Sage Journals: Discover world-class research

Abstract

Prodrug development is an important strategy for improving tumor cell targeting and the selectivity of anticancer drugs. In this study, poly(ethylene glycol) and melphalan, an anticancer drug, were linked to the backbone of hyaluronic acid via amide bonds using carbodiimide chemistry to synthesize a poly(ethylene glycol)–hyaluronic acid–melphalan prodrug. The physicochemical properties of the prodrug were characterized by Fourier transform infrared, proton nuclear magnetic resonance, ultraviolet–visible spectroscopy, and dynamic light scattering and transmission electron microscopy. The in vitro drug release profiles and the corresponding in vitro cell evaluation of the prodrug were investigated. The poly(ethylene glycol)–hyaluronic acid–melphalan prodrug was successfully synthesized and self-assembled into 116.4-nm nanoparticles. The release profiles demonstrated that controlled release of the prodrug could be achieved with a sensitive property involving both pH and enzymatic degradation. The poly(ethylene glycol)–hyaluronic acid–melphalan prodrug was more effectively transferred into the ovarian tumor cell (SKOV₃) than into human ovarian fibroblast (HOF) cells. It also had a higher inhibition effect on SKOV₃ and a lower inhibition effect on HOF than melphalan. This poly(ethylene glycol)–hyaluronic acid–melphalan prodrug, with its controlled release properties and selectivity, is a promising drug delivery system for cancer therapy.

Keywords

Prodrugs poly(ethylene glycol)hyaluronic acid melphalan pH sensitive enzyme sensitive

Get full access to this article

View all access options for this article.

References

Zhang

. Antitumor drug Paclitaxel-loaded pH-sensitive nanoparticles targeting tumor extracellular pH. Carbohyd Polym 2009; 77(4): 773–778.

Dai

Jin

Jong

. Bioreducible cross-linked pluronic micelles: pH-triggered release of doxorubicin and folate-mediated cellular uptake. J Bioact Compat Pol 2013; 28(4): 341–354.

Bae

Kyung

Yoon

. Preparation and characterizations of in situ shell cross-linked 4-arm-poly(propylene oxide)–poly(ethylene oxide) micelles via enzyme-mediated reaction for controlled drug delivery. J Bioact Compat Pol 2012; 27(3): 185–197.

Luo

Yuan

Liu

. Self-assembled polyion complex micelles based on PVP-b-PAMPS and PVP-b-PDMAEMA for drug delivery. J Bioact Compat Pol 2010; 25(3): 292–304.

Shahin

Ahmed

Kaur

. Decoration of polymeric micelles with cancer-specific peptide ligands for active targeting of paclitaxel. Biomaterials 2011; 32(22): 5123–5133.

Musacchio

Laquintana

Latrofa

. PEG-PE micelles loaded with paclitaxel and surface-modified by a PBR-ligand: synergistic anticancer effect. Mol Pharm 2009; 6(2): 468–479.

Baracu

Balaban

Wilman

. Chemistry of antitumor agents. Glasgow: Blackie, 1990, pp. 62–130.

Hansson

Lewensohn

Ringborg

. Formation and removal of DNA cross-links induced by melphalan and nitrogen mustard in relation to drug-induced cytotoxicity in human melanoma cells. Cancer Res 1987; 47: 2631–2637.

Suzukake

Vistica

. Dechlorination of l-phenylalanine mustard by sensitive and resistant tumor cells and its relationship to intracellular glutathione content. Biochem Pharmacol 1983; 32(1): 165–167.

10.

Maze

Carney

Kelley

. Increasing DNA repair methyltransferase levels via bone marrow stem cell transduction rescues mice from the toxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, a chemotherapeutic alkylating agent. P Natl Acad Sci USA 1996; 93(1): 206–210.

11.

João

Natália

João

. New thermo-responsive hydrogels based on poly (N-isopropylacrylamide)/hyaluronic acid semi-interpenetrated polymer networks: swelling properties and drug release studies. J Bioact Compat Pol 2010; 25(2): 169–184.

12.

