nab-Paclitaxel (Abraxane®): an albumin-bound cytotoxic exploiting natural delivery mechanisms into tumors
- J Iglesias1
© BioMed Central Ltd. 2009
Published: 23 June 2009
Taxanes (paclitaxel and docetaxel) are highly active chemotherapeutic agents in the treatment of breast cancer. Being hydrophobic, taxanes require solvents (Cremphor EL or polysorbate) to enable parenteral administration. These solvents contribute to the main toxicities seen with taxanes (hypersensitivity, peripheral neuropathy, and myelo-suppression). Cremophor EL can also leach plasticizers from polyvinyl chloride tubing, which can result in severe, sometimes fatal, anaphylactic reactions. To prevent or limit the onset of hypersensitivity reactions, corticosteroids and antihistamines are standard premedica-tion with taxanes. Furthermore, Cremophor EL entraps paclitaxel into circulating micelles, which reduces its availability and delivery into tumors . Micelle formation with solvent-based paclitaxel results in nonlinear kinetics and the absence of a dose–response relationship: increasing the dose increases toxicity without an accompanying enhancement in efficacy.
nab-Paclitaxel is a solvent-free, albumin-bound nanoparticle formulation of paclitaxel that takes advantage of the increased delivery of albumin to tumors through receptor-mediated transport called transcytosis. nab-Paclitaxel binds to gp60, the albumin receptor on endothelial cells, which in turn activates caveolin-1 and the formation of caveolae. Caveolae transport the albumin–paclitaxel conjugate to the extracellular space, including the tumor interstitium. In the tumoral interstitium, SPARC (secreted protein, acidic and rich in cysteine) is selectively secreted by the tumors and binds to albumin-bound paclitaxel with the resultant release of paclitaxel in the vicinity of tumor cells. Together the absence of solvents and the receptor-mediated delivery result in decreased toxicity and increased antitumor activity of nab-paclitaxel compared with solvent-based paclitaxel .
nab-Paclitaxel (Abraxane®) has been approved for the treatment of metastatic breast cancer (MBC), based on a phase III trial in 460 patients comparing 260 mg/m2 nab-paclitaxel administered over 30 minutes every 3 weeks (Q3W) without premedication with 175 mg/m2 solvent-based paclitaxel given over 3 hours Q3W with premedication. Overall response rates were 33% and 19% and the median time to progression was 23.0 weeks and 19.6 weeks, respectively. A significant difference was reported in overall survival in patients receiving nab-paclitaxel versus solvent-based paclitaxel in ≥ 2nd lines of treatment (56.4 vs 46.7 weeks, respectively) .
Weekly schedules of nab-paclitaxel have proven more effective than Q3W schedules in a randomized phase II study in MBC. Furthermore, outcomes were more favorable for weekly nab-paclitaxel than for 100 mg/m2 docetaxel administered Q3W, with significantly less toxicity . Development of weekly nab-paclitaxel continues in MBC, NSCLC, melanoma, and pancreatic cancer.
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