Abstract
Liposomes have many advantages as therapeutic capsules over free drugs such as small molecule drugs and nucleic acids. Cholesterol is commonly used as a membrane stabilizing agent in liposomal drugs (e.g., mRNA-lipid nanoparticle COVID-19 vaccines). However, due to the vulnerability of cholesterol to oxidation and the etiological role of cholesterol in many disorders, it is desirable to find an alternative means to stabilize liposomal membranes for drug delivery. In this study, we demonstrated that the polar lipid fraction E (PLFE), which contains exclusively bipolar tetraether macrocyclic lipids, isolated from the thermoacidophilic archaeon S. acidocaldarius can greatly stabilize the liposomal formulation of the anti-vascular drug, combretastatin A4 disodium phosphate (CA4P). Stability was assessed by determining the leakage rate constant k of entrapped CA4P fluorometrically. We found that, at 37 °C, PLFE decreases the k value monotonically from 1.54 × 10−2 s−1 for 100% 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) liposomes to 3.4 × 10−5 s−1 for 100% PLFE archaeosomes, a change of k by two orders of magnitude. The changes in k of CA4P leakage are correlated well with the changes in liposomal CA4P’s cytotoxicity against MCF-7 breast cancer cells. We further showed that the reduction in spontaneous leakage of entrapped CA4P by PLFE can be attributed to the increased membrane surface charge and the increased membrane order and packing tightness in liposomes, as reflected by the zeta potential (−6.83 to −41.1 mV from 0 to 100 mol% PLFE) and diphenylhexatriene (DPH) fluorescence polarization (0.13 to 0.4 from 0 to 100 mol% PLFE) measurements. Moreover, we showed that PLFE slows down CA4P leakage more than cholesterol in POPC liposomes. These results together suggest that PLFE lipids can serve as an effective stabilizing agent for liposomal drugs and could potentially be useful for the optimization of liposomal CA4P for cancer treatment.
Highlights
The advantages of using liposomal drugs as opposed to free drugs are well-documented in the literature [1] which include the ability to selectively deliver liposomes to the desired site in the body, reducing the potential side effects, and increasing the therapeutic efficacy
We have determined the rate constant of combretastatin A4 disodium phosphate (CA4P) leakage from the interior of the polar lipid fraction E (PLFE)/POPC archaeosomes to the bulk aqueous phase outside the vesicles using the method previously described [7,12]
We have determined the rate constant of CA4P leakage from the interior of t4h7e9 PLFE/POPC archaeosomes to the bulk aqueous phase outside the vesicles using the method previously described [7,12]
Summary
The advantages of using liposomal drugs as opposed to free drugs are well-documented in the literature [1] which include the ability to selectively deliver liposomes to the desired site in the body, reducing the potential side effects, and increasing the therapeutic efficacy. At critical cholesterol mole fractions (Cr) (e.g., 20.0, 22.2, 25.0, 33.3, 40.0, and 50.0 mol%) for maximal sterol superlattice formation, CA4P can be released from the liposomes more readily than at non-critical cholesterol mole fractions, probably due to the increased domain boundaries between superlattice and non-superlattice regions, which results in increased cytotoxicity at Cr [7]. Taking into consideration these complexities and complications with cholesterol, a new membrane stabilizer for liposomal drugs is needed
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