Dual-Receptor-Targeted (DRT) Radiation Nanomedicine Labeled with <sup>177</sup>Lu Is More Potent for Killing Human Breast Cancer Cells That Coexpress HER2 and EGFR Than Single-Receptor-Targeted (SRT) Radiation Nanomedicines
Bibliographic record
Abstract
Resistance to HER2-targeted therapies in breast cancer (BC) is associated in some cases with an increased expression of epidermal growth factor receptors (EGFR). We describe a dual-receptor-targeted (DRT) radiation nanomedicine for local intratumoral (i.t.) treatment of BC composed of 15 nm sized gold nanoparticles (AuNPs) modified with trastuzumab (TmAb) to target HER2 and panitumumab (PmAb) to target EGFR. The AuNPs were modified with poly(ethylene glycol) (PEG 3k ) linked to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex the β-particle emitter, 177 Lu. Our aim was to compare the properties of these DRT-AuNP- 177 Lu with single-receptor-targeted (SRT)-TmAb-AuNP- 177 Lu or PmAb-AuNP- 177 Lu or nontargeted (NT)-AuNP- 177 Lu using human BC cells that expressed HER2, EGFR, or both receptors. To construct these radiation nanomedicines, PEG 5K was linked to TmAb or PmAb, while PEG 3k was linked to DOTA. These polymers were conjugated to AuNP via two Au–thiol bonds using a terminal lipoic acid (LA) group on the polymers. NT-AuNP- 177 Lu were constructed without modification with TmAb or PmAb. MDA-MB-231-H2N, MDA-MB-468, and BT-474 human BC cells were designated as HER2 mod /EGFR mod, EGFR high /HER2 neg, and HER2 high /EGFR low, respectively, based on the expression of these receptors. Specific binding to HER2 and/or EGFR was assessed by incubating BC cells with DRT-AuNP- 177 Lu or TmAb-AuNP- 177 Lu or PmAb-AuNP- 177 Lu, or NT-AuNP- 177 Lu in the absence or presence of an excess of TmAb or PmAb or both competitors. Binding and internalization of AuNP by BC cells were assessed by dark-field microscopy. Cell fractionation studies were conducted to quantify AuNP- 177 Lu bound and internalized. The cytotoxicity of DRT-AuNP- 177 Lu was determined in clonogenic survival (CS) assays after an exposure of 5 × 10 5 BC cells to 3 MBq (1.4 × 10 12 AuNP) for 16 h and then seeding and culturing the cells for 7−15 days. CS was compared to exposure to TmAb-AuNP- 177 Lu and PmAb-AuNP- 177 Lu or NT-AuNP- 177 Lu. The absorbed doses to the nucleus in these CS assays were estimated. DRT-AuNP- 177 Lu were specifically bound by BC cells that expressed HER2 or EGFR or both receptors. In contrast, SRT-TmAb-AuNP- 177 Lu and PmAb-AuNP- 177 Lu were bound and internalized only by BC cells that expressed HER2 or EGFR, respectively. NT-AuNP- 177 Lu exhibited very low binding to BC cells. DRT-AuNP- 177 Lu and SRT-TmAb-AuNP- 177 Lu or PmAb-AuNP- 177 Lu were internalized by BC cells in accordance with the receptor expression. Importantly, DRT-AuNP- 177 Lu were more potent in vitro than PmAb-AuNP- 177 Lu for killing MDA-MB-231-H2N cells that coexpress HER2 and EGFR (CS = 18.8 ± 1.0 vs 51.5 ± 10.4%; P = 0.006). Furthermore, DRT-AuNP- 177 Lu were more potent for killing BT-474 cells with high HER2 but low EGFR expression than TmAb-AuNP- 177 Lu (CS = 8.9 ± 3.3 vs 20.7 ± 2.4%; P = 0.007) or PmAb-AuNP- 177 Lu (CS = 63.9 ± 1.7%; P < 0.0001). Even for MDA-MB-468 cells that overexpress EGFR but have negligible HER2, DRT-AuNP- 177 Lu were more potent for cell killing than PmAb-AuNP- 177 Lu (CS = 3.2 ± 3.0 vs 7.5 ± 1.8%; P = 0.001) or TmAb-AuNP- 177 Lu (63.2 ± 3.2%; P = 0.0002). All targeted forms of AuNP- 177 Lu were more cytotoxic to BC cells than those of NT-AuNP- 177 Lu. High absorbed doses (36–119 Gy) were deposited in the nucleus of BC cells by DRT-AuNP- 177 Lu. We conclude that a DRT radiation nanomedicine is more potent for killing BC cells that coexpress HER2 and EGFR than SRT radiation nanomedicines. These results are promising for further evaluation of these DRT-AuNP- 177 Lu in vivo for the local radiation treatment of human BC tumors that coexpress HER2 and EGFR in mice following i.t. injection, especially tumors that are resistant to HER2-targeted therapies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".