Controlled Release and Capture of Aldehydes by Dynamic Imine Chemistry in Nanoemulsions: From Delivery to Detoxification

Abstract

Current biomedical applications of nanocarriers are focused on drug delivery, where encapsulated cargo is released in the target tissues under the control of external stimuli. Here, we propose a very different approach, where the active toxic molecules are removed from biological tissues by the nanocarrier. It is based on the drug-sponge concept, where specific molecules are captured by the lipid nanoemulsion (NE) droplets due to dynamic covalent chemistry inside their oil core. To this end, we designed a highly lipophilic amine (LipoAmine) capable of reacting with a free cargo-aldehyde (fluorescent dye and 4-hydroxynonenal toxin) directly inside lipid NEs, yielding a lipophilic imine conjugate well encapsulated in the oil core. The formation of imine bonds was first validated using a push-pull pyrene aldehyde dye, which changes its emission color during the reaction. The conjugate formation was independently confirmed by mass spectrometry. As a result, LipoAmine-loaded NEs spontaneously loaded cargo-aldehydes, yielding formulations stable against leakage at pH 7.4, which can further release the cargo in a low pH range (4–6) in solutions and living cells. Using fluorescence microscopy, we showed that LipoAmine NEs can extract pyrene aldehyde dye from cells as well as from an epithelial tissue (chicken skin). Moreover, successful extraction from cells was also achieved for a highly toxic aliphatic aldehyde 4-hydroxynonenal, which allowed obtaining the proof of concept for detoxification of living cells. Taken together, these results show that the dynamic imine chemistry inside NEs can be used to develop detoxification platforms.

Biomedical Nanosystems for <i>in vivo</i> Detoxification: From Passive Delivery Systems to Functional Nanodevices and Nanorobots

“…In a recent case, active toxic molecules have been removed from biological tissues using a lipophilic amine nanocarrier that is able to react with the toxin (cargo-aldehyde) inside the LEs, forming a lipophilic imine conjugate in the oil core. Successful elimination of highly toxic aliphatic aldehyde 4-hydroxynonenal from living cells is evidence in favor of the concept of living cells detoxification [ 34 ].…”

“…Недавно был представлен подход, при котором активные токсичные молекулы удаляют из биологических тканей с помощью наноносителя -липофильного амина, способного реагировать с токсином (карго-альдегидом) внутри ЛЭ, образуя липофильный конъюгат имина в масляном ядре. Успешное выведение из клеток высокотоксичного алифатического альдегида 4-гидроксиноненаля позволило получить доказательство в пользу концепции детоксикации живых клеток [34].…”

“…A completely opposite approach is assumed for detoxification nanodevices. These nanocarriers ensure the removal of drugs and xenobiotics from biological tissues [ 34 ]. This review provides the proof of concept and potential applications of micro/nanodevices for detoxification.…”

“…Как правило, адресные системы доставки лекарств направлены на инкапсулирование терапевтического агента и его высвобождение в тканях-мишенях под контролем внешних стимулов. Совершенно противоположный подход предполагается для нанодетоксицирующих устройств -наноносители обеспечивают удаление лекарств и ксенобиотиков из биологических тканей [34]. В обзоре представлены результаты «доказательства концепции» и потенциальные перспективы применения микро/наноустройств для детоксикации.…”

Tuning the Envelope Structure of Enzyme Nanoreactors for In Vivo Detoxification of Organophosphates

“…Conversely, drug delivery systems focus on encapsulating drugs and their release under the influence of external factors, for example [16][17][18][19]. The creation of nanoreactors for trapping toxicants involves the complete sealing of enzyme molecules inside an nR body, and must ensure long-term circulation in the body to trap and neutralize toxicants present in the bloodstream and may be slowly released from cellular and organ depot sites, e.g., OP molecules may accumulate in fat from where they are subsequently slowly released into the bloodstream again [2,20,21]. Attempts to use OP-reacting enzymes and their encapsulated forms for stoichiometric or catalytic inactivation of OPs have been undertaken for more than 20 years and have led to very effective formulations [22,23] and novel nanoscavenger devices for OP detoxification [24,25].…”