In situ radiochemical doping of functionalized inorganic nanoplatforms for theranostic applications: a paradigm shift in nanooncology

Abstract

In situ radiochemical doping presents a transformative approach for synthesizing radiolabeled inorganic nanoparticles (NPs) for cancer theranostics. Traditional radiolabeling techniques rely on bifunctional chelators, which often require harsh reaction conditions that can degrade the physicochemical properties of NPs. Additionally, the enzymatic dissociation of radiometals can potentially induce in vivo toxicity. In contrast, in situ doping directly incorporates radiometals into the NP crystal lattice, significantly enhancing both radiolabeling yield and radiochemical stability. This method preserves the pharmacokinetic profiles of the radiolabeled NPs, improving their theranostic efficacy. This review provides an up-to-date overview of the progress made in the development of radiolabeled inorganic nanoplatforms through in situ doping, with a focus on their stability, physicochemical characteristics, and applications in cancer theranostics. Our findings highlight the advantages in situ doping as a more efficient and stable alternative to conventional radiolabeling methods, offering substantial potential for the development of more effective cancer theranostic agents.

Keywords: Cancer; Doping; In situ; Nanoparticles; Precision oncology; Radiation therapy; Radiolabeling; Theranostics.

Fig. 1

Different types of nanoplatforms used for theranostic applications

Fig. 2

Schematic of different extrinsic radiolabeling methods for NPs

Fig. 3

Schematic of different intrinsic radiolabeling methods of NPs

Fig. 4

Schematic illustration of passive and active targeting of NPs into the tumor

Fig. 5

Schematic representation of how size, shape and surface charge of NPs affect the biodistribution in different organs

Fig. 6

Schematic representation of internalization of NPs into cells

Fig. 7

Different types of emissions from radionuclides and their penetration ranges in tissues

Fig. 8

a TEM micrograph of PEG-CuS NPs (inset: distribution of particle size); b PET/CT images of U87 glioma tumor bearing mice after intravenous injection of PEG-[⁶⁴Cu]CuS NPs at different time points (yellow arrow: tumor, orange arrow: bladder, red arrow: standard). Reproduced from ref. [32] with permission. Copyright 2010 ACS Publication. c TEM micrograph of [⁶⁴Cu]CuAuNPs after decay (scale bar = 10 nm); d PET/CT images at 1 h, 24 h, 48 h post injection and [¹⁸F]-FDG at 1 h post injection after injection of [⁶⁴Cu]CuAuNPs in tumor bearing mice. (T: tumor); e Quantitative plot of tumor uptake of [⁶⁴Cu]CuAuNPs and [¹⁸F]-FDG at different time points. Reproduced from ref. [146] with permission. Copyright 2014 Wiley. f Schematic representation of synthesis of [⁶⁴Cu]CIS/ZnS QDs for PET/CRET imaging; g whole body PET images after intravenous injection of [⁶⁴Cu]CuCl₂, GSH-[⁶⁴Cu]CIS/ZnS and PEGylated GSH-[⁶⁴Cu]CIS/ZnS QDs in U87MG tumor-bearing mice at different time points (white arrow indicates tumor). Reproduced from ref. [130] with permission. Copyright 2015 ACS Publication

Fig. 9

a Synthetic scheme of [⁶⁸Ga]Ga-C-IONP functionalized with RGD peptide using 1,4-(butanediol) diglycidyl ether linker; b TEM images of [⁶⁸Ga]Ga-C-IONP; c phantom images acquired by MRI (above) and PET (below) at various concentration; d T₁ weighted MRI images of tumor bearing mouse before (left) and 24 h post injection (right) of [⁶⁸ Ga]Ga-C-IONP-RGD; e PET/CT images of tumor bearing mouse at 1 h post injection of [⁶⁸ Ga]Ga-C-IONP-RGD; f PET/CT images of tumor bearing mouse at 1 h post injection of [⁶⁸Ga]Ga-C-IONP; g biodistribution pattern of ([⁶⁸Ga]Ga-C-IONP-RGD and [⁶⁸Ga]Ga-C-IONP after intratumoral injection. Reproduced form ref. [75] with permission. Copyright 2016 John Wiley & Sons, Ltd

Fig. 10

a Schematic representation of synthesis of [⁶⁹Ge]Ge:Ga₂O₃-GA NPs; b PET images of Wistar rat after (i) intravenous injection of [⁶⁹Ge]Ge:Ga₂O₃-GA NPs via tail vein and (ii) subcutaneous injection of [⁶⁹Ge]Ge:Ga₂O₃-GA NPs for visualization of lymph node; c biodistribution pattern of Wistar rat after intravenous injection of [⁶⁹Ge]Ge:Ga₂O₃-GA NPs. Reproduced from ref. [150] with permission. Copyright 2023 ACS Publication

