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

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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

In this study, pH-sensitive multi-targeted liposomes were developed for the co-delivery of doxorubicin and lonidamine to brain tumors. These liposomes exhibited excellent pharmacokinetic properties, crossed the blood-brain barrier, and targeted tumor cells. Once inside the cells, the liposomes were positively charged and accumulated in the mitochondria, resulting in the synergistic release of the two drugs and enhanced anti-tumor efficacy. In vitro and in vivo experiments demonstrated that these liposomes significantly inhibited tumor cell proliferation, migration, and invasion, induced apoptosis and necrosis, and interfered with mitochondrial function. They also prolonged the survival of mice with glioma, reduced tumor size, and inhibited tumor infiltration and metastasis.