MIT Biomedical Engineering Society


Vol. 4 No. 6 April 2006 BE FAQ BE.180 Programming BE.109 Lab Pfizer Tour Lauffenburger Interview Student Research Printable Version	The BioTECH Quarterly Student Research Spotlight Development of Cortisol-Targeted HPMA Copolymer-Bound Doxorubicin as a Treatment for Ovarian-Cancer University of Utah Bioengineering Department Summer Internship Program By Heather Pressler, '07 Heather Pressler is a Junior majoring in Biology. Her research was awarded second place in the November, 2005 BE Poster Session. Despite medical advances, 50% of the women diagnosed with ovarian cancer today will die within 5 years. Current treatment is limited to invasive and painful procedures such as chemotherapy, radiation, and surgery. Targeted cancer therapeutics have been proposed as a viable, less invasive treatment for ovarian cancer. Previously published studies on N-2-hydroxypropylmethacrylamide (HPMA) copolymer-bound Doxorubicin (DOX) or Mesochlorin-e6-monoethylene-diamine disodium salt (Mce6) show that these chemotherapy agents induce both necrosis and apoptosis.i,ii Necrosis is an unfavorable method of causing cell death because necrosis causes inflammation, leading to great discomfort in patients. A specific, improved polymer conjugate system with the potential to increase the efficacy accompanied by a reduction in the amount of necrosis following therapy may afford a promising treatment for ovarian cancer. In this study, a novel drug-targeting strategy was applied for the first time to target DOX to the nuclear subcompartment of ovarian carcinoma cells. This strategy is based on the strategy devised for Mce6 by Vaikunth Cuchelkar at the University of Utah. In this method DOX and cortisol are attached to the HPMA copolymer via a glycylphenylalanylleucylglycine (GFLG) linker. The HPMA polymer backbone passively accumulates in tumor tissue by the Enhanced Permeability and Retention (EPR) effect, allowing endocytosis into tumor cells. The GFLG linker is degraded in the lysosomes by Cathepsin B which releases the cortisol-DOX from HPMA. Once released, cortisol totes the drug into the nucleus via interaction with the glucocorticoid receptor. Targeting the nucleus with certain anticancer drugs increases the likelihood of inducing apoptosis and achieving a favorable clinical outcome. In addition, cytotoxicity tests show almost a four-fold increase in the efficacy of the cortisol-targeted Mce6 over the non-nuclear-targeted Mce6. Similar results can be expected with DOX. Cells transfected with green fluorescent protein (GFP) tagged glucocorticoid receptor (GR) demonstrated that the Cortisol does in fact use GR to enter the nucleus. Our results suggest that cortisol targeted DOX could become an efficacious technique to achieve nuclear targeting and thereby enhance the potency of DOX not only in ovarian cancer, but also in various other cancers. i Minko T, Kopeckova P, Kopecek J. Efficacy of the chemotherapeutic action of HPMA copolymer-bound doxorubicin in a solid tumor model of ovarian carcinoma. Int J Cancer. 2000 Apr 1;86(1):108-17. ii Tijerina M, Kopeckova P, Kopecek J. Mechanisms of cytotoxicity in human ovarian carcinoma cells exposed to free Mce6 or HPMA copolymer-Mce6 conjugates. Photochem Photobiol. 2003 Jun;77(6):645-52.
	©2005-2006 Biomedical Engineering Society of the Massachusetts Institute of Technology. All Rights Reserved. Webmaster Connie Yee and Kenny Yan

The BioTECH Quarterly

Student Research Spotlight
Development of Cortisol-Targeted HPMA Copolymer-Bound Doxorubicin as a Treatment for Ovarian-Cancer
University of Utah Bioengineering Department Summer Internship Program

By Heather Pressler, '07

Heather Pressler is a Junior majoring in Biology. Her research was awarded second place in the November, 2005 BE Poster Session.

Despite medical advances, 50% of the women diagnosed with ovarian cancer today will die within 5 years. Current treatment is limited to invasive and painful procedures such as chemotherapy, radiation, and surgery. Targeted cancer therapeutics have been proposed as a viable, less invasive treatment for ovarian cancer. Previously published studies on N-2-hydroxypropylmethacrylamide (HPMA) copolymer-bound Doxorubicin (DOX) or Mesochlorin-e6-monoethylene-diamine disodium salt (Mce6) show that these chemotherapy agents induce both necrosis and apoptosis.i,ii Necrosis is an unfavorable method of causing cell death because necrosis causes inflammation, leading to great discomfort in patients. A specific, improved polymer conjugate system with the potential to increase the efficacy accompanied by a reduction in the amount of necrosis following therapy may afford a promising treatment for ovarian cancer. In this study, a novel drug-targeting strategy was applied for the first time to target DOX to the nuclear subcompartment of ovarian carcinoma cells. This strategy is based on the strategy devised for Mce6 by Vaikunth Cuchelkar at the University of Utah. In this method DOX and cortisol are attached to the HPMA copolymer via a glycylphenylalanylleucylglycine (GFLG) linker.

The HPMA polymer backbone passively accumulates in tumor tissue by the Enhanced Permeability and Retention (EPR) effect, allowing endocytosis into tumor cells. The GFLG linker is degraded in the lysosomes by Cathepsin B which releases the cortisol-DOX from HPMA. Once released, cortisol totes the drug into the nucleus via interaction with the glucocorticoid receptor.

Targeting the nucleus with certain anticancer drugs increases the likelihood of inducing apoptosis and achieving a favorable clinical outcome. In addition, cytotoxicity tests show almost a four-fold increase in the efficacy of the cortisol-targeted Mce6 over the non-nuclear-targeted Mce6. Similar results can be expected with DOX. Cells transfected with green fluorescent protein (GFP) tagged glucocorticoid receptor (GR) demonstrated that the Cortisol does in fact use GR to enter the nucleus. Our results suggest that cortisol targeted DOX could become an efficacious technique to achieve nuclear targeting and thereby enhance the potency of DOX not only in ovarian cancer, but also in various other cancers.

i Minko T, Kopeckova P, Kopecek J. Efficacy of the chemotherapeutic action of HPMA copolymer-bound doxorubicin in a solid tumor model of ovarian carcinoma. Int J Cancer. 2000 Apr 1;86(1):108-17.
ii Tijerina M, Kopeckova P, Kopecek J. Mechanisms of cytotoxicity in human ovarian carcinoma cells exposed to free Mce6 or HPMA copolymer-Mce6 conjugates. Photochem Photobiol. 2003 Jun;77(6):645-52.