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Effects of Carrier on Disposition and Antitumor Activity of Intraperitoneal Paclitaxel

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Abstract

Purpose

The rationale for intraperitoneal (IP) chemotherapy is to expose peritoneal tumors to high drug concentrations. While multiple phase III trials have established the significant survival advantage by adding IP therapy to intravenous therapy in optimally debulked ovarian cancer patients, the use of IP chemotherapy is limited by the complications associated with indwelling catheters and by the local chemotherapy-related toxicity. The present study evaluated the effects of drug carrier on the disposition and efficacy of IP paclitaxel, for identifying strategies for further development of IP treatment.

Materials and Methods

Three paclitaxel formulations, i.e., Cremophor micelles, Cremophor-free paclitaxel-loaded gelatin nanoparticles and polymeric microparticles, were evaluated for peritoneal targeting advantage and antitumor activity in mice after IP injection. Whole body autoradiography and scanning electron microscopy were used to visualize the spatial drug distribution in tissues. A kinetic model, depicting the multiple processes involved in the peritoneal-to-plasma transfer of paclitaxel and its carriers, was established to determine the mechanisms by which a drug carrier alters the peritoneal targeting advantage.

Results

Autoradiographic results indicated that IP injection yielded much higher paclitaxel concentrations in intestinal tissues relative to intravenous injection. Compared to the Cremophor and nanoparticle formulations, the microparticles showed slower drug clearance from the peritoneal cavity, slower absorption into the systemic circulation, longer residence time, 10- to 45-times greater peritoneal targeting advantage and ∼2-times longer increase in survival time (p < 0.01 for all parameters).

Conclusions

Our results indicate the important roles of drug carrier in determining the peritoneal targeting advantage and antitumor activity of IP treatment.

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Abbreviations

AUC:

area under curve

AUMC:

area under moment curve

HPLC:

high pressure liquid chromatography

IP:

intraperitoneal

MRT:

mean residence time

MST:

median survival time

PBS:

phosphate-buffered saline

PLG:

poly(D,L-lactide-co-glycolide)

SEM:

scanning electron microscope.

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Acknowledgements

This work was supported in part by a research grant R37CA49816 and R43CA103133 from the National Cancer Institute, NIH, DHHS.

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Author notes

  1. Max Tsai

    Present address: Schering Plough, Kenilworth, New Jersey, USA

  2. Teng-Kuang Yeh

    Present address: National Health Research Institute, Taipei, Taiwan

Authors and Affiliations

  1. College of Pharmacy, The Ohio State University, Columbus, Ohio, USA

    Max Tsai, Ze Lu, Jie Wang, Teng-Kuang Yeh, M. Guillaume Wientjes & Jessie L.-S. Au

  2. Optimum Therapeutics, LLC, Columbus, Ohio, USA

    Ze Lu, Jie Wang & Teng-Kuang Yeh

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  1. Max Tsai
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Correspondence to Jessie L.-S. Au.

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Tsai, M., Lu, Z., Wang, J. et al. Effects of Carrier on Disposition and Antitumor Activity of Intraperitoneal Paclitaxel. Pharm Res 24, 1691–1701 (2007). https://doi.org/10.1007/s11095-007-9298-0

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