Topotecan (
TPT), a highly active anticancer
camptothecin drug, would benefit from nanocarrier-mediated site-specific and intracellular delivery because of a labile
lactone ring whose hydrolysis inactivates the drug, poor cellular uptake resulting from both
lactone hydrolysis and a titratable
phenol hydroxyl, and the schedule-dependency of its efficacy due to its mechanism of action. We have encapsulated
topotecan in
liposomes using transmembrane gradients of triethylammonium
salts of
polyphosphate (Pn) or sucroseoctasulfate (SOS). Circulation lifetimes were prolonged, and the rate of drug release in vivo depended on the drug load (T(1/2)=5.4 h vs. 11.2 h for 124 and 260 g
TPT/mol PL, respectively) and the nature of intraliposomal drug complexing agent used to stabilize the nanoliposome formulation (T(1/2)=11.2 h vs. 27.3 h for Pn and SOS, respectively). Anti-EGFR and anti-HER2-immunoliposomal formulations dramatically increased uptake of
topotecan compared to nontargeted nanoliposomal
topotecan and poorly permeable free
topotecan in receptor-overexpressing
cancer cell lines, with a corresponding increase in cytotoxicity in multiple
breast cancer cell lines and improved antitumor activity against HER2-overexpressing human
breast cancer (BT474) xenografts. We conclude that stabilization of
topotecan in nanoliposomes significantly improves the targetability and pharmacokinetic profile of
topotecan, allowing for highly active formulations against solid
tumors and immunotargeting to
cancer-overexpressing
cell surface receptors.