Imidazole-Based pH-Sensitive Convertible Liposomes for Anticancer Drug Delivery.

Ruiqi Huang,Shen Zhao,Xin Guo,Yifan Lu,Vijay Gyanani

doi:10.3390/ph15030306

Abstract

In efforts to enhance the activity of liposomal drugs against solid tumors, three novel lipids that carry imidazole-based headgroups of incremental basicity were prepared and incorporated into the membrane of PEGylated liposomes containing doxorubicin (DOX) to render pH-sensitive convertible liposomes (ICL). The imidazole lipids were designed to protonate and cluster with negatively charged phosphatidylethanolamine-polyethylene glycol when pH drops from 7.4 to 6.0, thereby triggering ICL in acidic tumor interstitium. Upon the drop of pH, ICL gained more positive surface charges, displayed lipid phase separation in TEM and DSC, and aggregated with cell membrane-mimetic model liposomes. The drop of pH also enhanced DOX release from ICL consisting of one of the imidazole lipids, sn-2-((2,3-dihexadecyloxypropyl)thio)-5-methyl-1H-imidazole. ICL demonstrated superior activities against monolayer cells and several 3D MCS than the analogous PEGylated, pH-insensitive liposomes containing DOX, which serves as a control and clinical benchmark. The presence of cholesterol in ICL enhanced their colloidal stability but diminished their pH-sensitivity. ICL with the most basic imidazole lipid showed the highest activity in monolayer Hela cells; ICL with the imidazole lipid of medium basicity showed the highest anticancer activity in 3D MCS. ICL that balances the needs of tissue penetration, cell-binding, and drug release would yield optimal activity against solid tumors.

Highlights

The past two decades have seen a surge in the medical use of nanotechnology.Tens of nanomedicines, mostly liposomes, have been approved by Food and DrugAdministration (FDA) or European Medicines Agency (EMA) to treat or diagnose many serious diseases, especially various types of cancer [1–4]
The nano-formulations can accumulate in solid tumors due to their lack of lymphatic drainage, a phenomenon known as the enhanced permeability and retention (EPR) effect
Our goal is to develop imidazole lipids that trigger the liposomes in cooperation with phosphatidylethanolamine-polyethylene glycol conjugates (PE-PEG), which is a key component to stabilize liposomes in blood circulation for anticancer drug delivery

Summary

Introduction

The past two decades have seen a surge in the medical use of nanotechnology.Tens of nanomedicines, mostly liposomes, have been approved by Food and DrugAdministration (FDA) or European Medicines Agency (EMA) to treat or diagnose many serious diseases, especially various types of cancer [1–4]. Liposomal formulations of doxorubicin (DOX) [4–6] represent an important group of nanomedicines, which are indicated for a wide range of cancers. One abnormal feature in many solid tumors is a fenestrated vasculature [9], which allows nano-formulations of anticancer drugs to permeate selectively from the blood circulation to the tumor interstitium. The nano-formulations can accumulate in solid tumors due to their lack of lymphatic drainage, a phenomenon known as the enhanced permeability and retention (EPR) effect. Many long-circulating nano-formulations have been developed to take advantage of the EPR effect, including PEGylated liposomes, hydrophilic polymers, and solid lipid nanoparticles [10,11]. The fenestrated vasculature distributes mainly in the peripheral of solid tumors, which could limit the distribution of nano-drug formulations to the tumor core, and limit their ability to eradicate the entire tumor cell population [12]

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