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Investigational New Drugs

, Volume 28, Issue 3, pp 284–290 | Cite as

Suppression of in vivo tumor growth by using a biodegradable thermosensitive hydrogel polymer containing chemotherapeutic agent

  • Mi Kyung Kwak
  • Keun Hur
  • Ji Eun Yu
  • Tae Su Han
  • Kazuyoshi Yanagihara
  • Woo Ho Kim
  • Sun Mi Lee
  • Soo-Chang Song
  • Han-Kwang YangEmail author
PRECLINICAL STUDIES

Summary

Current systemic chemotherapy in the treatment of solid tumors inevitably induces various systemic adverse effects. Locally injected chemotherapy is expected to overcome this limitation of systemic therapy. We evaluated by luminescence imaging the effects of chemotherapy administered locally by means of a biodegradable thermosensitive hydrogel polymer. The human gastric cancer cell line HSC44Luc was used for tumor induction, and it was confirmed to be sensitive to doxorubicin by MTT assay. Cells were injected subcutaneously into Balb/c-nude mice. When the mean volume of tumor reached 400 mm3, we divided the mice into 6 groups (5 per group) according to treatment: 1) control (intratumor injection of PBS), 2) systemic injection of doxorubicin, 3) intratumor injection of polymer gel, 4) intratumor injection of polymer gel physically mixed with a low dose of doxorubicin, 5) intratumor injection of polymer gel physically mixed with a high dose of doxorubicin, 6) intratumor injection of conjugated polymer gel with doxorubicin. Body weight and tumor volume were measured every 2 or 3 days for 30 days after treatment. One mouse in each group was sacrificed for histopathologic examination every week. Reductions in body weight were not significantly different among groups. The relative rate of tumor growth was 774% in Group 1, 267% in Group 2, 813% in Group 3, -186% in Group 4, and 155% in Group 6, respectively. Thus the relative rate of tumor growth in the groups treated with polymer gel mixed with doxorubicin and the groups treated with conjugated polymer gel with doxorubicin were lower than that in the control group. Locally injectable chemotherapy using a thermosensitive hydrogel polymer with doxorubicin can suppress tumor growth effectively without severe systemic toxicity.

