Lactic acidosis is one of the key characteristics of the tumor microenvironment (TME), and plays a critical role in therapy resistance, making it an attractive target for enhancing anticancer treatment. However, no effective systems exhibit the ability to selectively neutralize tumor lactic acidosis in a controlled manner. Here, we have developed novel ultrasound-responsive alkaline nanorobots (AN-DSP), composed of PLGA nanoparticles containing doxorubicin (DOX), sodium carbonate (Na2CO3) and perfluorocarbon (PFC), for recovering from lactic acidosis-mediated drug resistance. AN-DSP exhibit sensitive response to ultrasound stimulation, and rapidly release Na2CO3 to neutralize lactic acidosis, consequently enhancing DOX susceptibility in vitro and in vivo. Particularly, our nanorobots autonomously accumulate in tumors by an enhanced permeability and retention effect, and can specifically disrupt the tumor acidic microenvironment in response to external ultrasonic powering, resulting in the inhibition of tumor growth with minimal adverse effects. Therefore, AN-DSP represent a promising approach for selectively overcoming tumor lactic acidosis induced therapeutic resistance.
Intracellular calcium ions (Ca2+) influence the proliferation–apoptosis balance, and lactic acidosis is an innate feature of a malignant tumor. In this study, a calcium hydroxide/oleic acid/phospholipid nanoparticle [CUR–Ca(OH)2-OA/PL NP] with lipase/pH dual responsive delivery of Ca2+ and curcumin (CUR) was developed for inducing cancer cell apoptosis by a combination of intracellular calcium overload and lactic acidosis elimination. The nanoparticle showed a core–shell structure with some good performance, including an adequate nano-size, negative charge, good blood circulation stability, and non-hemolysis. MDA-MB-231 breast cancer cells exhibited a higher lipase activity than A549 human lung adenocarcinoma cells and L929 mouse fibroblasts by fluorescence analysis. CUR–Ca(OH)2-OA/PL NPs were highly internalized by MDA-MB-231 cells, intracellularly released CUR and Ca2+, triggered the activation of caspase 3 and caspase 9, and caused apoptosis by intracellular calcium overload via a mitochondrial-mediated pathway. Lactic acid of 20 mM inhibited the apoptosis of MDA-MB-231 cells depending on the glucose insufficiency level, but this inhibition could be eliminated by CUR–Ca(OH)2-OA/PL NPs, leading to nearly complete apoptosis. Herein, CUR–Ca(OH)2-OA/PL NPs are a potential killer of cancer cells with high lipase activity by a combination of intracellular calcium overload and lactic acidosis elimination.
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