Development of 5-FU and doxorubicin-loaded cationic liposomes against human pancreatic cancer: Implications for tumor vascular targeting.
OBJECTIVE
Human pancreatic adenocarcinoma is a major leading cause of cancer mortality in the United States. Given that current strategies are relatively ineffective against this disease, new treatments are being developed. Liposomes possessing relatively high cationic lipid content preferentially accumulate in tumor angiogenic vessels compared to vessels in normal tissues. We therefore seek to develop cationic liposomes for targeting pancreatic tumor vessels.


METHODS
We report development of 5-fluorouracil (5-FU) and doxorubicin hydrochloride (DOX) loaded in PEGylated cationic liposomes (PCLs). We evaluate cell association, intracellular fate, and cytotoxicity. Human pancreatic cancer cells HPAF-II and Capan-1, and endothelial cells HMEC-1 and HUVEC were used in this study. Intratumoral distribution of PCLs in (HPAF-II) tumors was determined by intravital microscopy.


RESULTS
HUVEC and HMEC-1 were most susceptible to 5-FU after 24 and 48 h, compared to HPAF-II and Capan-1. We observed >90% incorporation of 5-FU and DOX in PCLs for 3-20 mol% preparations, with reduced incorporation for >20 mol% formulations. PCLs showed significantly higher association with human endothelial versus pancreatic cancer cells, and improved growth inhibitory properties of DOX. Intravital microscopy revealed distribution of PCLs along HPAF-II vessels.


CONCLUSIONS
Targeting human pancreatic cancer with PCLs may represent a rational alternative to conventional strategies.
Kalra
Ashish V
AV
Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, 360 Huntington Avenue, 110 Mugar Hall, Boston, Massachusetts 02115, USA.
Campbell
Robert B
RB
D000230:Adenocarcinoma / Q000098:blood supply* / Q000188:drug therapy*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use*; D001808:Blood Vessels / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use*; D004339:Drug Compounding; D004563:Electrochemistry; D042783:Endothelial Cells / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use*; D006801:Humans; D008081:Liposomes; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D012039:Regional Blood Flow / Q000187:drug effects; D013056:Spectrophotometry, Ultraviolet
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin; D005472:Fluorouracil