Doxorubicin Loaded Thermosensitive Magneto-Liposomes Obtained by a Gel Hydration Technique: Characterization and In Vitro Magneto-Chemotherapeutic Effect Assessment

Abstract

The combination of magnetic hyperthermia with chemotherapy is considered a promising strategy in cancer therapy due to the synergy between the high temperatures and the chemotherapeutic effects, which can be further developed for targeted and remote-controlled drug release. In this paper we report a simple, rapid, and reproducible method for the preparation of thermosensitive magnetoliposomes (TsMLs) loaded with doxorubicin (DOX), consisting of a lipidic gel formation from a previously obtained water-in-oil microemulsion with fine aqueous droplets containing magnetic nanoparticles (MNPs) dispersed in an organic solution of thermosensitive lipids (transition temperature of ~43 °C), followed by the gel hydration with an aqueous solution of DOX. The obtained thermosensitive magnetoliposomes (TsMLs) were around 300 nm in diameter and exhibited 40% DOX incorporation efficiency. The most suitable MNPs to incorporate into the liposomal aqueous lumen were Zn ferrites, with a very low coercive field at 300 K (7 kA/m) close to the superparamagnetic regime, exhibiting a maximum absorption rate (SAR) of 1130 W/gFe when dispersed in water and 635 W/gFe when confined inside TsMLs. No toxicity of Zn ferrite MNPs or of TsMLs was noticed against the A459 cancer cell line after 48 h incubation over the tested concentration range. The passive release of DOX from the TsMLs after 48h incubation induced a toxicity starting with a dosage level of 62.5 ug/cm2. Below this threshold, the subsequent exposure to an alternating magnetic field (20–30 kA/m, 355 kHz) for 30 min drastically reduced the viability of the A459 cells due to the release of incorporated DOX. Our results strongly suggest that TsMLs represent a viable strategy for anticancer therapies using the magnetic field-controlled release of DOX.

Multifunctional and stimuli-responsive liposomes in hepatocellular carcinoma diagnosis and therapy

“…Doxorubicin can be co-delivered with simvastatin in suppressing lung cancer progression [220] . Another type is thermosensitive magnetic liposomes for doxorubicin delivery [221] and adjusting protein corona component around liposomes improves their potential in doxorubicin delivery [222] . However, more progressed liposomes have been employed for doxorubicin delivery in HCC and they have been dually modified with glycyrrhetinic acid (GA) and peanut agglutinin (PNA) to selectively target liver tumor cells in inhibiting tumorigenesis in vitro and in vivo [223] .…”

Hybrid Magnetic Lipid-Based Nanoparticles for Cancer Therapy

“…The release of both drugs significantly increased when an external magnetic field was applied [ 41 ]. A similar strategy was also used by Nitica and coworkers to improve the release of doxorubicin from thermosensitive magnetoliposomes for in vitro chemotherapeutic effect [ 42 ]. Despite the heat-activated drug release, other stimuli can also influence the drug release, including internal (e.g., pH, redox, hypoxia, and enzymes) and external stimuli (e.g., light irradiation, temperature, and ultrasound) [ 43 ].…”

Advances in smart delivery of magnetic field-targeted drugs in cardiovascular diseases

“…Nitica et al. developed a simple and rapid method for the synthesis of thermosensitive magnetic liposomes, including two core steps of synthesizing the lipid gel and driving the drug incorporation [ 54 ]. The 300 nm magnetoliposomes prepared by this method had good physical properties, and DOX release resulted in the death of more than 90% of A549 cancer cells when placed in an alternating magnetic field of 20–30 kA/m, 355 kHz for 30 min.…”

“…The magnetic field itself can also be used to "extrude" the drug from the carrier by mechanical force [ 52 ]. In addition, controlled drug release from magnetic carriers through alternating magnetic fields combined with thermal effects, as described above, is the main application of electromagnetic binding at present [ 54 ].…”