Nanoheterostructures (NHS) and Their Applications in Nanomedicine: Focusing on In Vivo Studies

Abstract

Inorganic nanoparticles have great potential for application in many fields, including nanomedicine. Within this class of materials, inorganic nanoheterostructures (NHS) look particularly promising as they can be formulated as the combination of different domains; this can lead to nanosystems with different functional properties, which, therefore, can perform different functions at the same time. This review reports on the latest development in the synthesis of advanced NHS for biomedicine and on the tests of their functional properties in in vivo studies. The literature discussed here focuses on the diagnostic and therapeutic applications with special emphasis on cancer. Considering the diagnostics, a description of the NHS for cancer imaging and multimodal imaging is reported; more specifically, NHS for magnetic resonance, computed tomography and luminescence imaging are considered. As for the therapeutics, NHS employed in magnetic hyperthermia or photothermal therapies are reported. Examples of NHS for cancer theranostics are also presented, emphasizing their dual usability in vivo, as imaging and therapeutic tools. Overall, NHS show a great potential for biomedicine application; further studies, however, are necessary regarding the safety associated to their use.

Keywords: biomedicine; hyperthermia; imaging; in vivo testing; nanoheterostructures; photothermal therapy.

Scheme 1

Overview of the imaging techniques most used in heterostructures-based diagnostics. Owing to the multiple domains structure, the patient model can be examined by different imaging methods after administration and delivery of a single nanostructure.

Figure 1

Fe₃O₄@TaO_x core@shell NPs for dual imaging. (a,b) TEM images of magnetite NPs before and after the growth of tantalum oxide shell. (c–e) The panel (e) shows the overlay of the iron elemental analysis (c) and the corresponding bright field image, highlighting the core@shell architecture of the nanostructure. The central panel and the lower one represent the imaging of a rat after administration of the heterostructure, following the intensity of the signal during a time lapse of 24 h. In MRI, the tumor (dashed lines) became darker after a short time from the injection, whereas for CT-imaging the accumulation in different organ was detected during the observation. TV, Li, Tu, and Sp indicate the tumor-associated vessel, liver, tumor, and spleen, respectively. Adapted with permission from J. Am. Chem. Soc. 2012, 134, 10309−10312 [39]. Copyright 2012 American Chemical Society.

Figure 2

Design of a trimeric dumbbell for T₁/T₂ MRI analysis. The coating of iron oxide NPs with Gd-chelates hampers the exploitation as T₁ imaging probe, due to the close proximity of the magnetite core. The presence of the Pt spacer between iron oxide and gold NPs allows increasing the distance between the two MR contrast agents (Gd-chelate anchored on gold domain) and to achieve an effective dual MR imaging. In the lower panel, MRI was performed before and 4 h after the injection of heterostructure. For each time point, gray scale and pseudo-colored images are reported. Adapted with permission from ACS NANO 2014, 8, 9884–9896 [47]. Copyright 2014 American Chemical Society.

Figure 3

Sketch illustrating the synthesis of HA coated Fe₃O₄–NaYF₄@TiO₂ nanocomposites. (a) TEM and EDX maps of the distribution of Fe, Ti, and Y elements in the nanoparticles. (b) In vivo UCL images of the nanocomposites injected in tumor-bearing mice in bright field (left), dark field (middle), and overlay (right) under a magnetic field (bottom) and without a magnetic field (top). Adapted with permission from J. Mater. Chem. B 2014, 2, 5775–5784 [54]. Copyright 2014 Royal Society of Chemistry.

Figure 4

(a) Sketch showing the preparation of the multi-shelled NaYF₄:Yb/Tm@NaLuF₄@NaYF₄@NaGdF₄ NPs. (b) Trimodal imaging potential of the nanoparticles. (c) TEM images of the nanoparticles at each step of preparation. (d) In vivo UCL imaging of Hela tumor-bearing nude mice at 3 h after intravenous injection of nanoparticles with (left) and without (right) folic acid functionalization. Adapted with permission from Anal. Chem. 2013, 85, 12166−12172 [59]. Copyright 2013 American Chemical Society.

Scheme 2

The sketch depicts the most common techniques in nanoparticle-based therapy, magnetic hyperthermia and photothermal therapy. The target is the ablation of malignant cancer cells. To this aim, both techniques exploit the generation of local heat as therapeutic effect, actuated by alternating magnetic field for magnetic hyperthermia and by laser irradiation for PTT, respectively.

Figure 5

(a) Scheme of synthesis of Fe₃O₄@Au nanostars and corresponding TEM image. (b) In vivo MRI/CT imaging of a xenografted tumor model before and at 0.5 h post intratumor and at 6 h post intravenous injections of Fe₃O₄@Au NHS. (c) In vivo ultrasound/PA images of tumors before and at 0.5 h post intratumor injection of Fe₃O₄@Au nanostars. (d) Full-body photothermal images of mice after intratumor injection with 0.1 mL PBS (control, left mouse) or Fe₃O₄@Au NSs (right mouse), followed by exposure to an 808 nm laser with a power density of 1.0 W/cm², at a time point of 0 and 5 min. Adapted with permission from Sci. Rep. 2016, 6, 28325 [93]. Copyright 2016 Nature Publishing Group, licensed under a Creative Commons Attribution 4.0 International License.