasound and optical imaging. Here, we review the recent advances, challenges and future perspectives and opportunities in stem cell tracking and functional assessment, as well as the advantages and challenges of each imaging approach

Magnetic Fields and Cancer: Epidemiology, Cellular Biology, and Theranostics

Humans are exposed to a complex mix of man-made electric and magnetic fields (MFs) at many different frequencies, at home and at work. Epidemiological studies indicate that there is a positive relationship between residential/domestic and occupational exposure to extremely low frequency electromagnetic fields and some types of cancer, although some other studies indicate no relationship. In this review, after an introduction on the MF definition and a description of natural/anthropogenic sources, the epidemiology of residential/domestic and occupational exposure to MFs and cancer is reviewed, with reference to leukemia, brain, and breast cancer. The in vivo and in vitro effects of MFs on cancer are reviewed considering both human and animal cells, with particular reference to the involvement of reactive oxygen species (ROS). MF application on cancer diagnostic and therapy (theranostic) are also reviewed by describing the use of different magnetic resonance imaging (MRI) applications for the detection of several cancers. Finally, the use of magnetic nanoparticles is described in terms of treatment of cancer by nanomedical applications for the precise delivery of anticancer drugs, nanosurgery by magnetomechanic methods, and selective killing of cancer cells by magnetic hyperthermia. The supplementary tables provide quantitative data and methodologies in epidemiological and cell biology studies. Although scientists do not generally agree that there is a cause-effect relationship between exposure to MF and cancer, MFs might not be the direct cause of cancer but may contribute to produce ROS and generate oxidative stress, which could trigger or enhance the expression of oncogenes

The Era of Radiogenomics in Precision Medicine: An Emerging Approach to Support Diagnosis, Treatment Decisions, and Prognostication in Oncology

With the rapid development of new technologies, including artificial intelligence and genome sequencing, radiogenomics has emerged as a state-of-the-art science in the field of individualized medicine. Radiogenomics combines a large volume of quantitative data extracted from medical images with individual genomic phenotypes and constructs a prediction model through deep learning to stratify patients, guide therapeutic strategies, and evaluate clinical outcomes. Recent studies of various types of tumors demonstrate the predictive value of radiogenomics. And some of the issues in the radiogenomic analysis and the solutions from prior works are presented. Although the workflow criteria and international agreed guidelines for statistical methods need to be confirmed, radiogenomics represents a repeatable and cost-effective approach for the detection of continuous changes and is a promising surrogate for invasive interventions. Therefore, radiogenomics could facilitate computer-aided diagnosis, treatment, and prediction of the prognosis in patients with tumors in the routine clinical setting. Here, we summarize the integrated process of radiogenomics and introduce the crucial strategies and statistical algorithms involved in current studies