Asian Pacific Journal of Cancer Prevention

Asian Pacific Organization for Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Isomeric Folate-Conjugated Polymeric Micelles Bind to Folate Receptors and Display Anticancer Effects

  • Dong, Qing (Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University) ;
  • Xie, Zuo-Xu (Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University) ;
  • Xie, Cao (Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University) ;
  • Lu, Wei-Yue (Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University) ;
  • Zhang, Qian (Department of Medicinal Chemistry, School of Pharmacy, Fudan University) ;
  • Li, Xue (Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University) ;
  • Liu, Min (Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University)
  • Published : 2014.09.15

Abstract

The present study aimed to prepare and evaluate polymeric micelles conjugated with folic acid through ${\alpha}$- or ${\gamma}$-carboxyl groups for antitumor efficacy. The isomeric block copolymers, ${\alpha}$- and ${\gamma}$-folate-polyethyleneglycol-distearoyl phosphatidylethanolamine (${\alpha}$- and ${\gamma}$-Fol-PEG-DSPE), were produced by solid phase peptide synthesis. Three types of doxorubicin (DOX)-loaded polymeric micelles (MPEG-DSPE-DOX and ${\alpha}$- / ${\gamma}$-Fol-PEG-DSPEDOX micelles) were prepared via the film formation method. Compared with MPEG-DSPE-DOX micelles, the ${\alpha}$- / ${\gamma}$-Fol-PEG-DSPE-DOX micelles presented a higher cellular uptake behavior in the live cell study. Cell viability percentages were 81.8%, 57.3%, 56.6% at 2 hours for MPEG-DSPE-DOX, ${\alpha}$- and ${\gamma}$-Fol-PEG-DSPE-DOX micelles, respectively (p<0.05). Using the KB xenograft tumor model, both ${\alpha}$- and ${\gamma}$-folate-conjugated micelles were found to have better antitumor effects with lower toxicity in comparison with MPEG-DSPE-DOX micelles. No difference in in vivo antitumor efficacy was found between ${\alpha}$- and ${\gamma}$-Fol-PEG-DSPE-DOX micelles. The folate-conjugated micelles might be a potentially useful strategy for tumor targeting of therapeutic agents, whether grafting with folic acid through ${\alpha}$- or ${\gamma}$-carboxyl groups.

