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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

Isomeric ${\alpha}-/{\gamma}$-folate conjugation;polymeric micelles;tumor targeting

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