Spermine modified polymeric micelles with pH-sensitive drug release for targeted and enhanced antitumor therapy

Tumor targeting delivery of chemotherapeutic drugs by nanocarriers has been demonstrated to be a promising strategy for cancer therapy with improved therapeutic efficacy. In this work, we reported a novel type of active targeting micelle with pH-responsive drug release by using biodegradable poly(lactide)-poly(2-ethyl-2-oxazoline) di-block copolymers functionalized with spermine (SPM). SPM has been considered as a tumor binding ligand through its specific interaction with the polyamine transport system (PTS), a transmembrane protein overexpressed on various types of cancer cell, while its application in nano-drug delivery systems has rarely been explored. The micelles with spherical shape (∼110 nm) could load hydrophobic paclitaxel (PTX) with high capacity, and release the payload much faster at acidic pH (4.5-6.5) than at pH 7.4. This pH-responsive property assisted the rapid escape of drug from the endo/lysosome after internalization as demonstrated by confocal laser scanning microscopy images using coumarin-6 (Cou-6) as a fluorescent probe. With surface SPM modification, the micelles displayed much higher cellular uptake than SPM lacking micelles in various types of cancer cells, demonstrating tumor targeting ability. The uptake mechanism of SPM modified micelles was explored by flow cytometry, which suggested an energy-consuming sag vesicle-mediated endocytosis pathway. As expected, the micelles displayed significantly enhanced anti-cancer activity. This work demonstrates that SPM modified pH-sensitive micelles may be potential drug delivery vehicles for targeting and effective cancer therapy.