The selective transportation of therapeutic agents to tumoral cells is usually achieved by their conjugation with targeting moieties able to recognize these cells. Unfortunately, simple and static targeting systems usually show a lack in selectivity. Herein, a double sequential encrypted targeting system is proposed as a stimuli-responsive targeting analogue for selectivity enhancement. The system is able to recognize diseased bone tissue in the first place, and once there, a hidden secondary targeting group is activated by the presence of an enzyme overproduced in the malignant tissue (cathepsin K), thereby triggering the recognition of diseased cells. Transporting the cell targeting agent in a hidden conformation that contains a high selective tissular primary targeting, could avoid not only its binding to similar cell receptors but also the apparition of the binding-site barrier effect, which can enhance the penetration of the therapeutic agent within the affected zone. This strategy could be applied not only to conjugate drugs but also to drug-loaded nanocarriers to improve the efficiency for bone cancer treatments.
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