Tumor microenvironment responded naturally extracted FOF1-ATPase loaded chromatophores for antitumor therapy

Abstract

Tumor microenvironment (TME) plays an important role in the growth, invasion, and metastasis of tumor cells. The pH of TME is more acidic in solid tumors than in normal tissues. Although targeted delivery in TME has progressed, the complex and expensive construction of delivery systems has limited their application. F_OF1-ATP synthase (F_OF1-ATPase) is a rotation molecular motor found in bacteria, chloroplasts, and mitochondria. Here, F_OF1-ATPase loaded chromatophores (chroma) isolated from thermophilic bacteria were extracted and utilized as a new delivery system targeting TME for the first time. Curcumin as model drug was successfully loaded by a filming-rehydration ultrasonic dispersion method to prepare a curcumin-loaded chroma delivery system (Cur-Chroma). The mobility and propensity distributions of Cur-Chroma reveal its specific pH-sensitive targeting driven by the transmembrane proton kinetic potential, demonstrating its distinct distribution in the TME and more favorable targeting delivery. Cellular uptake experiments indicated that Cur-Chroma entered cells through grid pathway-mediated endocytosis. In vivo studies have shown that Cur-Chroma can specifically target tumor tissue and effectively inhibit tumor growth with good safety. Curcumin's bioavailability and anti-tumor effects were significantly improved. These studies demonstrate that ATPase-loaded chromatophores are potentially ideal vehicles for anti-tumor drug delivery and have promising applications.

Keywords: Chromatophores; Curcumin; F(O)F1-ATP synthase; Molecular motor; Targeted delivery; Tumor microenvironment.