Increased AntitumorActivity, Intratumor Paclitaxel Concentrations, and Endothelial CellTransport of Cremophor-Free, Albumin-Bound Paclitaxel, ABI-007, Compared with Cremophor-Based Paclitaxel
ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid
Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit
albumin receptor-mediated endothelial transport.We studied the antitumor activity, intratumoral
paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel.
Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts
[lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated
with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX1-tumored
mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel.
In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and
albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and
Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of
sensitivity was lung > breast ffi ovary > prostate > colon. The LD50 and maximum tolerated dose
for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4
mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete
regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal
dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophorbased
paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial
binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophorbased
paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60
receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel
to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007
and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater
efficacy and intratumor delivery of ABI-007.