Search

Nanomedicines are considered next generation therapeutics with advanced therapeutic properties and reduced side effects. Herein, we introduce tailored linear and star-like water-soluble nanosystems as stimuli-sensitive nanomedicines for the treatment of solid tumors or hematological malignancies. The polymer carrier and drug pharmacokinetics were independently evaluated to elucidate the relationship between the nanosystem structure and its distribution in the body. Positron emission tomography and optical imaging demonstrated enhanced tumor accumulation of the polymer carriers in 4T1-bearing mice with increased tumor-to-blood and tumor-to-muscle ratios. Additionally, there was a significant accumulation of doxorubicin bound to various polymer carriers in EL4 tumors, as well as excellent in vivo therapeutic activity in EL4 lymphoma and moderate efficacy in 4T1 breast carcinoma. The linear nanomedicine showed at least comparable pharmacologic properties to the star-like nanomedicines regarding doxorubicin transport. Therefore, if multiple parameters are considered such as its optimized structure and simple and reproducible synthesis, this polymer carrier system is the most promising for further preclinical and clinical investigations.

The therapeutic potential of the Meitner-Auger- and conversion-electron emitting radionuclide 119Sb remains unexplored because of the difficulty of incorporating it into biologically targeted compounds. To address this challenge, we report the development of 119Sb production from electroplated tin cyclotron targets and its complexation by a novel trithiol chelate. The chelation reaction occurs in harsh solvent conditions even in the presence of large quantities of tin, which are necessary for production on small, low energy (16 MeV) cyclotrons. The 119Sb-trithiol complex has high stability and can be purified by HPLC. The third generation trithiol chelate and the analogous stable natSb-trithiol compound were synthesized and characterized, including by single-crystal X-ray diffraction analyses.

We report an extraction chromatography-based method via Actinide Resin for the isolation of radio- manganese from both natural chromium and isotopically enriched iron targets for cyclotron production of (52g)Mn and (51)Mn. For the separation of (52g)Mn from (Nat)Cr, a decay-corrected radiochemical yield of 83.7 ± 8.4% was achieved. For (51)Mn from (54)Fe, a decay-corrected radiochemical yield of 78 ± 11% was achieved. This automatable method efficiently isolates both radionuclides from accelerator target material.

During cerebral ischemia-reperfusion (I-R) injury, the infiltration of monocyte/macrophages (M

In breast cancer, the extracellular matrix (ECM) undergoes remodeling and changes the tumor microenvironment to support tumor progression and metastasis. Fibronectin (FN) assembly is an important step in the regulation of the tumor microenvironment since the FN matrix precedes the deposition of various other ECM proteins, controls immune cell infiltration, and serves as a reservoir for cytokines and growth factors. Therefore, FN is an attractive target for breast cancer therapy and imaging. Functional Upstream Domain (FUD) is a 6-kDa peptide targeting the N-terminal 70-kDa domain of FN, which is critical for fibrillogenesis. FUD has previously been shown to function as an anti-fibrotic peptide both in vitro and in vivo. In this work, we conjugated the FUD peptide with 20-kDa of PEG (PEG-FUD) and demonstrated its improved tumor exposure compared to non-PEGylated FUD in a murine breast cancer model via multiple imaging modalities. Importantly, PEG-FUD peptide retained a nanomolar binding affinity for FN and maintained in vitro plasma stability for up to 48 h. Cy5-labeled PEG-FUD bound to exogenous or endogenous FN assembled by fibroblasts. The in vivo fluorescence imaging with Cy5-labeled FUD and FUD conjugates demonstrated that PEGylation of the FUD peptide enhanced blood exposure after subcutaneous (SC) injection and significantly increased accumulation of FUD peptide in 4T1 mammary tumors. Intravital microscopy confirmed that Cy5-labeled PEG-FUD deposited mostly in the extravascular region of the tumor microenvironment after SC administration. Lastly, positron emission tomography/computed tomography imaging showed that (64)Cu-labeled PEG-FUD preferentially accumulated in the 4T1 tumors with improved tumor uptake compared to (64)Cu-labeled FUD (48 h: 1.35 ± 0.05 vs. 0.59 ± 0.03 %IA/g, P< 0.001) when injected intravenously (IV). The results indicate that PEG-FUD targets 4T1 breast cancer with enhanced tumor retention compared to non-PEGylated FUD, and biodistribution profiles of PEG-FUD after SC and IV injection may guide the optimization of PEG-FUD as a therapeutic and/or imaging agent for use in vivo.

