Multiple targeted doxorubicin-lonidamine liposomes modified with p-hydroxybenzoic acid and triphenylphosphonium to synergistically treat glioma

  • Eur J Med Chem. 2022 Feb 15;230:114093. doi: 10.1016/j.ejmech.2021.114093.
Jiaqi Lu  1 ,  Ru Li  1 ,  Binsong Mu  1 ,  Yao Peng  1 ,  Yi Zhao  2 ,  Yuesen Shi  1 ,  Li Guo  1 ,  Li Hai  3 ,  Yong Wu  4
Affiliations
  • 1. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 2. Department of Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 3. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 4. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 35007860 DOI: 10.1016/j.ejmech.2021.114093
Abstract

A type of pH-sensitive multi-targeted brain tumor site-specific liposomes (Lip-CTPP) co-modified with p-hydroxybenzoic acid (p-HA) and triphenylphosphonium (TPP) were designed and prepared to co-load doxorubicin (DOX) and lonidamine (LND). Lip-CTPP are promising potential carriers to exert the anti-glioma effect of DOX and LND collaboratively given the following features: 1) Lip-CTPP have a good pharmacokinetic behavior; 2) Lip-CTPP can cross the blood-brain barrier (BBB) and recognize tumor cells through the affinity of p-HA and dopamine/sigma receptors; 3) Lip-CTPP are highly positive charged once the acid-sensitive amide bonds are cleaved in endo/lysosomes to expose TPP and protonate amine groups; 4) the positive charged Lip-CTPP escape from endo/lysosomes and accumulate in mitochondria through electrostatic adsorption; 5) DOX and LND are released and synergistically increase anti-tumor efficacy. Our in vitro and in vivo results confirmed that Lip-CTPP could greatly elevate the inhibition rate of tumor cell proliferation, migration and invasion, promote Apoptosis and necrosis, and interfere with mitochondrial function. In addition, Lip-CTPP could significantly prolong the survival time of glioma bearing mice, narrow the tumor region and inhibit the infiltration and metastasis capability of glioma cells. Collectively, Lip-CTPP are promising nano formulations to enhance the synergistic effect of DOX and LND in glioma treatment.

Keywords
Doxorubicin; Glioma; Liposome; Lonidamine; Triphenylphosphonium; p-Hydroxybenzoic acid.
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