Platinum nanoparticles labelled with iodine-125 for combined "chemo-Auger electron" therapy of hepatocellular carcinoma

Abstract

Convenient therapeutic protocols against hepatocellular carcinoma (HCC) exhibit low treatment effectiveness, especially in the context of long-term effects, which is primarily related to late diagnosis and high tumor heterogeneity. Current trends in medicine concern combined therapy to achieve new powerful tools against the most aggressive diseases. When designing modern, multimodal therapeutics, it is necessary to look for alternative routes of specific drug delivery to the cell, its selective (with respect to the tumor) activity and multidirectional action, enhancing the therapeutic effect. Targeting the physiology of the tumor makes it possible to take advantage of certain characteristic properties of the tumor that differentiate it from other cells. In the present paper we designed for the first time iodine-125 labeled platinum nanoparticles for combined "chemo-Auger electron" therapy of hepatocellular carcinoma. High selectivity achieved by targeting the tumor microenvironment of these cells was associated with effective radionuclide desorption in the presence of H₂O₂. The therapeutic effect was found to be correlated with cell damage at various molecular levels including DNA DSBs and was observed in a dose-dependent manner. A three-dimensional tumor spheroid revealed successful radioconjugate anticancer activity with a significant treatment response. A possible concept for clinical application after prior in vivo trials may be achieved via transarterial injection of micrometer range lipiodol emulsions with encapsulated ¹²⁵I-NP. Ethiodized oil gives several advantages especially for HCC treatment; thus bearing in mind a suitable particle size for embolization, the obtained results highlight the exciting prospects for the development of PtNP-based combined therapy.

Fig. 1. Postulated mechanism of combined “chemo-Auger electron” therapy.

Fig. 2. Surface saturation of AuNPs, Au@Pt I PtNPs with 10–100 MBq mL^{−1 131}I (n = 3).

Fig. 3. Stability studies of the synthesized radioconjugates in PBS and human serum (n = 3).

Fig. 4. Iodine release under oxidative conditions induced with 10 mM–10 nM H₂O₂ from Au@Pt NP (left) and PtNP (right) radioconjugates (n = 3).

Fig. 5. Viability studies of HepG2 (A) and HeLa (B) cells treated with 0–100 MBq mL⁻¹ of ¹²⁵I and radioconjugates – ¹²⁵I–Au@Pt and ¹²⁵I–PtNPs. Data presented for “0” MBq mL⁻¹ correspond to non-radioactive compounds used at the same Pt concentration (145 μg mL⁻¹) as that during radioconjugate evaluation (n = 3).

Fig. 6. Morphological changes in HepG2 cells induced by non-radioactive (0 MBq mL⁻¹) PtNPs as a “chemotoxic effect” and radioconjugates (25–100 MBq mL⁻¹) as presentation of a dose-dependent manner of the induced chemo-Auger electron effect.

Fig. 7. DNA DSBs visualized with γH2A.X staining – the average number of γH2A.X foci per cell at different times and activity concentrations (A); merged images of γH2A.X foci distribution over the genetic material of treated cells (B and C) (n = 3).

Fig. 8. Effects of ¹²⁵I–PtNPs radioconjugates against a HepG2 tumor spheroid model (n = 3).