INTRODUCTION: The radioisotopes of bromine are uniquely suitable radiolabels for small molecule theranostic radiopharmaceuticals but are of limited availability due to production challenges. Significantly improved methods were developed for the production and radiochemical isolation of clinical quality (76)Br, (77)Br, and (80m)Br. The radiochemical quality of the radiobromine produced using these methods was tested through the synthesis of a novel (77)Br-labeled inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), a DNA damage response protein. METHODS: (76)Br, (77)Br, and (80m)Br were produced in high radionuclidic purity via the proton irradiation of novel isotopically-enriched Co(76)Se, Co(77)Se, and Co(80)Se intermetallic targets, respectively. Radiobromine was isolated through thermal chromatographic distillation in a vertical furnace assembly. The (77)Br-labeled PARP inhibitor was synthesized via copper-mediated aryl boronic ester radiobromination. RESULTS: Cyclotron production yields were 103 ± 10 MBq∙μA(−1)∙h(−1) for 76Br, 88 ± 10 MBq∙μA(−1)∙h(−1) for (80m)Br at 16 MeV and 17 ± 1 MBq∙μA(−1)∙h(−1) for (77)Br at 13 MeV. Radiobromide isolation yields were 76 ± 11% in a small volume of aqueous solution. The synthesized (77)Br-labeled PARP-1 inhibitor had a measured apparent molar activity up to 700 GBq/μmol at end of synthesis. CONCLUSIONS: A novel selenium alloy target enabled clinical-scale production of (76)Br, (77)Br, and (80m)Br with high apparent molar activities, which was used to for the production of a new (77)Br-labeled inhibitor of PARP-1. ADVANCES IN KNOWLEDGE: New methods for the cyclotron production and isolation of radiobromine improved the production capacity of (77)Br by a factor of three and (76)Br by a factor of six compared with previous methods. IMPLICATIONS FOR PATIENT CARE: Preclinical translational research of 77Br-based Auger electron radiotherapeutics, such as those targeting PARP-1, will require the production of GBq-scale (77)Br, which necessitates next-generation, high-yielding, isotopically-enriched cyclotron targets, such as the novel intermetallic Co(77)Se.

We report a novel, precipitation-based method for the isolation of Mn from Cr targets for cyclotron production of 52gMn. The separation produces no-carrier-added 52gMn with a decay corrected radiochemical yield of 85 ± 3% and apparent molar activity for DOTA of 1.3 GBq/μmol. This method reduces stable metallic impurities in the purified 52gMn compared to previously reported chromatographic methods.

Targeted Radionuclide Therapies (TRTs) based on Auger emitting radionuclides have the potential to deliver extremely selective therapeutic payloads on the cellular level. However, to fully exploit this potential, suitable radionuclides need to be applied in combination with appropriate delivery systems. In this review, we summarize the state-of-the-art production, purification, chelation and applications of two promising candidates for Targeted Auger Therapy, namely antimony- 119 (119Sb) and mercury-197 (197Hg). Both radionuclides have great potential to become efficient tools for TRT. We also highlight our current progress on the production of both radionuclides at TRIUMF and the University of Wisconsin.

We report the first targeted nuclear medicine application of the lanthanum radionuclides (132/135)La. These isotopes represent a matched pair for diagnosis via the positron emissions of (132)La and therapy mediated by the Auger electron emissions of (135)La. We identify two effective chelators, known as DO3Apic and macropa, for these radionuclides. The 18-membered macrocycle, macropa, bound (132/135)La with superior molar activity than DO3Apic under similar conditions. These chelators were conjugated to the prostate-specific membrane antigen (PSMA)-targeting agent DUPA to assess the use of radiolanthanum for in vivo imaging. The (132/135)La-labeled targeted constructs showed high uptake in tumor xenografts expressing PSMA. This study validates the use of these radioactive lanthanum isotopes for imaging applications and motivates future work to assess the therapeutic effects of the Auger electron emissions of (135)La.

