Tumor-Targeting NIRF/MR Dual-Modal Molecular Imaging Probe for Surgery Navigation

Abstract

Multimodality imaging recognized as a promising monitoring strategy can serve the needs of accurate diagnosis and treatment of cancer by providing molecular and anatomic information about tumor sites. However, the probes based on multiple imaging modalities for surgery navigation remain limited due to poor biocompatibility and tumor targeting specificity. Herein, we present a small-molecule near-infrared fluorescence/magnetic resonance (NIRF/MR) imaging probe, Gd-NMC-3, covalently coupled with DCDSTCY and Gd-DOTA via butane diamine, for precise detection and intraoperative visualization. The in vitro and in vivo studies demonstrated that Gd-NMC-3 could be effectively accumulated in tumor sites as a bimodal imaging molecule exhibiting significant fluorescence accumulation and reasonable relaxation property in tumors with low cytotoxicity and good biocompatibility. Furthermore, Gd-NMC-3 was successfully applied to provide real-time visual navigation in LM3 orthotopic and subcutaneous tumor models to guide the resection of tumors. Importantly, no more fluorescence was observed in mice after operation, implying the total removal of tumor tissues. In conclusion, Gd-NMC-3 has great potential to be applied in the clinic based on its high resolution and sensitivity in tumor imaging.

PET/NIR Fluorescence Bimodal Imaging for Targeted Tumor Detection

“…To ensure the imaging quality and targeting ability, DOTA-NPC was designed as the cold precursor. The near-infrared fluorophore DCDSTCY was synthesized as described elsewhere and reacted with N -Boc-ethylenediamine through amide condensation, followed by removal of the protective group (Boc-) to obtain compound 2 . The chelating agent DOTA was combined with compound 2 to obtain the precursor DOTA-NPC (Supporting Information and Figures S1–S4).…”

“…39,40 Previous studies have described fluorescence dyes for highsensitivity tumor detection with long retention times. 18,19,41,42 We 30,43 and others 17,18 have reported ICG dye detection of human and mouse tumor with HCC-specific NIRF signals.…”

“…A synergistic combination of complementary PET and NIRF imaging signals could be used to improve perioperative tumor visualization. PET/NIRF bimodal imaging has been used to differentiate tumor and healthy tissue by concurrently linking an NIR fluorophore and radioisotope to an antibody − and polypeptide. , Previous studies have described fluorescence dyes for high-sensitivity tumor detection with long retention times. ,,, We , and others , have reported ICG dye detection of human and mouse tumor with HCC-specific NIRF signals. There have been few reports on colon cancer.…”

Design of Water–Soluble Rotaxane-Capped Superparamagnetic, Ultrasmall Fe3O4 Nanoparticles for Targeted NIR Fluorescence Imaging in Combination with Magnetic Resonance Imaging

“…13 However, integration of NIR-FL and MRI is advantageous because they do not require harmful high-energy ionizing radiation exposure and radioactive tracers like CT and PET or SPECT imaging, respectively, and could be a superior diagnostic device to determine both molecular and anatomical information. 4,14 There are some reports of multimodal imaging probes based on MRI contrast agents conjugated to organic dyes like rhodamine and naphthalimide; however, visible light is required to excite these fluorophores, as well as they suffer from low relaxivities. 15,16 Meade and co-workers have reported a multimodal imaging probe that comprises three Gd 3+ chelates tethered with a fluorescein residue that possesses high relaxivity and water solubility; however, its biological application is limited due to the low excitation wavelength of fluorescein.…”

“…A single imaging modality is unlikely to meet all of the criteria to resolve a precise diagnostic problem and is unable to provide comprehensive information. − Several efforts have been made to develop multimodal imaging agents based on amalgamation of suitable imaging modalities utilizing synergistic advantages to overcome the limitations of conventional single imaging methods. − The combinations of imaging techniques like PET/CT and PET/MRI are already in use for commercial imaging purposes . However, integration of NIR-FL and MRI is advantageous because they do not require harmful high-energy ionizing radiation exposure and radioactive tracers like CT and PET or SPECT imaging, respectively, and could be a superior diagnostic device to determine both molecular and anatomical information. , There are some reports of multimodal imaging probes based on MRI contrast agents conjugated to organic dyes like rhodamine and naphthalimide; however, visible light is required to excite these fluorophores, as well as they suffer from low relaxivities. , Meade and co-workers have reported a multimodal imaging probe that comprises three Gd 3+ chelates tethered with a fluorescein residue that possesses high relaxivity and water solubility; however, its biological application is limited due to the low excitation wavelength of fluorescein . Integrating the NIR dye with a magnetic nanoparticle (NP)-based MR agent to harvest complementary imaging information is challenging, and several problems need to be addressed due to the presence of different physical phenomena within a single platform.…”