Polymeric Nanogels Containing the Triphosphate Form of Cytotoxic Nucleoside Analogues Show Antitumor Activity Against Breast and Colorectal Cancer Cell Lines

Overview

Journal Mol Cancer Ther

Date 2008 Oct 15

PMID 18852140

Citations 11

Authors

Carlos M Galmarini

Galya Warren

Ekta Kohli

Arin Zeman

Anton Mitin

Serguei V Vinogradov

Affiliations

Soon will be listed here.

Abstract

The therapeutic efficiency of anticancer nucleoside analogues (NA) strongly depends on their intracellular accumulation and conversion into 5'-triphosphates. Because active NATP cannot be directly administrated due to instability, we present here a strategy of nanoencapsulation of these active drugs for efficient delivery to tumors. Stable lyophilized formulations of 5'-triphosphates of cytarabine (araCTP), gemcitabine (dFdCTP), and floxuridine (FdUTP) encapsulated in biodegradable PEG-cl-PEI or F127-cl-PEI nanogel networks (NGC and NGM, respectively) were prepared by a self-assembly procedure. Cellular penetration, in vitro cytotoxicity, and drug-induced cell cycle perturbations of these nanoformulations were analyzed in breast and colorectal cancer cell lines. Cellular accumulation and NATP release from nanogel was studied by confocal microscopy and direct high-performance liquid chromatography analysis of cellular lysates. Antiproliferative effect of dFdCTP nanoformulations was evaluated in human breast carcinoma MCF7 xenograft animal model. Nanoencapsulated araCTP, dFdCTP, and FdUTP showed similar to NA cytotoxicity and cell cycle perturbations. Nanogels without drugs showed very low cytotoxicity, although NGM was more toxic than NGC. Treatment by NATP nanoformulations induced fast increase of free intracellular drug concentration. In human breast carcinoma MCF7 xenograft animal model, i.v. dFdCTP-nanogel was equally effective in inhibiting tumor growth at four times lower administered drug dose compared with free gemcitabine. Active triphosphates of NA encapsulated in nanogels exhibit similar cytotoxicity and cell cycle perturbations in vitro and faster cell accumulation and equal tumor growth-inhibitory activity in vivo at much lower dose compared with parental drugs, illustrating their therapeutic potential for cancer chemotherapy.

Citing Articles

Old drug, new tricks: polymer-based nanoscale systems for effective cytarabine delivery.

Jan N, Shah H, Khan S, Nasar F, Madni A, Badshah S Naunyn Schmiedebergs Arch Pharmacol. 2023; 397(6):3565-3584.

PMID: 38015258 DOI: 10.1007/s00210-023-02865-z.

Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation.

Soni K, Desale S, Bronich T J Control Release. 2015; 240:109-126.

PMID: 26571000 PMC: 4862943. DOI: 10.1016/j.jconrel.2015.11.009.

Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals.

Gollnest T, Dinis de Oliveira T, Schols D, Balzarini J, Meier C Nat Commun. 2015; 6:8716.

PMID: 26503889 PMC: 4640093. DOI: 10.1038/ncomms9716.

Amphiphilic cationic nanogels as brain-targeted carriers for activated nucleoside reverse transcriptase inhibitors.

Warren G, Makarov E, Lu Y, Senanayake T, Rivera K, Gorantla S J Neuroimmune Pharmacol. 2015; 10(1):88-101.

PMID: 25559020 PMC: 4336642. DOI: 10.1007/s11481-014-9576-7.

Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy.

Bailey C, Sullivan T, Iyidogan P, Tirado-Rives J, Chung R, Ruiz-Caro J J Med Chem. 2013; 56(10):3959-68.

PMID: 23659183 PMC: 3733247. DOI: 10.1021/jm400160s.

