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Biodegradable paclitaxel-loaded plga microspheres for regional treatment of peritoneal cancers

Tsai, Max Chia-Shin
http://rave.ohiolink.edu/etdc/view?acc_num=osu1066335356

Abstract Details

2003, Doctor of Philosophy, Ohio State University, Pharmacy.
There has been interest in applying intraperitoneal (IP) chemotherapy to treat malignant peritoneal-confined tumors where clinical trials have demonstrated a pharmacokinetic advantage, improved objective response, and prolonged survival using IP chemotherapy. However, treatment efficacy has been limited to microscopic residual disease (i.e. tumor diameter < 2 cm) presumably due to poor tumor penetration. For this reason, plus the high costs and potential complications associated with peritoneal catheters, IP treatment has not gained wide acceptance, despite its demonstrated survival advantage. The goal of this dissertation was to develop an approach to improve the utility of IP chemotherapy. Our laboratory has shown that at apoptosis-inducing concentrations, paclitaxel, which has shown significant activity against many types of human solid tumors, can enhance tumor porosity and consequently drug penetration in solid tumors. The FDA-approved formulation (TaxolÒ) uses Cremophor EL to solubilize paclitaxel. Cremophor causes potential life-threatening hypersensitivity reactions and Cremophor micelles sequester and reduce the free fraction of paclitaxel, thereby limiting drug uptake into tissues. Thus, we have developed paclitaxel-loaded PLGA microspheres that release the drug at specified rates to exploit the unique pharmacodynamic properties of paclitaxel and eliminate Cremophor-associated complications. We developed three paclitaxel microsphere formulations that release paclitaxel at different rates so that the fast-release microspheres would induce apoptosis, thereby enhancing the tumor penetration of the slow-release microspheres. Pharmacokinetic studies of IP administered paclitaxel microspheres showed a lower plasma AUC and higher drug concentrations in the peritoneal cavity, compared to the Cremophor formulation. The spatial distribution of paclitaxel microspheres after IP administration demonstrated a passive targeting advantage with localization of the microspheres at metastatic IP tumor sites. Dose fractionation by using two types of microspheres with different release rates resulted in prolonged survival time and enhanced drug delivery into solid tumors, compared to the Cremophor formulation or individual microsphere treatment. Microsphere penetration in tumors enhanced drug exposure and retention within the tumor over time. In summary, the paclitaxel-loaded PLGA microspheres may be useful for IP therapy of peritoneal cancers. There has been interest in applying intraperitoneal (IP) chemotherapy to treat malignant peritoneal-confined tumors where clinical trials have demonstrated a pharmacokinetic advantage, improved objective response, and prolonged survival using IP chemotherapy. However, treatment efficacy has been limited to microscopic residual disease (i.e. tumor diameter < 2 cm) presumably due to poor tumor penetration. For this reason, plus the high costs and potential complications associated with peritoneal catheters, IP treatment has not gained wide acceptance, despite its demonstrated survival advantage. The goal of this dissertation was to develop an approach to improve the utility of IP chemotherapy. Our laboratory has shown that at apoptosis-inducing concentrations, paclitaxel, which has shown significant activity against many types of human solid tumors, can enhance tumor porosity and consequently drug penetration in solid tumors. The FDA-approved formulation (Taxol&Ograve;) uses Cremophor EL to solubilize paclitaxel. Cremophor causes potential life-threatening hypersensitivity reactions and Cremophor micelles sequester and reduce the free fraction of paclitaxel, thereby limiting drug uptake into tissues. Thus, we have developed paclitaxel-loaded PLGA microspheres that release the drug at specified rates to exploit the unique pharmacodynamic properties of paclitaxel and eliminate Cremophor-associated complications. We developed three paclitaxel microsphere formulations that release paclitaxel at different rates so that the fast-release microspheres would induce apoptosis, thereby enhancing the tumor penetration of the slow-release microspheres. Pharmacokinetic studies of IP administered paclitaxel microspheres showed a lower plasma AUC and higher drug concentrations in the peritoneal cavity, compared to the Cremophor formulation. The spatial distribution of paclitaxel microspheres after IP administration demonstrated a passive targeting advantage with localization of the microspheres at metastatic IP tumor sites. Dose fractionation by using two types of microspheres with different release rates resulted in prolonged survival time and enhanced drug delivery into solid tumors, compared to the Cremophor formulation or individual microsphere treatment. Microsphere penetration in tumors enhanced drug exposure and retention within the tumor over time. In summary, the paclitaxel-loaded PLGA microspheres may be useful for IP therapy of peritoneal cancers.
Jessie Au (Advisor)
190 p.
Health Sciences, Pharmacy
paclitaxel (Taxol); intraperitoneal administration; microspheres

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Citations

  • Tsai, M. C.-S. (2003). Biodegradable paclitaxel-loaded plga microspheres for regional treatment of peritoneal cancers [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1066335356

    APA Style (7th edition)

  • Tsai, Max. Biodegradable paclitaxel-loaded plga microspheres for regional treatment of peritoneal cancers. 2003. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1066335356.

    MLA Style (8th edition)

  • Tsai, Max. "Biodegradable paclitaxel-loaded plga microspheres for regional treatment of peritoneal cancers." Doctoral dissertation, Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1066335356

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.