A "lysosomal bomb" constructed based on amorphous calcium carbonate to induce tumor apoptosis by amplified sonodynamic therapy

Abstract

The acidic nature of malignant tumors leads to increased drug sequestration and the evasion of apoptotic damage, which is further exacerbated by abnormal lysosomes in tumor cells. In this study, a "lysosomal bomb" will be constructed using a type of acid-neutralized amorphous calcium carbonate (ACC) to encapsulate the sonosensitizer protoporphyrin IX (PpIX), and then coated with homologous tumor cell membranes to increase water solubility and homologous targeting. The PpIX-ACC@CMs designed in this paper are popcorn-like structures, which can not only neutralize the tumor's acidic microenvironment to balance the pH value and release excess Ca²⁺, but also cause lysosomal dysfunction and achieve drug lysosomal escape to increase drug accumulation. Additionally, the CO₂ gas nucleus produced by the acid reaction of ACC can increase the ultrasonic cavitation effect to amplify the sonodynamic therapy (SDT) effect. In vitro and in vivo experiments demonstrated that PpIX-ACC@CMs, serving as a "lysosomal bomb," successfully localized to lysosomes of tumor cells and exhibited lysosomal escape ability through its acid reaction ability, achieving excellent SDT efficacy under ultrasound stimulation. Furthermore, exogenous Ca²⁺ overload also increased the likelihood of tumor calcification, which could contribute to in vivo tumor inhibition and facilitate CT medical imaging to monitor treatment efficacy.