Simultaneous hyperthermia-chemotherapy with controlled drug delivery using single-drug nanoparticles

Abstract

We previously investigated the utility of μ-oxo N,N′- bis(salicylidene)ethylenediamine iron (Fe(Salen)) nanoparticles as a new anti-cancer agent for magnet-guided delivery with anti-cancer activity. Fe(Salen) nanoparticles should rapidly heat up in an alternating magnetic field (AMF), and we hypothesized that these single-drug nanoparticles would be effective for combined hyperthermia-chemotherapy. Conventional hyperthermic particles are usually made of iron oxide, and thus cannot exhibit anti-cancer activity in the absence of an AMF. We found that Fe(Salen) nanoparticles induced apoptosis in cultured cancer cells, and that AMF exposure enhanced the apoptotic effect. Therefore, we evaluated the combined three-fold strategy, i.e., chemotherapy with Fe(Salen) nanoparticles, magnetically guided delivery of the nanoparticles to the tumor, and AMF-induced heating of the nanoparticles to induce local hyperthermia, in a rabbit model of tongue cancer. Intravenous administration of Fe(Salen) nanoparticles per se inhibited tumor growth before the other two modalities were applied. This inhibition was enhanced when a magnet was used to accumulate Fe(Salen) nanoparticles at the tongue. When an AMF was further applied (magnet-guided chemotherapy plus hyperthermia), the tumor masses were dramatically reduced. These results indicate that our strategy of combined hyperthermia-chemotherapy using Fe(Salen) nanoparticles specifically delivered with magnetic guidance represents a powerful new approach for cancer treatment.

Magnetic metal-complex-conducting copolymer core–shell nanoassemblies for a single-drug anticancer platform

“…When Fe(salen) was dispersed in aqueous solution (saline), it immediately aggregated due to its hydrophobic nature, exhibiting ferromagnetic-like behavior by the attachment of a magnet, in accordance with our previous reports. 13,14 Prolonged exposure to air (47 days) during the recrystallization process caused a significant loss of magnetism of Fe(salen) NPs, presumably due to oxidation. On the other hand, the CSNAs showed stable magnetism for at least 6 months of subsequent air exposure, implying that the formation of the homogeneous PPy-shell prevents oxidative modification of the Fe(salen) core.…”

“…14 A thermometer (hand-held thermometer HA-200, Anritsu Meter Co., Tokyo, Japan) or a thermograph (InfraRed camera, Nippon Avionics Co., Ltd., Tokyo, Japan) was used to determine temperature in vitro. 14 For the in vivo imaging system test, 2.5 mg ml − 1 of the BSA-CSNA sample was prepared with saline solution, and 1 ml of the sample solution was added into a cell culture dish (~5000 cells) containing 3 ml of DMEM buffer (final concentration of 0.625 mg ml − 1 ). For the pH-dependent AMF-hyperthermal platform, the U87 cell culture media were adjusted to either pH 7.4 or pH 6.0 immediately before introducing the BSA-CSNA samples.…”

“…In other words, the Fe(salen) metal complexes, which have been used in the last few decades as asymmetric catalysts [17][18][19][20] and molecular magnets, 21,22 can be employed as magnetically guided anticancer agents. 13,14 Other molecular magnets have been reported but cannot be practically applied due to the very low critical temperature at which they exhibit positive values of magnetization in response to a room temperature magnetic field. [23][24][25][26] However, Fe(salen) also has some drawbacks, such as poor water solubility, loss of magnetic properties in solvents and potential cytotoxicity when accumulated in organs.…”

“…5,6 To address these problems, a single low-molecular-weight drug component having multifunctional capabilities is required. Metal complexes are useful for this purpose [13][14][15][16] because a metal complex is not only small but also can be therapeutically active with magnetic 13,14 or optical properties. 15,16 Therefore, a single-step fabrication method for a metal-salt-free, magnetic metal-complex-based local DDS platform might shift the synthetic paradigm to realize advanced DDS applications.…”

“…We have previously reported a metal-complex-based DDS agent, Fe(salen) nanoparticles in a water suspension, 13,14 which proved suitable for magnetic DDS, chemotherapy, magnetic resonance imaging (MRI) and AMF-induced local hyperthermal therapy.…”