Login Register Cart 0
Generic placeholder image

Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Liposomal Formulation of a Melphalan Lipophilic Prodrug: Studies of Acute Toxicity, Tolerability, and Antitumor Efficacy

Author(s): Daria Tretiakova, Elena Svirshchevskaya, Natalia Onishchenko, Anna Alekseeva , Ivan Boldyrev, ">Roman Kamyshinsky , Alexey Natykan, Anton Lokhmotov, Diana Arantseva, Dmitry Shobolov and Elena Vodovozova*

Volume 17, Issue 4, 2020

Page: [312 - 323] Pages: 12

DOI: 10.2174/1567201817666200214105357

Price: $65

Abstract

Background: Recently we developed a scalable scheme of synthesis of melphalan ester conjugate with 1,2-dioleoyl-sn-glycerol (MlphDG) and a protocol for the fabrication of its lyophilized liposomal formulation.

Objective: Herein we compared this new convenient in use formulation of MlphDG with parent drug Alkeran® in rats concerning several toxicological parameters and evaluated its antitumor efficacy in the model of breast cancer in mice.

Method: Liposomes of approximately 100 nm in diameter, consisting of egg phosphatidylcholine, soybean phosphatidylinositol, and MlphDG, or placebo liposomes without the drug were produced by extrusion and lyophilized. Alkeran® or liposomes recovered by the addition of water were injected into the tail vein of animals. Clinical examination of rats consisted of detailed inspection of the behavior, general status, and hematological parameters. Mice with transplanted breast cancer WNT-1 were subjected to multiple treatments with the drugs; tumor growth inhibition was assessed, together with cellular immunity parameters.

Results: Liposomes showed approximately two times lower acute toxicity and better tolerability than Alkeran® in terms of behavioral criteria. The toxic effects of liposomes on hemopoiesis were manifested at higher doses than in the case of Alkeran®, proportionally to the difference in LD50 values. The formulation inhibited tumor growth significantly more effectively than Alkeran®, delaying the start of the exponential growth phase and exhibiting no additional toxic effects toward bone marrow.

Conclusion: Lower toxicity of the liposomal formulation of MlphDG promises improved quality of life for cancer patients in need of treatment with melphalan. Presumably, the list of indications for melphalan therapy could be extended.

Keywords: Melphalan, lipophilic prodrug, lyophilized nano-sized liposomes, natural phospholipids, acute toxicity in rats, hemopoiesis, mouse breast cancer, antitumor efficacy.

