X-ray and MR contrast bearing nanoparticles enhance the therapeutic response of image-guided radiation therapy for oral cancer

INTRODUCTION: Radiation therapy for head and neck squamous cell carcinoma is constrained by radiotoxicity to normal tissue. We demonstrate 100 nm theranostic nanoparticles for image-guided radiation therapy planning and enhancement in rat head and neck squamous cell carcinoma models. METHODS: PEG conjugated theranostic nanoparticles comprising of Au nanorods coated with Gadolinium oxide layers were tested for radiation therapy enhancement in 2D cultures of OSC-19-GFP-luc cells, and orthotopic tongue xenografts in male immunocompromised Salt sensitive or SS rats via both intratumoral and intravenous delivery. The radiation therapy enhancement mechanism was investigated. RESULTS: Theranostic nanoparticles demonstrated both X-ray/magnetic resonance contrast in a dose-dependent manner. Magnetic resonance images depicted optimal tumor-to-background uptake at 4 h post injection. Theranostic nanoparticle + Radiation treated rats experienced reduced tumor growth compared to controls, and reduction in lung metastasis. CONCLUSIONS: Theranostic nanoparticles enable preprocedure radiotherapy planning, as well as enhance radiation treatment efficacy for head and neck tumors

Functionalized multiwalled carbon nanotubes as ultrasound contrast agents

Ultrasonography is a fundamental diagnostic imaging tool in everyday clinical practice. Here, we are unique in describing the use of functionalized multiwalled carbon nanotubes (MWCNTs) as hyperechogenic material, suggesting their potential application as ultrasound contrast agents. Initially, we carried out a thorough investigation to assess the echogenic property of the nanotubes in vitro. We demonstrated their long-lasting ultrasound contrast properties. We also showed that ultrasound signal of functionalized MWCNTs is higher than graphene oxide, pristine MWCNTs, and functionalized single-walled CNTs. Qualitatively, the ultrasound signal of CNTs was equal to that of sulfur hexafluoride (SonoVue), a commercially available contrast agent. Then, we found that MWCNTs were highly echogenic in liver and heart through ex vivo experiments using pig as an animal model. In contrast to the majority of ultrasound contrast agents, we observed in a phantom bladder that the tubes can be visualized within a wide variety of frequencies (i.e., 5.5–10 MHz) and 12.5 MHz using tissue harmonic imaging modality. Finally, we demonstrated in vivo in the pig bladder that MWCNTs can be observed at low frequencies, which are appropriate for abdominal organs. Importantly, we did not report any toxicity of CNTs after 7 d from the injection by animal autopsy, organ histology and immunostaining, blood count, and chemical profile. Our results reveal the enormous potential of CNTs as ultrasound contrast agents, giving support for their future applications as theranostic nanoparticles, combining diagnostic and therapeutic modalities

Nanomedical Theranostics in Cardiovascular Disease

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. New diagnostic and therapeutic strategies are needed to mitigate this public health issue. Advances in nanotechnology have generated innovative strategies for diagnosis and therapy in a variety of diseases, foremost in cancer. Based on these studies, a novel concept referred to as nanomedical theranostics, or the combinatory application of nanoparticulate agents to allow diagnostic therapy, is being explored to enable image-guided, personalized, or targeted treatment. Preclinically, theranostics have been gradually applied to CVD with several interesting and encouraging findings. This article summarizes studies and challenges of nanotheranostic strategies in CVD. It also evaluates nanotheranostic strategies that may potentially be utilized to benefit patients

Nanomaterials as Novel Cardiovascular Theranostics

Cardiovascular diseases (CVDs) are a group of conditions associated with heart and blood vessels and are considered the leading cause of death globally. Coronary heart disease, atherosclerosis, myocardial infarction represents the CVDs. Since CVDs are associated with a series of pathophysiological conditions with an alarming mortality and morbidity rate, early diagnosis and appropriate therapeutic approaches are critical for saving patients’ lives. Conventionally, diagnostic tools are employed to detect disease conditions, whereas therapeutic drug candidates are administered to mitigate diseases. However, the advent of nanotechnological platforms has revolutionized the current understanding of pathophysiology and therapeutic measures. The concept of combinatorial therapy using both diagnosis and therapeutics through a single platform is known as theranostics. Nano-based theranostics are widely used in cancer detection and treatment, as evident from pre-clinical and clinical studies. Nanotheranostics have gained considerable attention for the efficient management of CVDs. The differential physicochemical properties of engineered nanoparticles have been exploited for early diagnosis and therapy of atherosclerosis, myocardial infarction and aneurysms. Herein, we provided the information on the evolution of nano-based theranostics to detect and treat CVDs such as atherosclerosis, myocardial infarction, and angiogenesis. The review also aims to provide novel avenues on how nanotherapeutics’ trending concept could transform our conventional diagnostic and therapeutic tools in the near future

An endoscope with integrated transparent bioelectronics and theranostic nanoparticles for colon cancer treatment

