Schilt Y, Berman T, Wei X, Nativ-Roth E, Barenholz Y, Raviv U. Effect of the ammonium salt anion on the structure of doxorubicin complex and PEGylated liposomal doxorubicin nanodrugs. Biochimica et Biophysica Acta (BBA) - General Subjects [Internet]. 2021;1865 (5) :129849. Publisher's VersionAbstract

Background In Doxil®, PEGylated nanoliposomes are created by hydration of the lipids in ammonium sulfate, and are remotely loaded with doxorubicin by a transmembrane ammonium gradient. The ammonium sulfate is then removed from the external aqueous phase, surrounding the liposomes, and replaced by an isoosmotic sucrose solution in 10 mM histidine buffer at pH 6.5. Methods We prepared PEGylated liposomal doxorubicin (PLD) with a series of ammonium monovalent salts that after remote loading became the intraliposome doxorubicin counteranions. We analyzed the liposomes by solution X-ray scattering, differential scanning calorimetry, and electron micropscopy. Results PLDs prepared with sulfonic acid derivatives as counteranion exhibited chemical and physical stabilities. We determined the effect of these ammonium salt counteranions on the structure, morphology, and thermotropic behavior of the PEGylated nanoliposomes, formed before and after doxorubicin loading, and the bulk properties of the doxorubicin-counteranion complexes. By comparing the structure of the doxorubicin complexes in the bulk and inside the nanoliposomes, we revealed the effect of confinement on the structure and doxorubicin release rate for each of the derivatives of the ammonium sulfonic acid counteranions. Conclusions We found that the extent and direction of the doxorubicin confinement effect and its release rate were strongly dependent on the type of counteranion. The counteranions, however, neither affected the structure and thermotropic behavior of the liposome membrane, nor the thickness and density of the liposome PEG layers. In an additional study, it was demonstrated that PLD made with ammonium-methane sulfonate exhibit a much lower Hand and Foot syndrome. General significance The structure, physical state, and pharmacokinetics of doxorubicin in PEGylated nanoliposomes, prepared by transmembrane remote loading using gradients of ammonium salts, strongly depend on the counteranions.

Fink L, Allolio C, Feitelson J, Tamburu C, Harries D, Raviv U. Bridges of Calcium Bicarbonate Tightly Couple Dipolar Lipid Membranes. Langmuir [Internet]. 2020;36 (36) :10715–10724. Publisher's Version
Fink L, Steiner A, Szekely O, Szekely P, Raviv U. Structure and Interactions between Charged Lipid Membranes in the Presence of Multivalent Ions. Langmuir [Internet]. 2019;35 (30) :9694-9703. Publisher's Version
Raviv U. Interacting Bacteria Surfaces. Biophysical journal [Internet]. 2018;114 (7) :1515-1517. Publisher's Version
Eyal LB, Choubeh RR, Cohen E, Eisenberg I, Tamburu C, Dorogi M, Ünnep R, Appavou M-S, Nevo R, Raviv U, et al. Changes in aggregation states of light-harvesting complexes as a mechanism for modulating energy transfer in desert crust cyanobacteria. Proceedings of the National Academy of Sciences [Internet]. 2017;114 (35) :9481-9486. Publisher's Version
Fink L, Feitelson J, Noff R, Dvir T, Tamburu C, Raviv U. Osmotic stress induced desorption of calcium ions from dipolar lipid membranes. Langmuir [Internet]. 2017;33 (23) :5636-5641. Publisher's Version
Eisenberg I, Harris D, Levi-Kalisman Y, Yochelis S, Shemesh A, Ben-Nissan G, Sharon M, Raviv U, Adir N, Keren N. Concentration-based self-assembly of phycocyanin. Photosynthesis research [Internet]. 2017;134 (1) :39-49. Publisher's Version
Schilt Y, Berman T, Wei X, Barenholz Y, Raviv U. Using solution X-ray scattering to determine the high-resolution structure and morphology of PEGylated liposomal doxorubicin nanodrugs. Biochimica et Biophysica Acta (BBA)-General Subjects [Internet]. 2016;1860 (1) :108-119. Publisher's Version
Lotan O, Fink L, Shemesh A, Tamburu C, Raviv U. Critical Conditions for Adsorption of Calcium Ions onto Dipolar Lipid Membranes. The Journal of Physical Chemistry A [Internet]. 2016;120 (19) :3390-3396. Publisher's Version
Turjeman K, Bavli Y, Kizelsztein P, Schilt Y, Allon N, Katzir TB, Sasson E, Raviv U, Ovadia H, Barenholz Y. Nano-drugs based on nano sterically stabilized liposomes for the treatment of inflammatory neurodegenerative diseases. PLoS One [Internet]. 2015;10 (7) :e0130442. Publisher's Version
Harries D, Raviv U. 1 Soft Matter Physics of Lipid Membrane–Based Assemblies. In: Liposomes, Lipid Bilayers and Model Membranes: From Basic Research to Application. CRC Press ; 2014. pp. 1. Publisher's Version
Dvir T, Fink L, Schilt Y, Raviv U. Charging and softening, collapse, and crystallization of dipolar phospholipid membranes by aqueous ionic liquid solutions. Langmuir [Internet]. 2014;30 (49) :14725-14733. Publisher's Version
Moshe L, Saper G, Szekely O, Linde Y, Gilon C, Harries D, Raviv U. Modulating the structure and interactions of lipid–peptide complexes by varying membrane composition and solution conditions. Soft Matter [Internet]. 2013;9 (29) :7117-7126. Publisher's Version
Dvir T, Fink L, Asor R, Schilt Y, Steinar A, Raviv U. Charged membranes under confinement induced by polymer-, salt-, or ionic liquid solutions. Soft Matter [Internet]. 2013;9 (44) :10640-10649. Publisher's Version
Steiner A, Szekely P, Szekely O, Dvir T, Asor R, Yuval-Naeh N, Keren N, Kesselman E, Danino D, Resh R. Entropic attraction condenses like-charged interfaces composed of self-assembled molecules. Langmuir [Internet]. 2012;28 (5) :2604-2613. Publisher's Version
Szekely P, Asor R, Dvir T, Szekely O, Raviv U. Effect of temperature on the interactions between dipolar membranes. The Journal of Physical Chemistry B [Internet]. 2012;116 (11) :3519-3524. Publisher's Version
Zucker D, Andriyanov AV, Steiner A, Raviv U, Barenholz Y. Characterization of PEGylated nanoliposomes co-remotely loaded with topotecan and vincristine: relating structure and pharmacokinetics to therapeutic efficacy. Journal of controlled release [Internet]. 2012;160 (2) :281-289. Publisher's Version
Nadler M, Steiner A, Dvir T, Szekely O, Szekely P, Ginsburg A, Asor R, Resh R, Tamburu C, Peres M. Following the structural changes during zinc-induced crystallization of charged membranes using time-resolved solution X-ray scattering. Soft Matter [Internet]. 2011;7 (4) :1512-1523. Publisher's Version
Szekely O, Steiner A, Szekely P, Amit E, Asor R, Tamburu C, Raviv U. The structure of ions and zwitterionic lipids regulates the charge of dipolar membranes. Langmuir [Internet]. 2011;27 (12) :7419-7438. Publisher's Version
Safinya CR, Raviv U, Needleman DJ, Zidovska A, Choi MC, Ojeda‐Lopez MA, Ewert KK, Li Y, Miller HP, Quispe J. Nanoscale assembly in biological systems: from neuronal cytoskeletal proteins to curvature stabilizing lipids. Advanced Materials [Internet]. 2011;23 (20) :2260-2270. Publisher's Version