Dominik J. Naczynski

Rare-earth-doped biological composites as in vivo shortwave infrared reporters

The extension of in vivo optical imaging for disease screening and image-guided surgical interventions requires brightly-emitting, tissue-specific materials that optically transmit through living tissue and can be imaged with portable systems that display data in real-time. Recent work suggests that a new window across the short wavelength infrared region can improve in vivo imaging sensitivity over near infrared light. Here we report on the first evidence of multispectral, real-time short wavelength infrared imaging offering anatomical resolution using brightly-emitting rare-earth nanomaterials and demonstrate their applicability toward disease-targeted imaging. Inorganic-protein nanocomposites of rare-earth nanomaterials with human serum albumin facilitated systemic biodistribution of the rare-earth nanomaterials resulting in the increased accumulation and retention in tumor tissue that was visualized by the localized enhancement of infrared signal intensity. Our findings lay the groundwork for a new generation of versatile, biomedical nanomaterials that can advance disease monitoring based on a pioneering infrared imaging technique.

Albumin nanoshell encapsulation of near-infrared-excitable rare-Earth nanoparticles enhances biocompatibility and enables targeted cell imaging.

The use of traditional fluorophores for in vivo imaging applications is limited by poor quantum yield, poor tissue penetration of the excitation light, and excessive tissue autofluorescence, while the use of inorganic fluorescent particles that offer a high quantum yield is frequently limited due to particle toxicity. Rare-earth-doped nanoparticles that utilize near-infrared upconversion overcome the optical limitations of traditional fluorophores, but are not typically suitable for biological application due to their insolubility in aqueous solution, lack of functional surface groups for conjugation of biomolecules, and potential cytotoxicity. A new approach to establish highly biocompatible and biologically targetable nanoshell complexes of luminescent rare-earth-doped NaYF(4) nanoparticles (REs) excitable with 920-980 nm near-infrared light for biomedical imaging applications is reported. The approach involves the encapsulation of NaYF(4) nanoparticles doped with Yb and Er within human serum albumin nanoshells to create water-dispersible, biologically functionalizable composite particles. These particles exhibit narrow size distributions around 200 nm and are stable in aqueous solution for over 4 weeks. The albumin shell confers cytoprotection and significantly enhances the biocompatibility of REs even at concentrations above 200 microg REs mL(-1). Composite particles conjugated with cyclic arginine-glycine-aspartic acid (cRGD) specifically target both human glioblastoma cell lines and melanoma cells expressing alpha(v)beta(3) integrin receptors. These findings highlight the promise of albumin-encapsulated rare-earth nanoparticles for imaging cancer cells in vitro and the potential for targeted imaging of disease sites in vivo.

Rare earth nanoprobes for functional biomolecular imaging and theranostics

Contrast agents designed to visualize the molecular mechanisms underlying cancer pathogenesis and progression have deepened our understanding of disease complexity and accelerated the development of enhanced drug strategies targeted to specific biochemical pathways. For the next generation probes and imaging systems to be viable, they must exhibit enhanced sensitivity and robust quantitation of morphologic and contrast features, while offering the ability to resolve the disease-specific molecular signatures that may be critical to reconstitute a more comprehensive portrait of pathobiology. This feature article provides an overview on the design and advancements of emerging biomedical optical probes in general and evaluates the promise of rare earth nanoprobes, in particular, for molecular imaging and theranostics. Combined with new breakthroughs in nanoscale probe configurations, and improved dopant compositions, and multimodal infrared optical imaging, rare-earth nanoprobes can be used to address a wide variety of biomedical challenges, including deep tissue imaging, real-time drug delivery tracking and multispectral molecular profiling.

X-ray-induced shortwave infrared biomedical imaging using rare-earth nanoprobes.

Shortwave infrared (SWIR or NIR-II) light provides significant advantages for imaging biological structures due to reduced autofluorescence and photon scattering. Here, we report on the development of rare-earth nanoprobes that exhibit SWIR luminescence following X-ray irradiation. We demonstrate the ability of X-ray-induced SWIR luminescence (X-IR) to monitor biodistribution and map lymphatic drainage. Our results indicate X-IR imaging is a promising new modality for preclinical applications and has potential for dual-modality molecular disease imaging.

