Drug Resistance Updates 6 (2003) 271–279 Liposome-based approaches to overcome anticancer drug resistance Christoph Mamot a , Daryl C. Drummond b,c , Keelung Hong c , Dmitri B. Kirpotin b,c , John W. Park a,c,∗ a Division of Hematology/Oncology, University of California, San Francisco (UCSF), 2340 Sutter Street, San Francisco, CA 94115, USA b California Pacific Medical Center Research Institute, Liposome Research Laboratory, 2200 Webster Street, San Francisco, CA 94115, USA c Hermes Biosciences, Inc., 61 Airport Blvd., Suite B, San Francisco, CA 94080, USA Received 24 July 2003; received in revised form 4 August 2003; accepted 5 August 2003 Abstract Drug resistance remains an important obstacle towards better outcomes in the treatment of cancer. One general approach to overcome this problem has been to inhibit specific resistance mechanisms, such as P-glycoprotein (PGP)-mediated drug efflux, using small molecule agents or other therapeutic strategies. Alternatively, drug delivery approaches using liposomes or other carriers can in principle target drugs to tumor tissue, tumor cells, or even compartments within tumor cells. By increasing bioavailability of drugs at sites of action, these ap- proaches may provide therapeutic advantages, including enhanced efficacy against resistant tumors. Current liposomal anthracyclines have achieved clinical use in cancer treatment by providing efficient encapsulation of drug in stable and non-reactive carriers, and there is evidence indicating potential benefit in some clinical settings involving resistant tumors. Other liposome-based strategies include constructs designed to be taken up by tumor cells, as well as further modifications to allow triggered drug release. These approaches seek to overcome drug resis- tance by more efficient delivery to tumor cells, and in some cases by concomitant avoidance or inhibition of drug efflux mechanisms. Newer agents employ molecular targeting, such as immunoliposomes using antibody-directed binding and internalization. These agents selectively deliver drug to tumor cells, can efficiently internalize for intracellular drug release, and can potentially enhance both efficacy and safety. © 2003 Elsevier Ltd. All rights reserved. Keywords: Liposomes; Immunoliposomes; Drug delivery; Multidrug resistance; MDR 1. Introduction Drug resistance continues to be a major challenge in cancer treatment. Intrinsic or acquired drug resistance occurs frequently in most cancers, and often involves resistance to multiple agents simultaneously (multidrug resistance, MDR). A number of mechanisms for drug re- sistance have been described. These include: overexpressed drug export pumps, such as P-glycoprotein (PGP) and multidrug-resistance protein (MRP); decreased drug uptake, such as altered folate carriers; inactivation of drugs, such as via glutathione-mediated reduction; overexpression of target enzymes, such as upregulated thymidylate synthase; altered drug targets, such as topoisomerase II; increased DNA repair capacity; reduced ability to undergo apop- tosis; and others (reviewed in Kellen, 1994; Broxterman et al., 2003). Among these mechanisms, the role of PGP in multidrug resistance has been one of the most intensively studied. PGP, encoded by the MDR1 gene, is a member of ∗ Corresponding author. Tel.: +1-415-502-3844; fax: +1-415-353-9571. E-mail address: jpark@cc.ucsf.edu (J.W. Park). the ABC (ATP-Binding Cassette) transport protein family and is frequently overexpressed in the MDR phenotype. Other membrane-bound transporters capable of mediating drug efflux include multidrug-resistance protein MRP and other related proteins (Renes et al., 2000). These proteins actively transport a variety of heterocyclic substrates, in- cluding cytotoxic drugs such as anthracyclines, vinca alka- loids, mitoxantrone, paclitaxel, and others out of the cell or into other cellular compartments (Juranka et al., 1989; Cole and Deeley, 1998; Renes et al., 2000). Specific inhibitors of these resistance mechanisms have been widely pursued as a means to restore drug sensitivity (for review, see Leonard et al., 2002). Although still actively under investigation, specific resistance inhibitors have yet to gain registration for clinical use. Progress towards therapeu- tic success has been hampered by such issues as inadequate specificity, both predictable and unforeseen toxicities, un- certainly about the true prevalence and contribution of the known resistance mechanisms, paucity of predictive assays to identify tumors dependent upon particular mechanisms, and multiplicity and redundancy of resistance mechanisms (West et al., 2002). 1368-7646/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1368-7646(03)00082-7