Chemically triggered release of 5-aminolevulinic acid from liposomes

Abstract

5-Aminolevulinic acid (5-ALA), a prodrug of Protoporphyrin IX (PpIX), is used for photodynamic therapy of several medical conditions, and as an adjunct for fluorescence guided surgery. The clinical problem of patient photosensitivity after systemic administration could likely be ameliorated if the 5-ALA was delivered more selectivity to the treatment site. Liposomal formulations are inherently attractive as targeted delivery vehicles but it is hard to regulate the spatiotemporal release of aqueous contents from a liposome. Here, we demonstrate chemically triggered leakage of 5-ALA from stealth liposomes in the presence of cell culture. The chemical trigger is a zinc(II)-dipicolylamine (ZnBDPA) coordination complex that selectively targets liposome membranes containing a small amount of anionic phosphatidylserine. Systematic screening of several ZnBDPA complexes uncovered a compound with excellent performance in biological media. Cell culture studies showed triggered release of 5-ALA from stealth liposomes followed by uptake into neighboring mammalian cells and intracellular biosynthesis to form fluorescent PpIX.

Small molecule additive enhances cell uptake of 5-aminolevulinic acid and conversion to protoporphyrin IX

“…The mechanism studies reported here, together with our previous work on the interaction of ZnBDPA compounds with biological membranes, 33–35 suggest that 2 forms transient pores at the membrane surface which substantially enhances 5-ALA entry and subsequent biosynthesis into PpIX. The next step in this research is to test the effect of additive 2 on 5-ALA uptake in clinically relevant models of topical transdermal delivery.…”

Calcium‐Responsive Liposomes via a Synthetic Lipid Switch

“…Additionally, Menger and co‐workers reported a morpholinocyclohexanol‐ (MOCH)‐lipid that undergoes a cyclohexanol chair flip upon morpholine protonation to help trigger release when the liposomes are tethered to spherical polycationic brushes . Regarding release driven by binding interactions, Smith and co‐workers utilized a sensor that targets the lipid phosphatidylserine (PS) to trigger release from liposomes containing PS . This last example demonstrates that a non‐covalent binding event can drive membrane disruption and release.…”

Lipid Switches: Stimuli‐Responsive Liposomes through Conformational Isomerism Driven by Molecular Recognition

“…Interestingly, the extent of release was also found to depend upon the identities of the PS acyl chains. This approach was then investigated for the encapsulation and release of 5‐aminolevulinic acid (5‐ALA), a prodrug used for photodynamic therapy . In this work, a series of modified ZnBDPA structures were synthesized and screened by fluorescence microscopy for the ability to enhance cellular uptake of 5‐ALA and promote the synthesis of protoporphyrin IX (PpIX).…”

“…This approachw as then investigated for the encapsulation and release of 5-aminolevulinic acid (5-ALA), ap rodrug used for photodynamic therapy. [19] In this work, as eries of modified ZnBDPAs tructures were synthesized and screened by fluorescence microscopy for the ability to enhancec ellular uptake of 5-ALA and promote the synthesis of protoporphyrin IX (PpIX). Here, the optimal trigger yielded the release of 71 %o fc ontents from liposomes and at hreefold increase in PpIX production.…”