Multifunctional Albumin Nanoparticles As Combination Drug Carriers for Intra-Tumoral Chemotherapy

Current cancer therapies are challenged by weakly soluble drugs and by drug combinations that exhibit non-uniform biodistribution and poor bioavailability. In this study, we have presented a new platform of advanced healthcare materials based on albumin nanoparticles (ANPs) engineered as tumor penetrating, delivery vehicles of combinatorially applied factors to solid tumors. These materials were designed to overcome three sequential key barriers: tissue level transport across solid tumor matrix; uptake kinetics into individual cancer cells; therapeutic resistance to single chemotherapeutic drugs. The ANPs were designed to penetrate deeper into solid tumor matrices using collagenase decoration and evaluated using a three-dimensional multicellular melanoma tumor spheroid model. Collagenase modified ANPs exhibited 1-2 orders of magnitude greater tumor penetration than unmodified ANPs into the spheroid mass after 96 hours, and showed preferential uptake into individual cancer cells for smaller sized ANPs (<100 nm). For enhanced efficacy, collagenase coated ANPs were modified with two therapeutic agents, curcumin and riluzole, with complementary mechanisms of action for combined cell cycle arrest and apoptosis in melanoma. The collagenase coated, drug loaded nanoparticles induced significantly more cell death within 3-D tumor models than the unmodified, dual drug loaded ANP particles and the kinetics of cytotoxicity was further influenced by the ANP size. Thus, multifunctional nanoparticles can be imbued with complementary size and protease activity features that allow them to penetrate solid tumors and deliver combinatorial therapeutic payload with enhanced cancer cytotoxicity but minimal collateral damage to healthy primary cells.

Engineering the Design of Brightly-Emitting Luminescent Nanostructured Photonic Composite Systems

Rare-earth doped infrared emitting composites have extensive applications in integrated optical devices such as fibre amplifiers and waveguides for telecommunications, remote sensing, and optoelectronics. In addition, recent advancements in infrared optical imaging systems have expanded the biomedical applications for infrared-emitting composites in diagnosis and imaging of living tissue systems both in vitro and in vivo. Composite systems combine the advantages of polymers (light weight, flexibility, good impact resistance, improved biomedical compatibility, and excellent processability) and inorganic phosphor host materials (low phonon energy, intense emissions, chemical durability, and high thermal stability). This paper provides a brief review of our research progress in the design and synthesis of luminescent photonic nanocomposite systems comprised of rare-earth doped particulates dispersed in a continuous polymeric matrix. The design of brightly-emitting rare-earth doped materials and the influence of host and dopant chemistries on the emission properties are discussed. Methods used to assess and measure the phosphors’ performance are also evaluated in this work. This paper will also examine the solvothermal synthesis method used to control the physical and chemical characteristics of the rare-earth doped particles, and how these characteristics impact the infrared optical properties. Also presented here are recent advances reported with luminescent nanocomposite systems fabricated for optical waveguides and biomedical imaging.

Monitoring external beam radiotherapy using real‐time beam visualization

PURPOSE To characterize the performance of a novel radiation therapy monitoring technique that utilizes a flexible scintillating film, common optical detectors, and image processing algorithms for real-time beam visualization (RT-BV). METHODS Scintillating films were formed by mixing Gd2O2S:Tb (GOS) with silicone and casting the mixture at room temperature. The films were placed in the path of therapeutic beams generated by medical linear accelerators (LINAC). The emitted light was subsequently captured using a CMOS digital camera. Image processing algorithms were used to extract the intensity, shape, and location of the radiation field at various beam energies, dose rates, and collimator locations. The measurement results were compared with known collimator settings to validate the performance of the imaging system. RESULTS The RT-BV system achieved a sufficient contrast-to-noise ratio to enable real-time monitoring of the LINAC beam at 20 fps with normal ambient lighting in the LINAC room. The RT-BV system successfully identified collimator movements with sub-millimeter resolution. CONCLUSIONS The RT-BV system is capable of localizing radiation therapy beams with sub-millimeter precision and tracking beam movement at video-rate exposure.

