Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery

Mol Biosyst. 2005 Sep;1(3):242-50. doi: 10.1039/b500266d. Epub 2005 Jun 30.

Abstract

A new type of multifunctional polymeric micelle drug carrier for active intracellular drug delivery was prepared and characterized in this study. The micelle is a nano-supramolecular assembly with a spherical core-shell structure, and its surface and core were modified with piloting molecules for cancer cells and pH-sensitive drug binding linkers for controlled drug release, respectively. In order to prepare such micelles, self-assembling amphiphilic block copolymers, folate-poly(ethylene glycol)-poly(aspartate hydrazone adriamycin) [Fol-PEG-P(Asp-Hyd-ADR)], were specially designed and synthesized by installing a molecular promoter to enhance intracellular transport, folate (Fol), at the end of the shell-forming PEG chain and conjugating the anticancer drug, adriamycin (ADR), to the side chain of the core-forming PAsp segment through an acid-sensitive hydrazone bond. Because folate-binding proteins (FBP) are selectively overexpressed on the cancer cell membranes, the folate-bound micelles (FMA) can be guided to the cancer cells in the body, and after the micelles enter the cells, hydrazone bonds are cleaved by the intracellular acidic environment (pH 5-6) so that the drug release profile of the micelles is controlled pH-dependently. In this regard, FBP-binding selectivity of the prepared FMA was evaluated by surface plasmon resonance (SPR) measurements. The tetrazolium dye method (MTT assay) using human pharyngeal cancer cells (KB cell) revealed that FMA significantly improved cell growth inhibitory activity in spite of a short exposure time due to the selective and strong interaction between folate molecules and their receptors. Subsequent flow cytometric analysis showed that cellular uptake of FMA significantly increased. Consequently, these findings would provide one of the most effective approaches for cancer treatment using intracellular environment-targeting supramolecular drug carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / drug effects
  • Chromatography, Gel
  • Drug Delivery Systems*
  • Flow Cytometry
  • Folic Acid / analogs & derivatives*
  • Folic Acid / pharmacology*
  • Humans
  • Hydrogen-Ion Concentration
  • KB Cells
  • Micelles
  • Polyethylene Glycols

Substances

  • Micelles
  • Polyethylene Glycols
  • Folic Acid