Taxane‐Grafted Metal‐Oxide Nanoparticles as a New Theranostic Tool against Cancer: The Promising Example of Docetaxel‐Functionalized Titanate Nanotubes on Prostate Tumors

Abstract

The combination of anticancer drugs and metal oxide nanoparticles is of great interest in cancer nanomedicine. Here, the development of a new nanohybrid, titanate nanotube-docetaxel (TiONts-DTX) is reported, the two parts of which are conjugated by covalent linkages. Unlike most nanoparticles currently being developed for biomedical purposes, TiONts present a needle-shaped morphology. The surface of TiONts is linked with 3-aminopropyl triethoxysilane and with a hetero-bifunctional polymer (polyethylene glycol) to create well-dispersed and biocompatible nanovectors. The prefunctionalized surface of this scaffold has valuable attachments to graft therapeutic agents (DTX in our case) as well as chelating agents (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to monitor the nanohybrids. To evaluate drug efficacy, in vitro tests have demonstrated that the association between TiONts and DTX shows cytotoxic activity against a hormone-refractory prostate cancer cell line (22Rv1) whereas TiONts without DTX do not. Finally, the first in vivo tests with intratumoral injections show that more than 70% of TiONts nanovectors are retained within the tumor for at least 7 d. Moreover, tumor growth in mice receiving TiONts-DTX is significantly slower than that in mice receiving free DTX. This nanohybrid can thus become a promising new tool in biomedicine to fight against prostate cancer.

Toxicological Risk Assessment of Emerging Nanomaterials: Cytotoxicity, Cellular Uptake, Effects on Biogenesis and Cell Organelle Activity, Acute Toxicity and Biodistribution of Oxide Nanoparticles

“…Bare TiONts were coated by APTES and PEG with protocols very similar to that used for SPIONs [8]. The method of chitosan (CT) grafting is based on electrostatic interactions between chitosan's amines and nanotubes' hydroxyl groups.…”

“…However, the subsequent surface functionalization of these nanotubes with Docetaxel reduces the drug availability and significantly increases Docetaxel IC50 in 22Rv1 cells, compared to free drug control [8]. As described in the next section, in vivo studies have shown that TiONts acts like an anchor in the tumor, which prevents drug from leaching out of the cancerous cells, and as a result, the loss in drug potency was not detrimental in this specific case [8].…”

“…The previously described metal oxide nanoparticles are excellent candidates for a variety of biomedical applications ranging from drug delivery to diagnostic aids, as well as implantable biomaterials [6,8,13,14]. However, a thorough evaluation of particles interaction with the targeted cells, circulatory immune cells and tissues is the first prerequisite.…”

“…The cytotoxicity of titanate nanotubes made by hydrothermal treatment has been assessed in H596 human lung tumor cells [30], cardiomyocytes [31], SNB19 and U87-MG glioblastomas [32], Caco-2 cells [33], as well as 22Rv1 prostate cancer cells [8]. Interestingly, the degree of ion exchange via acid treatment, which partly or entirely substitutes sodium cations by hydrogen cations, is a key parameter that drives the cytotoxicity of titanate nanowires [30].…”

“…All the obtained nanohybrids were purified by ultrafiltration on 30 kDa membranes and/or dialyzed on 3.5 kDa membranes to remove ungrafted stabilizing molecules and remaining salts finally yielding nanoparticle suspensions at the pH and the conductivity of ultrapure water. Finally, a portion of the suspensions was freeze-dried for powder characterizations: X-ray diffraction (XRD), infrared spectroscopy (IR), X-ray photoelectron spectroscopy (XPS) and thermogravimetric analysis (TGA) [8,10,11].…”