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.