Liposomes Co- encapsulating Anticancer Drugs in Synergistic Ratios as an Approach to Promote Increased Efficacy and Greater Safety

Author(s): Marina S. Franco , Mônica C. Oliveira* .

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 19 , Issue 1 , 2019

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Graphical Abstract:


The era of chemotherapy began in the 1940s, but it was in the 1960s that it was seen as really promising when the first patients with childhood acute lymphoblastic leukemia were cured with combination chemotherapy. Today, it is known that due to resistance to single agents, combination therapy is essential for tumor eradication and cure. In the last decade, studies have shown that anticancer drug combinations can act synergistically or antagonistically against tumor cells in vitro, depending on the ratios of the individual drugs forming the combination. From this observation and facing the possibility of maintaining the in vivo synergistic ratio of combinations came the idea of co-encapsulating anticancer agents in nanosystems. In vivo studies validated this idea by showing that the co-encapsulation of anticancer agents in liposomes allows the maintenance of drug ratios in the plasma and the delivery of fixed drug ratios directly to tumor tissue, leading to a better efficacy compared to the administration of the free drugs combination. Liposomes co-encapsulating irinotecan/floxuridine are now in Phase II trial, and liposomes co-encapsulating cytarabine/daunorubicin were recently approved by the FDA for treatment of patients with acute myeloid leukemia.

Keywords: Anticancer drugs, liposomes, cancer, co-encapsulation, combination chemotherapy, synergistic ratios, drug combination.