« Previous Next »
Graphical Abstract

[1]
Teicher, B.A. Antitumor alkylating agents. cancer principals and practice of oncology; De Vita, V.T.; Hellman, S; Rodenberg, S.A., Ed.; Lippincott-Raven Publishers: Philadelphia, 1997, pp. 405-418.
[2]
Wickström, M.; Lövborg, H.; Gullbo, J. Future prospects for old chemotherapeutic drugs in the target-specific era; pharmaceutics, combinations, co-drugs and prodrugs with melphalan as an example. Lett. Drug Des. Discov., 2006, 10, 695-703.
[http://dx.doi.org/10.2174/157018006778631893]
[3]
Musto, P.; D’Auria, F. Melphalan: old and new uses of a still master drug for multiple myeloma. Expert Opin. Investig. Drugs, 2007, 16(9), 1467-1487.
[http://dx.doi.org/10.1517/13543784.16.9.1467] [PMID: 17714032]
[4]
Bayraktar, U.D.; Bashir, Q.; Qazilbash, M.; Champlin, R.E.; Ciurea, S.O. Fifty years of melphalan use in hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant., 2013, 19(3), 344-356.
[http://dx.doi.org/10.1016/j.bbmt.2012.08.011] [PMID: 22922522]
[5]
Bergel, F.; Stock, J.A. Cytotoxic alpha amino acids and endopeptidase. Br. Emp. Cancer Comp. Annu., 1953, 31, 6-21.
[6]
Bergel, F.; Stock, J.A. Cyto-active amino-acid and peptide derrivatives. Part I. Substituted phenylalanines. J. Chem. Soc., 1954, 2409-2417.
[http://dx.doi.org/10.1039/jr9540002409]
[7]
Larionov, L.F.; Shkodinskaja, E.N.; Troosheikina, V.I.; Khokhlov, A.S.; Vasina, O.S.; Novikova, M.A. Studies on the anti-tumour activity of p-di-(2-chloroethyl) aminophenylalanine (sarcolysine). Lancet, 1955, 269(6882), 169-171.
[http://dx.doi.org/10.1016/S0140-6736(55)92736-7] [PMID: 13243678]
[8]
Available from. chemocare.com/chemotherapy/drug-info/Melphalan.aspx
[9]
Facon, T.; Lee, J.H.; Moreau, P.; Niesvizky, R.; Dimopoulos, M.; Hajek, R.; Pour, L.; Jurczyszyn, A.; Qiu, L.; Klippel, Z.; Zahlten-Kumeli, A.; Osman, M.; Paiva, B.; San-Miguel, J. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood, 2019, 133(18), 1953-1963.
[http://dx.doi.org/10.1182/blood-2018-09-874396] [PMID: 30819926]
[10]
Wawrzyniak-Dzierżek, E.; Gajek, K.; Rybka, B.; Ryczan-Krawczyk, R.; Węcławek-Tompol, J.; Raciborska, A.; Mielcarek-Siedziuk, M.; Frączkiewicz, J.; Salamonowicz, M.; Kałwak, K.; Rosa, M.; Ślęzak, A.; Ussowicz, M. Feasibility and safety of treosulfan, melphalan, and thiotepa-based megachemotherapy with autologous or allogeneic stem cell transplantation in heavily pretreated children with relapsed or refractory neuroblastoma. Biol. Blood Marrow Transplant, 2019, S1083- 8791(19), 30290-3.
[http://dx.doi.org/10.1016/j.bbmt.2019.05.006]
[11]
Jones, R.B. Clinical pharmacology of melphalan and its implications for clinical resistance to anticancer agents. Cancer Treat. Res., 2002, 112, 305-322.
[http://dx.doi.org/10.1007/978-1-4615-1173-1_15] [PMID: 12481722]
[12]
Hurley, L.H. DNA and its associated processes as targets for cancer therapy. Nat. Rev. Cancer, 2002, 2(3), 188-200.
[http://dx.doi.org/10.1038/nrc749] [PMID: 11990855]
[13]
McHugh, P.J.; Spanswick, V.J.; Hartley, J.A. Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance. Lancet Oncol., 2001, 2(8), 483-490.
