Hyaluronic acid modified bubble-generating magnetic liposomes for targeted delivery of doxorubicin

Abstract

Abstract The combination of liposomes and magnetic nanoparticles (MNPs) is a promising approach for cancer therapy due to its capability for magnetic field-directed targeted drug delivery at the diseased area. Contemporaneously, bubble-generating liposomes are of great interest in the field of cancer therapy, due to its triggered drug release properties and its ability to rupture cancer cells through cavitation induction. Therefore, the objective of the current study is to develop a bubble-generating magnetic liposomal (BMLs) drug delivery system with triggered drug release properties for targeted delivery of doxorubicin (DOX) in cancer therapy. Citric acid-coated iron oxide MNPs was co-entrapped with ammonium bicarbonate to produce BMLs by lipid film hydration method. BMLs were further modified by coating hyaluronic acid-polyethylene glycol (HA-PEG) on liposome surface to produce HA-PEG-BMLs for ligand-mediated active targeting of tumor cells. The resultant liposomes were found to be spherical in shape with an average particle size ranging from 100 to 170 nm. The physico-chemical properties and bubble-generating properties of liposomes were studied. In vitro drug release studies showed enhanced drug release under hyperthermia condition (43 °C) from BMLs/DOX and HA-PEG-BMLs/DOX due to more intense CO2 bubbles generation with faster decomposition rates of co-entrapped ammonium bicarbonate. In vitro cell culture studies using human glioblastoma cells (U87) were performed to evaluate the targeting efficiencies and anti-tumor efficacy of DOX-loaded liposomes. Magnetic targeted delivery of DOX was also demonstrated from LIVE/DEAD cell viability assays. The confocal microscopy and flow cytometry analysis confirmed enhanced intracellular uptake of HA-PEG-BMLs by U87 though binding of HA to overexpressed CD44 receptors on cell surface, which facilitated internalization of HA-PEG-BMLs/DOX through endocytosis and resulted in elevated DOX concentration in cancer cells. The combination of elevated intracellular DOX concentration and triggered DOX release at 43 °C led to enhanced cytotoxicity toward U87 cells in vitro. Thus, HA-PEG-BMLs will be useful for hyperthermia-induced targeted delivery of DOX for cancer therapy.