Over the past decade, the tumor microenvironment (TME) has become a new paradigm of cancer diagnosis and therapy due to its unique biological features, mainly the interconnection between cancer and stromal cells. Within the TME, cancer-associated fibroblasts (CAFs) demonstrate as one of the most critical stromal cells that regulate tumor cell growth, progression, immunosuppression, and metastasis. CAFs are identified by various biomarkers that are expressed on their surfaces, such as fibroblast activation protein (FAP), which could be utilized as a useful target for diagnostic imaging and treatment. One of the advantages of targeting FAP-expressing CAFs is the absence of FAP expression in quiescent fibroblasts, leading to a controlled targetability of diagnostic and therapeutic compounds to the malignant tumor stromal area using radiolabeled FAP-based ligands. FAP-based radiopharmaceuticals have been investigated strenuously for the visualization of malignancies and delivery of theranostic radiopharmaceuticals to the TME. This review provides an overview of the state of the art in TME compositions, particularly CAFs and FAP, and their roles in cancer biology. Moreover, relevant reports on radiolabeled FAP inhibitors until the year 2021 are highlighted—as well as the current limitations, challenges, and requirements for those radiolabeled FAP inhibitors in clinical translation.

Metastatic melanoma can be difficult to detect until at the advanced state that decreases the survival rate of patients. Several FDA‐approved BRAF inhibitors have been used for treatment of metastatic melanoma, but overall therapeutic efficacy has been limited. Lutetium‐177 (¹⁷⁷Lu) enables simultaneous tracking of tracer accumulation with single‐photon emission computed tomography and radiotherapy. Therefore, the codelivery of ¹⁷⁷Lu alongside chemotherapeutic agents using nanoparticles (NPs) might improve the therapeutic outcome in metastatic melanoma. Cellulose nanocrystals (CNC NPs) can particularly deliver payloads to lung capillaries in vivo. Herein, ¹⁷⁷Lu‐labeled CNC NPs loaded with vemurafenib ([¹⁷⁷Lu]Lu‐CNC‐V NPs) is developed and the therapeutic effect in BRAF V600E mutation‐harboring YUMM1.G1 murine model of lung metastatic melanoma is investigated. The [¹⁷⁷Lu]Lu‐CNC‐V NPs demonstrate favorable radiolabel stability, drug release profile, cellular uptake, and cell growth inhibition in vitro. In vivo biodistribution reveals significant retention of the [¹⁷⁷Lu]Lu‐CNC‐V NPs in the lung, liver, and spleen. Ultimately, the median survival time of animals is doubly increased after treatment with [¹⁷⁷Lu]Lu‐CNC‐V NPs compared to control groups. The enhanced therapeutic efficacy of [¹⁷⁷Lu]Lu‐CNC‐V NPs in the lung metastatic melanoma animal model provides convincing evidence for the potential of clinical translation for theranostic CNC NP‐based drug delivery systems after intravenous administration.

Boron Neutron Capture Therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modelling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing towards the significant potential embedded in this approach.