[http://dx.doi.org/10.1016/S1470-2045(01)00454-5] [PMID: 11905724]
[14]
Stout, S.A.; Riley, C.M. The hydrolysis of L-phenylalanine mustard (melphalan). Int. J. Pharm., 1985, 24, 193-208.
[http://dx.doi.org/10.1016/0378-5173(85)90020-1]
[15]
Bosanquet, A.G.; Gilby, E.D. Pharmacokinetics of oral and intravenous melphalan during routine treatment of multiple myeloma. Eur. J. Cancer Clin. Oncol., 1982, 18(4), 355-362.
[http://dx.doi.org/10.1016/0277-5379(82)90006-2] [PMID: 6889512]
[16]
Pinguet, F.; Culine, S.; Bressolle, F.; Astre, C.; Serre, M.P.; Chevillard, C.; Fabbro, M. A phase I and pharmacokinetic study of melphalan using a 24-hour continuous infusion in patients with advanced malignancies. Clin. Cancer Res., 2000, 6(1), 57-63.
[PMID: 10656432]
[17]
Zhdanova, E.A.; Smirnova, L.I.; Krasnov, V.P. The synthesis and biological activity of 4-[bis(2-chloroethyl)amino]-DL-, L, and D-phenylalanine amides and peptides. Russ. Chem. Rev., 1995, 64, 1049-1065.
[http://dx.doi.org/10.1070/RC1995v064n11ABEH000193]
[18]
Mittal, S.; Song, X.; Vig, B.S.; Amidon, G.L. Proline prodrug of melphalan targeted to prolidase, a prodrug activating enzyme overexpressed in melanoma. Pharm. Res., 2007, 24(7), 1290-1298.
[http://dx.doi.org/10.1007/s11095-007-9249-9] [PMID: 17377743]
[19]
Wickström, M.; Johnsen, J.I.; Ponthan, F.; Segerström, L.; Sveinbjörnsson, B.; Lindskog, M.; Lövborg, H.; Viktorsson, K.; Lewensohn, R.; Kogner, P.; Larsson, R.; Gullbo, J. The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo. Mol. Cancer Ther., 2007, 6(9), 2409-2417.
[http://dx.doi.org/10.1158/1535-7163.MCT-07-0156] [PMID: 17876040]
[20]
Aljitawi, O.S.; Hari, P. Propylene glycol-free melphalan as conditioning regimen for autologous transplantation in myeloma. Int. J. Hematol. Oncol., 2016, 5(1), 5-10.
[http://dx.doi.org/10.2217/ijh-2015-0006] [PMID: 30302199]
[21]
Allen, C. Why I’m holding onto hope for nano in oncology. Mol. Pharm., 2016, 13(8), 2603-2604.
[http://dx.doi.org/10.1021/acs.molpharmaceut.6b00547] [PMID: 27404330]
[22]
Matsumura, Y.; Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res., 1986, 46(12 Pt 1), 6387-6392.
[PMID: 2946403]
[23]
Maeda, H.; Nakamura, H.; Fang, J. The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Deliv. Rev., 2013, 65(1), 71-79.
[http://dx.doi.org/10.1016/j.addr.2012.10.002] [PMID: 23088862]
[24]
Maeda, H.; Tsukigawa, K.; Fang, J. A retrospective 30 years after discovery of the enhanced permeability and retention effect of solid tumors: next generation chemotherapeutics and photodynamic therapy problems, solutions, and prospects. Microcirculation, 2016, 23(3), 173-182.
[http://dx.doi.org/10.1111/micc.12228] [PMID: 26237291]
[25]
Wilhelm, S.; Tavares, A.J.; Dai, Q.; Ohta, S.; Audet, J.; Dvorak, H.F.; Chan, W.C.W. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater., 2016, 1, 1-12.
[http://dx.doi.org/10.1038/natrevmats.2016.14]
[26]