The gastrointestinal tract is a challenging anatomical target for diagnostic and therapeutic procedures for bleeding, polyps and cancerous growths. Advanced endoscopes that combine imaging and therapies within the gastrointestinal tract provide an advantage over stand-alone diagnostic or therapeutic devices. However, current multimodal endoscopes lack the spatial resolution necessary to detect and treat small cancers and other abnormalities. Here we present a multifunctional endoscope-based interventional system that integrates transparent bioelectronics with theranostic nanoparticles, which are photoactivated within highly localized space near tumours or benign growths. These advanced electronics and nanoparticles collectively enable optical fluorescence-based mapping, electrical impedance and pH sensing, contact/temperature monitoring, radio frequency ablation and localized photo/chemotherapy, as the basis of a closed-loop solution for colon cancer treatment. In vitro, ex vivo and in vivo experiments highlight the utility of this technology for accurate detection, delineation and rapid targeted therapy of colon cancer or precancerous lesions.

Role of Superparamagnetic Iron Oxide (SPIO) Nanoparticles in MR Imaging

Nanotechnology is a scientific movement that has the potential to transform the diagnosis and treatment of disease in the 21st century. It offers many opportunities for enhanced diagnostic and therapeutic medicine against cancer and other diseases. Already, the special properties that result from the nanoscale size of quantum dots, metal colloids, superparamagnetic iron oxide (SPIO), and carbon-based nanostructures are reviewed and interpreted against a background of the structural and electronic detail that gives rise to their nanotechnologic behavior. The detection and treatment of cancer is emphasized, with special attention paid to the biologic targeting of the disease. The future of nanotechnology in cancer research and clinical practice is projected to focus on 'theranostic' nanoparticles that are both diagnostic and therapeutic by design. Superparamagnetic iron oxide (SPIO) nanoparticles are unique MR contrast agents and have a higher diagnostic accuracy for detecting metastatic lymph nodes than conventional MR studies. This review presents the impact of superparamagnetic iron oxide (SPIO) for detecting metastatic lymph nodes and also physiologic properties of SPIO, technical considerations and other potential applications of SPIO agents

Theranostics for Antiretroviral Biodistribution and Pharmacokinetics

RATIONALE: Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification, treatment and inevitable elimination of virus in cell and tissue compartments. By employing theranostics, antiretroviral drugs (ARVs) can be tracked in lymph nodes, gut, spleen and liver. Cellular viral reservoirs including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) along with subcellular endosomal structures can now be targeted for drug delivery bringing therapeutics to areas where virus replicates. The overarching idea rests in improving precision targeted ARV delivery. Bringing ART to anatomically privileged tissues can be visualized and confirmed through single photon emission computed tomography (SPECT) imaging facilitated by multimodal antiretroviral drug (ARV) nanoprobes. To deploy such technologies, we have successfully placed rilpivirine into a theranostic nano system, taking advantage of state of the art physical and chemical properties of nano-sized particles for maximal biodistribution to viral sites. This allowed measurements of optimal antiretroviral responses. To achieve this outcome, we made particles with combinations of bioimaging detectors and ARV deliverers. This platform, in future studies, will utilize LASER ART and HIV-1 excision payloads (for example, CRISPR Cas9) for the inevitable elimination of viral infection. Our overall goal is to facilitate long-acting slow effective release antiretroviral therapy (LASER ART) development. To this end, in a first step analysis we created “multimodal imaging theranostic nanoprobes” with the hydrophobic antiretroviral drug rilpivirine (RPV). These unique nanoprobes allowed combined bioimaging, drug pharmacokinetics and tissue biodistribution tests in animal models. Combination of SPECT/CT and MR imaging modalities resulted in a highly accurate and sensitive nanoprobe. Because of this combination, the imaging data acquired from these nanoprobes after administration in mice proved predictive of future drug pharmacokinetics and biodistribution. METHODS: 111Indium (111In) and Europium (Eu3+)-doped cobalt ferrite (CF) rilpivirine (RPV)-loaded (111InEuCF-RPV) nanoparticles were synthesized then fully characterized based on their size, shape and stability. The particles were tested in vitro for uptake, retention and antiretroviral efficacy in human monocyte-derived macrophages (MDMs) along with the intracellular location of particles. These were then used as platforms for nanoformulated drug biodistribution. For multimodal imaging and biodistribution studies; 111InEuCF-RPV, ultra-small lipid coated 177LuEuCF and NRPV particles were injected intravenously into mice at various concentrations of drug or radioisotope. One group was treated with ultra-small lipid-coated 177LuEuCF particles at ∼ 74 MBq (2000 μCi) to assess the effect of particle size on biodistribution. Drug levels were quantified in plasma and tissues by UPLC-MS/MS and cobalt levels were quantified by ICP-MS. Pearson’s correlations were used to assess the predicative potential of imaging data and future ARV biodistribution and pharmacokinetics. RESULTS: 111InEuCF-RPV particles were synthesized and were shown to be of consistent size and were stable in a variety of different media conditions for over a week. Physiochemical characterizations and TEM imaging confirmed the structure and components of the system were correct. Formed theranostic particles were shown to be non-toxic to MDMs and at high concentrations were much less cytotoxic than native RPV. Particles demonstrated excellent intracellular relaxivity values of r2 = 732.8 mM-1s-1 and thus served as excellent MRI contrast agents. Drug particles were detected in macrophage Rab compartments by dual fluorescence labeling. Replicate particles elicited sustained antiretroviral responses similar to nanoformulated RPV. After administration to Balb/c mice particles could be localized to the spleen, liver, as well as popliteal and axillary lymph nodes. Imaging showed that nanoparticles accumulated in the spleen over 5 days and gradually left the liver as confirmed by ex vivo autoradiographic imaging and gamma scintillation spectrometry. Imaging data acquired up to 5 days proved predicative of drug biodistribution and pharmacokinetics up to 28 days post administration. CONCLUSIONS: We conclude that this novel nano system can be used broadly for theranostic antiretroviral drug biodistribution. In particular, in the not so distant future, it will enable the merger of LASER ART with detection methods to realize the long term goal of improving patient outcomes by assessing where and to what levels antiretroviral drugs are delivered into viral compartments. The long term goals are to best prevent new infections, achieve viral elimination, and facilitate drug delivery to human immunodeficiency virus cell and tissue reservoirs

