Copper–topotecan complexation mediates drug accumulation into liposomes

The Role of the Transition Metal Copper and the Ionophore A23187 in the Development of Irinophore C™

“…It is now well established that divalent metals can, even in the absence of a pH gradient, facilitate the encapsulation of selected anticancer drugs with chemical groups capable of forming coordination complexes with transition metals trapped inside liposomal vesicles (3,6,7,(13)(14)(15)(16)(17). When assessing the role of transmembrane pH gradients on this loading process, our research suggested that copper exhibited a distinct advantage over manganese (another metal commonly employed to facilitate encapsulation), in terms drug retention (6,10,17).…”

“…It is now well established that divalent metals can, even in the absence of a pH gradient, facilitate the encapsulation of selected anticancer drugs with chemical groups capable of forming coordination complexes with transition metals trapped inside liposomal vesicles (3,6,7,(13)(14)(15)(16)(17). When assessing the role of transmembrane pH gradients on this loading process, our research suggested that copper exhibited a distinct advantage over manganese (another metal commonly employed to facilitate encapsulation), in terms drug retention (6,10,17). Transmembrane pH gradients can be created in a number of ways: i) preparing liposomes using acidic aqueous buffers (14,18), ii) using aqueous solution of ammonium sulfate (5), or iii) preparing liposomes with aqueous solutions of monovalent or divalent metal ions in combination with an appropriate transmembrane ionophore (7,14,17).…”

Intra and Inter-Molecular Interactions Dictate the Aggregation State of Irinotecan Co-Encapsulated with Floxuridine Inside Liposomes

“…The lack of an observable change in either liposome morphology or internal structure by cryo-EM led to the hypothesis that the addition of copper gluconate might have some chemical and/ or physical effect within the liposome that was manifested in augmented release characteristics for irinotecan in CPX-1. It should be noted that formation of copper-irinotecan and copper-topotecan complexes have been shown to result in drug precipitation inside liposomes that is observable by cryo-EM (14,23). We have previously reported that irinotecan was capable of forming a complex with unbuffered copper sulfate solution but unlikely with copper gluconate due to the presence of the strongly chelating gluconate ligands (log K= 18.2;15,24).…”

“…We have demonstrated that liposomes containing copper gluconate/triethanolamine (TEA) at pH 7.0 are able to actively sequester irinotecan (5) without employing acidic pH gradients that could lead to lipid and/or drug instability during storage due to acid-mediated hydrolysis (10)(11)(12)(13)(14). Although unbuffered copper sulfate can be used to encapsulate irinotecan, high copper concentrations are required and the pH inside the liposomes is very low (pH 3.5).…”

Targeted Delivery of Surface Modified Nanoparticles: Modulation of Inflammation for Acute Lung Injury

“…144,191 However, one of the most widely used encapsulation methods employs transmembrane gradients to efficiently load and subsequently stabilize weakly basic amphipathic drugs inside the core of liposomes. These include: (I) simple pH gradients using citric acid solutions, 192,193 (II) ammonium ion gradients employing citrate 194 or sulfate, 195 (III) alkyl, 196 (di-alkyl) or trialkyl ammonium salts, 197 (IV) transition metal concentration gradients (Cu 2+ , Mn 2+ , Zn 2+ and Mg 2+ ) [198][199][200] and (V) transmembrane gradients of drug solubility. 201 The cation entrapped in the liposome interior plays a role either in establishing a pH gradient across the membrane that drives the accumulation of weakly basic drugs into the liposome interior, or directly exchanging with the drug molecule.…”