Ojha, T.; Pathak, V.; Shi, Y.; Hennink, W.E.; Moonen, C.T.W.; Storm, G.; Kiessling, F.; Lammers, T. Pharmacological and physical vessel modulation strategies to improve EPR-mediated drug targeting to tumors. Adv. Drug Deliv. Rev., 2017, 119, 44-60.
[http://dx.doi.org/10.1016/j.addr.2017.07.007] [PMID: 28697952]
[27]
Krasnov, V.P.; Korolyova, M.A.; Vodovozova, E.L. Nano-sized melphalan and sarcolysine drug delivery systems: synthesis and prospects of application. Russ. Chem. Rev., 2013, 82, 783-814.
[http://dx.doi.org/10.1070/RC2013v082n08ABEH004358]
[28]
Gregoriadis, G. Liposome Technology, 3rd ed; Informa Healthcare USA: New York, London, 2007, Vol. I-III, .
[29]
Gregoriadis, G.; Wills, E.J.; Swain, C.P.; Tavill, A.S. Drug-carrier potential of liposomes in cancer chemotherapy. Lancet, 1974, 1(7870), 1313-1316.
[http://dx.doi.org/10.1016/S0140-6736(74)90682-5] [PMID: 4134296]
[30]
Barenholz, Y. Doxil®--the first FDA-approved nano-drug: lessons learned. J. Control. Release, 2012, 160(2), 117-134.
[http://dx.doi.org/10.1016/j.jconrel.2012.03.020] [PMID: 22484195]
[31]
Gabizon, A.; Dagan, A.; Goren, D.; Barenholz, Y.; Fuks, Z. Liposomes as in vivo carriers of adriamycin: reduced cardiac uptake and preserved antitumor activity in mice. Cancer Res., 1982, 42(11), 4734-4739.
[PMID: 7127308]
[32]
Lasic, D.D.; Papahadjopoulos, D. Liposomes revisited. Science, 1995, 267(5202), 1275-1276.
[http://dx.doi.org/10.1126/science.7871422] [PMID: 7871422]
[33]
Torchilin, V.P. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov., 2005, 4(2), 145-160.
[http://dx.doi.org/10.1038/nrd1632] [PMID: 15688077]
[34]
Allen, T.M.; Cullis, P.R. Liposomal drug delivery systems: from concept to clinical applications. Adv. Drug Deliv. Rev., 2013, 65(1), 36-48.
[http://dx.doi.org/10.1016/j.addr.2012.09.037] [PMID: 23036225]
[35]
Schwendener, R.A. Liposomes as vaccine delivery systems: a review of the recent advances. Ther. Adv. Vaccines, 2014, 2(6), 159-182.
[http://dx.doi.org/10.1177/2051013614541440] [PMID: 25364509]
[36]
Weissig, V.; Pettinger, T.K.; Murdock, N. Nanopharmaceuticals (part 1): products on the market. Int. J. Nanomedicine, 2014, 9, 4357-4373.
[http://dx.doi.org/10.2147/IJN.S46900] [PMID: 25258527]
[37]
Bulbake, U.; Doppalapudi, S.; Kommineni, N.; Khan, W. Liposomal formulations in clinical use: an updated review. Pharmaceutics, 2017, 9(2), E12
[http://dx.doi.org/10.3390/pharmaceutics9020012] [PMID: 28346375]
[38]
Anchordoquy, T.J.; Barenholz, Y.; Boraschi, D.; Chorny, M.; Decuzzi, P.; Dobrovolskaia, M.A.; Farhangrazi, Z.S.; Farrell, D.; Gabizon, A.; Ghandehari, H.; Godin, B.; La-Beck, N.M.; Ljubimova, J.; Moghimi, S.M.; Pagliaro, L.; Park, J.H.; Peer, D.; Ruoslahti, E.; Serkova, N.J.; Simberg, D. Mechanisms and barriers in cancer nanomedicine: addressing challenges, looking for solutions. ACS Nano, 2017, 11(1), 12-18.
[http://dx.doi.org/10.1021/acsnano.6b08244] [PMID: 28068099]
[39]
Vodovozova, E.L.; Kuznetsova, N.R.; Kadykov, V.A.; Khutsyan, S.S.; Gaenko, G.P.; Molotkovsky, Y.G. Liposomes as nanocarriers of lipid-conjugated antitumor drugs melphalan and methotrexate. Nanotechnol. Russ., 2008, 3, 228-239.
[http://dx.doi.org/10.1134/S1995078008030105]
