Some heptamethine cyanine dyes accumulate in solid tumors in vivo and persist there for several days. The reasons why they accumulate and persist in tumors were incompletely defined, but explanations based on uptake into cancer cells via organic anion transporting polypeptides (OATPs) have been widely discussed. All cyanine-based "tumor-seeking dyes" have a chloride centrally placed on the heptamethine bridge (a "meso-chloride"). We were intrigued and perplexed by the correlation between this particular functional group and tumor uptake, so the following study was designed. It features four dyes (1-Cl, 1-Ph, 5-Cl, and 5-Ph) with complementary properties. Dye 1-Cl is otherwise known as MHI-148, and 1-Ph is a close analog wherein the meso-chloride has been replaced by a phenyl group. Data presented here shows that both 1-Cl and 1-Ph form noncovalent adducts with albumin, but only 1-Cl can form a covalent one. Both dyes 5-Cl and 5-Ph have a methylene (CH 2 ) unit replaced by a dimethylammonium functionality (N + Me 2 ). Data presented here shows that both these dyes 5 do not form tight noncovalent adducts with albumin, and only 5-Cl can form a covalent one (though much more slowly than 1-Cl). In tissue culture experiments, uptake of dyes 1 is more impacted by the albumin in the media than by the pan-OATP uptake inhibitor (BSP) that has been used to connect uptake of tumor-seeking dyes in vivo with the OATPs. Uptake of 1-Cl in media containing fluorescein-labeled albumin gave a high degree of colocalization of intracellular fluorescence. No evidence was found for the involvement of OATPs in uptake of the dyes into cells in media containing albumin. In an in vivo tumor model, only the two dyes that can form albumin adducts (1-Cl and 5-Cl) gave intratumor fluorescence that persisted long enough to be clearly discerned over the background (~4 h); this fluorescence was still observed at 48 h. Tumors could be imaged with a higher contrast if 5-Cl is used instead of 1-Cl, because 5-Cl is cleared more rapidly from healthy tissues. Overall, the

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Longitudinal tracking of living cells is crucial to understand the mechanism of action and toxicity of cell-based therapeutics. To quantify the presence of administered cells in the host tissue without sacrifice of animals, labeling of the target cells with a nontoxic and stable contrast agent is a prerequisite. However, such long-term live cell tracking is currently limited by lacking fluorophores in the near-infrared (NIR) window with steady optical and physicochemical properties. Here we report, for the first time, the design of fixable cell tracking NIR fluorophores (CTNFs) with high optical properties, excellent cell permeation and retention, and high stability against chemical treatments. We demonstrated efficient cellular labeling and tracking of CTNFs using intraoperative optical fluorescence imaging by following the fate of NIR labeled cells from the time of injection into animals to ex vivo cellular analysis after resection of the target tissue. Due to the lipophilic cationicity and primary amine docking group, CTNF126 outperforms among the tested with rapid diffusion into the cytoplasmic membrane and sequestration inside the lysosomes, which prevents cellular efflux and improves cellular retention. Thus, CTNF126 will be useful to track cells in living organisms for the mechanism of action at the single cell level.

Prostate-specific membrane antigen (PSMA) can serve as a molecular cell surface target for the detection and treatment of prostate cancer. Near-infrared (NIR) fluorescence imaging enables highly sensitive, rapid, and non-radioactive imaging of PSMA, though specific targeting still remains a challenge because no optimized contrast agents exist.