Aruffo

Stamenkovic

Melnick

. CD44 is the principal cell surface receptor for hyaluronate. Cell 1990; 61(7): 1303–1313.

13.

Jedrzejas

Stern

. Structures of vertebrate hyaluronidases and their unique enzymatic mechanism of hydrolysis. Proteins 2005; 61(2): 227–238.

14.

Girish

Kemparaju

. The magic glue hyaluronan and its eraser hyaluronidase: a biological overview. Life Sci 2007; 80(21): 1921–1943.

15.

Akima

Ito

Iwata

. Evaluation of antitumor activities of hyaluronate binding antitumor drugs: synthesis, characterization and antitumor activity. J Drug Target 1996; 4(1): 1–8.

16.

Taetz

Bochot

Surace

. Hyaluronic acid-modified DOTAP/DOPE liposomes for the targeted delivery of anti-telomerase siRNA to CD44-expressing lung cancer cells. Oligonucleotides 2009; 19(2): 103–116.

17.

Sonia

Ana

Carmen

. Microspheres loaded with polysaccharide nanoparticles for pulmonary delivery: preparation, structure and surface analysis. Carbohyd Polym 2011; 86(1): 25–34.

18.

Schante

Zuber

Herlin

. Chemical modifications of hyaluronic acid for the synthesis of derivatives for a broad range of biomedical applications. Carbohyd Polym 2011; 85(3): 469–489.

19.

Pouyani

Prestwich

. Functionalized derivatives of hyaluronic acid oligosaccharides: drug carriers and novel biomaterials. Bioconjugate Chem 1994; 5(4): 339–347.

20.

Luo

Prestwich

. Synthesis and selective cytotoxicity of a hyaluronic acid-antitumor bioconjugate. Bioconjugate Chem 1999; 10(5): 755–763.

21.

Luo

Ziebell

Prestwich

. A hyaluronic acid—taxol antitumor bioconjugate targeted to cancer cells. Biomacromolecules 2000; 1(2): 208–218.

22.

Xin

Wang

Xiang

. The use of amino acid linkers in the conjugation of paclitaxel with hyaluronic acid as drug delivery system: synthesis, self-assembled property, drug release, and in vitro efficiency. Pharm Res 2010; 27(2): 380–389.

23.

Khushboo

Olga

Kenneth

. Poly(ethylene glycol)-armed hyperbranched polyoxetanes for anticancer drug delivery. J Bioact Compat Pol 2012; 27(6): 525–539.

24.

Min

Kim

Bae

. Tumoral acidic pH-responsive MPEG-poly (beta-amino ester) polymeric micelles for cancer targeting therapy. J Control Release 2010; 144(2): 259–266.

25.

Lee

Bae

. Super pH-sensitive multifunctional polymeric micelle. Nano Lett 2005; 5(2): 325–329.

26.

Klibanov

Maruyama

Beckerleg

. Activity of amphipathic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target. BBA: Biomembranes 1991; 1062(2): 142–148.

27.

Moghimi

Hunter

Murray

. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 2001; 53(2): 283–318.

28.

Moghimi

Szebeni

. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res 2003; 42(6): 463–478.

29.

Choi

Ipe

Misra

. Tissue- and organ-selective biodistribution of NIR fluorescent quantum dots. Nano Lett 2009; 9(6): 2354–2359.

30.

Shan

Cui

. A paclitaxel-conjugated adenovirus vector for targeted drug delivery for tumor therapy. Biomaterials 2012; 33(1): 146–162.

31.

Homma

Sato

Okamachi

. Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment. Bioorgan Med Chem 2009; 17(13): 4647–4656.

32.

Cho

Choi

Lee

. Cyclotriphosphazene-Pt-DACH conjugates with dipeptide spacers for drug delivery systems. J Bioact Compat Pol 2010; 25(3): 274–291.

33.

Mannelli

Gallo

. Cancer stem cells hypothesis and stem cells in head and neck cancers. Cancer Treat Rev 2012; 38(5): 515–539.

Synthesis and characterization of a pH- and enzyme-sensitive poly(ethylene glycol)–hyaluronic acid–melphalan prodrug

Abstract

Keywords

Get full access to this article

References