Abstract
Purpose
Hemolysis is a serious side effect of antitumor alkylphospholipids (APLs) that limits dose levels and is a constraint in their use in therapeutic regimen. Nine prodrugs of promising APLs (miltefosine, perifosine, and erufosine) were synthesized so as to decrease their membrane activity and improve their toxicity profile while preserving their antineoplastic potency.
Methods
The synthesis of the pro-APLs was straightforwardly achieved in one step starting from the parent APLs. The critical aggregation concentration of the prodrugs, their hydrolytic stability under various pH conditions, their blood compatibility and cytotoxicity in three different cell lines were determined and compared to those of the parent antitumor lipids.
Results
The APL prodrugs display antitumor activity which is similar to that of the parent alkylphospholipids but without associated hemolytic toxicity.
Conclusion
The pro-APL compounds may be considered as intravenously injectable derivatives of APLs. They could thus address one of the major issues met in cancer therapies involving antitumor lipids and restricting their utilization to oral and topical administration because of limited maximum tolerated dose.
Similar content being viewed by others
References
Modolell M, Andreesen R, Pahlke W, Brugger U, Munder PG. Disturbance of phospholipid metabolism during the selective destruction of tumor cells induced by alkyl lysophospholipids. Cancer Res. 1979;39(11):4681–6.
Kostadinova A, Topouzova-Hristova T, Momchilova A, Tzoneva R, Berger MR. Antitumor lipids - structure, functions, and medical applications. Adv Protein Chem Struct Biol. 2015;101:27–66.
Breiser A, Kim DJ, Fleer EAM, Damenz W, Drube A, Berger M, et al. Distribution and metabolism of hexadecylphosphocholine in mice. Lipids. 1987;22:925–6.
Yanapirut P, Berger MR, Reinhardt M, Schmähl D. In vitro investigations on the antineoplastic effect of hexadecylphosphocholine. Arzneimittelforschung. 1991;41:652–5.
Eibl H, Hilgard P, Stekar J, Voegeli R, Harleman JH. Experimental therapeutic studies with miltefosine in rats and mice. Prog Exp Tumor Res. 1992;34:116–30.
Verweij J, Planting AST, Stoter G, Gandia D, Armand JP. Phase II study of oral miltefosine in patients with squamous cell head and neck cancer. Eur J Cancer. 1993;29:778–9.
Kötting J, Marschner NW, Neumuller W, Unger C, Eibl H. Hexadecylphosphocholine and octadecyl-methyl-glycero-3-phosphocholine: a comparison of hemolytic activity, serum binding and tissue distribution. Prog Exp Tumor Res. 1992;34:131–42.
Hilgard P, Klenner T, Stekar J, Nössner G, Kutscher B, Engel J. D-21266, a new heterocyclic alkylphospholipid with antitumour activity. Eur J Cancer. 1997;33:442–6.
Gills JJ, Dennis PA. Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep. 2009;11:102–10.
Vink SR, Schellens JHM, van Blitterswijk WJ, Verheij M. Tumor and normal tissue pharmacokinetics of perifosine, an oral anti-cancer alkylphospholipid. Investig New Drugs. 2005;23:279–86.
Mravljak J, Reiner Z, Pečar S. Synthesis and biological evaluation of spin-labeled alkylphospholipid analogs. J Med Chem. 2005;48:6393–9.
Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006;107:4053–62.
Ernst DS, Eisenhauer E, Wainman N, Davis M, Lohmann R, Baetz T, et al. Phase II study of perifosine in previously untreated patients with metastatic melanoma. Investig New Drugs. 2005;23:569–75.
Leighl NB, Dent S, Clemons M, Vandenberg TA, Tozer R, Warr DG, et al. A phase II study of perifosine in advanced or metastatic breast cancer. Breast Cancer Res Treat. 2008;108:87–92.
Cirstea D, Hideshima T, Rodig S, Santo L, Pozzi S, Vallet S, et al. Dual inhibition of Akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther. 2010;9:963–75.
Kötting J, Berger MR, Unger C, Eibl H. Alkylphosphocholines: influence of structural variation on biodistribution at antineoplastically active concentrations. Cancer Chemother Pharmacol. 1992;30:105–12.
Eibl H, Kaufmann-Kolle P. Medical application of synthetic phospholipids as liposomes and drugs. J Liposome Res. 1995;5:131–48.
Yosifov DY, Todorov PT, Zaharieva MM, Georgiev KD, Pilicheva BA, Konstantinov SM, Berger MR. Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity. Cancer Chemother Pharmacol 2011;67:13–25.
Bagley RG, Kurtzberg L, Rouleau C, Yao M, Teicher BA. Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells. Cancer Chemother Pharmacol. 2011;68:1537–46.
Ríos-Marco P, Marco C, Gálvez X, Jiménez-López JM, Carrasco MP. Alkylphospholipids: an update on molecular mechanisms and clinical relevance. Biochim Biophys Acta-Biomembr. 1859;2017:1657–67.
Wang L, Koynova R, Parikh H, MacDonald RC. Transfection activity of binary mixtures of cationic O-substituted phosphatidylcholine derivatives: the hydrophobic core strongly modulates physical properties and DNA delivery efficacy. Biophys J. 2006;91:3692–706.
