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Synthesis of Thermoresponsive Polymers for Drug Delivery

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Drug Delivery System

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1141))

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Abstract

A protocol for synthesizing thermosensitive copolymers of N-isopropylacrylamide (NIPAM) and N-vinylpyrrolidone (VP), cross-linked with N,N′-methylene-bis-acrylamide (MBA) has been described in this chapter. The copolymers have been formed at different concentrations of NIPAM and VP and at two different temperatures (70 °C and 30 °C). The lower critical solution temperature (LCST) of the samples has been measured, and the size of the particles formed with the highest concentration of NIPAM and lowest concentration of VP (MG1 and NG1) has been measured at three different temperatures of 25 °C, 35 °C, and 37 °C. Both MG1 and NG1 showed the lowest size at 37 °C. The MG1 and NG1 samples were further characterized using TEM and SEM. The MG1 particles were subsequently used for protein drug delivery, using BSA as a model. The release profile showed the best fit with the zero-order model. Finally, cytotoxicity studies of the synthesized MG1 and NG1 particles were carried out, using in vitro MTT assay, so as to determine the overall biocompatibility of the materials.

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References

  1. Roy D, Cambre JN, Sumerlin BS (2010) Future perspectives and recent advances in stimuli-responsive materials. Prog Polym Sci 35:278–301

    Article  CAS  Google Scholar 

  2. Mano JF (2008) Stimuli-responsive polymeric systems for biomedical applications. Adv Eng Mater 10:515–527

    Article  CAS  Google Scholar 

  3. Kamaly N, Xiao Z, Valencia PM, Radovic-Moreno AF, Farokhzad OC (2012) Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem Soc Rev 41:2971–3010

    Article  CAS  Google Scholar 

  4. Bae YH, Okano T, Hsu R, Kim SW (1987) Thermo‐sensitive polymers as on‐off switches for drug release. Makromol Chem Rapid Commun 8:481–485

    Article  CAS  Google Scholar 

  5. Jeong B, Bae YH, Lee DS, Kim SW (1997) Biodegradable block copolymers as injectable drug-delivery systems. Nature 388:860–862

    Article  CAS  Google Scholar 

  6. Pillai O, Panchagnula R (2001) Polymers in drug delivery. Curr Opin Chem Biol 5:447–451

    Article  CAS  Google Scholar 

  7. Aguilar M, Elvira C, Gallardo A, Vázquez B, Román J (2007) Smart polymers and their applications as biomaterials. In: Ashammakhi N, Reis R, Chiellini E (ed) Topics in tissue engineering, Vol 3, University of Oulu (Expert issues e-books), Finland, pp. 1–27

    Google Scholar 

  8. Li S (2010) Smart polymer materials for biomedical applications. Nova Science Publishers, Incorporated

    Google Scholar 

  9. Gerasimov OV, Boomer JA, Qualls MM, Thompson DH (1999) Cytosolic drug delivery using pH- and light-sensitive liposomes. Adv Drug Deliv Rev 38:317–338

    Article  CAS  Google Scholar 

  10. Alvarez-Lorenzo C, Bromberg L, Concheiro A (2009) Light-sensitive intelligent drug delivery systems. Photochem Photobiol 85:848–860

    Article  CAS  Google Scholar 

  11. Chung JE, Yokoyama M, Yamato M, Aoyagi T, Sakurai Y, Okano T (1999) Thermo-responsive drug delivery from polymeric micelles constructed using block copolymers of poly(N-isopropylacrylamide) and poly(butylmethacrylate). J Control Release 62:115–127

    Article  CAS  Google Scholar 

  12. Li Y, Pan S, Zhang W, Du Z (2009) Novel thermo-sensitive core-shell nanoparticles for targeted paclitaxel delivery. Nanotechnology 20:065104

    Article  Google Scholar 

  13. Chung JE, Yokoyama M, Okano T (2000) Inner core segment design for drug delivery control of thermo-responsive polymeric micelles. J Control Release 65:93–103

    Article  CAS  Google Scholar 

  14. Satturwar P, Eddine MN, Ravenelle F, Leroux J-C (2007) pH-responsive polymeric micelles of poly (ethylene glycol)-b-poly (alkyl (meth) acrylate-co-methacrylic acid): influence of the copolymer composition on self-assembling properties and release of candesartan cilexetil. Eur J Pharm Biopharm 65:379–387

    Article  CAS  Google Scholar 

  15. Na K, Lee KH, Bae YH (2004) pH-sensitivity and pH-dependent interior structural change of self-assembled hydrogel nanoparticles of pullulan acetate/oligo-sulfonamide conjugate. J Control Release 97:513–525

