APTES monolayer coverage on self-assembled magnetic nanospheres for controlled release of anticancer drug Nintedanib

Abstract

The use of an appropriate delivery system capable of protecting, translocating, and selectively releasing therapeutic moieties to desired sites can promote the efficacy of an active compound. In this work, we have developed a nanoformulation which preserves its magnetization to load a model anticancerous drug and to explore the controlled release of the drug in a cancerous environment. For the preparation of the nanoformulation, self-assembled magnetic nanospheres (MNS) made of superparamagnetic iron oxide nanoparticles were grafted with a monolayer of (3-aminopropyl)triethoxysilane (APTES). A direct functionalization strategy was used to avoid the loss of the MNS magnetization. The successful preparation of the nanoformulation was validated by structural, microstructural, and magnetic investigations. X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) were used to establish the presence of APTES on the MNS surface. The amine content quantified by a ninhydrin assay revealed the monolayer coverage of APTES over MNS. The monolayer coverage of APTES reduced only negligibly the saturation magnetization from 77 emu/g (for MNS) to 74 emu/g (for MNS-APTES). Detailed investigations of the thermoremanent magnetization were carried out to assess the superparamagnetism in the MNS. To make the nanoformulation pH-responsive, the anticancerous drug Nintedanib (NTD) was conjugated with MNS-APTES through the acid liable imine bond. At pH 5.5, which mimics a cancerous environment, a controlled release of 85% in 48 h was observed. On the other hand, prolonged release of NTD was found at physiological conditions (i.e., pH 7.4). In vitro cytotoxicity study showed dose-dependent activity of MNS-APTES-NTD for human lung cancer cells L-132. About 75% reduction in cellular viability for a 100 μg/mL concentration of nanoformulation was observed. The nanoformulation designed using MNS and monolayer coverage of APTES has potential in cancer therapy as well as in other nanobiological applications.

Scheme 1

Schematic representation of the surface modification and loading of the drug over the MNS surface.

Figure 1

The XRD pattern and the Rietveld refinement profile using the Fullprof program (a), FE-SEM micrograph (b), TEM micrograph (c), and SAED pattern of MNS (d).

Figure 2

FTIR spectra of (a) MNS, (b) MNS-APTES, (c) MNS-APTES-NTD, and (d) NTD.

Figure 3

(a) XPS survey spectra of bare and APTES MNS. The observed spectral features are labelled with relevant elemental peaks. The regions for (b) Fe(2p), (c) O(1 s), (d) N(1 s), and (e) Si(2p) for the APTES coated MNS.

Figure 4

(a) Room-temperature M-H curves of MNS and MNS-APTES and (b) temperature-dependent FC-ZFC magnetization curves of MNS and MNS-APTES.

Figure 5

(a) The thermoremanent magnetization (black circles) and its first-order derivative (red circles) as a function of temperature, (b) The coercive field (H_C) vs. T^1/2 (left vs. bottom axis) and saturation magnetization (M_S) vs. T^3/2 (right vs. top axis) for MNS (circles) and MNS-APTES (squares).

Figure 6

The loading and release of NTD (a) Drug loading efficiency and drug loading capacity when 1 mg MNS was reacted with different amounts of NTD, (b) Drug release from MNS-APTES-NTD nanoformulation at pH 7.4 and pH 5.5 in PBS (37 °C).

Scheme 2

Protonation and release of NTD from the MNS-APTES-NTD nanoformulation.

Figure 7

In vitro L-132 cancer cell viability after exposure to MNS-APTES, MNS-APTES-NTD, and free NTD at different concentrations.