Biomimetic Magnetic Nanocarriers Drive Choline Kinase Alpha Inhibitor inside Cancer Cells for Combined Chemo-Hyperthermia Therapy

Abstract

Choline kinase α1 (ChoKα1) has become an excellent antitumor target. Among all the inhibitors synthetized, the new compound Ff35 shows an excellent capacity to inhibit ChoKα1 activity. However, soluble Ff35 is also capable of inhibiting choline uptake, making the inhibitor not selective for ChoKα1. In this study, we designed a new protocol with the aim of disentangling whether the Ff35 biological action is due to the inhibition of the enzyme and/or to the choline uptake. Moreover, we offer an alternative to avoid the inhibition of choline uptake caused by Ff35, since the coupling of Ff35 to novel biomimetic magnetic nanoparticles (BMNPs) allows it to enter the cell through endocytosis without interacting with the choline transporter. This opens the possibility of a clinical use of Ff35. Our results indicate that Ff35-BMNPs nanoassemblies increase the selectivity of Ff35 and have an antiproliferative effect. Also, we demonstrate the effectiveness of the tandem Ff35-BMNPs and hyperthermia.

Nanoformulation Design Including MamC-Mediated Biomimetic Nanoparticles Allows the Simultaneous Application of Targeted Drug Delivery and Magnetic Hyperthermia

“…Figure 7 A shows the cell viability compared to that of the untreated controls (CTRL-). As previously shown by our groups [ 20 , 22 , 30 , 42 ], BM are cytocompatible. Indeed, both M and DOXO-free 25 BM + 75 M nanoformulations display low cytotoxicity, and in all cases cell viability is above 80%, which is considered the cut-off indicated by ISO 10993–5:2009 [ 43 ].…”

“…To determine the effect of magnetic hyperthermia on cell viability, in another set of experiments, HT-29 were incubated with the maximum concentration (300 µg/mL) of M, TBM, and the nanoassembly 25 TBM + 75 M for 24 h to allow the internalization of the nanoassemblies. After the incubation time, cells were exposed to AMF for 2 h. Finally, the viability was evaluated by the MTT colorimetric assay, as already described [ 30 ]. Briefly, 10 μL of the MTT 5 mg/mL in phosphate buffered saline (PBS) solution was added to the plate, incubated at 37 °C for 2 h, and supernatants were removed.…”

Biomimetic Magnetoliposomes as Oxaliplatin Nanocarriers: In Vitro Study for Potential Application in Colon Cancer

“…However, these MmsF-mediated magnetic nanoparticles are still not characterized enough to determine whether or not they could be of use in nanotechnology. On the contrary, MamC-mediated biomimetic nanoparticles (here referred as BMNPs) have demonstrated their potential as promising drug nanocarriers [5,6,14,15] and as hyperthermia agents [16,17], opening the possibility of a combined therapy by using the same nanoplatform. MamC controls magnetite nucleation and growth by both template and ionotropic effects [18], remaining attached to the nanoparticles and forming a nanocomposite (95 wt% magnetite + 5 wt% MamC) that results, not only in magnetic nanoparticles of different size and morphology (and thus magnetic properties) compared to those of chemically produced ones, but also in nanoparticles with novel surface properties [5].…”

“…In fact, a previous proof of concept showed that BMNPs were biocompatible and could be coupled with Oxaliplatin (Oxa) [14]. Therefore, these MamC-mediated BMNPs have been proposed as efficient nanocarriers [5,6,14,15] of a number of molecules offering crucial advantages over the use of inorganically synthesized magnetic nanoparticles to this end.…”

Biomimetic Magnetite Nanoparticles as Targeted Drug Nanocarriers and Mediators of Hyperthermia in an Experimental Cancer Model

“…Active targeting can be achieved both by functionalization of the nanoparticle with probes against tumor-associated markers [ 15 , 19 , 20 ] or/and, as in the case of MNPs, by the application of a gradient magnetic field (GMF), usually a linear variation in the static magnetic field, which can enhance NP accumulation within the tumor [ 5 , 21 , 22 ]. Moreover, MNPs can also serve as magnetic hyperthermia (MH) agents, able to induce a local intratumor temperature increase—around 43–46 °C, which is effective against tumor cells—when exposed to an alternating magnetic field (AMF) [ 15 , 23 , 24 ]. Furthermore, MH also promotes the release or activation of therapeutic molecules coupled to the nanocarriers, thus locally increasing the concentration of the chemotherapeutic drug at the tumor site and prompting the effectiveness of the treatment [ 15 , 25 , 26 , 27 ].…”