Cleavage chemistry offers a new chance to activate chemotherapeutic prodrugs in a tumor-selective manner, yet developing spatiotemporally controllable cleavage chemistry with deep tissue penetration is still a great challenge. Herein, we present a novel radiotherapy-triggered cleavage chemistry that enables controlled drug release in tumors. Quaternary ammonium groups are identified as masking groups that can be efficiently removed by hydrated electrons (e À aq ) from water radiolysis. The subsequently released tertiary amines can be anti-cancer toxins or readily release functional molecules via 1,6-elimination. This radiotherapy-induced cleavage works successfully in living cells and tumor-bearing mice, showing remarkable treatment efficacy when the mice are given carfilzomib prodrug and radiotherapy. This strategy provides a new perspective for combinational radiochemotherapy, which is the first-line treatment for over 50 % of cancer patients.
The emerging strategies of accelerating the cleavage reaction in tumors through locally enriching the reactants is promising.Y et, the applications are limited due to the lack of the tumor-selectivity for most of the reactants.H ere we explored an alternative approach to leverage the rate constant by locally inducing an in vivo catalyst. We found that the desilylation-induced cleavage chemistry could be catalyzedi n vivo by cationic micelles,and accelerated over 1400-fold under physiological condition. This micelle-catalyzed controlled release platform is demonstrated by the release of a6hydroxyl-quinoline-2-benzothiazole derivative (HQB) in two cancer cell lines and aN IR dye in mouse tumor xenografts. Through intravenous injection of ap H-sensitive polymer micelles,w es uccessfully applied this strategy to ap rodrug activation of hydroxyl camptothecin (OH-CPT) in tumors.Its "decaging" efficiency is 42-fold to that without cationic micelles-mediated catalysis.This micelle-catalyzed desilylation strategy unveils the potential that micelle may act beyond ac arrier but ac atalyst for local perturbing or activation.
Similar to glycolysis, glutaminolysis acts as a vital energy source in tumor cells, providing building blocks for the metabolic needs of tumor cells. To capture glutaminolysis in tumors, 18F-(2S,4R)4-fluoroglutamine ([18F]FGln) and 18F-fluoroboronoglutamine ([18F]FBQ) have been successfully developed for positron emission tomography (PET) imaging, but these two molecules lack stability, resulting in undesired yet significant bone uptake. In this study, we found that [18F]FBQ-C2 is a stable Gln PET tracer by adding two more methylene groups to the side chain of [18F]FBQ. [18F]FBQ-C2 was synthesized with a good radiochemical yield of 35% and over 98% radiochemical purity. [18F]FBQ-C2 showed extreme stability in vitro, and no defluorination was observed after 2 h in phosphate buffered saline at 37 °C. The competitive inhibition assay results indicated that [18F]FBQ-C2 enters cells via the system ASC and N, similar to natural glutamine, and can be transported by tumor-overexpressed ASCT2. PET imaging and biodistribution results indicated that [18F]FBQ-C2 is stable in vivo with low bone uptake (0.81 ± 0.20% ID/g) and can be cleared rapidly from most tissues. Dynamic scan and pharmacokinetic studies using BGC823-xenograft-bearing mice revealed that [18F]FBQ-C2 accumulates specifically in tumors, with a longer half-life (101.18 ± 6.50 min) in tumor tissues than in other tissues (52.70 ± 12.44 min in muscle). Biodistribution exhibits a high tumor-to-normal tissue ratio (4.8 ± 1.7 for the muscle, 2.5 ± 1.0 for the stomach, 2.2 ± 0.9 for the liver, and 17.8 ± 8.4 for the brain). In conclusion, [18F]FBQ-C2 can be used to perform high-contrast Gln imaging of tumors and can serve as a PET tracer for clinical research.
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