Keywords

File

Download PDF

References

  1. Bettio A, Honer M, Muller C, et al (2006). Synthesis and preclinical evaluation of a folic acid derivative labeled with F-18 for PET imaging of folate receptor-positive tumors. J Nucl Med, 47, 1153-60.
  2. Chang DK, Chiu CK, Kuo SY, et al (2009). Antiangiogenic targeting liposomes increase therapeutic efficacy for solid tumors. J Biol Chem, 284, 12905-16. https://doi.org/10.1074/jbc.M900280200
  3. Chen C, Ke J, Zhou XE, et al (2013). Structural basis for molecular recognition of folic acid by folate receptors. Nature, 500, 486-9. https://doi.org/10.1038/nature12327
  4. Elnakat H, Ratnam M (2004). Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev, 56, 1067-84. https://doi.org/10.1016/j.addr.2004.01.001
  5. Gabizon A, Shmeeda H, Horowitz AT, et al (2004). Tumor cell targeting of liposome-entrapped drugs with phospholipidanchored folic acid-PEG conjugates. Adv Drug Deliv Rev, 56, 1177-92. https://doi.org/10.1016/j.addr.2004.01.011
  6. Han X, Liu J, Liu M, et al (2009). 9-NC-loaded folate-conjugated polymer micelles as tumor targeted drug delivery system: Preparation and evaluation in vitro. Int J Pharm, 372, 125-31. https://doi.org/10.1016/j.ijpharm.2008.12.035
  7. Hawley AE, Davis SS, Illum L (1995). Targeting of colloids to lymph-nodes - influence of lymphatic physiology and colloidal characteristics. Advanced Drug Delivery Reviews, 17, 129-48. https://doi.org/10.1016/0169-409X(95)00045-9
  8. Khemapech N, Oranratanaphan S, Termrungruanglert W, et al (2013). Salvage chemotherapy in recurrent platinumresistant or refractory epithelial ovarian cancer with carboplatin and distearoylphosphatidylcholine pegylated liposomal doxorubicin (Lipo-Dox (R)). Asian Pac J Cancer Prev, 14, 2131-5. https://doi.org/10.7314/APJCP.2013.14.3.2131
  9. Leamon CP, De Prince RB, Hendren RW (1999). Folatemediated drug delivery: Effect of alternative conjugation chemistry. J Drug Targeting, 7, 157-69. https://doi.org/10.3109/10611869909085499
  10. Liu B, Han SM, Tang XY, et al (2014). Cervical cancer gene therapy by gene loaded PEG-PLA nanomedicine. Asian Pac J Cancer Prev, 15, 4915-8. https://doi.org/10.7314/APJCP.2014.15.12.4915
  11. Liu M, Xu W, Xu LJ, et al (2005). Synthesis and biological evaluation of diethylenetriamine pentaacetic acidpolyethylene glycol-folate: a new folate-derived, (99m)Tcbased radiopharmaceutical. Bioconjuge Chem, 16, 1126-32. https://doi.org/10.1021/bc050122m
  12. Lukyanov AN, Gao ZG, Mazzola L, et al (2002). Polyethylene glycol-diacyllipid micelles demonstrate increased accumulation in subcutaneous tumors in mice. Pharm Res, 19, 1424-9. https://doi.org/10.1023/A:1020488012264
  13. Park EK, Kim SY, Lee SB, et al (2005). Folate-conjugated methoxy poly (ethylene glycol)/poly (epsilon-caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery. J Control Release, 109, 158-68. https://doi.org/10.1016/j.jconrel.2005.09.039
  14. Torchilin VP (2002). PEG-based micelles as carriers of contrast agents for different imaging modalities. Adv Drug Deliv Rev, 54, 235-52. https://doi.org/10.1016/S0169-409X(02)00019-4
  15. Torchilin VP (2004). Targeted polymeric micelles for delivery of poorly soluble drugs. Cell Mol Life Sci, 61, 2549-59. https://doi.org/10.1007/s00018-004-4153-5
  16. Torchilin VP (2007). Micellar nanocarriers: Pharmaceutical perspectives. Pharm Res, 24, 1-16.
  17. VertutDoi A, Ishiwata H, Miyajima K (1996). Binding and uptake of liposomes containing a poly (ethylene glycol) derivative of cholesterol (stealth liposomes) by the macrophage cell line J774: Influence of PEG content and its molecular weight. Bba-Biomembranes, 1278, 19-28.
  18. Wang S, Lee RJ, Mathias CJ, et al (1996). Synthesis, purification, and tumor cell uptake of Ga-67-deferoxamine-folate, a potential radiopharmaceutical for tumor imaging. Bioconjugate Chem, 7, 56-62. https://doi.org/10.1021/bc9500709
  19. Wang S, Luo J, Lantrip DA, et al (1997). Design and synthesis of In-111 DTPA-folate for use as a tumor-targeted radiopharmaceutical. Bioconjugate Chemistry, 8, 673-9. https://doi.org/10.1021/bc9701297
  20. Wang YG, Wang RQ, Lu XY, et al (2010). Pegylated phospholipids-based self-assembly with water-soluble drugs. Pharm Res, 27, 361-70. https://doi.org/10.1007/s11095-009-0029-6
  21. Xu X, Wang L, Xu HQ, et al (2013). Clinical comparison between paclitaxel liposome (Lipusu (r)) and paclitaxel for treatment of patients with metastatic gastric cancer. Asian Pac J Cancer Prev, 14, 2591-4. https://doi.org/10.7314/APJCP.2013.14.4.2591
  22. Yoo HS, Park TG (2004). Folate receptor targeted biodegradable polymeric doxorubicin micelles. J Controll Release, 96, 273-83. https://doi.org/10.1016/j.jconrel.2004.02.003
  23. Zong H, Thomas TP, Lee KH, et al (2012). Bifunctional PAMAM dendrimer conjugates of folic acid and methotrexate with defined ratio. Biomacromolecules, 13, 982-91. https://doi.org/10.1021/bm201639c

Cited by

  1. Improved radiopharmaceutical based on 99mTc-Bombesin–folate for breast tumour imaging vol.37, pp.4, 2016, https://doi.org/10.1097/MNM.0000000000000460
  2. Design and interaction mechanism of ligand targeted with folate receptor α and β vol.31, pp.1, 2017, https://doi.org/10.1002/poc.3719