tumors. [2] Despite advances in imaging techniques and the development of new localization procedures, tumors less than 1 cm in size remain difficult to localize by conventional means [3] because of the difficulty in specific delivery of contrast agents to the tumor site and a low tumorto-background ratio (TBR) resulting from high nonspecific uptake and background retention. Chemotherapeutic agents such as imatinib (IM) can be used to treat GIST with locally advanced, recurrent, primary unresectable, and metastasized tumors. [4] IM is the first approved selective tyrosine kinase inhibitor for KIT (also known as mast/stem cell growth factor receptor Kit, receptor tyrosine kinase Kit, proto-oncogene c-Kit, or CD117) and platelet derived growth factor receptor alpha (PDGFRA) in GIST. [5] Importantly, IM continuation is crucial for long-term survival of advanced GIST patients since IM typically suppresses GIST growth but does not eradicate the tumors. IM can occasionally cause serious adverse effects including myelosuppression, tumor bleeding, gastrointestinal perforation, interstitial pneumonia, and severe skin symptoms. [6] Recently, drug delivery technology has advanced, making it possible for small molecules to be delivered to target tumors with the use of nanoparticles (NPs). [7] This development has Advances in molecular imaging modalities have accelerated the diagnosis and treatment of human diseases. However, tumors less than 1 cm in size still remain difficult to localize by conventional means because of the difficulty in specific targeting/delivery to the tumor site. Furthermore, high nonspecific uptake in the major organs and persistent background retention results in low tumor-to-background ratio. The targeting and therapy of gastrointestinal stromal tumors (GIST) using nonsticky and renal clearable theranostic nanoparticles (a.k.a. H-Dots) are demonstrated. H-Dots not only target GIST for image-guided surgery, but also tailor the fate of anticancer drugs such as imatinib (IM) to the tumor site resulting in efficient treatment of unresectable GIST. In addition, H-Dots can monitor targetability, pharmacokinetics, and drug delivery, while also showing therapeutic efficacy in GIST-bearing xenograft mice following surgical resection. More importantly, IM loaded H-Dots exhibit lower uptake into the immune system, improved tumor selectivity, and increased tumor suppression compared to free IM, which accumulates in the spleen/liver. Precisely designed H-Dots can be used as a promising theranostic nanoplatform that can potentially reduce the side effects of conventional chemotherapies.Gastrointestinal stromal tumors (GIST) are the most common mesenchymal malignancies of the gastrointestinal tract. Surgical resection with negative margins is the standard for GIST therapy, which allows most patients with operable GIST to be cured by primary surgery. [1] However, a critical clinical challenge with GIST surgery lies in its localization of small

Background: Tumor-associated macrophages (TAMs) are one of the most abundant immune cell types in solid tumors and implicated in tumor progression. Toll-like receptor 4 (TLR4) is expressed in TAMs and plays a key role in immune surveillance and tumor progression. Therefore, molecular imaging of TLR4 has potential not only for detection of TAM-enriched progressing tumors, but also evaluation of TLR4 expression in tumor microenvironment.Methods: Here, we report that near-infrared (NIR) fluorescence imaging can provide a real-time imaging of a syngeneic model of murine hepatocellular carcinoma using targeted strategy against TLR4.We conjugated a zwitterionic NIR fluorophore ZW800-1C with minimal nonspecific tissue interactions to anti-TLR4 antibody and observed its targetability. The bioconjugates showed high affinity to murine macrophages in cell culture and in vivo.Results: Interestingly, we observed predominant NIR signals in the tumor site, which persisted for more than 48 h after single intravenous administration of the bioconjugate.Conclusions: This result suggests that TLR4 targeting combined with NIR fluorescence imaging is a useful tool for cancer imaging. This imaging strategy could be used to detect cancerous tissue with the increased TAM content and evaluate the status of TLR4 signaling in solid tumors, ultimately impacting on the diagnostic and prognostic imaging of human cancers.

Early diagnosis and monitoring of disease progress are of significant importance in the effective treatment of rheumatoid arthritis (RA), because the continuing inflammation can lead to irreversible joint damage and systemic complications. However, applying imaging modalities for the prognosis of RA remains challenging, because no tissue‐specific guidelines are available to monitor the progressive course of RA. In this study, fluorometric imaging of RA is reported using bioengineered targeted agents of the blood vessel, bone, and cartilage in combination with the customized optical fluorescence imaging system. Separate but simultaneous tissue‐specific images of synovitis, cartilage destruction, and bone resorption are obtained from a mouse model of RA, which allows quantification of the prognosis of diseases at each stage. Thus, the fluorometric imaging of RA by using tissue‐specific contrast agents plays a key role in the systemic treatment of RA by monitoring structural damage and disease progression.