Chabner, B.A.; Roberts, T.G. Chemotherapy and the war on cancer. Nat. Rev. Cancer, 2005, 5, 65-72.
DeVita, V.T.; Chu, E. A history of cancer chemotherapy. Cancer Res., 2008, 68(21), 8643-8653.
Al-Lazikani, B.; Banerji, U.; Workman, P. Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol., 2012, 30(7), 679-692.
Mayer, L.D.; Janoff, A.S. Optimizing combination chemotherapy by controlling drug ratios. Mol. Interv., 2007, 7(4), 216-223.
Mayer, L.D.; Harasym, T.O.; Tardi, P.G.; Harasym, N.L.; Shew, C.R.; Johnstone, S.A.; Ramsay, E.C.; Bally, M.B.; Janoff, A.S. Ratiometric dosing of anticancer drug combinations: Controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Mol. Cancer Ther., 2006, 5(7), 1854-1863.
Zucker, D.; Barenholz, Y. Optimization of vincristine-topotecan combination - Paving the way for improved chemotherapy regimens by nanoliposomes. J. Control. Release, 2010, 146(3), 326-333.
Wong, M.Y.; Chiu, G.N.C. Liposome formulation of co-encapsulated vincristine and quercetin enhanced antitumor activity in a trastuzumab-insensitive breast tumor xenograft model. Nanomed-Nanotechnol, 2011, 7, 834-840.
Ciofani, T.; Harasym, T.; Juan, M.C.Y.; Mayer, L.; Cabral-Lilly, D.; Xie, S. Determination of total and encapsulated drug pharmacokinetics for CPX-351, a nanoscale liposomal fixed molar ratio of cytarabine-daunorubicin (Cyt:Daun). In:. Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research, Orlando, US, Apr 2-6. 2011, 71, (8), 5464.
Shaikh, I.M.; Tan, K.B.; Chaudhury, A.; Liu, Y.; Tan, B.J.; Tan, B.M.J.; Chiu, G.N.C. Liposome co-encapsulation of synergistic combination of irinotecan anddoxorubicin for the treatment of intraperitoneally grown ovarian tumor xenograft. J. Control. Release, 2013, 172(3), 852-861.
Liu, Y.; Fang, J.; Kim, Y.J.; Wong, M.K.; Wang, P. Codelivery of doxorubicin and paclitaxel by cross-linked multilamellar liposome enables synergistic antitumor activity. Mol. Pharm., 2014, 11(5), 1651-1661.
Batist, G.; Gelmon, K.A.; Chi, K.N.; Miller, W.H., Jr; Chia, S.K.; Mayer, L.D.; Swenson, C.E.; Janoff, A.S.; Louie, A.C. Safety, pharmacokinetics, and efficacy of CPX-1 liposome injection in patients with advanced solid tumors. Clin. Cancer Res., 2009, 15(2), 692-700.
Feldman, E.J.; Kolitz, J.E.; Trang, J.M.; Liboiron, B.D.; Swenson, C.E.; Chiarella, M.T.; Mayer, L.D.; Louie, A.C.; Lancet, J.E. Pharmacokinetics of CPX-351; A nano-scale liposomal fixed molar ratio formulation of cytarabine: Daunorubicin, in patients with advanced leukemia. Leuk. Res., 2012, 36(10), 1283-1289.
Chou, T.C.; Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul., 1984, 22, 27-55.
Chou, J.H.; Chou, T.C. Dose-effect analysis with microcomputers: Quantitation of ED50, ID50, synergism, antagonism, low-dose risk, receptor ligand binding and enzyme kinetics: computer software for the IBM PC series; Elsevier-Biosoft: Cambridge, 1989.
Chou, T.C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev., 2006, 58(3), 621-681.
Chou, T.C.; Martin, N. CompuSyn for drug combinations: PC software and user’s guide: A computer program for quantitation of synergism and antagonism in drug combinations, and the determination of IC50 and ED50 and LD50 values. ComboSyn Inc; Paramus, 2005.
Chou, T.C. Drug combination studies and their synergy quantification. Cancer Res., 2010, 70(2), 440-446.
Tardi, P.G.; Gallagher, R.C.; Johnstone, S.; Harasym, N.; Webb, M.; Bally, M.B.; Mayer, L.D. Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo. Biochim. Biophys. Acta, 2007, 1768(3), 678-687.
New, R.R.C. Introduction.In Liposomes: A pratical approach; New, R.R.C., Ed.; Oxford University Press: New York, 1990, pp. 1-32.
Lopes, S.C.A.; Giuberti, C.S.; Rocha, T.G.R.; Ferreira, D.S.; Leite, E.A.; Oliveira, M.C. Liposomes as Carriers of Anticancer Drugs.In Cancer Treatment - Conventional and Innovative Approaches; Rangel, L., Ed.; InTech: Vienna, 2013.
Klibanov, A.L.; Maruyama, K.; Torchilin, V.P.; Huang, L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett., 1990, 268(1), 235-237.
Narang, A.S.; Varia, S. Role of tumor vascular architecture in drug delivery. Adv. Drug Deliv. Rev., 2011, 63(8), 640-658.
Danhier, F.; Feron, O.; Préat, V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J. Control. Release, 2010, 148(2), 135-146.
Yuan, F.; Leunig, M.; Huang, S.K.; Berk, D.A.; Papahadjopoulos, D.; Jain, R.K. Microvascular permeability and interstitial penetration of sterically stabilized (Stealth) liposomes in a human tumor xenograft. Cancer Res., 1994, 54(13), 3352-3356.
Torchilin, V.P. Passive and active drug targeting: Drug delivery to tumors as an example. In:. andbook of Experimental Pharmacology;, Schafer-Korting, M., Ed.; Springer-Verlag, Berlin, 2010, 4-36/
Ferreira, D.S.; Lopes, S.C.; Franco, M.S.; Oliveira, M.C. ph-sensitive liposomes for drug delivery in cancer treatment. Therap. Del., 2013, 4(9), 1099-1123.
Harasym, T.O.; Tardi, P.G.; Harasym, N.L.; Harvie, P.; Johnstone, S.A.; Mayer, L.D. Increased preclinical efficacy of irinotecan and floxuridine coencapsulated inside liposomes is associated with tumor delivery of synergistic drug ratios. Oncol. Res., 2007, 16(8), 361-374.
Riviere, K.; Kieler-Ferguson, H.M.; Jerger, K.; Szoka, F.C., Jr Anti-tumor activity of liposome encapsulated fluoroorotic acid as a single agent and in combination with liposome irinotecan. J. Control. Release, 2011, 153(3), 288-296.
Agrawal, V.; Paul, M.K.; Mukhopadhyay, A.K. 6-Mercaptopurine and daunorubicin double drug liposomes-preparation, drug-drug interaction and characterization. J. Liposome Res., 2005, 15(3-4), 141-155.
