Albumin-bound nanoparticle (nab) paclitaxel exhibits enhanced paclitaxel tissue distribution and tumor penetration

Abstract

Purposenab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL-paclitaxel and the underlying mechanisms.MethodsUptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation.ResultsLive imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL-paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose.ConclusionsCompared with CrEL-paclitaxel, nab-paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-015-2833-5) contains supplementary material, which is available to authorized users.

Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial

“…Albumin has a high affinity for hydrophobic drugs including PTX [4] and is transported across the endothelial barrier of blood vessels through binding to the gp60 albumin receptor and activation of caveolae-mediated endothelial transcytosis [5][6][7]. Simulations based on population pharmacokinetic modeling showed that the tissue distribution of nab-PTX was more dependent upon an active transport mechanism, i.e., endothelial transcytosis for drug distribution into tissues than that of sb-PTX [8]. A preclinical study in rabbits, in which nab-PTX and sb-PTX were intraperitoneally administered, showed that nab-PTX penetrated the peritoneum tissue better than sb-PTX [9].…”

Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-paclitaxel Reduces the Number of Cancer-associated Fibroblasts Through Depletion of Pancreatic Stroma

“…This is best reflected by changes in CAF density, which appears to differ in untreated patients and those treated with conventional GS. The nab-paclitaxel also increases the amount of gemcitabine inside tumor cells by inhibiting cytidine deaminase, the enzyme that degrades gemcitabine (24). Because gemcitabine efficacy is reportedly unaltered in myofibroblast and type I collagen-depleted tumors (25), nab-paclitaxel is capable of altering the stroma in PDAC.…”

Systemic effects of angiogenesis inhibition alter pharmacokinetics and intratumoral delivery of nab-paclitaxel

“…administration while t 1/2 remained the same (Gustafson et al, 2005). This corresponds to studies demonstrating more efficient transport of NPTX across endothelial cells compared to sb-PTX, in which albumin results in an advantageous pharmacokinetic profile (Yardley, 2013;Chen et al, 2015). Figure 6.…”