He Wang1, Wenwen Shi2, Danning Zeng2,1, Qiudi Huang2, Jiacui Xie2, Huaying Wen2, Jinfang Li3, Xiyong Yu2, Linghao Qin4, Yi Zhou5. 1. Center of Cancer Research, The Second Affiliated Hospital, Guangzhou Medical University, Guangdong, 510260, Guangzhou, People's Republic of China. 2. The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangdong, 511436, Guangzhou, People's Republic of China. 3. Department of Pharmaceutical Sciences, Xinjiang Second Medical College, Kelamayi, 830011, Xinjiang, People's Republic of China. 4. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, People's Republic of China. qins_lab@163.com. 5. The Fifth Affiliated Hospital, Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangdong, 511436, Guangzhou, People's Republic of China. zhouyi0264@126.com.
Abstract
BACKGROUND: Mitochondria play a role in the occurrence, development, drug resistance, metastasis, and other functions of cancer and thus are a drug target. An acid-activated mitochondria-targeting drug nanocarrier with redox-responsive function was constructed in the present study. However, whether this vector can precisely delivery paclitaxel (PTX) to enhance therapeutic efficacy in drug-resistant lung cancer is unknown. RESULTS: Acid-cleavable dimethylmaleic anhydride (DA) was used to modify pluronic P85-conjugated mitochondria-targeting triphenylphosphonium (TPP) using disulfide bonds as intermediate linkers (DA-P85-SS-TPP and DA-P-SS-T). The constructed nanocarriers demonstrated enhanced cellular uptake and selective mitochondrial targeting at extracellular pH characteristic for a tumor (6.5) and were characterized by extended circulation in the blood. TPP promoted the targeting of the DA-P-SS-T/PTX nanomicelles to the mitochondrial outer membrane to decrease the membrane potential and ATP level, resulting in inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. PTX was also rapidly released in the presence of high glutathione (GSH) levels and directly diffused into the mitochondria, resulting in apoptosis of drug-resistant lung cancer cells. CONCLUSIONS: These promising results indicated that acid-activated mitochondria-targeting and redox-responsive nanomicelles potentially represent a significant advancement in cancer treatment. GRAPHIC ABSTARCT.
BACKGROUND: Mitochondria play a role in the occurrence, development, drug resistance, metastasis, and other functions of cancer and thus are a drug target. An acid-activated mitochondria-targeting drug nanocarrier with redox-responsive function was constructed in the present study. However, whether this vector can precisely delivery paclitaxel (PTX) to enhance therapeutic efficacy in drug-resistant lung cancer is unknown. RESULTS: Acid-cleavable dimethylmaleic anhydride (DA) was used to modify pluronic P85-conjugated mitochondria-targeting triphenylphosphonium (TPP) using disulfide bonds as intermediate linkers (DA-P85-SS-TPP and DA-P-SS-T). The constructed nanocarriers demonstrated enhanced cellular uptake and selective mitochondrial targeting at extracellular pH characteristic for a tumor (6.5) and were characterized by extended circulation in the blood. TPP promoted the targeting of the DA-P-SS-T/PTX nanomicelles to the mitochondrial outer membrane to decrease the membrane potential and ATP level, resulting in inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. PTX was also rapidly released in the presence of high glutathione (GSH) levels and directly diffused into the mitochondria, resulting in apoptosis of drug-resistant lung cancer cells. CONCLUSIONS: These promising results indicated that acid-activated mitochondria-targeting and redox-responsive nanomicelles potentially represent a significant advancement in cancer treatment. GRAPHIC ABSTARCT.
Entities:
Keywords:
Drug resistance; Lung cancer; Metastasis; Redox-responsive; pH-Activated Mitochondria-Targeted Delivery
Authors: Vladimir F Mironov; Andrey V Nemtarev; Olga V Tsepaeva; Mudaris N Dimukhametov; Igor A Litvinov; Alexandra D Voloshina; Tatiana N Pashirova; Eugenii A Titov; Anna P Lyubina; Syumbelya K Amerhanova; Aidar T Gubaidullin; Daut R Islamov Journal: Molecules Date: 2021-10-20 Impact factor: 4.411