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. 2024 Jun 2;22(1):306.
doi: 10.1186/s12951-024-02520-6.

Development of 225Ac-doped biocompatible nanoparticles for targeted alpha therapy

Miguel Toro-González  1 , Ngozi Akingbesote  1   2 , Amber Bible  3 , Debjani Pal  1 , Brian Sanders  3 , Alexander S Ivanov  4 , Santa Jansone-Popova  4 , Ilja Popovs  4 , Paul Benny  1 , Rachel Perry  2 , Sandra Davern  5
Affiliations

Development of 225Ac-doped biocompatible nanoparticles for targeted alpha therapy

Miguel Toro-González et al. J Nanobiotechnology. .

Abstract

Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous tissue. These strategies can be affected by transmetalation of the parent radionuclide by competing ions in vivo and the bond-breaking recoil energy of decay daughters. The retention of α-emitting radionuclides and the dose delivered to cancer cells are influenced by these processes. Encapsulating α-emitting radionuclides within nanoparticles can help overcome many of these challenges. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are a biodegradable and biocompatible delivery platform that has been used for drug delivery. In this study, PLGA nanoparticles are utilized for encapsulation and retention of actinium-225 ([225Ac]Ac3+). Encapsulation of [225Ac]Ac3+ within PLGA nanoparticles (Zave = 155.3 nm) was achieved by adapting a double-emulsion solvent evaporation method. The encapsulation efficiency was affected by both the solvent conditions and the chelation of [225Ac]Ac3+. Chelation of [225Ac]Ac3+ to a lipophilic 2,9-bis-lactam-1,10-phenanthroline ligand ([225Ac]AcBLPhen) significantly decreased its release (< 2%) and that of its decay daughters (< 50%) from PLGA nanoparticles. PLGA nanoparticles encapsulating [225Ac]AcBLPhen significantly increased the delivery of [225Ac]Ac3+ to murine (E0771) and human (MCF-7 and MDA-MB-231) breast cancer cells with a concomitant increase in cell death over free [225Ac]Ac3+ in solution. These results demonstrate that PLGA nanoparticles have potential as radionuclide delivery platforms for TAT to advance precision radiotherapy for cancer. In addition, this technology offers an alternative use for ligands with poor aqueous solubility, low stability, or low affinity, allowing them to be repurposed for TAT by encapsulation within PLGA nanoparticles.

Keywords: Actinium-225; Ligand; Nanoparticles; Poly(lactic-co-glycolic acid); Therapy.

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Conflict of interest statement

All authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Controlled synthesis of PLGA nanoparticles with a cup-horn sonicator. Schematic representation of PLGA nanoparticles synthesized with a double-emulsion solvent evaporation method. Chemical structure of PLGA and TPGS are shown as a reference. The presence of methyl side groups in poly(lactic acid) [gray] makes it more hydrophobic than poly(glycolic acid) [orange]
Fig. 2
Fig. 2
Spherical PLGA nanoparticles with on average a uniform size distribution were obtained by a double-emulsion solvent evaporation method. a SEM image of PLGA nanoparticles synthesized using standard conditions and evaporated through stirring. Inset corresponds to higher magnification micrograph of PLGA nanoparticles synthesized as described previously. b Intensity size distribution of PLGA nanoparticles synthesized with stirring or dialysis for solvent evaporation
Fig. 3
Fig. 3
Understanding the chelation and coordination of [225Ac]Ac3+ by the lipophilic BLPhen ligand. a Autoradiographic images of [225Ac]Ac3+ and [225Ac]AcBLPhen at different times after co-mixing. Color scale shows different activities/intensities of [225Ac]Ac3+ and decay daughters with blue and red as the lowest and highest, respectively. b Histograms of autoradiographic images of [225Ac]Ac3+ and [225Ac]AcBLPhen at different times after co-mixing. c Chelation of [225Ac]Ac3+ as a function of BLPhen ligand concentration, 5 min after co-mixing. Insert corresponds to the chemical structure of the lipophilic BLPhen ligand.47. d Chemical structure of BLPhen with plotted electrostatic potential map (0.01 e/a03 isovalue) and charges on O and N atoms obtained from natural population analysis. e Structure of the [225Ac][Ac(BLPhen)2]3+ complex optimized at the B3LYP-D3/LC/6–31 + G(d) level of theory. Color scheme: Ac, sky blue; C. grey; H, white; N, blue; O, red
Fig. 4
Fig. 4
Encapsulation of [225Ac]Ac3+ within PLGA nanoparticles favors a hydrophobic environment. The encapsulation efficiency of [225Ac]Ac3+ within PLGA nanoparticles increased by decreasing the water content of the [225Ac]Ac3+ solution. The plot represents the encapsulation efficiency of [225Ac]Ac3+ within PLGA nanoparticles as free cations and when chelated to a BLPhen ligand, using a MeOH/DI H2O mixture with different water contents. Values and error bars correspond to the mean and standard error of three replicates, respectively. *P < 0.05 one-way ANOVA followed by Tukey multiple comparisons post-test
Fig. 5
Fig. 5
Enhanced retention of [225Ac]Ac3+ and its decay daughters, [221Fr]Fr+ and [213Bi]Bi+, was achieved by encapsulating [225Ac]AcBLPhen within PLGA nanoparticles. The fraction of a [225Ac]Ac3+, b [221Fr]Fr+, and c [213Bi]Bi3+ detected in the dialysate for PLGA nanoparticles encapsulating [225Ac]Ac3+ in a MeOH/DI mixture, [225Ac]Ac3+ in NH4OAc solution, and [225Ac]AcBLPhen. Values and error bars correspond to the mean and standard error of three replicates, respectively. The release of [221Fr]Fr+ and [213Bi]Bi3+ considers the fraction of activity originating from [225Ac]Ac3+ in the dialysate as defined by the equations in the supporting information
Fig. 6
Fig. 6
PLGA nanoparticles encapsulating [225Ac]AcBLPhen are cytotoxic to breast cancer cells. The viability of E0771, MCF-7, and MDA-MB-231 breast cancer cells after exposure for 24 h to free [225Ac]Ac3+, [225Ac]AcBLPhen, and PLGA nanoparticles encapsulating [225Ac]AcBLPhen. Cell viability relative to untreated cells was assessed (a, c, e) 1 h and (b, d, f) 72 h after exposure to [225Ac]Ac3+ using alamarBlue. Data is presented as the mean and standard deviation for at least three biological replicates. **P < 0.01 (relative to both free [225Ac]Ac3+ and [225Ac]AcBLPhen) one-way ANOVA followed by Tukey multiple comparisons post-test
Fig. 7
Fig. 7
A similar cytotoxic effect was observed when [225Ac]Ac3+ was delivered with different concentrations of PLGA. Delivering [225Ac]Ac3+ with different concentrations of PLGA nanoparticles did not influence its cytotoxic effect on a E0771, b MCF-7, and c MDA-MB-231 cells. Cell viability after exposure to [225Ac]Ac3+ in PBS and PLGA nanoparticles encapsulating [225Ac]AcBLPhen at 10 mg/mL, 20 mg/mL, and 40 mg/mL for 24 h. Cell viability was assessed 1 h post-exposure to [225Ac]Ac3+ using alamarBlue assay relative to untreated cells. Cells were exposed to free [225Ac]Ac3+ (0.6 kBq/mL, 1.1 kBq/mL, and 2.3 kBq/mL), PLGA([225Ac]AcBLPhen) [10 mg/mL] (0.4 kBq/mL, 0.8 kBq/mL, and 1.7 kBq/mL), PLGA([225Ac]AcBLPhen) [20 mg/mL] (0.4 kBq/mL, 0.8 kBq/mL, and 1.7 kBq/mL), and PLGA([225Ac]AcBLPhen) [40 mg/mL] (0.5 kBq/mL, 0.9 kBq/mL, and 1.8 kBq/mL). Reported values correspond to the mean of 12 technical replicates and n = 1 experiment. Error bars show the relative error
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