# Rate-Tunable, Metal-Mediated Amide Bond Cleavage for the Controlled Release of Pharmaceuticals

## TL;DR

Scientists developed a way to control how fast drugs release in the body using metal complexes, which could improve cancer treatments.

## Contribution

A new method for rate-tunable amide bond cleavage using metal complexes is introduced for pharmaceutical release control.

## Key findings

- Metal-mediated amide bond cleavage rates can be tuned by amino acid side chains and methylation.
- TMAC improves radiopharmaceutical targeting by minimizing blood and liver accumulation while maximizing tumor uptake.
- NMR and X-ray diffraction confirmed two coordination isomers with distinct cleavage rates.

## Abstract

That the incorporation of N-methyl amino
acids
adjacent to a hydrolytic, azamacrocyclic metal complex results in
rate-tunable, metal-mediated amide bond cleavage (TMAC) under physiological
conditions. Spectroscopic and crystallographic data provide unprecedented
mechanistic insight: the Ga3+ complex of (7-amido-1,4,7-triazonane-1,4-diyl)­diacetic
acid polarizes the amide bond proximal to canonical and noncanonical
amino acids, forming two coordination isomers with different cleavage
rates, N3O3 (fast) and N4O2 (slow) in aqueous solution. Both were characterized by NMR spectroscopy
and identified by single-crystal X-ray diffraction. Subsequent hydrolysis
of the amide bond occurs by exogenous nucleophilic attack, as demonstrated
by 18O-isotope labeling experiments and proceeds with a
variable rate, depending on the nature of the amino acid side chain
and amide-methylation status. The in vivo applicability of TMAC was
subsequently demonstrated by pharmacokinetic modulation of a cancer
targeted, 68Ga-labeled radiopharmaceutical. Specifically,
6 serum-albumin binding chelates, linked to a peptide targeting the
prostate specific membrane antigen (PSMA) were constructed. Variable
amino-acid-chelate linkers allow tuning of the rate of release and
clearance of the radioactive isotope. Indeed, diagnostic positron
emission tomography (PET) imaging, metabolite and biodistribution
analysis indicate that rate tunable cleavage and release of the 68Ga-chelate minimize tracer accumulation in blood and liver
compartments while maximizing tumor uptake. In contrast, a [68Ga]­Ga-chelate incorporating a noncleavable glycine linker, exhibited
elevated blood and liver uptake with moderate tumor localization.
Taken together, TMAC provides remarkable control over the in vivo
behavior of targeted pharmaceuticals.