    Article  CAS  Google Scholar 

  16. Chen S-C, Wu Y-C, Mi F-L, Lin Y-H, Yu L-C, Sung H-W (2004) A novel pH-sensitive hydrogel composed of N, O-carboxymethyl chitosan and alginate cross-linked by genipin for protein drug delivery. J Control Release 96:285–300

    Article  CAS  Google Scholar 

  17. Hrubý M, Koňák Č, Ulbrich K (2005) Polymeric micellar pH-sensitive drug delivery system for doxorubicin. J Control Release 103:137–148

    Article  Google Scholar 

  18. Sawahata K, Hara M, Yasunaga H, Osada Y (1990) Electrically controlled drug delivery system using polyelectrolyte gels. J Control Release 14:253–262

    Article  CAS  Google Scholar 

  19. Kwon IC, Bae YH, Okano T, Kim SW (1991) Drug release from electric current sensitive polymers. J Control Release 17:149–156

    Article  CAS  Google Scholar 

  20. Yuk SH, Cho SH, Lee HB (1992) Electric current-sensitive drug delivery systems using sodium alginate/polyacrylic acid composites. Pharm Res 9:955–957

    Article  CAS  Google Scholar 

  21. Kost J, Leong K, Langer R (1988) Ultrasonically controlled polymeric drug delivery. Paper presented at Makromolekulare Chemie. Macromolecular Symposia, 1988

    Google Scholar 

  22. Kost J, Leong K, Langer R (1989) Ultrasound-enhanced polymer degradation and release of incorporated substances. Proc Natl Acad Sci U S A 86:7663–7666

    Article  CAS  Google Scholar 

  23. Ito Y, Casolaro M, Kono K, Imanishi Y (1989) An insulin-releasing system that is responsive to glucose. J Control Release 10:195–203

    Article  CAS  Google Scholar 

  24. Shiino D, Murata Y, Kataoka K et al (1994) Preparation and characterization of a glucose-responsive insulin-releasing polymer device. Biomaterials 15:121–128

    Article  CAS  Google Scholar 

  25. Hisamitsu I, Kataoka K, Okano T, Sakurai Y (1997) Glucose-responsive gel from phenylborate polymer and poly (vinyl alcohol): prompt response at physiological pH through the interaction of borate with amino group in the gel. Pharm Res 14:289–293

    Article  CAS  Google Scholar 

  26. Dong-June C, Yoshihiro I, Yukio I (1992) An insulin-releasing membrane system on the basis of oxidation reaction of glucose. J Control Release 18:45–53

    Article  Google Scholar 

  27. Ulijn RV (2006) Enzyme-responsive materials: a new class of smart biomaterials. J Mater Chem 16:2217–2225

    Article  CAS  Google Scholar 

  28. Thornton PD, McConnell G, Ulijn RV (2005) Enzyme responsive polymer hydrogel beads. Chem Commun 47:5913–5915

    Article  Google Scholar 

  29. Toledano S, Williams RJ, Jayawarna V, Ulijn RV (2006) Enzyme-triggered self-assembly of peptide hydrogels via reversed hydrolysis. J Am Chem Soc 128:1070–1071

    Article  CAS  Google Scholar 

  30. Miyata T, Asami N, Uragami T (1999) Preparation of an antigen-sensitive hydrogel using antigen-antibody bindings. Macromolecules 32:2082–2084

    Article  CAS  Google Scholar 

  31. Lu ZR, KopeČková P, KopeČek J (2003) Antigen responsive hydrogels based on polymerizable antibody Fab′ fragment. Macromol Biosci 3:296–300

    Article  CAS  Google Scholar 

  32. Zhang R, Bowyer A, Eisenthal R, Hubble J (2007) A smart membrane based on an antigen-responsive hydrogel. Biotechnol Bioeng 97:976–984

    Article  CAS  Google Scholar 

  33. Koo AN, Lee HJ, Kim SE et al (2008) Disulfide-cross-linked PEG-poly (amino acid)s copolymer micelles for glutathione-mediated intracellular drug delivery. Chem Commun:6570–6572

    Google Scholar 

  34. Tsarevsky NV, Matyjaszewski K (2005) Combining atom transfer radical polymerization and disulfide/thiol redox chemistry: a route to well-defined (bio) degradable polymeric materials. Macromolecules 38:3087–3092

