PACM-07 PHARMACOLOGIC BLOOD-BRAIN BARRIER MODULATION WITH REGADENOSON IMPROVES DRUG DELIVERY IN BRAIN METASTASIS

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ID: 324434
2026
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Abstract
Abstract Background Brain metastases are a frequent and clinically devastating complication of metastatic breast cancer, in part because many systemic therapies fail to achieve therapeutic concentrations in the central nervous system (CNS). Regadenoson (Reg), an FDA-approved A2A adenosine receptor agonist used for cardiac stress testing, has been proposed as a pharmacologic modulator of blood-brain barrier (BBB) permeability. Methods We evaluated whether Reg enhances CNS delivery of doxorubicin (Dox) and a 70-kDa fluorescent dextran tracer in non-tumor-bearing brain and in models of triple-negative breast cancer (TNBC) brain metastasis. In non-tumor-bearing mice, Reg was administered with Dox to define dose and timing conditions that maximize brain accumulation. Brain delivery was quantified by tissue-based analysis. Macromolecular delivery was assessed using whole-brain imaging of 70-kDa dextran. Reg was then tested in TNBC brain metastasis models, where intralesional Dox accumulation and tumor killing were measured. Results Co-administration of Reg with Dox produced the greatest effect, whereas longer lag times reduced efficacy. The optimal Reg dose was 0.005 mg/kg, equivalent to the FDA-approved cardiac stress test dose. At this dose, Reg increased brain Dox accumulation 6-fold in non-tumor-bearing mice versus Dox alone (P < 0.001). Reg also increased the distribution of a 70-kDa dextran by 4.5-fold (P < 0.01). In TNBC brain metastasis models, Dox was not detectable in lesions after Dox alone but became detectable following co-administration with Reg. This was accompanied by a 12- to 16-fold increase in the expression of pro-apoptotic markers γ-H2AX and BAX (P < 0.02) in cancer cells. Conclusions Reg transiently enhances CNS drug delivery across both the non-tumor-bearing BBB and the BBB/blood-tumor barrier in TNBC brain metastases, supporting further evaluation as a pharmacologic adjunct to improve therapy for breast cancer brain metastasis.
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Authors Yi Shi, Alyssa Weinstein, Swathi Talluri, Harsh Oza, Inês Godet, David Kamson, Stuart Grossman, Saraswati Sukumar, Daniele Gilkes
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Journal Neuro-Oncology Advances
Year 2026
DOI
10.1093/noajnl/vdag161.072
URL
https://academic.oup.com/noa/article-pdf/8/Supplement_6/vdag161.072/70398995/vdag161.072.pdf
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