[40]
Kuznetsova, N.; Kandyba, A.; Vostrov, I.; Kadykov, V.; Gaenko, G.; Molotkovsky, J.; Vodovozova, E. Liposomes loaded with lipophilic prodrugs of methotrexate and melphalan as convenient drug delivery vehicles. J. Drug Deliv. Sci. Technol., 2009, 19, 51-59.
[http://dx.doi.org/10.1016/S1773-2247(09)50007-X]
[41]
Tabatabaei, S.N.; Derbali, R.M.; Yang, C.; Superstein, R.; Hamel, P.; Chain, J.L.; Hardy, P. Co-delivery of miR-181a and melphalan by lipid nanoparticles for treatment of seeded retinoblastoma. J. Control. Release, 2019, 298, 177-185.
[http://dx.doi.org/10.1016/j.jconrel.2019.02.014] [PMID: 30776396]
[42]
Sims, L.B.; Tyo, K.M.; Stocke, S.; Mahmoud, M.Y.; Ramasubramanian, A.; Steinbach-Rankins, J.M. Surface-modified melphalan nanoparticles for intravitreal chemotherapy of retinoblastoma. Invest. Ophthalmol. Vis. Sci., 2019, 60(5), 1696-1705.
[http://dx.doi.org/10.1167/iovs.18-26251] [PMID: 31009525]
[43]
Kalimuthu, K.; Lubin, B.C.; Bazylevich, A.; Gellerman, G.; Shpilberg, O.; Luboshits, G.; Firer, M.A. Gold nanoparticles stabilize peptide-drug-conjugates for sustained targeted drug delivery to cancer cells. J. Nanobiotechnology, 2018, 16(1), 34.
[http://dx.doi.org/10.1186/s12951-018-0362-1] [PMID: 29602308]
[44]
Mura, S.; Bui, D.T.; Couvreur, P.; Nicolas, J. Lipid prodrug nanocarriers in cancer therapy. J. Control. Release, 2015, 208, 25-41.
[http://dx.doi.org/10.1016/j.jconrel.2015.01.021] [PMID: 25617724]
[45]
Mikhalin, A.A.; Evdokimov, N.M.; Frolova, L.V.; Magedov, I.V.; Kornienko, A.; Johnston, R.; Rogelj, S.; Tartis, M.S. Lipophilic prodrug conjugates allow facile and rapid synthesis of high-loading capacity liposomes without the need for post-assembly purification. J. Liposome Res., 2015, 25(3), 232-260.
[http://dx.doi.org/10.3109/08982104.2014.992022] [PMID: 25534989]
[46]
Signorell, R.D.; Luciani, P.; Brambilla, D.; Leroux, J-C. Pharmacokinetics of lipid-drug conjugates loaded into liposomes. Eur. J. Pharm. Biopharm., 2018, 128, 188-199.
[http://dx.doi.org/10.1016/j.ejpb.2018.04.003] [PMID: 29678733]
[47]
Pedersen, P.J.; Christensen, M.S.; Ruysschaert, T.; Linderoth, L.; Andresen, T.L.; Melander, F.; Mouritsen, O.G.; Madsen, R.; Clausen, M.H. Synthesis and biophysical characterization of chlorambucil anticancer ether lipid prodrugs. J. Med. Chem., 2009, 52(10), 3408-3415.
[http://dx.doi.org/10.1021/jm900091h] [PMID: 19402667]
[48]
Funaki, N.O.; Tanaka, J.; Kohmoto, M.; Sugiyama, T.; Ohshio, G.; Nonaka, A.; Yotsumoto, F.; Takeda, Y.; Imamura, M. Membrane fluidity correlates with liver cancer cell proliferation and infiltration potential. Oncol. Rep., 2001, 8(3), 527-532.
[http://dx.doi.org/10.3892/or.8.3.527] [PMID: 11295074]
[49]
Liederer, B.M.; Borchardt, R.T. Enzymes involved in the bioconversion of ester-based prodrugs. J. Pharm. Sci., 2006, 95(6), 1177-1195.
[http://dx.doi.org/10.1002/jps.20542] [PMID: 16639719]
[50]
Gabizon, A.; Papahadjopoulos, D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc. Natl. Acad. Sci. USA, 1988, 85(18), 6949-6953.
