Application of pharmaceutical technologies to improve the activity of cancer chemotherapeutic agents

Cancer is a leading cause of death worldwide. Chemotherapy remains a major therapeutic modality in cancer treatment. Conventional chemotherapeutic agents usually have limited efficacy. Furthermore, chemotherapeutic agent- and/or excipient-related toxicities comprise a serious problem that may, in many cases, deteriorate the patient’s quality of life. In this dissertation, different pharmaceutical technology approaches, including nanotechnology and pharmaceutical chemistry, were utilized to improve the activity of chemotherapeutic agents. Docetaxel is a second generation taxane used as a single agent in breast cancer, non-small cell lung cancer, and other cancers. Side effects related to the drug itself and one of the excipients (i.e. Tween 80) are extensive. I designed a solid lipid nanoparticle (DCX-SLNs) formulation to improve the delivery of docetaxel into solid tumors and to avoid excipient-related side effects associated with the current Tween 80-based docetaxel formulation. The DCX-SLNs showed improved in vitro cytotoxicity in various cell lines and significantly inhibited tumor growth in an aggressive mouse model of lung cancer, while the Tween 80-based docetaxel formulation was not effective at the dose and dosing frequency tested. Higher drug accumulation in tumor tissues was achieved when the DCX-SLNs were injected intravenously, as compared to the Tween 80-based docetaxel formulation. Gemcitabine (2̕, 2̕-difluorodeoxycytidine, dFdC) is the first line treatment for advanced pancreatic cancer. It is also used in other cancers (e.g. ovarian and breast cancers). In this dissertation, docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, was conjugated to gemcitabine in the 4(N)-amine group to synthesize a new compound (DHA-dFdC). DHA-dFdC shows potent and broad spectrum cytotoxicity against all NCI/DTP60 human cancer cell lines. DHA-dFdC is also 100000-fold more cytotoxic than gemcitabine against human and mouse pancreatic cancer cells. In addition, DHA-dFdC shows high accumulation in mouse pancreas following intravenous injection, prompting the evaluation of its antitumor activity in mouse models of pancreatic cancer. In nude mice with subcutaneous or orthotopic human Panc-1 tumors, DHA-dFdC is more effective than the molar equivalent dose of gemcitabine in inhibiting the tumor growth. In conclusion, the activity of cancer chemotherapeutic agents can be significantly improved by formulating them with innovative pharmaceutical technologies.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Grantor

The University of Texas at Austin

Year dc:date.issued

2015

Author dc:creator

• Ibrahim, Youssef Wahib Naguib

Advisor dc:contributor.advisor

• Cui, Zhengrong

Committee members dc:contributor.committeemember

• Smyth, Hugh D
• Williams, Robert O
• Hursting, Stephen D
• Stavchansky, Salomon

• Cancer
• Nanomedicine
• Gemitabine conjugate
• Nanoparticles
• Docetaxel

Language dc:language.iso

en

Identifier

doi:10.15781/T2Z02ZF3C

OAI identifier oai:identifier

oai:repositories.lib.utexas.edu:2152/46674