    Article  CAS  Google Scholar 

  35. He C, Kim SW, Lee DS (2008) In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. J Control Release 127:189–207

    Article  CAS  Google Scholar 

  36. Gil ES, Hudson SM (2004) Stimuli-responsive polymers and their bioconjugates. Prog Polym Sci 29:1173–1222

    Article  CAS  Google Scholar 

  37. Dirk S (2006) Thermo- and pH-responsive polymers in drug delivery. Adv Drug Deliv Rev 58:1655–1670

    Article  Google Scholar 

  38. Klouda L, Mikos AG (2008) Thermoresponsive hydrogels in biomedical applications. Eur J Pharm Biopharm 68:34–45

    Article  CAS  Google Scholar 

  39. Schild HG (1992) Poly(N-isopropylacrylamide): experiment, theory and application. Prog Polym Sci 17:163–249

    Article  CAS  Google Scholar 

  40. Yan H, Tsujii K (2005) Potential application of poly(N-isopropylacrylamide) gel containing polymeric micelles to drug delivery systems. Colloids Surf B Biointerfaces 46:142–146

    Article  CAS  Google Scholar 

  41. Fitzpatrick SD, Jafar Mazumder MA, Muirhead B, Sheardown H (2012) Development of injectable, resorbable drug-releasing copolymer scaffolds for minimally invasive sustained ophthalmic therapeutics. Acta Biomater 8:2517–2528

    Article  CAS  Google Scholar 

  42. Karir T, Sarma HD, Samuel G, Hassan PA, Padmanabhan D, Venkatesh M (2013) Preparation and evaluation of radioiodinated thermoresponsive polymer based on poly(N-isopropyl acrylamide) for radiotherapy. J Appl Polym Sci 130:860–868

    Article  CAS  Google Scholar 

  43. Chen Y-Y, Wu H-C, Sun J-S, Dong G-C, Wang T-W (2013) Injectable and thermoresponsive self-assembled nanocomposite hydrogel for long-term anticancer drug delivery. Langmuir 29:3721–3729

    Article  CAS  Google Scholar 

  44. Jiang B, Larson JC, Drapala PW, Pérez‐Luna VH, Kang‐Mieler JJ, Brey EM (2012) Investigation of lysine acrylate containing poly (N‐isopropylacrylamide) hydrogels as wound dressings in normal and infected wounds. J Biomed Mater Res B Appl Biomater 100:668–676

    Article  Google Scholar 

  45. Tan H, Ramirez CM, Miljkovic N, Li H, Rubin JP, Marra KG (2009) Thermosensitive injectable hyaluronic acid hydrogel for adipose tissue engineering. Biomaterials 30:6844–6853

    Article  CAS  Google Scholar 

  46. Luo L, Ranger M, Lessard DG et al (2004) Novel amphiphilic diblock copolymer of low molecular weight poly(N-vinylpyrrolidone)-block-poly(d, l-lactide): synthesis, characterization and micellization. Macromolecules 37:4008–4013

    Article  CAS  Google Scholar 

  47. Haaf F, Sanner A, Straub F (1985) Polymers of N-vinylpyrrolidone: synthesis, characterization and uses. Polymer J 17:143–152

    Article  CAS  Google Scholar 

  48. D’Souza AJM, Schowen RL, Topp EM (2004) Polyvinylpyrrolidone–drug conjugate: synthesis and release mechanism. J Control Release 94:91–100

    Article  Google Scholar 

  49. Zhang L, Liang Y, Meng L, Lu X, Liu Y (2007) Preparation and PCR-amplification properties of a novel amphiphilic poly(N-vinylpyrrolidone) (PVP) copolymer. Chem Biodivers 4:163–174

    Article  Google Scholar 

  50. Indian Pharmacopoeia Delhi, Government of India, Ministry of Health and Family Welfare: Published by the controller of Publication; 1996

    Google Scholar 

  51. Niles AL, Moravec RA, Riss TL (2009) In vitro viability and cytotoxicity testing and same-well multi-parametric combinations for high throughput screening. Curr Chem Genomics 3:33–41

    Article  CAS  Google Scholar 

  52. Cook JA, Mitchell JB (1989) Viability measurements in mammalian cell systems. Anal Biochem 179:1–7

    Article  CAS  Google Scholar 

  53. Weyermann J, Lochmann D, Zimmer A (2005) A practical note on the use of cytotoxicity assays. Int J Pharm 288:369–376

    Article  CAS  Google Scholar 

  54. Fotakis G, Timbrell JA (2006) In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol Lett 160:171–177

    Article  CAS  Google Scholar 

  55. Korzeniewski C, Callewaert DM (1983) An enzyme-release assay for natural cytotoxicity. J Immunol Methods 64:313–320

    Article  CAS  Google Scholar 

  56. Decker T, Lohmann-Matthes M-L (1988) A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity. J Immunol Methods 115:61–69