Opstad CL, Zeeshan M, Zaidi A, Sliwka H-R, Partali V, Nicholson DG, et al. Novel cationic polyene glycol phospholipids as DNA transfer reagents-lack of a structure-activity relationship due to uncontrolled self-assembling processes. Chem Phys Lipids. 2014;183:117–36.
Pierrat P, Creusat G, Laverny G, Pons F, Zuber G, Lebeau L. A cationic phospholipid-detergent conjugate as a new efficient carrier for siRNA delivery. Chem-Eur J. 2012;18:3835–9.
Pierrat P, Kereselidze D, Wehrung P, Zuber G, Pons F, Lebeau L. Bioresponsive deciduous-charge amphiphiles for liposomal delivery of DNA and siRNA. Pharm Res. 2013;30:1362–79.
Pierrat P, Laverny G, Creusat G, Wehrung P, Strub J-M, VanDorsselaer A, et al. Phospholipid-detergent conjugates as novel tools for siRNA delivery. Chem-Eur J. 2013;19:2344–55.
Gaillard B, Remy J-S, Pons F, Lebeau L. Cationic erufosine (ErPC3) prodrugs as gene delivery reagents for antitumor combined therapy. Chem-Eur J. 2019;25:15662–79.
Heyes JA, Niculescu-Duvaz D, Cooper RG, Springer CJ. Synthesis of novel cationic lipids: effect of structural modification on the efficiency of gene transfer. J Med Chem. 2002;45:99–114.
North EJ, Osborne DA, Bridson PK, Baker DL, Parrill AL. Autotaxin structure–activity relationships revealed through lysophosphatidylcholine analogs. Bioorg Med Chem. 2009;17:3433–42.
Noseda A, White JG, Godwin PL, Jerome WG, Modest EJ. Membrane damage in leukemic cells induced by ether and ester lipids - an electron microscopic study. Exp Mol Pathol. 1989;50:69–83.
Yaseen M, Wang Y, Su TJ, Lu JR. Surface adsorption of zwitterionic surfactants: n-alkyl phosphocholines characterised by surface tensiometry and neutron reflection. J Colloid Interface Sci. 2005;288:361–70.
Rakotomanga M, Loiseau PM, Saint-Pierre-Chazalet M. Hexadecylphosphocholine interaction with lipid monolayers. Biochim Biophys Acta-Biomembr. 1661;2004:212–8.
Fichtner I, Zeisig R, Naundorf H, Jungmann S, Arndt D, Asongwe G, et al. Antineoplastic activity of allkylphosphocholines (APC) in human breast carcinomas in vivo and in vitro - use of liposomes. Breast Cancer Res Treat. 1994;32:269–79.
Kaufmann-Kolle P, Drevs J, Berger MR, Kotting J, Marschner N, Unger C, et al. Pharmacokinetic behavior and antineoplastic activity of liposomal hexadecylphosphocholine. Cancer Chemother Pharmacol. 1994;34:393–8.
Zeisig R, Jungmann S, Arndt D, Schutt A, Nissen E. Antineoplastic activity in vitro of free and liposomal alkylphosphocholines. Anti-Cancer Drugs. 1993;4:57–64.
Heerklotz H. Interactions of surfactants with lipid membranes. Q Rev Biophys. 2008;41:205–64.
Fleer EAM, Berkovic D, Unger C, Eibl H. Cellular uptake and metabolic-fate of hexadecylphosphocholine. Prog Exp Tumor Res. 1992;34:33–46.
Berger M, Sobottka S, Konstantinov SM, Eibl H. Erucylphosphocholine is the prototype of i.v. injectable alkylphosphocholines. Drugs today. 1998;34:73–81.
Lohmeyer M, Workman P. Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro antitumor activity of ether lipids. Brit J Cancer. 1995;72:277–86.
Henke G, Lindner LH, Vogeser M, Eibl H-J, Woerner J, Mueller AC, et al. Pharmacokinetics and biodistribution of Erufosine in nude mice - implications for combination with radiotherapy. Radiat Oncol. 2009;4:46.
Ríos-Marco P, Marco C, Cueto FJ, Carrasco MP, Jimenez-Lopez JM. Pleiotropic effects of antitumour alkylphospholipids on cholesterol transport and metabolism. Exp Cell Res. 2016;340:81–90.
Sobottka SB, Berger MR. Assessment of antineoplastic agents by MTT assay - partial underestimation of antiproliferative properties. Cancer Chemother Pharmacol. 1992;30:385–93.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors have no competing interests to declare.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
The detailed description of the materials and methods used to characterize the hydrolytic stability, self-assembly properties, hemolytic activity, and cytotoxicity of the compounds as well as the 1H-, 13C-, and 31P-NMR spectra for compounds Ma, Mb, Mc, Pa, Pb, and Pc are provided as Supplementary Information and can be found at http://… (PDF 10173 kb)
Rights and permissions
About this article
Cite this article
Gaillard, B., Remy, JS., Pons, F. et al. Synthesis and Evaluation of Antitumor Alkylphospholipid Prodrugs. Pharm Res 37, 106 (2020). https://doi.org/10.1007/s11095-020-02830-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11095-020-02830-y