Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 356

chromatography. Approximately 90% of the label became liposome-
associated. Patients were imaged using a dose of ~700 mCi of 111 In
and 300 mg phospholipid given by i.v. bolus. Whole body anterior
and posterior images were obtained immediately after injection, 2
h and 24 h later, using a Gamma camera (Apex 415 Elscint, Haifa,
Israel). For details see Gabizon et al., 1991). The results show clearly
that the 111 In-OLV were cleared predominantly by liver and spleen
and to a lesser extent by bone marrow in seven out of nine patients.
In two patients with active hepatitis and severe liver dysfunction,
there was minimal liver uptake and increased spleen and bone
marrow uptake. For all patients analyzed except one hepatoma
patient, intrahepatic and extrahepatic tumors were not imaged by
liposomes (Figures 4, 6-9 in Gabizon et al., 1991), suggesting that
liposome uptake is restricted to cells of the reticuloendothelial
system (RES). These observations indicate that a major fraction of
this OLV-DOX formulation is rapidly cleared by the RES, and that the
mechanism of drug delivery should probably be the combined result
of slow release from the RES depot and drug leakage from circulating
liposomes. However, the contribution of the RES is dependent on
the level of drug remaining in the liposomes while being taken up
by the RES, and the level of free drug should be dependent on the
rate of drug release from the liposomes. The slower the release
rate, the larger should be the benefits. If drug release in plasma is
fast, no beneficial gain of delivery via the administered liposomes
(over administration of free drug) is expected. Unfortunately, in
human subjects the latter occurred. As shown in Figure 12.2, the
OLV-DOX shows fast release of their doxorubicin payload in plasma,
and therefore, the therapeutic benefits expected of these liposomes
compared to free doxorubicin should be minimal, if any. Figure 12.4
clearly demonstrates that conventional liposomes (OLV-DOX) do not
target liver tumor and behave similarly to 99 Tc-colloid.
The same OLV-DOX that failed in humans has been shown to have
reduced toxicity and improved antitumor efficacy in experimental
animal models (rev. in Gabizon and Barenholz, 1988). Namely, the
beneficial eff ects in mice were not reproduced in our Phase I clinical
study (Gabizon et al., 1989a, 1989b). Although the maximal tolerated
dose (MTD) of DOX-OLV was increased in relation to the MTD of
free drug administered at the conventional 3-weekly schedule; in
humans the dose-limiting toxicity (the myelotoxicity) of OLV-DOX is