Lanthanides: Applications in Cancer Diagnosis and Therapy

Abstract

Lanthanide complexes are of increasing importance in cancer diagnosis and therapy, owing to the versatile chemical and magnetic properties of the lanthanide-ion 4f electronic configuration. Following the first implementation of gadolinium(III)-based contrast agents in magnetic resonance imaging in the 1980s, lanthanide-based small molecules and nanomaterials have been investigated as cytotoxic agents and inhibitors, in photodynamic therapy, radiation therapy, drug/gene delivery, biosensing, and bioimaging. As the potential utility of lanthanides in these areas continues to increase, this timely review of current applications will be useful to medicinal chemists and other investigators interested in the latest developments and trends in this emerging field.

Figure 1

Number of articles in Web of Science on the topic “lanthanide” and “cancer” from 2005 to 2015.

Figure 2

Molecular structures of porphyrin-based lanthanide complexes, Er-L and Yb-L (Yb-L served as the control). Reproduced from ref. with permission of the Royal Society of Chemistry.

Figure 3

a) Structure of “smart” cancer cell-specific PDT agent (Gd-N) and control analogs Yb-N and Gd-RhB. b) 3D in vitro imaging of Gd-N after 15-h incubation in HeLa cells. Subcellular localization of Gd-N in c) cancer cells (HeLa) and d) normal cells (WPMY-1). Reproduced with permission from ref. (© 2014 National Academy of Sciences, USA).

Figure 4

Variation of (a) tumor volumes and (b) body weights of mice in experimental and control groups, respectively. Each data point represents the average value of 5 mice. (c) Representative photos of a mouse showing tumors at 14 days after treatment in experimental and control groups, respectively. (d) Images (left) and the corresponding high-resolution images (right) of hematoxylin–eosin stained tumor tissues harvested from the experimental and control groups after 14 days. Reproduced from ref. with permission of the Royal Society of Chemistry.

Figure 5

Schematic of dual-modal imaging and PDT using UCNP–Ce6. Reproduced with permission from ref. (© 2012 John Wiley & Sons Inc.).

Figure 6

Left panels: Anterior (A) and posterior (B) ^99mTc-MDP bone scan images of pre- treatment bony metastases. Right panels: Anterior (C) and posterior (D) total body images obtained (via dual head gamma camera) of sites of uptake 7 days after ¹⁷⁷Lu-J591 administration. Note ¹⁷⁷Lu-J591 is cleared via the liver. Reproduced with permission from ref. (© 2010 John Wiley & Sons Inc.).

Figure 7

Formation pathway for Sm₂O₃ and Gd₂O₃ nanostructures, as well as pH-controlled anticancer drug delivery. Reproduced with permission from ref. (© 2015 John Wiley & Sons Inc.).

Figure 8

Comparative statistical analysis of multiplexed detection with sb-UCNPs and IHC. (a) using two breast cancer cell-lines: MCF-7 and MDA-MB-231 (b) using three formaldehyde fixed-paraffin embedded (FFPE) human breast cancer tissues with primary antibodies-conjugated sb-UCNPs. Scale bar, 20 μm. Reproduced with permission from ref. (© 2015 Nature Publishing Group).

Figure 9

miRNAs were northern blotted and incubated with lanthanide-labeled DNA probes. After hybridization and washing, the membrane was analyzed by laser ablation inductively coupled plasma mass spectrometry. The dry aerosol created by laser ablation was introduced to the ICP-MS for online detection of the lanthanide composition, thereby enabling multiplex detection of miRNAs.

Figure 10

Structure of a seven-coordinate lanthanide-peptide tagged to ubiquitin (PDB accession code 2OJR). Color coding: Tb³⁺ (pink spheres), N (blue), O (red), C (cyan).

Figure 11

a,b) Upconversion luminescence images of nude mice after 1.5 h intravenous injection a) without and b) with UCNPs. Left are bright field images, middle are red luminescence images, and right are green luminescence images. c,d) Upconversion luminescence images of nude mice bearing tumors after intravenous injection of c) UCNPs and d) UCNP-Ce6. Arrows indicate tumor sites. Top row, bright field images, middle row, true-color images of green luminescence, and bottom row, pseudo-color images converted from the corresponding true-color images (middle row) using ImageJ image analysis software (http://rsb.info.nih.gov/ij/). Red luminescence was recorded using a red band pass filter (641.5 − 708.5 nm, Semrock), and green luminescence was recorded using a combination of a green band pass filter (517 − 567 nm, Semrock) and an 850 nm short pass filter (SPF-850, CVI). Reproduced with permission from ref. (© 2012 John Wiley & Sons Inc.).

Figure 12

a) Procedure for the synthesis of upconverting nanoparticles coated with a mesoporous silica outer layer. b) NIR light-triggered doxorubicin release by making use of the upconversion property of UCNPs and trans–cis photoisomerization of azo molecules grafted in the mesopore network of a mesoporous silica layer. Reproduced with permission from ref. (© 2013 John Wiley & Sons Inc.).

Figure 13

Merged bright-field and time-resolved luminescence microscopy of HeLa cells loaded with [Eu₂(L^C5)₃]. Top row: Cells incubated with various concentrations of [Eu₂(L^C5)₃] in RPMI-1640 for 6 h at 37 °C; conditions: Pan-Fluor lens 40× magnification, 365 nm excitation (BP 80 nm), 420 nm LP emission filter, 100 μs delay, 30 s exposure time. Bottom row: Time-course of the uptake upon incubation at 37 °C with [Eu₂(L^C5)₃] 200 μM; same conditions as above, but for magnification (100×) and excitation (340 nm, BP 70 nm). Reproduced with permission from ref. (© 2009 John Wiley & Sons Inc.).

Scheme 1

Structures of lanthanide-based molecules and nanoparticles that function as cytotoxic agents and inhibitors.