Theranostic nanoparticles enhance the response of glioblastomas to radiation

YesDespite considerable progress with our understanding of glioblastoma multiforme (GBM) and the precise delivery of radiotherapy, the prognosis for GBM patients is still unfavorable with tumor recurrence due to radioresistance being a major concern. We recently developed a cross-linked iron oxide nanoparticle conjugated to azademethylcolchicine (CLIO-ICT) to target and eradicate a subpopulation of quiescent cells, glioblastoma initiating cells (GICs), which could be a reason for radioresistance and tumor relapse. The purpose of our study was to investigate if CLIO-ICT has an additive therapeutic effect to enhance the response of GBMs to ionizing radiation. Methods: NSG™ mice bearing human GBMs and C57BL/6J mice bearing murine GBMs received CLIO-ICT, radiation, or combination treatment. The mice underwent pre- and post-treatment magnetic resonance imaging (MRI) scans, bioluminescence imaging (BLI), and histological analysis. Tumor nanoparticle enhancement, tumor flux, microvessel density, GIC, and apoptosis markers were compared between different groups using a one-way ANOVA and two-tailed Mann-Whitney test. Additional NSG™ mice underwent survival analyses with Kaplan–Meier curves and a log rank (Mantel–Cox) test. Results: At 2 weeks post-treatment, BLI and MRI scans revealed significant reduction in tumor size for CLIO-ICT plus radiation treated tumors compared to monotherapy or vehicle-treated tumors. Combining CLIO-ICT with radiation therapy significantly decreased microvessel density, decreased GICs, increased caspase-3 expression, and prolonged the survival of GBM-bearing mice. CLIO-ICT delivery to GBM could be monitored with MRI. and was not significantly different before and after radiation. There was no significant caspase-3 expression in normal brain at therapeutic doses of CLIO-ICT administered. Conclusion: Our data shows additive anti-tumor effects of CLIO-ICT nanoparticles in combination with radiotherapy. The combination therapy proposed here could potentially be a clinically translatable strategy for treating GBMs

Syndecan-1 tagged liposomes as a theranostic nanoparticle for pancreatic adenocarcinoma.

Theranostic nanoparticles are emerging as a novel mechanism for detecting and treating cancer. Due to the difficulties in detection and treatment of pancreatic cancer, these particles could serve within this unique niche. In this study, a Syndecan-1 ligand was utilized to increase tumor specificity of fluorescent dye encapsulated liposomes which were evaluated as a potential theranostic nanoparticle for pancreatic adenocarcinoma. Their diagnostic capabilities and specificity to pancreatic adenocarcinoma were determined in vitro using immunocytochemistry and in vivo using multi-spectral optoacoustic tomography (MSOT). Immunocytochemistry showed that liposomes preferentially bound and released their contents into cells expressing high levels of Insulin-Like Growth Factor 1 Receptor. In an orthotopic pancreatic cancer mouse model, the liposomes preferentially targeted the pancreatic tumor with little off-target binding in the liver and spleen. Peak accumulation of the liposomes in the tumor occurred at 8 h post-injection. MSOT imaging was able to provide high-resolution 3D images of the tumor and liposome location. Ex vivo analysis showed that non-targeted liposomes accumulated in the liver suggesting that specificity of the liposomes for pancreatic adenocarcinoma was due to the presence of the Syndecan-1 ligand. Syndecan-1 tagged liposomes specifically target pancreatic adenocarcinoma both in vitro and in vivo. Once bound, the liposomes released the dye in vitro as indicated by red fluorescence of DNA-bound propidium iodide. The therapeutic drug-delivering capabilities of Syndecan-1 liposomes remain to be tested