Pharmaceutical Manufacturing Handbook: Production and

498 LIPOSOMES AND DRUG DELIVERY
while antitumor activity was observed for patients with relapsed small cell lung
carcinoma with survival duration of 5 months. The latter is similar to what is achieved
using only camptothecin analogues taxanes or vinorelbine (survival duration ≤ 6
months).
Also, paclitaxel is the most widely used anticancer agent for non – small cell
lung cancer [420] . Liposomal encapsulated paclitaxel faces the problem of formulation
due to the drug ’ s high hydrophobicity. However, a phase I trial with liposomal
paclitaxel reported dose - limiting toxicity at the dose of 150 mg/m 2 /week. Besides,
the whole blood clearance of paclitaxel was similar for liposomal and free
paclitaxel.
Promising results that were referred to liposomal encapsulated paclitaxel easy to
use (LEP - ETU; NeoPharm) consisted of DSPC/Chol/cardiolipin molar ratio 90 : 5 : 5,
lipid/drug molar ratio 33 : 1, and paclitaxel concentration 2 mg/mL (mean liposome
size 150 nm). In a phase I study of increasing doses of liposomal paclitaxel (135 –
375 mg/m 2 ) in 25 patients, the enhanced effectiveness was proved with much better
tolerability and with 3 partial remissions and 11 patients with stable disease. Lurtotecan,
a camptothecin analogue, was incorporated in PC/Chol (2 : 1 molar ratio)
liposomes (size 50 – 100 nm) with a lipid/drug molar ratio 20 : 1. A remarkable 1500 -
fold AUC increase was obtained after administration in nude mice and several
xenograft models.
9 - Nitro - 20( S ) - camptothecin (9NC), another lipophilic camptothecin analogue,
showed antitumor effects in mice and milder effect in humans after oral administration.
Thus, the potency of 9NC - loaded di-lauryl-PC (DLPC) liposomes was investigated
in patients with primary or metastatic lung cancer after aerosol administration
(aerosol droplet size 1 – 3 μ m) for fi ve consecutive days per week [373] . Indeed, the
most serious side effect of 9NC, hematological toxicity, did not appear in any of the
patients, while the dose - limiting toxicity, chemical pharyngitis, was observed at a
dose of 26.6 μ g/kg/day. 9NC plasma levels, after aerosol administration (13.3 μ g/kg/
day), were similar to that given orally (2 mg/m 2 ), despite the lower dose administered
in the fi rst case. More specifi cally, C max and AUC were 76.7 ± 39.1 ng/mL and 275 ±
149 ng - h/mL, respectively, after aerosol administration and 111 ng/mL and 194.4 ±
108.4 ng - h/mL, respectively, after oral administration. The recommended dose for
phase II studies is 13.3 μ g/kg/day on a 1 - h exposure for fi ve consecutive days per
week and for eight weeks, with 0.4 mg/mL 9NC concentration in the nebulizer.
Moreover, targeting moieties have been grafted on the vesicle surface, exploiting
the fact that antigen/receptor overexpression on cancer cell membranes increases
the specifi city of the active substance. For example, antagonist - G is a hexapeptide
which blocks the action of multiple mitogenic neuropeptides by interacting with
their receptors [170] . Antagonist - G was chemically attached at the distal end of
PEG molecules of stealth liposomes (HSPC/Chol/mPEG – DSPE/PDP – PEG – DSPE,
2 : 1 : 0.08 : 0.02 molar ratio) (SLG) loaded with doxorubicin. The antiproliferative
activity of doxorubicin was estimated on the human variant small cell lung carcinoma
(SCLC) H82 cell line. Indeed, 20 - to 30 - fold increase of both, binding, and
internalization took place after SLG incubation on cells in comparison to stealth
liposomes only, or PEGylated liposomes without the antagonist - G. The 0.03 μ g of
antagonist - G on the liposome surface was enough to cause 50% cell liposome association.
Doxorubicin accumulation in the whole cell was 20 - fold higher with SLG.
Eventually, there was the suggestion that the main antagonist - G mechanism of