This dual-agent formulation dramatically enhanced the overall efficacy of each drug against breast and ovarian cancer cells at reduced doses. Combination index and isobologram analysis confirmed higher synergistic drug effects over a wider range of concentrations compared to combinations of either the free drugs or nanopackaged single drugs. The extent of synergism was further dependent
on the individual drug ratios which highlights the importance of single carrier-mediated combination drug delivery platforms that allow such tunable drug loading. In vitro studies with the PCN system further demonstrated that during cellular uptake via endocytosis, Inhibitors,research,lifescience,medical the initial drug-combination ratio in the liposome was preserved [67]. Attaching targeting ligands such as antibodies and peptides to a drug carrier Inhibitors,research,lifescience,medical is a widely applied strategy drastically increasing carrier accumulation in the desired cells, tissues, and organs. Several such targeted liposomes have been developed for combination drug delivery applications [68]. Wu et al. synthesized and evaluated transferring- (Tf-) conjugated liposomes Inhibitors,research,lifescience,medical coloaded with doxorubicin (Dox) and verapamil (Ver). The targeted liposome showed high specificity for Tf receptor overexpressing cancer
cells. Due to the weakly basic nature of Dox and Ver, it was possible to load both agents into liposomes via a Apoptosis inhibitor transmembrane pH gradient. The Dox and Ver coloaded liposome showed threefold increase in anticancer activity compared to liposomal Dox alone while concurrently minimizing Ver-related adverse effects Inhibitors,research,lifescience,medical including cardiotoxicity, which typically
occur with systemic administration of Ver [69]. In addition, the combination of Tf receptor targeting and coencapsulation of Dox and Ver was highly effective in overcoming MDR in Dox resistant cells. These results indicate that active targeting plays a pivotal role in enhancing receptor-mediated endocytosis Inhibitors,research,lifescience,medical of the drug delivery carrier bypassing Pgp-mediated efflux and resistance mechanisms. As with any carrier-mediated codelivery system, determination of the optimal dose as the relative ratio of multiple drugs is a complex aspect in liposome-based combination drug delivery system. Mayer et al. reported precise control over combinatorial drug dosing in liposomes [70]. The combination of no drugs loaded into liposomes at desirable ratios could be achieved by adjusting liposome synthesis and drug encapsulation process. Various products based on this formulation such as CPX-351 (cytarabine + daunorubicin) [71] and CPX-1 (irinotecan + floxuridine) [72] are currently investigated in clinical trials. 4.2. Combination Drug Delivery Systems Based on Dendrimers Dendrimers are well-established three-dimensional, branched polymers that have been thoroughly investigated as controlled and targeted drug delivery systems.