Concentration-Induced J-Aggregate Formation Causes a Biphasic Change in the Release of trans-Combretastatin A4 Disodium Phosphate from Archaeosomes and the Subsequent Cytotoxicity on Mammary Cancer Cells

Abstract

Combretastatin A4 disodium phosphate (CA4P) is a fluorescent, water-soluble prodrug able to induce vascular shutdown within tumors at doses less than one-tenth of the maximum tolerated dose. As a continued effort to develop efficient liposomal CA4P to treat solid tumor, we herein investigate the physical and spectroscopic properties of CA4P in aqueous solution and the mechanism of CA4P release from archaeal tetraether liposomes (archaeosomes). We found that cis-CA4P can be photoisomerized to trans-CA4P. This photoisomerization results in an increase in fluorescence intensity. Both cis- and trans-CA4P undergo fluorescence intensity self-quenching after they reach a critical concentration Cq (∼0.15-0.25 mM). Moreover, both cis- and trans-CA4P in buffer exhibit a red shift in their excitation spectrum and an increase in excitation spectrum band sharpness with increasing concentration, which can be attributed to the formation of J-aggregates. The onset of the dramatic change in excitation maximum occurs at concentrations close to Cq, suggesting that the self-quenching arises from extensive J-aggregate formation and that, when CA4P concentration exceeds Cq, J-aggregate formation begins to increase sharply. Our data also suggest that the extent of J-aggregate formation plays a critical role in CA4P release from tetraether archaeosomes and in the subsequent cytotoxicity on cultured human breast cancer MCF-7 cells. The drug leakage and cytotoxicity rate constants vary with the initial CA4P concentration entrapped inside archaeosomes in a biphasic manner, reaching a local maximum at 0.25-0.50 mM. A mechanism based on the concept of J-aggregate formation has been proposed to explain the biphasic changes in drug release and cytotoxicity with increasing drug concentration. Tetraether archaeosomes are extraordinarily stable and relatively nontoxic to animals; thus, they are promising nano drug carriers. The results obtained from this study pave the way for future development of archaeosomal CA4P to treat solid tumors.

Polar Lipid Fraction E from Sulfolobus acidocaldarius and Dipalmitoylphosphatidylcholine Can Form Stable yet Thermo-Sensitive Tetraether/Diester Hybrid Archaeosomes with Controlled Release Capability

“…Archaea tetraether lipids have been applied to the bloodstreams of animals, which showed no sign of toxicity [65,86,87]. They have high stability in the circulation, thus being promising nano-carriers for therapeutics [52][53][54]65,[87][88][89]. In the past, the main obstacle of using archaeosomes for therapeutics delivery has been the lack of an efficient method to trigger the release of entrapped content from the otherwise extremely stable structure.…”

Theranostic MRI liposomes for magnetic targeting and ultrasound triggered release of the antivascular CA4P

“…In fact, unlike lysolipid-containing liposomes such as ThermoDox® [42], which releases 80% of its content in about 20 seconds at 42°C thanks to the formation of pores, UMLs remain more stable and the increase of permeability observed at the transition temperature is due to the presence of defects between gel and liquid crystal phase domains in the UML membrane. In addition, it has been shown by Daswani et al that the CA4P molecules could associate with each other by π interactions within the liposomes thus limiting their release [37]. This slower release could be advantageous for our treatment strategy providing a sustained release of the drug, eventually avoiding repeated administrations.…”

“…Jiang et al had encapsulated 5% of CA4P in their liposomes [35], Venegas has synthetized the same formulations as Pattillo's [36]. and Daswani et al have obtained 0.25-0.5mM of CA4P in archaeal tetraether liposomes (archaeosomes) [37]. Gu et al have synthetized prodrug acylated CA4P loaded liposomes in 2019 [38] and Sitnikov et al [39] have improved by a selectin to their CA4P liposomes for targeting.…”

Engineered nanomedicines for tumor vasculature blockade therapy

“…Through binding to the CA4 site on tubulin, CA4 could depolymerize tubulin, leading to a strong vascular blocking effect (Dupeyre et al, 2006). Archaeal tetraether liposome was used to deliver CA4P, a CA4 prodrug (Daswani, Ayesa, Venegas, & Chong, 2015), to achieve the safe and stable release of CA4P. Similarly, nanospheres composed of poly(ethylene glycol)‐ block ‐polylactide (PEG‐ b ‐PLA), poly(lactic‐ co ‐glycolic acid) (PLGA), or poly( l ‐glutamic acid) (PLG) could solve the problem of the low solubility of CA4 while also achieving controlled drug release (T. Liu et al, 2017; L. Wu & Qiu, 2016).…”