[http://dx.doi.org/10.1073/pnas.85.18.6949] [PMID: 3413128]
[51]
Allen, T.M.; Hansen, C.; Rutledge, J. Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues. Biochim. Biophys. Acta, 1989, 981(1), 27-35.
[http://dx.doi.org/10.1016/0005-2736(89)90078-3] [PMID: 2719971]
[52]
Müller, M.; Zschörnig, O.; Ohki, S.; Arnold, K. Fusion, leakage and surface hydrophobicity of vesicles containing phosphoinositides: influence of steric and electrostatic effects. J. Membr. Biol., 2003, 192(1), 33-43.
[http://dx.doi.org/10.1007/s00232-002-1062-0] [PMID: 12647032]
[53]
Moghimi, S.M.; Andersen, A.J.; Hashemi, S.H.; Lettiero, B.; Ahmadvand, D.; Hunter, A.C.; Andresen, T.L.; Hamad, I.; Szebeni, J. Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: the challenges ahead. J. Control. Release, 2010, 146(2), 175-181.
[http://dx.doi.org/10.1016/j.jconrel.2010.04.003] [PMID: 20388529]
[54]
Szebeni, J.; Muggia, F.; Gabizon, A.; Barenholz, Y. Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv. Drug Deliv. Rev., 2011, 63(12), 1020-1030.
[http://dx.doi.org/10.1016/j.addr.2011.06.017] [PMID: 21787819]
[55]
Alberts, D.S.; Muggia, F.M.; Carmichael, J.; Winer, E.P.; Jahanzeb, M.; Venook, A.P.; Skubitz, K.M.; Rivera, E.; Sparano, J.A.; DiBella, N.J.; Stewart, S.J.; Kavanagh, J.J.; Gabizon, A.A. Efficacy and safety of liposomal anthracyclines in phase I/II clinical trials. Semin. Oncol., 2004, 31(6)(Suppl. 13), 53-90.
[http://dx.doi.org/10.1053/j.seminoncol.2004.08.010] [PMID: 15717738]
[56]
Ishida, T.; Ichihara, M.; Wang, X.; Yamamoto, K.; Kimura, J.; Majima, E.; Kiwada, H. Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J. Control. Release, 2006, 112(1), 15-25.
[http://dx.doi.org/10.1016/j.jconrel.2006.01.005] [PMID: 16515818]
[57]
Garay, R.P.; El-Gewely, R.; Armstrong, J.K.; Garratty, G.; Richette, P.; Hunter, A.C.; Andresen, T.L.; Hamad, I.; Garay, R.P.; El-Gewely, R.; Armstrong, J.K.; Garratty, G.; Richette, P. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin. Drug Deliv., 2012, 9(11), 1319-1323.
[http://dx.doi.org/10.1517/17425247.2012.720969] [PMID: 22931049]
[58]
Yang, Q.; Lai, S.K. Anti-PEG immunity: emergence, characteristics, and unaddressed questions. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2015, 7(5), 655-677.
[http://dx.doi.org/10.1002/wnan.1339] [PMID: 25707913]
[59]
Ilinskaya, A.N.; Dobrovolskaia, M.A. Understanding the immunogenicity and antigenicity of nanomaterials: Past, present and future. Toxicol. Appl. Pharmacol., 2016, 299, 70-77.
[http://dx.doi.org/10.1016/j.taap.2016.01.005] [PMID: 26773813]
[60]
Anchordoquy, T.J.; Simberg, D. Watching the gorilla and questioning delivery dogma. J. Control. Release, 2017, 262, 87-90.
[http://dx.doi.org/10.1016/j.jconrel.2017.07.021] [PMID: 28713040]
[61]
Kuznetsova, N.R.; Sevrin, C.; Lespineux, D.; Bovin, N.V.; Vodovozova, E.L.; Mészáros, T.; Szebeni, J.; Grandfils, C. Hemocompatibility of liposomes loaded with lipophilic prodrugs of methotrexate and melphalan in the lipid bilayer. J. Control. Release, 2012, 160(2), 394-400.
[http://dx.doi.org/10.1016/j.jconrel.2011.12.010] [PMID: 22210161]
