Lessons Learned from Pharmaceutical Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 126

Desai 2008). Albumin is a natural carrier protein of endogenous hydrophobic mole-
cules. It binds them in a reversible and noncovalent fashion (Hawkins, Soon-Shiong,
and Desai 2008; Paal, Muller, and Hegedus 2001; Purcell, Neault, and Tajmir-Riahi
2000). The formulation takes advantage of the following mechanism: it consists of
paclitaxel nanoparticles stabilized with human serum albumin through hydropho-
bic interactions. Its size of about 130 nm allows it to form a colloidal suspension
in saline solution (0.9% NaCl) for iv injection. Desai et al. showed a higher pen-
etration of Abraxane into tumor cells compared to an equal dose of standard pacli-
taxel, probably due to the fact that Cremophor EL inhibits transcytosis of paclitaxel
(Desai et al. 2006). Clinical studies of the formulation showed lower toxicity, shorter
infusion times, and less hypersensitivity reactions, meaning no premedication is
required. Moreover, Abraxane showed higher response rates and increased survival
(Gradishar et al. 2005; Ibrahim et al. 2002).
6.5.2.3 AmBisome ® (Amphotericin B)
The use of amphotericin B, which offers a broad fungicidal activity, is limited by
its toxicity. Although topical administration is well tolerated, acute toxic reactions
and chronic nephrotoxicity can occur when the drug is administered via infusion
(Adler-Moore and Proffitt 1993).
AmBisome ® is a formulation of amphotericin B incorporated into unilamellar lipo-
somes with a diameter of less than 100 nm. The antifungal drug is integrated tightly
within the liposomal membrane by forming a noncovalent charge-mediated complex
with the membrane material, which consists of various lipids, phospholipids, and cho-
lesterol. The special properties of this liposomal formulation, such as small particle
size and formation of a noncovalent charge complex between drug and carrier, result in
a prolonged circulation of the intact liposome in the bloodstream. Therefore, its clini-
cal pharmacokinetic profile is different from other amphotericin B formulations: a pro-
longed half-life, combined with a lower toxicological profile, shows that AmBisome
has potential therapeutic advantage compared to other amphotericin B formulations
(Adler-Moore and Proffitt 1993; Bekersky et al. 2002; Boswell et al. 1998).
6.5.2.4 Doxil/Caelyx ® (Doxorubicin)
Doxorubicin shows antitumor activity by intercalating DNA strands. Doxil (named
Caelyx outside the US) is a unilamellar liposomal formulation, with a size of less
than 100 nm, which is sterically stabilized with polyethylene glycol (PEG) (Lasic
1996). PEGylation can improve the therapeutic value of drugs (Veronese and Pasut
2005). Coating with inert polymers, such as PEG, can effectively reduce nonspecific
interactions of liposomes with their milieu, hence prolonging their blood circulation
times. These STEALTH ® liposomes can target tumor tissue via the EPR effect more
efficiently, as they are not recognized by the MPS as fast as without PEGylation
(Vaage et al. 1994; Lasic 1995). Studies on Doxil ® /Caelyx ® in rabbits and dogs have
shown decreased cardiotoxicity compared to free doxorubicin (Working et al. 1999).
6.5.2.5 First siRNA Carrier in Clinical Trials (CALAA-01)
The delivery technology is based on a cyclodextrin containing cationic polymer,
which builds a charge-based complex with nucleic acid actives. The addition of a