Evans Blue Attachment Enhances Somatostatin Receptor Subtype-2 Imaging and Radiotherapy

Abstract

Purpose: Radionuclide therapy directed against tumors that express somatostatin receptors (SSTRs) has proven effective for the treatment of advanced, low- to intermediate-grade neuroendocrine tumors in the clinic. In clinical usage, somatostatin peptide-based analogs, labeled with therapeutic radionuclides, provide an overall response rate of about 30%, despite the high cumulative activity injected per patient. We set out to improve the effectiveness of somatostatin radiotherapy by preparing a chemical analog that would clear more slowly through the urinary tract and, concomitantly, have increased blood circulation half-life and higher targeted accumulation in the tumors. Experimental Design: We conjugated a common, clinically-used SST peptide derivative, DOTA-octreotate, to an Evans blue analog (EB), which reversibly binds to circulating serum albumin. The resulting molecule was used to chelate 86Y and 90Y, a diagnostic and a therapeutic radionuclide, respectively. The imaging capabilities and the radiotherapeutic efficacy of the resulting radioligand was evaluated in HCT116/SSTR2, HCT116, and AR42J cell lines that express differing levels of SST2 receptors. Results: The synthesized radiopharmaceutical retained affinity and specificity to SSTR2. The new molecule also retained the high internalization rate of DOTA-octreotate, and therefore, showed significantly higher accumulation in SSTR2-positive tumors. Labeling of our novel EB-octreotate derivative with the therapeutic, pure beta emitter, 90Y, resulted in improved tumor response and survival rates of mice bearing SSTR2 xenografts and had long term efficacy when compared to DOTA-octreotate itself. Conclusions: The coupling of a targeted peptide, a therapeutic radionuclide, and the EB‑based albumin binding provides for effective treatment of SSTR2-containing tumors.

Repurposing Cyanine NIR‐I Dyes Accelerates Clinical Translation of Near‐Infrared‐II (NIR‐II) Bioimaging

“…Animal hematology testing of complete blood counts from mice injected with IR‐12N3 at 24 h p.i. indicated the normal level of all measured blood cell subtypes compared with the reported healthy mice (Table S3, Supporting Information) . Pathology analysis by H&E staining indicated no morphological changes in all the tested organs (Figure S9, Supporting Information).…”

Ultrasmall Quantum Dots with Broad‐Spectrum Metal Doping Ability for Trimodal Molecular Imaging

“…Time–activity curves (TACs) drawn over the tumors showed that radiolabeled Ag 2 Se@Mn@TATE in SSTR2 + tumor xenografts had much higher accumulation than both the control agent in SSTR2 + and Ag 2 Se@Mn@TATE in SSTR2 − tumors. The Ag 2 Se@Mn‐ 64 Cu@TATE reached 10%ID g −1 at 4 h time point in AR42J tumor (Figure b), which was comparable to that of radiolabeled DOTA‐TATE in the same tumor model . By contrast, Ag 2 Se@Mn‐ 64 Cu@TATE in SSTR2 − tumor mice and Ag 2 Se@Mn‐ 64 Cu in SSTR2 + tumor mice showed minimal uptake (≈2%ID g −1 at 4 h p.i.).…”

“…The body weight results were similar between the control and Ag 2 Se@Mn QDs treated groups (Figure S11, Supporting Information). At 24 h p.i., the animal blood samples were collected for hematology test and serum biochemistry analysis, and all the percentages of cell subgroups and serum biochemistry levels were in the normal range (Table S2, Supporting Information) . Pathology analysis by hematoxylin and eosin (H&E) staining indicated no morphological changes in all the tested organs (Figure S12, Supporting Information).…”

“…We next explored the conjugation parameters and condition that could facilitate trimodal molecular imaging based on Ag 2 Se@Mn QDs . We first conjugated them with TATE peptide to specifically target to somatostatin receptor subtype‐2 (SSTR2), which is overexpressed in neuroendocrine tumors (NETs) . Then we performed the fluorescence imaging with the TATE conjugated Ag 2 Se@Mn (Ag 2 Se@Mn@TATE) in vitro (AR42J cells) and in vivo (AR42J tumor‐bearing mice).…”

“Albumin Hitchhiking” with an Evans Blue Analog for Cancer Theranostics

“…In this issue of Theranostics, Chen and colleagues reported the use of an Evans blue analog (EB) for albumin hitchhiking to improve both the PET imaging performance and therapeutic efficacy of radiolabeled TATE in several animal tumor models, targeting SSTR2 5 . Both the imaging and therapy results in these animal tumor models are very exciting, which could have significant clinical impact in the near future, once they are translated into the clinic.…”