[62]
Tretiakova, D.; Onishchenko, N.; Boldyrev, I.; Mikhalyov, I.; Tuzikov, A.; Bovin, N.; Evtushenko, E.; Vodovozova, E. Influence of stabilizing components on the integrity of antitumor liposomes loaded with lipophilic prodrug in the bilayer. Colloids Surf. B Biointerfaces, 2018, 166, 45-53.
[http://dx.doi.org/10.1016/j.colsurfb.2018.02.061] [PMID: 29533843]
[63]
Kuznetsova, N.R.; Stepanova, E.V.; Peretolchina, N.M.; Khochenkov, D.A.; Boldyrev, I.A.; Bovin, N.V.; Vodovozova, E.L. Targeting liposomes loaded with melphalan prodrug to tumour vasculature via the Sialyl Lewis X selectin ligand. J. Drug Target., 2014, 22(3), 242-250.
[http://dx.doi.org/10.3109/1061186X.2013.862805] [PMID: 24313904]
[64]
Kozlov, A.M.; Korchagina, E.Yu.; Vodovozova, E.L.; Bovin, N.V. Molotkovsky, Jul.G.; Syrkin, A.B. Increase in sarcolysin antitumor activity by transforming it into a lipid derivative and incorporation into the membrane of liposomes containing a carbohydrate vector. Bull. Exp. Biol. Med., 1997, 123, 381-383.
[http://dx.doi.org/10.1007/BF02766193]
[65]
Morris, A.D.; Atassi, G.; Guilbaud, N.; Cordi, A.A. The synthesis of novel melphalan derivatives as potential antineoplastic agents. Eur. J. Med. Chem., 1997, 32, 343-349.
[http://dx.doi.org/10.1016/S0223-5234(97)89087-3]
[66]
Stewart, J.C.M. Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal. Biochem., 1980, 104(1), 10-14.
[http://dx.doi.org/10.1016/0003-2697(80)90269-9] [PMID: 6892980]
[67]
Bland, M. An introduction to medical statistics, 3rd ed; Oxford Medical Publications, 2000.
[68]
Altman, D.G.; Bland, J.M. How to randomise. BMJ, 1999, 319(7211), 703-704.
[http://dx.doi.org/10.1136/bmj.319.7211.703] [PMID: 10480833]
[69]
Prozorovsky, V.B. Least square method for probit analysis of mortality curves. Farmakologiya i Toxikologiya, 1962, 1, 41-63.
[70]
Hall, C.S. Emotional behavior in the rat. III. The relationship between emotionality and ambulatory activity. J. Comp. Physiol. Psychol., 1936, 22, 345-352.
[http://dx.doi.org/10.1037/h0059253]
[71]
Svirshchevskaya, E.V.; Mariotti, J.; Wright, M.H.; Viskova, N.Y.; Telford, W.; Fowler, D.H.; Varticovski, L. Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity. BMC Cancer, 2008, 8, 176.
[http://dx.doi.org/10.1186/1471-2407-8-176] [PMID: 18570671]
[72]
BritishPharmacopoeia. Safety data sheet according to, 1907, 2006.https://www.pharmacopoeia.com/Catalogue/Preview?uri=%2Fcontent%2Ffile%2Fproducts%2Fhealthandsafety%2FCat_296_GB.pdf
[73]
https://www.oecd.org/env/ehs/testing/oecdguidelinesforthetestingofchemicals.htm
[74]
Gabizon, A.A. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest., 2001, 19(4), 424-436.
[http://dx.doi.org/10.1081/CNV-100103136] [PMID: 11405181]
[75]
Zar, T.; Graeber, C.; Perazella, M.A. Recognition, treatment, and prevention of propylene glycol toxicity. Semin. Dial., 2007, 20(3), 217-219.
[http://dx.doi.org/10.1111/j.1525-139X.2007.00280.x] [PMID: 17555487]

Rights & Permissions Print Cite
Article Metrics
34
1
© 2024 Bentham Science Publishers | Privacy Policy