Advisor(s)

Robert B. Campbell

Contributor(s)

Samuel J. Gatley, Tara Pouyani

Date of Award

2008

Date Accepted

3-2008

Degree Grantor

Northeastern University

Degree Level

M.S.

Degree Name

Master of Science

Department or Academic Unit

Bouvé College of Health Sciences. Department of Pharmaceutical Sciences.

Keywords

Pharmaceutical sciences, Immunoliposomes, MUC4, Pancreatic cancer, Gemcitabine

Subject Categories

Pancreas--Diseases, Cancer--Treatment

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

The purpose of this study is to understand the extent to which MUC4 (mucin) can be used to improve targeted delivery to pancreatic tumors and specifically whether gemcitabine-loaded, anti-MUC4 immunoliposomes offer any significant advantage over the conventional liposome and free drug in pancreatic cancer treatment. MUC4 glycoprotein has been established as a tumor specific antigen. MUC4 is expressed in normal tissues such as the lungs, ovaries and kidneys but in greater quantities in pancreatic adenocarcinomas. In my thesis, the overexpression of MUC4 in pancreatic adenocarcinoma has been considered as an effective means of targeting chemotherapeutic agents to pancreatic tumors. Anti-MUC4 immunoliposomes were prepared for targeted drug delivery and were compared to non-targeted liposomes to evaluate the role of MUC4 in pancreatic cancer management. The lipid composition was optimized for maximum incorporation of the chemotherapeutic agent, gemcitabine. The percentage of gemcitabine incorporated in stealth liposomes was 78.4 percent. Loading of hydrophilic drugs into liposomes generally results in relatively low drug incorporation. But in our study, we have reported a relatively high incorporation of gemcitabine compared to studies published elsewhere. Gemcitabine-loaded stealth liposomes were stable over the period evaluated (48 hrs). Average particle size of the gemcitabine-loaded stealth liposomes (non-targeted) was 126.8 nm and of the immunoliposomes was 128.2 nm. U-87 MG and PANC-1 (Controls) did not show MUC4 mRNA expression whereas HPAF-II and Capan-1 showed relatively high expression. Immunoliposomes showed significantly high association with Capan-1 and HPAF-II, MUC4 expressing cell lines. Cytotoxic effects for gemcitabine and gemcitabine-loaded stealth and immunoliposomes with 20 and 50 mole % of gemcitabine were observed In vitro. Stealth liposomes were more cytotoxic compared to free drug for 20 mole% formulation. Immunoliposomal formulations were not beneficial in terms of cytotoxicity. In vivo distribution profiles of stealth and immunoliposomes showed significant uptake by the MUC4 expressing tissues like lungs and kidneys. Anti-MUC4 immunoliposomes might be beneficial in treatment of human pancreatic tumors given the sensitivity and specificity of MUC4 for mucin-expressing cell lines.

Document Type

Master's Thesis

Rights Holder

Prasanthi Tata


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