Catechol-linker and receptor-mediated site-specific delivery of bortezomib against non-small cell lung cancer

TL;DR

A new method targets bortezomib to lung cancer cells using a receptor and a special linker, reducing side effects and improving treatment effectiveness.

Contribution

First demonstration of site-specific delivery of bortezomib to non-small cell lung cancer via ACE2 receptor and bio-orthogonal chemistry.

Findings

Bortezomib was site-specifically delivered to NSCLC cells via ACE2 receptor-mediated endocytosis.

The method showed significant tumor growth inhibition in mice with reduced toxicity to normal organs.

The approach enables controlled release of bortezomib in subcellular endosomes, inhibiting proteasome function.

Abstract

Angiotensin-converting enzyme-2 (ACE2) receptor-targeting bio-orthogonally conjugated bortezomib (BTZ) was site-specifically delivered against non-small cell lung cancer (NSCLC). Through rational screening, three ACE2 receptor-binding domain (RBD) variants (mutant RBD1, mutant RBD2, and mutant RBD3) were identified to introduce the genetic linker DOPA (3,4-dihydroxyphenyl-L-alanine) to bio-orthogonally load BTZ through a catechol-boronate ester with enhanced receptor binding. Extensive biophysical characterization, such as UV-Vis spectroscopy, B11-NMR spectroscopy, RP-HPLC, microscale thermophoresis, and X-ray photoelectron spectroscopy, confirms the homogeneous preparation and controlled release of BTZ. In vitro analysis, including 2D monolayer and 3D spheroid models, revealed the site-specific and controlled release of BTZ through ACE2 receptor-mediated endocytosis in subcellular endosomes, which inhibits the proteasome function of NSCLC cells (A549). Finally, in vivo, animal studies (Lewis lung carcinoma (LLC1) cells-induced C57BL/6 mice) showed significant inhibition of lung tumor growth with reduced toxicity in normal ACE2-expressing organs. To our knowledge, site-specific labeling and high-potential bio-orthogonal delivery of BTZ in the NSCLC were demonstrated for the first time. More attractively, this concept strengthens future applications for delivering other boronic acid-containing therapeutics against metabolic and cardiovascular diseases.

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