Endoscopic detection of cancer with lensless radioluminescence imaging and machine vision.

Complete removal of residual tumor tissue during surgical resection improves patient outcomes. However, it is often difficult for surgeons to delineate the tumor beyond its visible boundary. This has led to the development of intraoperative detectors that can image radiotracers accumulated within tumors, thus facilitating the removal of residual tumor tissue during surgical procedures. We introduce a beta imaging system that converts the beta radiation from the radiotracer into photons close to the decay origin through a CdWO4 scintillator and does not use any optical elements. The signal is relayed onto an EMCCD chip through a wound imaging fiber. The sensitivity of the device allows imaging of activity down to 100 nCi and the system has a resolution of at least 500 μm with a field of view of 4.80 × 6.51 mm. Advances in handheld beta cameras have focused on hardware improvements, but we apply machine vision to the recorded images to extract more information. We automatically classify sample regions in human renal cancer tissue ex-vivo into tumor or benign tissue based on image features. Machine vision boosts the ability of our system to distinguish tumor from healthy tissue by a factor of 9 ± 3 and can be applied to other beta imaging probes.

Rare-Earth-Doped Nanoparticles for Short-Wave Infrared Fluorescence Bioimaging and Molecular Targeting of αVβ3-Expressing Tumors

The use of short-wave infrared (SWIR) light for fluorescence bioimaging offers the advantage of reduced photon scattering and improved tissue penetration compared to traditional shorter wavelength imaging approaches. While several nanomaterials have been shown capable of generating SWIR emissions, rare-earth-doped nanoparticles (REs) have emerged as an exceptionally bright and biocompatible class of SWIR emitters. Here, we demonstrate SWIR imaging of REs for several applications, including lymphatic mapping, real-time monitoring of probe biodistribution, and molecular targeting of the αvβ3 integrin in a tumor model. We further quantified the resolution and depth penetration limits of SWIR light emitted by REs in a customized imaging unit engineered for SWIR imaging of live small animals. Our results indicate that SWIR light has broad utility for preclinical biomedical imaging and demonstrates the potential for molecular imaging using targeted REs.

Automating quality assurance of digital linear accelerators using a radioluminescent phosphor coated phantom and optical imaging.

Performing mechanical and geometric quality assurance (QA) tests for medical linear accelerators (LINAC) is a predominantly manual process that consumes significant time and resources. In order to alleviate this burden this study proposes a novel strategy to automate the process of performing these tests. The autonomous QA system consists of three parts: (1) a customized phantom coated with radioluminescent material; (2) an optical imaging system capable of visualizing the incidence of the radiation beam, light field or lasers on the phantom; and (3) software to process the captured signals. The radioluminescent phantom, which enables visualization of the radiation beam on the same surface as the light field and lasers, is placed on the couch and imaged while a predefined treatment plan is delivered from the LINAC. The captured images are then processed to self-calibrate the system and perform measurements for evaluating light field/radiation coincidence, jaw position indicators, cross-hair centering, treatment couch position indicators and localizing laser alignment. System accuracy is probed by intentionally introducing errors and by comparing with current clinical methods. The accuracy of self-calibration is evaluated by examining measurement repeatability under fixed and variable phantom setups. The integrated system was able to automatically collect, analyze and report the results for the mechanical alignment tests specified by TG-142. The average difference between introduced and measured errors was 0.13 mm. The system was shown to be consistent with current techniques. Measurement variability increased slightly from 0.1 mm to 0.2 mm when the phantom setup was varied, but no significant difference in the mean measurement value was detected. Total measurement time was less than 10 minutes for all tests as a result of automation. The systems unique features of a phosphor-coated phantom and fully automated, operator independent self-calibration offer the potential to streamline the QA process for modern LINACs.