Intratumorally Injected 177Lu-Labeled Gold Nanoparticles – Gold Nanoseed Brachytherapy with Application for Neo-Adjuvant Treatment of Locally Advanced Breast Cancer (LABC)

RATIONALE: Improvements in the treatment of locally advanced breast cancer (LABC) are needed. Our objective was to study a radiation nanomedicine (gold nanoseeds) composed of 30 nm gold nanoparticles (AuNP) modified with polyethyleneglycol (PEG) chains linked to DOTA for complexing the β-particle emitter, 177Lu and to panitumumab for targeting epidermal growth factor receptors (EGFR) (177Lu-T-AuNP) as a novel neo-adjuvant brachytherapy (BRT) for LABC. Non-targeted gold nanoseeds (177Lu-NT-AuNP) were constructed without panitumumab for comparison.
METHODS: 177Lu-T-AuNP or 177Lu-NT-AuNP were injected intratumorally (i.t.) in CD-1 athymic mice bearing s.c. EGFR-positive MDA-MB-468 human breast cancer (BC) tumors. Biodistribution and microSPECT/CT imaging studies were performed to evaluate tumor and normal organ localization. A short-term (15 d) study was conducted to select the most effective amount of 177Lu-T-AuNP or 177Lu-NT-AuNP for treatment with long-term observation (90-120 d). Normal organ toxicities were assessed by monitoring body weight, blood cell counts and serum alanine aminotransferase and creatinine. Radiation absorbed doses in the tumor and normal organs were estimated by Monte-Carlo N-Particle (MCNP5) modeling.
RESULTS: Tumor radioactivity concentrations were very high at 1 h post-injection (p.i.) (>300-400% ID/g) but decreased by 2-3 fold at 48 h p.i. Normal organ uptake was very low (<0.5% ID/g) except for liver and spleen (<2% ID/g) which increased by 2-5 fold at 48 h p.i. Treatment with 4.5 MBq (6 × 10E11 AuNP) of 177Lu-T-AuNP or 177Lu-NT-AuNP arrested tumor growth over 90 d without normal organ toxicity, whereas tumors continued to grow in mice treated with unlabeled T-AuNP or 177Lu-labeled PEG polymer not linked to AuNP. Survival was prolonged up to 120 d in mice treated with 177Lu-T-AuNP or 177Lu-NT-AuNP. Radiation absorbed doses to the tumor were 30 Gy and 22 Gy for 177Lu-T-AuNP or 177Lu-NT-AuNP, respectively. Some tumor regions received very high radiation doses (250-1,300 Gy). Normal organ doses were low (0.04-0.6 Gy).
CONCLUSION: Gold nanoseeds injected i.t. were highly effective for inhibiting the growth of BC tumors in CD-1 athymic mice and caused no normal organ toxicity. These results are promising for their application for neo-adjuvant BRT of LABC. Since EGFR-targeting was not required, the approach is broadly applicable to LABC with different phenotypes.