The small-cavity, bifunctional chelator picaga coordinates Sc-44 at room temperature and enables PET imaging of an in vivo tumor target., Scandium-44 has emerged as an attractive, novel PET radioisotope with ideal emission properties and half-life (t1/2 = 3.97 h, Emean β+ = 632 keV) well matched to the pharmacokinetics of small molecules, peptides and small biologics. Conjugates of the current gold-standard chelator for 44Sc, 1,4,7,10-tetraaza-cyclododecane-1,4,7,10-tetraacetic acid (DOTA), require heating to achieve radiochemical complexation, limiting application of this isotope in conjunction with temperature-sensitive biologics. To establish Sc(iii) isotopes as broadly applicable tools for nuclear medicine, development of alternative bifunctional chelators is required. To address this need, we characterized the Sc(iii)-chelation properties of the small-cavity triaza-macrocycle-based, picolinate-functionalized chelator H3mpatcn. Spectroscopic and radiochemical studies establish the [Sc(mpatcn)] complex as kinetically inert and appropriate for biological applications. A proof-of-concept bifunctional conjugate targeting the prostate-specific membrane antigen (PSMA), picaga-DUPA, chelates 44Sc to form 44Sc(picaga)-DUPA at room temperature with an apparent molar activity of 60 MBq μmol–1 and formation of inert RRR-Λ and SSS-Δ-twist isomers. Sc(picaga)-DUPA exhibits a Ki of 1.6 nM for PSMA, comparable to the 18F-based imaging probe DCFPyL (Ki = 1.1 nM) currently in phase 3 clinical trials for imaging prostate cancer. Finally, we successfully employed 44Sc(picaga)-DUPA to image PSMA-expressing tumors in a preclinical mouse model, establishing the picaga bifunctional chelator as an optimal choice for the 44Sc PET nuclide.

The present study describes a novel method for the low energy cyclotron production and radiochemical isolation of no-carrier-added 132/135La3+ from bulk natBa. This separation strategy combines precipitation and single-column extraction chromatography to afford an overall radiochemical yield (92 ± 2%) and apparent molar activity (22 ± 4 Mbq/nmol) suitable for the radiolabeling of DOTA-conjugated vectors. The produced 132/135La3+ has a radiochemical and radionuclidic purity amenable for 132La/135La-based cancer theranostic applications. Longitudinal PET/CT images acquired using the positron-emitting 132La and ex vivo biodistribution data separately corroborated the accumulation of unchelated 132/135La3+ ions in bone and the liver.

We report a novel, precipitation-based method for the isolation of Mn from Cr targets for cyclotron production of

We demonstrate super-resolution chemical imaging with plasmonic nanoholes via surface-enhanced Raman spectroscopy (SERS). Due to large field enhancements, blinking behavior of SERS hot spots was observed and processed using a stochastic optical reconstruction microscopy (STORM) algorithm. This enabled localization to within 10 nm and high-resolution imaging. However, illumination of the sample with a static laser beam produced only SERS hot spots in fixed locations, leaving noticeable gaps in the final images. By randomly altering the phase profile of the incident beam with a simple optical diffuser, the hot spots were shifted across the plasmonic surface to illuminate different areas of the sample, thereby rendering a final image without the gaps. A tunable band-pass filter was used to preserve spectral information, allowing chemical contrast imaging. Images were then compared to those obtained with a scanning electron microscope. Finally, we show that super-resolution SERS images can also be obtained wi...

We show super-resolution chemical imaging with plasmonic nanoholes, Surface Enhanced Raman Spectroscopy and Stochastic Optical Reconstruction Microscopy. Spectral and spatial content are obtained simultaneously by imaging through filters or gratings.

We demonstrate dynamic placement of plasmonic “hotspots” for super-resolution chemical imaging via Surface Enhanced Raman Spectroscopy (SERS). A silver nanohole array surface was coated with biological samples and illuminated with a laser. Due to the large plasmonic field enhancements, blinking behavior of the SERS hotspots was observed and processed using a Stochastic Optical Reconstruction Microscopy (STORM) algorithm enabling localization to within 10 nm. However, illumination of the sample with a single static laser beam (i.e., a slightly defocused Gaussian beam) only produced SERS hotspots in fixed locations on the surface, leaving noticeable gaps in any final image. But, by using a spatial light modulator (SLM), the illumination profile of the beam could be altered, shifting any hotspots across the nanohole array surface in sub-wavelength steps. Therefore, by properly structuring an illuminating light field with the SLM, we show the possibility of positioning plasmonic hotspots over a metallic nanohole surface on-the-fly. Using this and our SERS-STORM imaging technique, we show potential for high-resolution chemical imaging without the noticeable gaps that were present with static laser illumination. Interestingly, even illuminating the surface with randomly shifting SLM phase profiles was sufficient to completely fill in a wide field of view for super-resolution SERS imaging of a single strand of 100-nm thick collagen protein fibrils. Images were then compared to those obtained with a scanning electron microscope (SEM). Additionally, we explored alternative methods of phase shifting other than holographic illumination through the SLM to create localization of hotspots necessary for SERS-STORM imaging.