Local Targeting of Lung-Tumor-Associated Macrophages with Pulmonary Delivery of a CSF-1R Inhibitor for the Treatment of Breast Cancer Lung Metastases

• DOI: 10.1021/acs.molpharmaceut.0c00983
• Publication Date: 2020-11-10T22:50:42Z
• Authors: Sulaiman S. Alhud...; Rashed M. Almuqbil; Hanming Zhang; Elizabeth R. Bielski; Wei Du; Fatemah S. Sunbul; Paula D. Bos; Sandro R. P. da R...
• Keywords: Concomitant

The lungs are major sites of metastases for several cancer types, including breast (BC). Prognosis and quality life BC patients that develop pulmonary negatively impacted. development strategies to slow the growth relieve symptoms lung (BCLM) is thus an important goal in management BC. However, systemically administered first line small molecule chemotherapeutics have poor pharmacokinetic profiles biodistribution significant off-target toxicity, severely compromising their effectiveness. In this work, we propose local delivery add-on immunotherapy support chemotherapy treatment advanced a syngeneic murine model BCLM, show administration (p.a.) PLX-3397 (PLX), colony-stimulating factor 1 receptor inhibitor (CSF-1Ri), capable overcoming physiological barriers epithelium, penetrating tumor microenvironment (TME), decreasing phosphorylation CSF-1 receptors, as shown by Western blot nodules. That inhibition accompanied overall decrease abundance protumorigenic (M2-like) macrophages TME, with concomitant increase amount antitumor (M1-like) when compared vehicle-treated control. These effects PLX were achieved using much smaller dose (1 mg/kg, every other day) systemic doses typically used preclinical studies (40–800 mg/kg/day). As additive combination intravenous (i.v.) paclitaxel (PTX), leads burden without additional toxicity. results suggested proposed immunochemotherapy, regional along i.v. standard care chemotherapy, may lead new opportunities improve treatment, life, survival BCLM.