Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 373

(For more details see Barenholz and Haran, 1993, 1994; Haran et al.,
1993, Bolotin et al., 1994; Lasic et al., 1992; Lasic et al., 1995; Clerc
and Barenholz, 1998; Barenholz, 2001; Barenholz, 2007; Zucker et
al., 2009).

External medium
(Med)

Intraliposomal aqueous phase
(Lip)

(NH 4 ) 2 SO 4

2DOX-NH 3 + + 2Cl -

2NH 3 + 2H + 2NH 4 + + SO 4 2-

2NH 3

2DOX-NH 2 + 2H + (DOX-NH 3 ) 2 SO 4 2DOX NH 2

Precipitate

Figure 12.6 doxorubicin remote loading into nSSL exhibiting a
transmembrane ammonium ion gradient. The thick arrows represent the
processes occurring during drug loading, and the thin arrows represent the
processes occurring during drug release.

The efficiency of loading by this method and its stability are
dependent on
( 1 ) The large (~10 12 ) diff erence in permeability coefficient of
the neutral ammonia (10 − 1 cm/sec) and the SO 4 2 − anion
(>10 − 12 cm/sec)
(2) The initial pH gradient having the [H + ] lip >> [H + ] med
(3) The low solubility of (doxorubicin) 2 -SO 4 (<2 mM), which also
minimizes intraliposomal osmotic pressure and therefore
helps keep liposome integrity
(4) The asymmetry in doxorubicin partition coefficient ( K p )
( K p lip/external med > K p lip/intra lip med)
( K p oct/external med > K p oct/intra lip med)
(Barenhoz and Cohen, 1995; Barenholz, 1998).
K p is a partition coefficient between the two phases defined in
the brackets. Lip = liposome membrane, med = aqueous medium
either external or intraliposomal, oct = bulk octanol phase.