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Nanoparticle Paclitaxel Promising in Metastatic Breast Cancer

Nanoparticle Paclitaxel Promising in Metastatic Breast Cancer

ORLANDO—ABI-007, an alternative, Cremophor-free intravenous paclitaxel
(Taxol), developed using nanoparticle technology, provided pronounced
single-agent efficacy in two multicenter phase II trials in metastatic breast
cancer, according to data presented at the 38th Annual Meeting of the American
Society of Clinical Oncology (abstract 209). In preclinical studies, ABI-007
resulted in significantly less toxicity than paclitaxel (abstract 462).

The novel cytotoxic agent, currently under study in a phase III trial, is a
nanoparticle, albumin-stabilized paclitaxel. The nanoparticles have an average
size of 130 to 150 nm, or about 1/80th the size of a red blood cell.

To date, ABI-007 has been administered to nearly 300 patients, many at
higher doses than is standard with Taxol therapy, yet all patients were treated
without steroid premedication and, in the majority of cases, without G-CSF
(Neupogen), Patrick Soon-Shiong, MD, told ONI in an interview. In addition, the
infusion is given over 30 minutes, compared with the standard 3-hour Taxol

There has been no evidence of anaphylaxis, and researchers have noted
"reduced myelosuppression," compared to what might be expected with
Taxol, so that G-CSF support was generally not needed, said Dr. Soon-Shiong,
chairman and CEO of Los Angeles-based American Pharmaceutical Partners, which
is developing ABI-007. "I am hopeful that this lack of serious hematologic
toxicity and potential increased efficacy will change the course of how taxane
therapy is given," he said. "If one could give a higher dose safely,
there is a potential then for achieving a higher response rate."

ABI-007 is just one current strategy for overcoming limitations of current
taxane delivery methods, notably those limitations attributed to the vehicle—a
1:1 mixture of Cremophor EL and dehydrated ethanol. Cremophor vehicle has been
associated with a variety of pharmaceutical concerns, including serious
hypersensitivity reactions.

According to Dr. Soon-Shiong, the nanoparticles prolong the activity of the
parent molecule because nonmetabolized paclitaxel is stored in red blood cells
and eventually recycled to the tumor. Additionally, the drug can concentrate in
the tumor due to the Enhanced Permeation and Retention (EPR) effect known to
occur with nanoparticles of this size. Thus, ABI-007 provides a
protein-engineered biological nanotransporter mechanism for enhanced cellular
penetration of paclitaxel (see Figure).

It has not been well recognized that in addition to the toxicity effect, the
Cremophor solvent entraps the paclitaxel molecule within the plasma, resulting
in reduced tissue and tumor availability of the active compound. The enhanced
cellular penetration afforded by ABI-007 may account for the safety and
efficacy effects reported in this phase II study.


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