Superparamagnetic nanoparticles (SPIONs) could enable cancer theranostics if magnetic resonance imaging (MRI) and magnetic hyperthermia treatment (MHT) were combined. However, the particle size of SPIONs is smaller than the pores of fenestrated capillaries in normal tissues because superparamagnetism is expressed only at a particle size <10 nm. Therefore, SPIONs leak from the capillaries of normal tissues, resulting in low accumulation in tumors. Furthermore, MHT studies have been conducted in an impractical way: direct injection of magnetic materials into tumor and application of hazardous alternating current (AC) magnetic fields. To accomplish effective enhancement of MRI contrast agents in tumors and inhibition of tumor growth by MHT with intravenous injection and a safe AC magnetic field, we clustered SPIONs not only to prevent their leakage from fenestrated capillaries in normal tissues, but also for increasing their relaxivity and the specific absorption rate. We modified the clusters with folic acid (FA) and polyethylene glycol (PEG) to promote their accumulation in tumors. SPION clustering and cluster modification with FA and PEG were achieved simultaneously via the thiol-ene click reaction. Twenty-four hours after intravenous injection of FA- and PEG-modified SPION nanoclusters (FA-PEG-SPION NCs), they accumulated locally in cancer (not necrotic) tissues within the tumor and enhanced the MRI contrast. Furthermore, 24 h after intravenous injection of the NCs, the mice were placed in an AC magnetic field with H = 8 kA/m and f = 230 kHz (Hf = 1.8×10⁹ A/m∙s) for 20 min. The tumors of the mice underwent local heating by application of an AC magnetic field. The temperature of the tumor was higher than the surrounding tissues by ≈6°C at 20 min after treatment. Thirty-five days after treatment, the tumor volume of treated mice was one-tenth that of the control mice. Furthermore, the treated mice were alive after 12 weeks; control mice died up to 8 weeks after treatment.

We report the synthesis of smart nanoparticles (NPs) that generate heat in response to an alternating current magnetic field (ACMF) and that sequentially release an anticancer drug (doxorubicin, DOX). We further study the in vivo therapeutic efficacy of the combination of magnetic hyperthermia (MHT) and chemotherapy using the smart NPs for the treatment of multiple myeloma. The smart NPs are composed of a polymer with a glass-transition temperature (T_g) of 44°C, which contains clustered Fe₃O₄ NPs and DOX. The clustered Fe₃O₄ NPs produce heat when the ACMF is applied and rise above 44°C, which softens the polymer phase and leads to the release of DOX. The combination of MHT and chemotherapy using the smart NPs destroys cancer cells in the entire tumor and achieves a complete cure in one treatment without the recurrence of malignancy. Furthermore, the smart NPs have no significant toxicity.

Two kinds of organosilica nanoparticles (NPs) which were fabricated from thiol containing precursors, (3-mercaptopropyl)trimethoxysilane (MPMS) and (3-mercaptopropyl)methyldimethoxysilane (MPDMS), are potential delivery vehicles of anticancer drugs. MPMS can form three siloxane bonds, but MPDMS forms two siloxane bonds at a maximum limit. Hence, disulfide bonds can be involved in the three-dimensional (3D) morphology of MPDMS NPs. In addition, NPs containing disulfide bonds are potentially degraded by reduced form of glutathione (GSH). To examine reactions between the organosilica NPs and GSH, the NPs were incubated in 10 mM GSH aqueous solution at 37 °C for 7 d and the products were analyzed using a field-emission scanning electron microscopy (FE-SEM), Raman spectroscopy and soft X-ray photoelectron spectroscopy (XPS). The Raman spectra showed the presence of disulfide bonds in the MPDMS NPs and the absence of disulfide bonds in MPMS NPs. The results of XPS measurements suggested that the disulfide bonds in the outer layer of MPDMS-NP were reduced to thiol groups. FE-SEM observations of MPDMS NPs detected changes in NP morphology after the GSH incubation. These results support the idea that MPDMS NPs contain disulfide bonds and are degradable by GSH. Therefore, MPDMS NPs possess biodegradable feature that is advantageous for clinical translation, i.e., nanomedicine.