Keywords

Hydrogel polymer Cancer growth Bioluminescence imaging 

Reference

  1. 1.
    Shapiro CL, Recht A (2001) Side effects of adjuvant treatment of breast cancer. N Engl J Med 344:1997–2008. doi: 10.1056/NEJM200106283442607 CrossRefPubMedGoogle Scholar
  2. 2.
    Partridge AH, Burstein HJ, Winer EP (2001) Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer. J Natl Cancer Inst Monogr 2001:135–142Google Scholar
  3. 3.
    Ramanan RMK, Chellamuthu P, Tang L, Nguyen KT (2006) Development of a temperature-sensitive composite hydrogel for drug delivery applications. Biotechnol Prog 22:118–125. doi: 10.1021/bp0501367 CrossRefPubMedGoogle Scholar
  4. 4.
    Couffin-Hoarau AC, Leroux JC (2004) Report on the use of poly(organo-phosphazenes) for the design of stimuli-responsive vesicles. Biomacromolecules 5:2082–2087. doi: 10.1021/bm0400527 CrossRefPubMedGoogle Scholar
  5. 5.
    Ankareddi I, Brazel CS (2007) Synthesis and characterization of grafted thermosensitive hydrogels for heating activated controlled release. Int J Pharm 336(2):241–247. doi: 10.1016/j.ijpharm.2006.11.065 CrossRefPubMedGoogle Scholar
  6. 6.
    Rathi R, Zentner GM, Jeong B (2000) Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties. US Patent 6(117):949Google Scholar
  7. 7.
    Rathi R, Zentner GM (1999) Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties. US Patent 6(004):573Google Scholar
  8. 8.
    Cha Y, Choi YK, Bae YH (1997) Thermosensitive biodegradable polymers based on poly(ether-ester) block copolymers. US Patent 5(702):717Google Scholar
  9. 9.
    Jeong B, Bae YH, Lee DS, Kim SW (1997) Biodegradable block copolymers as injectable drug-delivery system. Nature 388:860–862. doi: 10.1038/42218 CrossRefPubMedGoogle Scholar
  10. 10.
    Zentner GM (1999) Biodegradable, thermally reversible gels for drug delivery. The 9th International Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, UTGoogle Scholar
  11. 11.
    Zhang J, Misra RDK (2007) Magnetic drug-targeting carrier encapsulated with thermosensitive smart polymer: core–shell nanoparticle carrier and drug release response. Acta Biomater 3:838–850. doi: 10.1016/j.actbio.2007.05.011 CrossRefPubMedGoogle Scholar
  12. 12.
    Rapoport N (2007) Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery. Prog Polym Sci 32:962–990. doi: 10.1016/j.progpolymsci.2007.05.009 CrossRefGoogle Scholar
  13. 13.
    Choi SW, Kim JH (2007) Design of surface-modified poly(d, llactide-co-glycolide) nanoparticles for targeted drug delivery to bone. J Control Release 122:24–30. doi: 10.1016/j.jconrel.2007.06.003 CrossRefPubMedGoogle Scholar
  14. 14.
    Bilensoy E, Gurkaynak O, Dogan AL, Hıncal AA (2008) Safety and efficacy of amphiphilic ß-cyclodextrin nanoparticles for paclitaxel delivery. Int J Pharm 347:163–170. doi: 10.1016/j.ijpharm.2007.06.051 CrossRefPubMedGoogle Scholar
  15. 15.
    Pison U, Welte T, Giersig M, Groneberg DA (2006) Nanomedicine for respiratory diseases. Eur J Pharmacol 533:341–350. doi: 10.1016/j.ejphar.2005.12.068 CrossRefPubMedGoogle Scholar
  16. 16.
    John AE, Lukacs NW, Berlin AA et al (2003) Discovery of a potent nanoparticle P-selectin antagonist with anti-inflammatory effects in allergic airway disease. FASEB J 17:2296–2298PubMedGoogle Scholar
  17. 17.
    Lowenthal RM, Eaton K (1996) Toxicity of chemotherapy. Oncol. Clin. N Am. 10:967–990. doi: 10.1016/S0889-8588(05)70378-6 CrossRefGoogle Scholar
  18. 18.
    Klein-Szanto AJ (1992) Carcinogenic effects of chemotherapeutic compounds. Prog. Clin. 374:167–174Google Scholar
  19. 19.
    Song S-C, Lee SB, Lee BH, Ha H-W, Lee K-T, Sohn YS (2003) Synthesis and antitumor activity of novel thermosensitive platinum(II)-cyclotriphosphazene conjugates. J Control Release 90:303–311. doi: 10.1016/S0168-3659(03)00199-8 CrossRefPubMedGoogle Scholar
  20. 20.
    Ruel-Gariepy E, Shive M, Bichara A, Berrada M, Garrec DL, Chenite A, Leroux J-C (2004) A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel. Eur J Pharm Biopharm 57:53–63. doi: 10.1016/S0939-6411(03)00095-X CrossRefPubMedGoogle Scholar
  21. 21.
    Contag CH, Spilman SD, Contag PR, Oshiro M, Eames B, Dennery P, Stevenson DK, Benaron DA (1997) Visualizing gene expression in living mammals using a bioluminescent reporter. Photochem Photobiol 66:523–531. doi: 10.1111/j.1751-1097.1997.tb03184.x CrossRefPubMedGoogle Scholar
  22. 22.
    Kang GD, Cheon SH, Song SC (2006) Controlled release of doxorubicin from thermosensitive poly(organophosphazene) hydrogels. Int J Pharm 319:29–36. doi: 10.1016/j.ijpharm.2006.03.032 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Mi Kyung Kwak
    • 1
  • Keun Hur
    • 1
  • Ji Eun Yu
    • 1
  • Tae Su Han
    • 1
  • Kazuyoshi Yanagihara
    • 4
  • Woo Ho Kim
    • 1
    • 3
  • Sun Mi Lee
    • 5
  • Soo-Chang Song
    • 5
  • Han-Kwang Yang
    • 1
    • 2
    • 6
    Email author
  1. 1.Cancer Research InstituteSeoul National University College of MedicineSeoulKorea
  2. 2.Department of SurgerySeoul National University College of MedicineSeoulKorea
  3. 3.Department of PathologySeoul National University College of MedicineSeoulKorea
  4. 4.National Cancer Center Research InstituteTokyoJapan
  5. 5.Korea Institute of Science and TechnologySeoulKorea
  6. 6.College of Medicine, Department of Surgery and Cancer Research InstituteSeoul National UniversitySeoulKorea

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