Abstract LB-096: Blood-brain barrier-penetrating terpolymer nanoparticles deliver docetaxel and trastuzumab to brain metastases of breast cancer
Bibliographic record
Abstract
Abstract Background: Brain metastases occur in up to one third of all metastatic breast cancer patients, with high prevalence and earlier development in triple-negative and HER2-positive breast cancers. Treatment options for brain metastases are severely limited due to the inability of many therapeutic agents, including docetaxel (DTX), a small molecule hydrophobic drug, and trastuzumab (TRA), a macromolecular antibody, to cross the blood-brain barrier (BBB) at adequate levels. Here we developed multifunctional BBB-penetrating terpolymer-lipid nanoparticles (TPN) for delivering DTX and TRA to brain metastases of breast cancer, and evaluated their tumor accumulation and efficacy in multiple lesion brain metastases mouse models. Methods: Fluorescence-labeled TPN were prepared by microemulsion using poly(methacrylic acid) and polysorbate 80-grafted starch loaded with either DTX (DTX-TPN) or TRA (TRA-TPN). In vitro cytotoxicity of the formulations was evaluated by the MTT assay. Brain metastases of triple negative MDA-MB-231-luc-D3H2LN or HER2 positive BT474 human breast cancer were established in SCID mice by stereotactic intracranial inoculation of the cells into the cortex. The biodistribution and tumor accumulation of the NPs were examined by whole body fluorescence imaging at various times after tail vein injection. The NP distribution within the brain tumor microenvironment was detected ex vivo using laser scanning confocal microscopy. The efficacy of DTX-TPN against brain metastases was assessed by measuring bioluminescence intensity weekly following administration of 2×20 mg/kg DTX-TPN or Taxotere. Results: In vitro DTX-TPN exhibited greater cytotoxicity against MDA-MB-231 cells compared to free DTX (IC50 = 40 vs. 63 nM), while TRA-TPN decreased the IC50 by 4.5-fold (IC50 = 0.6 vs. 2.7 μg/mL) in the inhibition of BT474 cells compared to free TRA. In vivo TPN was able to transport DTX and TRA across the BBB to brain metastasis lesions. The TPNs were observed to extravasate the brain microvessels and accumulate within the perivascular tissue throughout the tumor core and periphery. DTX-TPN increased the median mouse survival time by 2-fold (Saline group: 20 ± 3 days; free Taxotore: 18 ± 4 days; DTX-TPN: 36 ± 3 days) and delayed tumor growth by 9.8-fold (58% vs. 5.9%) as compared to clinically used Taxotere in mice with brain metastasis of triple negative breast cancer. No change in tissue morphology was observed in the liver, lungs, heart and kidneys of mice treated with DTX-TPN compared to the saline control group. Conclusions: These results demonstrate that TPNs are a promising BBB-penetrating carrier for the delivery of small molecule therapeutic agents or antibodies to the brain and for the treatment of brain metastases of breast cancer. Citation Format: Chanson(Chunsheng) He, Ping Cai, Jason Li, Jeffrey T. Henderson, Andrew M. Rauth, Xiao Yu Wu. Blood-brain barrier-penetrating terpolymer nanoparticles deliver docetaxel and trastuzumab to brain metastases of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-096. doi:10.1158/1538-7445.AM2015-LB-096
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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".