Pharmaceutical Manufacturing Handbook: Production and

DXR plasma concentration (μg/mL)
100
10
1
0.1
APPLICATIONS OF LIPOSOMES IN THERAPEUTICS 499
Free DXR (10 mg/kg)
nt-LIP-DXR (10 mg/kg)
Doxil (10 mg/kg)
tHA-LIP-DXR (10 mg/kg)
0.01
C57BL/6
B16F10.9
0.001
0 20 40 60 80 100
Time (h)
FIGURE 14 Doxorubicin (DXR) plasma concentration ( μ g/mL) as function of time from
dosing: ( a ) C57BL/6 mice inoculated (by intraveneous injection) with B16F10.9 cells;
( b ) healthy C57BL/6 mice; ( c ) BALB/c mice inoculated with C - 26 cells (injected into right -
hind footpad). A single dose of the selected formulation was injected into the tail vein. DXR
formulations and doses are specifi ed. ( Reprinted from ref. 443 with permission of Neoplasia
Press, Inc .)
action is to bind to vasopressin receptor, which is expressed abundantly on the
SCLC cells.
Hyaluronan (HA) is another potential candidate for tumor targeting because it
has been proven that hyaluronan receptors CD44 and RHAMM are overexpressed
on several tumor types [443] . In this case, hyaluronan is used not only as a targeting
moiety but also to prolong the circulation half - life of the vesicles in question; in
other words, it replaces PEG molecules. HA was chemically attached on the vehicle
surface (57 μ g/ μ mol lipid), which was comprised of PC/PE/Chol (3 : 1 : 1) (HA – LIP).
Doxorubicin was entrapped in 78 ± 5% encapsulation effi ciency, while the ζ potential
and size of the targeted liposomes were − 13.1 ± 3.9 mV and 81 ± 13. Pharmacokinetic/biodistribution
studies were carried out with Doxil (PEGylated liposomal
doxorubicin) as a comparison to the new hyaluronan liposomes. Those studies plus
therapeutic responses were tested on three mice models, one of which was C57Bl/6 -
bearing B16F10.9 lung metastasis. Clearly, ha - liposomal (HA – LIP) – DXR exhibited
prolonged blood circulation similar to Doxil (approved formulation in the market),
which indicated that the amount of attached HA on the vehicle surface is enough
to stabilize and offer the steric stabilization required (Figure 14 ). Also, accumulation
of HA – LIP – DXR was much more reduced in liver of C57Bl/6 - bearing B16F10.9
lung metastasis mice, while DXR accumulation in the tumor site was threefold
higher to that achieved using Doxil. Signifi cant improvement was obtained in both
metastatic burden and survival with Doxil and HA – LIP – DXR (Figure 15 ). Besides,
the HA – LIP – DXR had positive results on all tumor types tested.
Manipulating the genetic material by injecting tumor - suppressing genes has been
an alternative way in cancer treatment. The 3p FUS1 gene is a tumor suppressor
(a)