LaPO₄ Nanoparticles Doped with Actinium-225 that Partially Sequester Daughter Radionuclides

Abstract

Nanoscale materials have been envisioned as carriers for various therapeutic drugs, including radioisotopes. Inorganic nanoparticles (NPs) are particularly appealing vehicles for targeted radiotherapy because they can package several radioactive atoms into a single carrier and can potentially retain daughter radioisotopes produced by in vivo generators such as actinium-225 ((225)Ac, t(1/2) = 10 d). Decay of this radioisotope to stable bismuth-209 proceeds through a chain of short-lived daughters accompanied by the emission of four α-particles that release >27 MeV of energy. The challenge in realizing the enhanced cytotoxic potential of in vivo generators lies in retaining the daughter nuclei at the therapy site. When (225)Ac is attached to targeting agents via standard chelate conjugation methods, all of the daughter radionuclides are released after the initial α-decay occurs. In this work, (225)Ac was incorporated into lanthanum phosphate NPs to determine whether the radioisotope and its daughters would be retained within the dense mineral lattice. Further, the (225)Ac-doped NPs were conjugated to the monoclonal antibody mAb 201B, which targets mouse lung endothelium through the vasculature, to ascertain the targeting efficacy and in vivo retention of radioisotopes. Standard biodistribution techniques and microSPECT/CT imaging of (225)Ac as well as the daughter radioisotopes showed that the NPs accumulated rapidly in mouse lung after intravenous injection. By showing that excess, competing, uncoupled antibodies or NPs coupled to control mAbs are deposited primarily in the liver and spleen, specific targeting of NP-mAb 201B conjugates was demonstrated. Biodistribution analysis showed that ∼30% of the total injected dose of La((225)Ac)PO(4) NPs accumulated in mouse lungs 1 h postinjection, yielding a value of % ID/g >200. Furthermore, after 24 h, 80% of the (213)Bi daughter produced from (225)Ac decay was retained within the target organ and (213)Bi retention increased to ∼87% at 120 h. In vitro analyses, conducted over a 1 month interval, demonstrated that ∼50% of the daughters were retained within the La((225)Ac)PO(4) NPs at any point over that time frame. Although most of the γ-rays from radionuclides in the (225)Ac decay chain are too energetic to be captured efficiently by SPECT detectors, appropriate energy windows were found that provided dramatic microSPECT images of the NP distribution in vivo. We conclude that La((225)Ac)PO(4)-mAb 201B conjugates can be targeted efficiently to mouse lung while partially retaining daughter products and that targeting can be monitored by biodistribution techniques and microSPECT imaging.

Therapeutic efficacy and toxicity of 225Ac-labelled vs. 213Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis

“…Another way to reduce renal toxicity following targeted 225 Ac therapy is to encase 225 Ac in nanoparticles. As has been shown for La( 225 Ac)PO 4 -mAb 201B conjugates specifically targeting mouse lung, the 225 Ac daughter nuclides 221 Fr and 213 Bi are partially retained within the nanoparticles and thus retention of the daughter nuclides in the target organ is increased [39].…”

Radioisotopes and Nanomedicine

“…The particles were conjugated with antibodies to lung endothelium. This system showed better retention of the daughter nuclides in the LaPO 4 NP and excellent dose deposition in mouse lung tissue (Woodward et al 2011). Effective targeting and daughter retention suggest this model may have therapeutic potential in humans.…”

Targeted and Nontargeted α-Particle Therapies

“…A different strategy to retain the radioactive daughters of 225 Ac was developed by the Mirzadeh group (100) by using lanthanide nanoparticles. In this approach, 5-nm-diameter lanthanum phosphate nanoparticles doped with 225 Ac and La( 225 Ac)PO 4 successfully sequestered radionuclides and daughter products due to the radiation-tolerant crystal structure of monazite.…”