Folate-Targeted Surface-Enhanced Resonance Raman Scattering Nanoprobe Ratiometry for Detection of Microscopic Ovarian Cancer

Ovarian cancer has a unique pattern of metastatic spread, in that it initially spreads locally within the peritoneal cavity. This is in contrast to most other cancer types, which metastasize early on <i>via</i> the bloodstream to distant sites. This unique behavior opens up an opportunity for local application of both therapeutic and imaging agents. Upon initial diagnosis, 75% of patients already present with diffuse peritoneal spread involving abdominal organs. Complete resection of all tumor implants has been shown to be a major factor for improved survival. Unfortunately, it is currently not possible for surgeons to visualize microscopic implants, impeding their removal and leading to tumor recurrences and poor outcomes in most patients. Thus, there is a great need for new intraoperative imaging techniques that can overcome this hurdle. We devised a method that employs folate receptor (FR)-targeted surface-enhanced resonance Raman scattering (SERRS) nanoparticles (NPs), as folate receptors are typically overexpressed in ovarian cancer. We report a robust ratiometric imaging approach using anti-FR-SERRS-NPs (αFR-NPs) and nontargeted SERRS-NPs (nt-NPs) multiplexing. We term this method “topically applied surface-enhanced resonance Raman ratiometric spectroscopy” (TAS3RS (“tasers”) for short). TAS3RS successfully enabled the detection of tumor lesions in a murine model of human ovarian adenocarcinoma regardless of their size or localization. Tumors as small as 370 μm were detected, as confirmed by bioluminescence imaging and histological staining. TAS3RS holds promise for intraoperative detection of microscopic residual tumors and could reduce recurrence rates in ovarian cancer and other diseases with peritoneal spread

Dynamic Magnetic Fields Remote-Control Apoptosis <i>via</i> Nanoparticle Rotation

The ability to control the movement of nanoparticles remotely and with high precision would have far-reaching implications in many areas of nanotechnology. We have designed a unique dynamic magnetic field (DMF) generator that can induce rotational movements of superparamagnetic iron oxide nanoparticles (SPIONs). We examined whether the rotational nanoparticle movement could be used for remote induction of cell death by injuring lysosomal membrane structures. We further hypothesized that the shear forces created by the generation of oscillatory torques (incomplete rotation) of SPIONs bound to lysosomal membranes would cause membrane permeabilization, lead to extravasation of lysosomal contents into the cytoplasm, and induce apoptosis. To this end, we covalently conjugated SPIONs with antibodies targeting the lysosomal protein marker LAMP1 (LAMP1-SPION). Remote activation of slow rotation of LAMP1-SPIONs significantly improved the efficacy of cellular internalization of the nanoparticles. LAMP1-SPIONs then preferentially accumulated along the membrane in lysosomes in both rat insulinoma tumor cells and human pancreatic beta cells due to binding of LAMP1-SPIONs to endogenous LAMP1. Further activation of torques by the LAMP1-SPIONs bound to lysosomes resulted in rapid decrease in size and number of lysosomes, attributable to tearing of the lysosomal membrane by the shear force of the rotationally activated LAMP1-SPIONs. This remote activation resulted in an increased expression of early and late apoptotic markers and impaired cell growth. Our findings suggest that DMF treatment of lysosome-targeted nanoparticles offers a noninvasive tool to induce apoptosis remotely and could serve as an important platform technology for a wide range of biomedical applications

Silica Nanoparticles as Substrates for Chelator-free Labeling of Oxophilic Radioisotopes

Chelator-free nanoparticles for intrinsic radiolabeling are highly desirable for whole-body imaging and therapeutic applications. Several reports have successfully demonstrated the principle of intrinsic radiolabeling. However, the work done to date has suffered from much of the same specificity issues as conventional molecular chelators, insofar as there is no singular nanoparticle substrate that has proven effective in binding a wide library of radiosotopes. Here we present amorphous silica nanoparticles as general substrates for chelator-free radiolabeling and demonstrate their ability to bind six medically relevant isotopes of various oxidation states with high radiochemical yield. We provide strong evidence that the stability of the binding correlates with the hardness of the radioisotope, corroborating the proposed operating principle. Intrinsically labeled silica nanoparticles prepared by this approach demonstrate excellent in vivo stability and efficacy in lymph node imaging

Imaging of Liver Tumors Using Surface-Enhanced Raman Scattering Nanoparticles

Complete surgical resection is the ideal first-line treatment for most liver malignancies. This goal would be facilitated by an intraoperative imaging method that enables more precise visualization of tumor margins and detection of otherwise invisible microscopic lesions. To this end, we synthesized silica-encapsulated surface-enhanced Raman scattering (SERS) nanoparticles (NPs) that act as a molecular imaging agent for liver malignancies. We hypothesized that, after intravenous administration, SERS NPs would avidly home to healthy liver tissue but not to intrahepatic malignancies. We tested these SERS NPs in genetically engineered mouse models of hepatocellular carcinoma and histiocytic sarcoma. After intravenous injection, liver tumors in both models were readily identifiable with Raman imaging. In addition, Raman imaging using SERS NPs enabled detection of microscopic lesions in liver and spleen. We compared the performance of SERS NPs to fluorescence imaging using indocyanine green (ICG). We found that SERS NPs delineate tumors more accurately and are less susceptible to photobleaching. Given the known advantages of SERS imaging, namely, high sensitivity and specific spectroscopic detection, these findings hold promise for improved resection of liver cancer