Efficient tumor regression by a single and low dose treatment with a novel and enhanced formulation of thermosensitive liposomal doxorubicin

We have developed a novel and simplified thermosensitive liposomal formulation (HaT: Hyperthermia-activated cytoToxic) composed of DPPC lipid and Brij78 (96:4, molar ratio). The HaT nanoparticles were loaded with doxorubicin (DOX) with > 95% efficiency when a pH gradient method and a drug/lipid ratio of 1/20 (w/w) were applied. Drug release from the HaT formulation was significantly faster at 40–41 °C (100% release in 2–3 min) with 3.4-fold increased membrane permeability compared to the LTSL (lyso-lipid temperature sensitive liposomes; DPPC: MSPC: DSPE-PEG2000 = 86:10:4, molar ratio), a formulation that is currently in clinical trials. Both formulations displayed similar stability at 37 °C in serum (10–20% release in 30 min), which corresponds to their comparable pharmacokinetics in the unheated mice. An approximately 1.4-fold increased drug delivery to the locally heated tumor (~ 43 °C) was detected with HaT–DOX compared to LTSL–DOX. Moreover, when compared with free DOX, HaT enhanced drug uptake in the heated tumor by 5.2-fold and reduced drug delivery to the heart by 15-fold. A single i.v. treatment with HaT–DOX at 3 mg DOX/kg in combination with localized hyperthermia demonstrated enhanced tumor regression compared to LTSL–DOX and free DOX, and exhibited little toxicity.

Graphical AbstractWe have developed a novel and enhanced thermosensitive liposomal formulation for targeted delivery of doxorubicin to locally heated tumors.Figure optionsDownload full-size imageDownload as PowerPoint slide