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90Y‑Labeled Gold Nanoparticle Depot (NPD) Combined with Anti- PD-L1 Antibodies Strongly Inhibits the Growth of 4T1 Tumors in Immunocompetent Mice and Induces an Abscopal Effect on a Distant Non-Irradiated Tumor

2022.10.16.

Zhongli Cai, Rella Liu, Conrad Chan, Yijie Lu, Mitchell A. Winnik, David W. Cescon and Raymond M. Reilly

Molecular Pharmaceutics, 2022

ABSTRACT:

The effectiveness and normal tissue toxicity of a novel nanoparticle depot (NPD) brachytherapy seed incorporating gold nanoparticles (AuNPs) labeled with β-particle emitting, 90Y (termed a “radiation nanomedicine”), were studied for the treatment of 4T1 triple-negative murine mammary carcinoma tumors in Balb/c mice and for inducing an abscopal effect on a distant nonirradiated tumor alone or combined with anti-PD-L1 immune checkpoint antibodies. Balb/c mice with two subcutaneous 4T1 tumors - a primary tumor and a distant secondary tumor were implanted intratumorally (i.t.) in the primary tumor with NPD incorporating 3.5 MBq of 90Y-AuNPs (1 × 1014 AuNPs) or unlabeled AuNPs, alone or combined with systemically administered anti-PD-L1 antibodies (200 μg i.p. three times/week for 2 weeks) or received anti-PD-L1 antibodies alone or no treatment. The primary tumor was strongly growthinhibited over 14 d by NPD incorporating 90Y-AuNPs but only very modestly inhibited by NPD incorporating unlabeled AuNPs. Anti-PD-L1 antibodies alone were ineffective, and combining anti-PD-L1 antibodies with NPD incorporating 90Y-AuNPs did not further inhibit the growth of the primary tumor. Secondary tumor growth was inhibited by treatment of the primary tumor with NPD incorporating 90Y-AuNPs, and growth inhibition was enhanced by anti-PD-L1 antibodies. Treatment of the primary tumor with NPD incorporating unlabeled AuNPs or anti-PD-L1 antibodies alone had no effect on secondary tumor growth. Biodistribution studies showed high uptake of 90Y in the primary tumor [516−810% implanted dose/g (%ID/g)] but very low uptake in the secondary tumor (0.033−0.16% ID/g) and in normal tissues (<0.5% ID/g) except for kidneys (5−8% ID/g). Very high radiation absorbed doses were estimated for the primary tumor (472 Gy) but very low doses in the secondary tumor (0.13 Gy). There was highdose-heterogeneity in the primary tumor with doses as high as 9964 Gy in close proximity to the NPD, decreasing rapidly with distance from the NPD. Normal organ doses were low (<1 Gy) except for kidneys (4 Gy). No normal tissue toxicity was observed, but white blood cell counts (WBC) decreased in tumor-bearing mice treated with NPD incorporating 90Y-AuNPs. Decreased WBC counts were interpreted as tumor response and not toxicity since these were higher than that in healthy non-tumor-bearing mice, and there was a direct association between WBC counts and 4T1 tumor burden. We conclude that implantation of NPD incorporating 90Y-AuNPs into a primary 4T1 tumor in Balb/c mice strongly inhibited tumor growth and combined with anti-PD-L1 antibodies induced an abscopal effect on a distant secondary tumor. This radiation nanomedicine is promising for the local treatment of triple-negative breast cancer tumors in patients, and these therapeutic effects may extend to non-irradiated lesions, especially when combined with checkpoint immunotherapy.

Results from the nanoScan SPECT/CT

Figure S1. (A) Posterior whole body SPECT/CT image of a Balb/c mouse bearing two s.c. 4T1 tumors (see Figure 1 in main manuscript) at 168 h post-implantation of a NPD incorporating 111In-AuNPs into the primary tumor (solid white arrow). The location of the secondary tumor is indicated by the broken white arrow. (B) Image intensity increased by 1,000-fold to visualize the uptake of re-distributed activity into the kidneys (blue arrow) but still negligible uptake was noted in the secondary tumor. (C) Transaxial image showing retention of activity in the primary tumor (arrow) but minor diffusion within the tumor (arrowhead) suggesting local release of some 90Y-AuNPs. The intensity bar for the unadjusted image is shown at the right.

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