Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity

Abstract

Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

Amphiphilic Triblock Copolymers from Poly(2‐oxazoline) with Different Hydrophobic Blocks: Changes of the Micellar Structures upon Addition of a Strongly Hydrophobic Cancer Drug

“…Possibly, PTX is located at the core–shell interface which we expect to be diffuse and which therefore provides a favorable environment for a complex molecule as PTX (Figure ). From the diffusion coefficient of PTX, which was previously estimated to be 9.5 × 10 −11 m 2 s −1 , we calculate the hydrodynamic radius of PTX of approximately 26 Å (via the Stokes‐Einstein law, using the viscosity of water). Thus, even at high loading, the PTX domains seem to consist of very few PTX molecules, which may associate with the POx triblock copolymers via nonpolar as well as polar interactions.…”

Development and Evaluation of 2-Amino-7-Fluorophenazine 5,10-Dioxide Polymeric Micelles as Antitumoral Agents for 4T1 Breast Cancer

“…After 5 days of inoculation, tumor diameters were measured daily with a sterile vernier caliper. The two tumor diameters, width and length, were measured and the tumor volume (V) was calculated using the following equation: V = (width 2 × length)/2 [ 15 , 54 , 55 , 56 , 57 ].…”

Photoacoustic Imaging Quantifies Drug Release from Nanocarriers via Redox Chemistry of Dye‐Labeled Cargo

“…The maximum solubility of PTX‐MB in 20 % v/v mouse serum (in PBS) was 4.18×10 −5 mol l −1 . This increased solubility of PTX‐MB in 20 % v/v mouse serum (in PBS) is attributed to the 10‐fold higher solubility of paclitaxel in the presence of serum protein …”