Ultrasound-Activated, Tumor-Specific <i>In Situ</i> Synthesis of a Chemotherapeutic Agent Using ZIF-8 Nanoreactors for Precision Cancer Therapy.

Abstract

The <i>in situ</i> transformation of low-toxicity precursors into a chemotherapeutic agent at a tumor site to enhance the efficacy of its treatment has long been an elusive goal. In this work, a zinc-based zeolitic imidazolate framework that incorporates pharmaceutically acceptable precursors is prepared as a nanoreactor (NR) system for the localized synthesis of an antitumor drug. The as-prepared NRs are administered intratumorally in a tumor-bearing mouse model and then irradiated with ultrasound (US) to activate the chemical synthesis. The US promotes the penetration of the administered NRs into the tumor tissue to cover the lesion entirely, although some NRs leak into the surrounding normal tissue. Nevertheless, only the tumor tissue, where the H₂O₂ concentration is high, is adequately exposed to the as-synthesized antitumor drug, which markedly impedes development of the tumor. No significant chemical synthesis is detected in the surrounding normal tissue, where the local H₂O₂ concentration is negligible and the US irradiation is not directly applied. The as-proposed tumor-specific <i>in</i> <i>situ</i> synthesis of therapeutic molecules induces hardly any significant <i>in vivo</i> toxicity and, thus, is potentially a potent biocompatible approach to precision chemotherapy.