Reactive Oxygen Species-Responsive Liposomes via Boronate-Caged Phosphatidylethanolamine

Abstract

Liposomes have proven to be effective nanocarriers due to their ability to encapsulate and deliver a wide variety of therapeutic cargo. A key goal of liposome research is to enhance control over content release at diseased sites. Though a number of stimuli have been explored for triggering liposomal release, reactive oxygen species (ROS), which have received significantly less attention, provide excellent targets due to their key roles in biology and overabundance in diseased cells. Here, we report a ROSresponsive liposome platform through the inclusion of lipid 1 bearing a boronate ester headgroup and a quinone-methide (QM) generating self-immolative linker attached onto a dioleoylphosphatidylethanolamine (DOPE) lipid scaffold. Fluorescence-based dye release assays validated that this system enables release of both hydrophobic and hydrophilic contents upon hydrogen peroxide (H 2 O 2 ) addition. Details of the release process were carefully studied, and data showed that oxidative removal of the boronate headgroup is sufficient to result in hydrophobic content release, while production of DOPE is needed for hydrophilic cargo leakage. These results showcase that lipid 1 can serve as a promising ROS-responsive liposomal delivery platform for controlled release.

Demolish and Rebuild: Controlling Lipid Self-Assembly toward Triggered Release and Artificial Cells

“…Our group developed ROSresponsive conjugate 8 designed to release the nonbilayer lipid DOPE upon treatment with hydrogen peroxide as a representative ROS. 35 This compound contains a boronate trigger that is oxidatively cleaved by ROS, feeding into immolation of a quinone methide linker to generate DOPE, and was capable of driving liposome release. Liposomes composed of 100% 8 with sizes of 150 nm released 50% hydrophobic cargo within 5 min upon H 2 O 2 treatment.…”

“…Liposomes composed of 7 with diameters around 100–120 nm exhibited ∼80% of encapsulated Dox release within the first 24 h. While the prior example consists of phospholipid analogues with trigger groups introduced within the acyl chains, modifications to lipid headgroups have also been effectively exploited to drive release. Our group developed ROS-responsive conjugate 8 designed to release the nonbilayer lipid DOPE upon treatment with hydrogen peroxide as a representative ROS . This compound contains a boronate trigger that is oxidatively cleaved by ROS, feeding into immolation of a quinone methide linker to generate DOPE, and was capable of driving liposome release.…”

Liposome-based Biosensors and Diagnosis Imaging Agents

“…(39) Recent evidence has shown that ROS play a key role as messengers in normal cell signal transduction and cell cycling. ROS-detectable liposomal systems have been reported, (27,40) such as a Förster resonance energy transfer (FRET) system for ROS detection. FRET is an effective technique for probing minimal changes occurring at a distance, such as the separation between donor and acceptor fluorophores of less than 10 nm.…”

Zinc Triggered Release of Encapsulated Cargo from Liposomes via a Synthetic Lipid Switch

“…For these reasons, intensive efforts have been focused on the development of liposome triggered release platforms of late. These approaches are categorized as passive release exploiting variations associated with pathophysiological conditions (i.e., acidity, redox environment, , or divergent enzyme expression , ) or active release employing an externally applied stimulus (i.e., light, heat, and ultrasound). Despite all this creative work, controlled release protocols have yet to emerge in clinical liposome formulations, which can be attributed to significant obstacles.…”