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Copper-topotecan complexation : development of a novel liposomal fromulation of topotecan Taggar, Amandeep S.


Previously it has been reported that transition metal complexation reactions can be used as a method to encapsulate the anticancer drug doxorubicin into liposomes. It has also been reported that a therapeutically promising formulation of topotecan could be prepared using methods that relied on encapsulated manganese(II) ions (Mn²⁺) and a divalent cation/proton ionophore A23187. In this formulation, however, it was not clear whether topotecan encapsulation was achieved as a result of an established pH gradient or as a consequence of transition metal cation complexation with topotecan. The studies described here assess the role of transition metal ions in the encapsulation of topotecan into liposome prepared from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CH) (55:45, mole ratio). Liposomes with Mn²⁺, copper(II) (Cu²⁺), zinc(II) (Zn²⁺) or cobalt(II) (Co²⁺) ion gradients (metal inside) were prepared. Subsequently, topotecan was added to the outside of these liposomes (final drug to lipid ratio (mo1:mol) of 0.2) and drug encapsulation was measured as a function of time and temperature. Consistent with previous results, topotecan could be encapsulated into Mn²⁺ -containing liposomes only in the presence of A23187. This result suggested that a transmembrane pH gradient was necessary for topotecan loading. No drug loading was achieved with liposomes containing Co²⁺ or Zn²⁺. However, Cu2²⁺ -containing liposomes, in the presence or absence of an imposed pH gradient, efficiently encapsulated topotecan. It has been reported that Cu²⁺ can form a complex with camptothecin and for this reason the complexation reaction between topotecan and Cu²⁺ was characterized in solution as a function of pH. These studies demonstrated that topotecan inhibited formation of an insoluble copper(II) hydroxide precipitate. Furthermore, analysis of the topotecan loaded liposomes indicated that only the active lactone form of the drug was encapsulated and that the inactive, carboxylate form, could not be encapsulated. Therefore, transition metal ion complexation reactions define a viable methodology to prepare liposomal topotecan formulation.

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