References

Schwendener R, Schott H . Lipophilic 1-beta-D-arabinofuranosyl cytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemia model. J Cancer Res Clin Oncol. 1996; 122(12):723-6. DOI: 10.1007/BF01209119. View

Schwendener R, Horber D, Odermatt B, Schott H . Oral antitumour activity in murine L1210 leukaemia and pharmacological properties of liposome formulations of N4-alkyl derivatives of 1-beta-D-arabinofuranosylcytosine. J Cancer Res Clin Oncol. 1996; 122(2):102-8. DOI: 10.1007/BF01226267. View

Twentyman P, Fox N, Rees J . Chemosensitivity testing of fresh leukaemia cells using the MTT colorimetric assay. Br J Haematol. 1989; 71(1):19-24. DOI: 10.1111/j.1365-2141.1989.tb06268.x. View

Vinogradov S, Bronich T, Kabanov A . Nanosized cationic hydrogels for drug delivery: preparation, properties and interactions with cells. Adv Drug Deliv Rev. 2002; 54(1):135-47. DOI: 10.1016/s0169-409x(01)00245-9. View

Cahard D, McGuigan C, Balzarini J . Aryloxy phosphoramidate triesters as pro-tides. Mini Rev Med Chem. 2004; 4(4):371-81. DOI: 10.2174/1389557043403936. View

Wang J, Sun X, Zhang Z . Enhanced brain targeting by synthesis of 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine and incorporation into solid lipid nanoparticles. Eur J Pharm Biopharm. 2002; 54(3):285-90. DOI: 10.1016/s0939-6411(02)00083-8. View

Losa R, Sierra M, Gion M, Esteban E, Buesa J . Simultaneous determination of gemcitabine di- and triphosphate in human blood mononuclear and cancer cells by RP-HPLC and UV detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2006; 840(1):44-9. DOI: 10.1016/j.jchromb.2006.04.036. View

Jain R . Barriers to drug delivery in solid tumors. Sci Am. 1994; 271(1):58-65. DOI: 10.1038/scientificamerican0794-58. View

Vinogradov S . Polymeric nanogel formulations of nucleoside analogs. Expert Opin Drug Deliv. 2006; 4(1):5-17. PMC: 2391300. DOI: 10.1517/17425247.4.1.5. View

10.

Maeda H . The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul. 2001; 41:189-207. DOI: 10.1016/s0065-2571(00)00013-3. View

11.

Fraternale A, Rossi L, Magnani M . Encapsulation, metabolism and release of 2-fluoro-ara-AMP from human erythrocytes. Biochim Biophys Acta. 1996; 1291(2):149-54. DOI: 10.1016/0304-4165(96)00059-1. View

12.

Couvreur P, Stella B, Reddy L, Hillaireau H, Dubernet C, Desmaele D . Squalenoyl nanomedicines as potential therapeutics. Nano Lett. 2006; 6(11):2544-8. DOI: 10.1021/nl061942q. View

13.

Vinogradov S, Kohli E, Zeman A . Cross-linked polymeric nanogel formulations of 5'-triphosphates of nucleoside analogues: role of the cellular membrane in drug release. Mol Pharm. 2005; 2(6):449-61. PMC: 1351166. DOI: 10.1021/mp0500364. View

14.

Jain . Delivery of molecular and cellular medicine to solid tumors. Adv Drug Deliv Rev. 1997; 26(2-3):71-90. DOI: 10.1016/s0169-409x(97)00027-6. View

15.

Pastor-Anglada M, Cano-Soldado P, Molina-Arcas M, Lostao M, Larrayoz I, Martinez-Picado J . Cell entry and export of nucleoside analogues. Virus Res. 2005; 107(2):151-64. DOI: 10.1016/j.virusres.2004.11.005. View

16.

Kohli E, Han H, Zeman A, Vinogradov S . Formulations of biodegradable Nanogel carriers with 5'-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity. J Control Release. 2007; 121(1-2):19-27. PMC: 2000331. DOI: 10.1016/j.jconrel.2007.04.007. View

17.

Vinogradov S, Kohli E, Zeman A . Comparison of nanogel drug carriers and their formulations with nucleoside 5'-triphosphates. Pharm Res. 2006; 23(5):920-30. PMC: 1615883. DOI: 10.1007/s11095-006-9788-5. View

18.

Meier C, Balzarini J . Application of the cycloSal-prodrug approach for improving the biological potential of phosphorylated biomolecules. Antiviral Res. 2006; 71(2-3):282-92. DOI: 10.1016/j.antiviral.2006.04.011. View

19.

Tredan O, Galmarini C, Patel K, Tannock I . Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst. 2007; 99(19):1441-54. DOI: 10.1093/jnci/djm135. View

20.

Erion M, van Poelje P, Mackenna D, Colby T, Montag A, Fujitaki J . Liver-targeted drug delivery using HepDirect prodrugs. J Pharmacol Exp Ther. 2004; 312(2):554-60. DOI: 10.1124/jpet.104.075903. View