    Article  CAS  Google Scholar 

  57. Jurišić V, Bumbaširević V (2008) In vitro assays for cell death determination. Arch Oncol 16:49–54

    Article  Google Scholar 

  58. Vihola H, Laukkanen A, Valtola L, Tenhu H, Hirvonen J (2005) Cytotoxicity of thermosensitive polymers poly(N-isopropylacrylamide), poly(N-vinylcaprolactam) and amphiphilically modified poly(N-vinylcaprolactam). Biomaterials 26:3055–3064

    Article  CAS  Google Scholar 

  59. Cheng N, Liu W, Cao Z et al (2006) A study of thermoresponsive poly(N-isopropylacrylamide)/polyarginine bioconjugate non-viral transgene vectors. Biomaterials 27:4984–4992

    Article  CAS  Google Scholar 

  60. Wang Z-C, Xu X-D, Chen C-S et al (2008) Study on novel hydrogels based on thermosensitive PNIPAAm with pH sensitive PDMAEMA grafts. Colloids Surf B Biointerfaces 67:245–252

    Article  CAS  Google Scholar 

  61. Barltrop JA, Owen TC, Cory AH, Cory JG (1991) 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfophenyl)tetrazolium, inner salt (MTS) and related analogs of 3-(4,5-dimethylthiazolyl)-2,5-diphenyl-tetrazolium bromide (MTT) reducing to purple water-soluble formazans as cell-viability indicators. Bioorg Med Chem Lett 1:611–614

    Article  CAS  Google Scholar 

  62. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  Google Scholar 

  63. Hansen MB, Nielsen SE, Berg K (1989) Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods 119:203–210

    Article  CAS  Google Scholar 

  64. Riss TL, Moravec RA, Niles AL, Benink HA, Worzella TJ, Minor L (2013) Cell viability assays. In: Sittampalam GS, Gal-Edd N, Arkin M et al (eds) Assay guidance manual. Bethesda, MD: Eli Lilly & Company and the National Center for Advancing Translational Sciences; Available from: http://www.ncbi.nlm.nih.gov/books/NBK144065/

  65. Masters JR (2002) HeLa cells 50 years on: the good, the bad and the ugly. Nat Rev Cancer 2:315–319

    Article  CAS  Google Scholar 

  66. Capes-Davis A, Theodosopoulos G, Atkin I et al (2010) Check your cultures! A list of cross-contaminated or misidentified cell lines. Int J Cancer 127:1–8

    Article  CAS  Google Scholar 

  67. Lucey BP, Nelson-Rees WA, Hutchins GM (2009) Henrietta lacks, HeLa cells, and cell culture contamination. Arch Pathol Lab Med 133:1463–1467

    Google Scholar 

  68. Aerry S, De A, Kumar A, Saxena A, Majumdar D, Mozumdar S (2013) Synthesis and characterization of thermoresponsive copolymers for drug delivery. J Biomed Mater Res A 101(7):2015–26

    Article  Google Scholar 

  69. Aerry S (2010) Synthesis and characterization of polymers and polymeric nanoparticles for applications in drug delivery. Ph.D. thesis submitted at the Department of Chemistry, University of Delhi, 2010

    Google Scholar 

  70. Rahbari R, Sheahan T, Modes V, Collier P, Macfarlane C, Badge RM (2009) A novel L1 retrotransposon marker for HeLa cell line identification. Biotechniques 46:277

    CAS  Google Scholar 

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Acknowledgement

This work was supported by Department of Biotechnology (DBT) New Delhi, India grant no. BT/PR8918/NNT/28/05/2007. The authors thank Swati Aerry and Mitasha Bharadwaj for this work and Dr. Y. Singh (Scientist “G”, IGIB, Delhi) for carrying out the cytotoxicity work in his lab.

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Authors and Affiliations

  1. Department of Chemistry, University of Delhi, Delhi, India

    Sushil Mishra & Subho Mozumdar

  2. Department of Microbiology and Immunology, Columbia University, New York, NY, USA

    Arnab De

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  1. Sushil Mishra
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  2. Arnab De
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  3. Subho Mozumdar
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Editors and Affiliations

  1. Jain PharmaBiotech, Basel, Switzerland

    Kewal K. Jain

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Mishra, S., De, A., Mozumdar, S. (2014). Synthesis of Thermoresponsive Polymers for Drug Delivery. In: Jain, K. (eds) Drug Delivery System. Methods in Molecular Biology, vol 1141. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0363-4_4

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  • DOI: https://doi.org/10.1007/978-1-4939-0363-4_4

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-0362-7

  • Online ISBN: 978-1-4939-0363-4

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