Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport 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 (MX-1-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 congruent with ovary > prostate > colon. The LD(50) 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 Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based 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.
American BioScience, Inc., Santa Monica, California 90403, USA. ndesai@americanbioscience.com
Neil
N
Desai
Vuong
V
Trieu
Zhiwen
Z
Yao
Leslie
L
Louie
Sherry
S
Ci
Andrew
A
Yang
Chunlin
C
Tao
Tapas
T
De
Bridget
B
Beals
Donald
D
Dykes
Patricia
P
Noker
Rosie
R
Yao
Elizabeth
E
Labao
Michael
M
Hawkins
Patrick
P
Soon-Shiong
D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D015996:Survival Rate; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000970:Antineoplastic Agents; C022131:cremophor; D011092:Polyethylene Glycols; D017239:Paclitaxel