Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo

Abstract

A liposomal delivery system that coordinates the release of irinotecan and floxuridine in vivo has been developed. The encapsulation of floxuridine was achieved through passive entrapment while irinotecan was actively loaded using a novel copper gluconate/triethanolamine based procedure. Coordinating the release rates of both drugs was achieved by altering the cholesterol content of distearoylphosphatidylcholine (DSPC)/distearoylphosphatidylglycerol (DSPG) based formulations. The liposomal retention of floxuridine in plasma after intravenous injection was dramatically improved by decreasing the cholesterol content of the formulation below 20 mol%. In the case of irinotecan, the opposite trend was observed where increasing cholesterol content enhanced drug retention. Liposomes composed of DSPC/DSPG/Chol (7:2:1, mole ratio) containing co-encapsulated irinotecan and floxuridine at a 1:1 molar ratio exhibited matched leakage rates for the two agents so that the 1:1 ratio was maintained after intravenous administration to mice. The encapsulation of irinotecan was optimal when copper gluconate/triethanolamine (pH 7.4) was used as the intraliposomal buffer. The efficiency of irinotecan loading was approximately 80% with a starting drug to lipid molar ratio of 0.1/1. Leakage of floxuridine from the liposomes during irinotecan loading at 50 degrees C complicated the ability to readily achieve the target 1:1 irinotecan/floxuridine ratio inside the formulation. As a result, a procedure for the simultaneous encapsulation of irinotecan and floxuridine was developed. This co-encapsulation method has the advantage over sequential loading in that extrusion can be performed in the absence of chemotherapeutic agents and the drug/drug ratios in the final formulation can be more precisely controlled.

Combination of the anti-tumour cell ether lipid edelfosine with sterols abolishes haemolytic side effects of the drug

“…In fact, all our binary mixtures are seen to form liposomes when dispersed in water. Liposomes have long been recognized as devices for the slow, sustained release of drugs [13,14]. The fact that the slow release of edelfosine reduces or abolishes haemolysis while keeping almost intact its apoptotic effect suggests that both phenomena occur through different mechanisms.…”

Combination Chemotherapy in Cancer: Principles, Evaluation and Drug Delivery Strategies

“…Although this approach has emerged as a promising strategy for cancer treatment, there are a limited number of research studies reporting successful drug coloading in the same carrier (Tardi et al, 2009;Zhao et al, 2008;Harasym et al, 2007;Mayer et al, 2006). This is likely the result of technical difficulties associated with the efficient and stable encapsulation of two drugs inside a single carrier as well as challenges in controlling the drug leakage rate and still maintaining the entrapped drug:drug ratio after systemic administration Tardi et al, 2007). There are three different approaches to formulate a drug combination involving liposomal design: i) combination of a liposomal drug with a free drug; ii) encapsulation of two drugs in individual liposomal carriers that are subsequently combined at the desired ratio and iii) co-encapsulation of two drugs in the same carrier by means of a simultaneous or a sequential drug loading.…”

“…iii. Co-encapsulation of two drugs in the same liposomal carrier seems to be a preferable solution as compared to administration of individual liposomal drugs since it reduces cost production, minimizes lipid load to the patient, which has been associated to infusion-related side effects, and eliminates the potential interference that each liposome population may exert in the pharmacokinetic profile of the other Tardi et al, 2007). Furthermore, co-encapsulation overcomes potential uncertainties about drug biodistribution provided by the different liposome compositions.…”

“…Nevertheless, the application of liposomes as carriers for anticancer drug combinations has been described in literature only in the last few years (Tardi et al, 2009;Harasym et al, 2007;Tardi et al, 2007;Mayer et al, 2006). To our knowledge, there are no liposomal drug combinations approved for clinical application.…”

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

“…These studies showed that combining either drugs or antigens can result in increased therapeutic effects over monotherapies of immunoliposomal drugs. Co-encapsulation of two different anticancer drugs in the same liposome have recently been described [141][142][143], making it possible to investigate the therapeutic effects of bispecific immunoliposomes coencapsulating a combination of drugs.…”