Tardi, P.; Johnstone, S.; Harasym, N.; Xie, S.; Harasym, T.; Zisman, N.; Harvie, P.; Bermudes, D.; Mayer, L. In vivo maintenance of synergistic cytarabine: Daunorubicin ratios greatly enhances therapeutic efficacy. Leuk. Res., 2009, 33(1), 129-139.
Zhao, X.; Wu, J.; Muthusamy, N.; Byrd, J.C.; Lee, R.J. Liposomal coencapsulated fludarabine and mitoxantrone for lymphoproliferative disorder treatment. J. Pharm. Sci., 2008, 97(4), 1508-1518.
Wong, M.Y.; Chiu, G.N.C. Simultaneous liposomal delivery of quercetin and vincristine for enhanced estrogen-receptor-negative breast cancer treatment. Anticancer Drugs, 2010, 21(4), 401-410.
Abraham, S.A.; McKenzie, C.; Masin, D.; Ng, R.; Harasym, T.O.; Mayer, L.D.; Bally, M.B. In vitro and in vivo characterization of doxorubicin and vincristine coencapsulated within liposomes through use of transition metal ion complexation and pH gradient loading. Clin. Cancer Res., 2004, 10(2), 728-738.
Zucker, D.; Andriyanov, A.V.; Steiner, A.; Raviv, U.; Barenholz, Y. Characterization of PEGylatednanoliposomes co-remotely loaded with topotecan and vincristine: Relating structure and pharmacokinetics to therapeutic efficacy. J. Control. Release, 2012, 160(2), 281-289.
Batist, G.; Sawyer, M.; Gabrail, N.; Christiansen, N.; Marshall, J.L.; Spigel, D.R.; Louie, A. A multicenter, phase II study of CPX-1 liposome injection in patients (pts) with advanced colorectal cancer (CRC). J. Clin. Oncol., 2008, 26(15S), 4108.
Lim, W.S.; Tardi, P.G.; Xie, X.; Fan, M.; Huang, R.; Ciofani, T.; Harasym, T.O.; Mayer, L.D. Schedule- and dose-dependency of CPX-351, a synergistic fixed ratio cytarabine: Daunorubicin formulation, in consolidation treatment against human leukemia xenografts. Leuk. Lymphoma, 2010, 51(8), 1536-1542.
Lim, W.S.; Tardi, P.G.; Dos Santos, N.; Xie, X.; Fan, M.; Liboiron, B.D.; Huang, X.; Harasym, T.O.; Bermudes, D.; Mayer, L.D. Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine: Daunorubicin formulation, in bone marrow xenografts. Leuk. Res., 2010, 34(9), 1214-1223.
Kim, H.P.; Gerhard, B.; Harasym, T.O.; Mayer, L.D.; Hogge, D.E. Liposomal encapsulation of a synergistic molar ratio of cytarabine and daunorubicin enhances selective toxicity for acute myeloid leukemia progenitors as compared to analogous normal hematopoietic cells. Exp. Hematol., 2011, 39(7), 741-750.
Feldman, E.J.; Lancet, J.E.; Kolitz, J.E. Ritchie; E.K.; Roboz, G.J.; List, A.F.; Allen, S.L.; Asatiani, E.; Mayer, L.D.; Swenson, C.; Louie, A.C. First-in-man study of CPX-351: A liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute Myeloid Leukemia. J. Clin. Oncol., 2011, 29(8), 979-985.
Feldman, E.J.; Lancet, J.E.; Kolitz, J.E.; Ritchie, E.K.; List, A.F.; Asatiani, E.; Curcio, T.J.; Burton, M.; Fricano, M.; Swenson, C.; Mayer, L.D.; Louie, A.C. In: Phase I study of a liposomal carrier (CPX-351) containing a synergistic, fixed molar ratio of cytarabine (Ara-C) and daunorubicin (DNR) in advanced leukemias). In: Proceedings of the 50th ASH Annual Meeting and Exposition, San Francisco, USA, December 8, 2008. Available at:. https://ash. (Accessed September 02, 2016).
Lancet. J.E.; Cortes, J.E.; Hogge, D.E.; Tallman, M.S.; Kovacsovics, T.J.; Damon, L.E.; Komrokji, R.; Solomon, S.R.; Kolitz, J.E.; Cooper, M.; Yeager, A.M.; Louie, A.C.; Feldman, E.J. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood, 2014, 123(21), 3239-3246.
Cortes, J.E.; Goldberg, S.L.; Feldman, E.J.; Rizzeri, D.A.; Hogge, D.E.; Larson, M.; Pigneux, A.; Recher, C.; Schiller, G.; Warzocha, K.; Kantarjian, H.; Louie, A.C.; Kolitz, J.E. Phase II, multicenter, randomized trial of CPX-351 (cytarabine: Daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer, 2015, 121(2), 234-242.
Celator Pharmaceuticals. Phase III Study of CPX-351 Versus 7+3 in Patients 60-75 Years Old with Untreated High Risk (Secondary) Acute Myeloid Leukemia. Available at. NCT01696084?term=cpx-351+phase+3&rank=1 (Accessed January 11, 2017).
Lancet. J.E.; Uy, G.L.; Cortes, J.E.; Newell, L.F.; Lin, T.L.; Ritchie, E.K.; Stuart, R.K.; Strickland, S.A.; Hogge, D.; Solomon, S.R.; Stone, R.M.; Bixby, D.L.; Kolitz, J.E.; Schiller, G.J.; Wieduwilt, M.J.; Ryan, D.H.; Hoering, A.; Chiarella, M.; Louie, A.C.; Medeiros, B.C. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J. Clin. Oncol., 2016, 34(15), 7000.
Lancet. J.E.; Rizzieri, D.; Schiller, G.J.; Stuart, R.K.; Kolitz, J.E.; Solomon, S.R.; Newell, L.F.; Erba, H.P.; Uy, G.L.; Ryan, R.; Chiarella, M.; Louie, A.C.; Cortes, J.E. Overall Survival (OS) with CPX-351 versus 7+3 in older adults with newly diagnosed, therapy-related acute myeloid leukemia (tAML): Subgroup analysis of a phase III study. J. Clin. Oncol., 2017, 35(15), 7035.
FDA approves first treatment for certain types of poor-prognosis acute myeloid leukemia. Available at. Events/Newsroom/PressAnnouncements/ucm569883.htm (Accessed January 11, 2018).
VYXEOS™ Prescribing Information, Jazz Pharmaceuticals, California, USA, 2017. Available at:. drugsatfda_docs/label/2017/209401s000lbl.pdf (Accessed January 11, 2018).
Franco, M.S.; Oliveira, M.C. Ratiometric drug delivery using non-liposomal nanocarriers as an approach to increase efficacy and safety of combination chemotherapy. Biomed. Pharmacother., 2017, 96, 584-595.

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Year: 2019
Page: [17 - 28]
Pages: 12
DOI: 10.2174/1871520618666180420170124
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