Fig. 11

TEM images of GdF₃:Y NPs synthesized at various reaction conditions: a ellipsoidal NPs (290 °C, 20 min) and rhombic NPs synthesized at b 320 °C for 40 min and c 290 °C for 4 h; d EDS spectrum of GdF₃:Y NPs. e–h Using YCl₃ is as the precursor, YF₃ nanowires were synthesized at 320 °C after 20 min (e, f), and bypiramidal LiYF₄ nanocrystals are synthesized at 320 °C for 40 min. i Optical images of GdF₃:⁹⁰Y/Y NPs having different amount of radioactivity (0.55–17.5 μCi); j quantification of radioluminescence of GdF₃:⁹⁰Y/Y NPs dispersed in aqueous medium. Reproduced from ref. [155] with permission. Copyright 2015 ACS Publication

Fig. 12

a Graphical representation of one pot synthesis technique of ¹⁰³Pd:Pd@Au-PEG NPs and ¹⁰³Pd:Pd@¹⁹⁸Au:Au-PEG; b HRTEM image of ¹⁰³Pd:Pd@¹⁹⁸Au:Au-PEG NPs. Reproduced from ref. [158] with permission. Copyright 2017 WILEY–VCH Verlag GmbH & Company. c Schematic representation of [¹⁰³Pd]AuPdNPs preparation and ¹⁰³Pd-nanogel formation; d Dissolution of ¹⁰³Pd-nanogel in ethanol (left) and formation of stable droplet of ¹⁰³Pd-nanogel in PBS (right); e Isolated tumor tissue after intratumoral injection of ¹⁰³Pd-nanogel in mice, (i) The injected ¹⁰³Pd-nanogel was visible under tumor surface, (ii) Image of separated injected gel surrounded by tumor tissue (white arrow). Reproduced from ref. [160] with permission. Copyright 2021 Wiley

Fig. 13

a TEM micrograph of Sm-UCNPs; b In vivo, in situ and ex vivo imaging of Kunming mouse at 1 h post injection of Sm-UCNPs via tail vein; c SPECT images at 1 h (left) and 24 h(right) after intravenous injection of Sm-UCNPs. The arrows indicate liver (L) and spleen (S). Reproduced from ref. [133] with permission. Copyright 2013 Elsevier. D) SPECT/CT images of Kunming mouse after intravenous injection of [¹⁵³Sm]Sm-PEG-UCNPs at different time points. The arrows indicate heart (He), liver (Li), spleen (Sp), kidney (Ki) and bladder (Bl). Reproduced from ref. [169] with permission. Copyright 2013 Elsevier

Fig. 14

a Synthetic process of core shell ¹⁵³Sm doped NaLuF₄:Yb,Tm@NaGdF₄ NPs; TEM images of b NaLuF₄:Yb,Tm and NaLuF₄:Yb,Tm@NaGdF₄(¹⁵³Sm) NPs; c UCL imaging and d X-ray CT imaging (focused on peritoneum) of nude mice after intravenous injection of NaLuF₄:Yb,Tm@NaGdF₄(¹⁵³Sm) NPs; e MR images of mouse pre and post injection intravenous of NaLuF₄:Yb,Tm@NaGdF₄(¹⁵³Sm) NPs; f SPECT/CT images after intravenous injection of NaLuF₄:Yb,Tm@NaGdF₄(¹⁵³Sm) NPs at different time points, g Four different types of images of tumor at 1 h after intravenous injection of NaLuF₄:Yb,Tm@NaGdF₄(¹⁵³Sm) NPs. Reproduced from ref [132] with permission. Copyright 2013 ACS Publication

Fig. 15

a Schematic illustration of synthesis of [¹⁶⁹Yb]Yb₂O₃-GA NPs; b SPECT/CT images of melanoma tumor bearing C57BL/6 mice after intratumoral injection of [¹⁶⁹Yb]Yb₂O₃-GA NPs at different time points; c biodistribution plot of tumor bearing mice after intratumoral injection of radiolabeled NPs; d H & E stained images of both treated and nontreated mice. Reproduced from ref. [171] with permission. Copyright 2023 Springer

Fig. 16

a Schematic illustration of synthesis of [¹⁸⁸Re]ReO_x-HSA NPs; b SPECT/CT images of melanoma tumor bearing C57BL/6 mice after intratumoral injection of [¹⁸⁸Re]ReO_x-HSA NPs at different time points; c tumor growth and d body weight index plot after combined radio-photothermal treatment; e H & E stained images of both treated and nontreated mice. Reproduced from ref. [176] with permission. Copyright 2025 Springer

Fig. 17

TEM images of a Au nanospheres; b Au nanodisks; c Au nanorods; and d Au nanocages; e in vivo luminescence image of tumor bearing mice at 24 h post injection after injection of different types of Au NPs; f Autoradiographic impression of tumor slices at 24 h post injection of i) ¹⁹⁸Au nanospheres, ii) ¹⁹⁸Au nanodisks, iii) ¹⁹⁸Au nanorods and iv) ¹⁹⁸Au nanocubes. Reproduced from ref. [183] with permission. Copyright 2014 ACS Publication. TEM micrographs of ¹⁹⁹Au doped gold NPs of g 5 nm and h 18 nm size after 90 days of decay; i SPECT/CT image of 4T1 tumor-bearing mouse at 24 h post injection after injection of 5 nm [¹⁹⁹Au]AuNP-DAPTA nanoprobe (T: tumor). Reproduced from ref. [184] with permission. Copyright 2016 Wiley Publication