Super pH-sensitive multifunctional polymeric micelle for tumor pHe specific TAT exposure and multidrug resistance

Eun Seong Lee, Zhonggao Gao, Dongin Kim, Kyeongsoon Park, Ick Chan Kwon, You Han Bae

Research output: Contribution to journalArticlepeer-review

390 Citations (Scopus)


As an alternative to cell specific cancer targeting strategies (which are often afflicted with the heterogeneity of cancer cells as with most biological systems), a novel polymeric micelle constitute of two block copolymers of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)-TAT (transactivator of transcription) and poly(l-histidine)-b-poly(ethylene glycol) was developed. The micelle formed via the dialysis method was approximately 95 nm in diameter and contained 15 wt.% of doxorubicin (DOX) by weight. The micelle surface hides TAT during circulation, which has the strong capability to translocate the micelle into cells, and exposes TAT at a slightly acidic tumor extracellular pH to facilitate the internalization process. The micelle core was engineered for disintegration in early endosomal pH of tumor cells, quickly releasing DOX. The ionization process of the block copolymers and ionized polymers assisted in disrupting the endosomal membrane. This processes permitted high DOX concentrations in the cytosol and its target site of the nucleus, thus increasing DOX potency in various wild and multidrug resistant (MDR) cell lines (3.8-8.8 times lower IC50 than free DOX, depending on cell line). When tested with the xenografted tumors of human ovarian tumor drug-resistant A2780/AD, human breast tumor drug-sensitive MCF-7, human lung tumor A549 and human epidermoid tumor KB in a nude mice model, all tumors significantly regressed in size by three bolus injections at a dose of DOX 10 mg equivalent/kg body per injection of DOX-loaded micelle at three day interval, while minimum weight loss was observed. This approach may replace the need for cell-specific antibodies or targeting ligands, thereby providing a general strategy for solid tumor targeting.

Original languageEnglish
Pages (from-to)228-236
Number of pages9
JournalJournal of Controlled Release
Issue number3
Publication statusPublished - 2008 Aug 7

Bibliographical note

Funding Information:
The authors thank Profs. D. W. Grainger, C. Lim (Dept of Pharmaceutics, University of Utah), and T. E. Cheatham (Dept of Bioengineering, University of Utah) for their kind discussion/suggestion and proof-reading. This work was supported by NIH CA 122356 and 101850.


  • Multidrug resistance
  • Pop-up pH-sensitive polymeric micelle
  • Triggering drug release
  • Tumor pH

ASJC Scopus subject areas

  • Pharmaceutical Science


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