RGD Peptide-Conjugated Dodecaborate with the Ga-DOTA Complex: A Preliminary Study for the Development of Theranostic Agents for Boron Neutron Capture Therapy and Its Companion Diagnostics

Abstract

A boron neutron capture therapy (BNCT) system, using boron-10-introduced agents coupled with companion diagnostics, is anticipated as a promising cancer theranostic. Thus, this study aimed to synthesize and evaluate a probe closo-dodecaborate-(Ga-DOTA)-c(RGDfK) (16) [Ga = gallium, DOTA =1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, and c(RGDfK) = cyclo(arginine-glycine-aspartate-d-phenylalanine-lysine] containing closo-dodecaborate ([B12H12]2–) as a boron cluster, a [67Ga]Ga-DOTA derivative for nuclear medicine imaging, and an RGD peptide for tumor targeting. Moreover, we prepared a radioiodinated probe [125I]17 in which I-125 is introduced into a closo-dodecaborate moiety of 16. [67Ga]16 and [125I]17 showed high stability and high uptake in cancer cells in vitro. Biodistribution experiments in tumor-bearing mice revealed similar biodistribution patterns between [67Ga]16 and [125I]17, such as a high uptake in the tumor and a low uptake in other non-target tissues. Meanwhile, [125I]17 exhibited higher accumulation in most tissues, including the tumor, than [67Ga]16, probably because of higher albumin binding. The higher the [125I]17 accumulation in the tumor, the more desirable it is for BNCT, with the possibility that the iodo-closo-dodecaborate site may work as an albumin binder.

Synthesis and Preclinical Evaluation of Urea-Based Prostate-Specific Membrane Antigen-Targeted Conjugates Labeled with 177Lu

“…DOTA chelating agent was chosen due to its excellent chelating properties toward both 68 Ga (PET/CT diagnostics) and 177 Lu (radionuclide therapy) radioisotopes and its numerous examples of successful biomedical applications. − …”

Identification of a pH-Responsive Peptide–Paclitaxel Conjugate as a Novel Drug with Improved Therapeutic Potential

“…23,24 Conjugation of CPP with PTX can not only improve the water solubility of PTX (avoiding the use of inorganic solvents such as Cremophor EL) but also enhance the delivery of PTX into tumor tissues, thus inhibiting drug resistance. 25,26 One such recently reported promising CPP is an effective, short-chain dual-targeting cyclic heptapeptide probe (having sequence c[RGDKLAK]) that consists of both tumor-homing motifs (RGD) 13 coupled with a proapoptotic motif (KLA). 27 This peptide probe can specifically interact with α v β 3 -integrin receptors highly expressed on endothelial cells as well as many types of tumor cells, most specifically brain tumor glioblastoma cells.…”

“…Zhao et al studied the effect of PLGA-encapsulated PTX conjugated with PEG-DMA as a delivery system and observed that a high therapeutic dose (3 μg/mL) is required for treatment even after resection of GBM . Mishiro et al reported the development of a theranostic agent [c­(RGDfK)- 67 Ga-DOTA-dodecaborate] for boron neutron capture therapy (BNCT) and observed that the proposed agent is not problem-free, as observed from some viable tumor cells left due to heterogeneity in accumulation in tumor tissues . Furthermore, the hydrophobicity (lower BBB penetration) of PTX limits its use as an efficient first-line chemotherapeutic drug that needs primary consideration when designing PTX-based formulations. , Hence, these issues give rise to the necessity to divert the attention of researchers for designing novel hydrophilic tumor-specific peptide-based PTX formulations (except the ideology of nanoformulations) to kill cancer cells efficiently with as much as possible reduced side effects.…”

“…One such recently reported promising CPP is an effective, short-chain dual-targeting cyclic heptapeptide probe (having sequence c­[RGDKLAK]) that consists of both tumor-homing motifs (RGD) coupled with a proapoptotic motif (KLA) . This peptide probe can specifically interact with α v β 3 -integrin receptors highly expressed on endothelial cells as well as many types of tumor cells, most specifically brain tumor glioblastoma cells.…”

Development of a Gadolinium–Boron-Conjugated Albumin for MRI-Guided Neutron Capture Therapy

“…Sodium mercaptoundecahydro- closo -dodecaborate (BSH), which is a boron cluster containing 12 boron atoms, was used for the treatment of glioma. , l -Boronophenylalanine (BPA) is currently the most-used boron agent in clinical BNCT because it is selectively taken up in tumors through l -type amino acid transporter 1 (LAT1) overexpressed in various cancer cells. ,, Moreover 18 F-labeled BPA-based positron emission tomography (PET) is available to estimate pharmacokinetics of BPA, enabling the prediction of the appropriate timing of neutron irradiation after administration of BPA. , However, it remains challenging to apply BNCT to tumors that express low levels of LAT1. To broaden cancer indications of BNCT, boron agents with different delivery mechanisms from BPA have been developed. − …”