Amphipathic weak base

Amphipathic Weak Base Loading into Preformed Liposomes Having a Transmembrane Ammonium Ion Gradient From the Bench to Approved Doxil... 

Doxil, the first liposomal drug that was approved by the Food and Drug Administration, in 1995, is a good example of the successful application of a transmembrane inner liposome high/outer liposome low ammonium ion gradient for remote loading of an amphipathic weak base, the anticancer... 

The role of the ammonium salt anion is not the loading of the amphipathic weak base per se, but rather to control the stability of loading and the profile and rate of release of the amphipathic weak base from the liposome to the external aqueous phase. Two major factors that differentiate the different anions are, firstly, their ability to induce precipitation/crystallization/ gelation in the intraliposome aqueous phase (1,12), and secondly, their effect on the membrane/buffer and octanol/buffer partition coefficient of the amphipathic weak base (1). Regarding the precipitation, the higher the amount of precipitated amphipathic weak base, the more stable is the loading and the slower is its release rate (10-12,18,33,35) and (Wasserman et al.). There are also some risks involved in the precipitation which in some cases reduce the mechanical stability of the liposomes and change liposome shape (36). 

THE DOXIL EXAMPLE FOR REMOTE LOADING OF AMPHIPATHIC WEAK BASE INTO LIPOSOMES... 

Use of AO as an amphipathic weak base, the fluorescence intensity of which is considered to be pH dependent Being an amphipathic weak... 

Haran G, Cohen R, Bar LK, Barenholz Y. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta 1993 1151 201-215. 

Bolotin EM, Cohen R, Bar LK, et al. Ammonium sulfate gradients for efficient and stable remote loading of amphipathic weak bases into liposomes and ligando-liposomes. J Liposome Res 1994 4 455-479. 

Figure 1 Chemical structures of some amphipathic weak bases that have been loaded and stabilized in liposomes using trialkylammonium salts of polyanionic trapping agents in our lab. (A) Doxorubicin, (B) epirubicin, (C) vinorelbine, (D) vincristine, (E) vinblastine, (E) topotecan, (G) irinotecan, (H) swainsonine, (I) 2-diethylami-noethyl-ellipticinium, (J) 6-(3-aminopropyl)ellipticine, and (K) LAQ824.

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