期刊
JOURNAL OF CONTROLLED RELEASE
卷 330, 期 -, 页码 1080-1094出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2020.11.013
关键词
Resiquimod; Thermosensitive liposomes; Immunotherapy; Breast cancer; alpha PD-1
资金
- National Institutes of Health [NIHR01CA112356, R01CA253316, NIHR01CA210553, NIHR01CA211602]
A formulation using R848-loaded thermosensitive liposomes (TSLs) was developed for intravenous delivery, showing efficacy in tumor regression and enhanced survival when combined with alpha PD-1 in mouse models of breast cancer.
Resiquimod (R848) is a toll-like receptor 7 and 8 (TLR7/8) agonist with potent antitumor and immunostimulatory activity. However, systemic delivery of R848 is poorly tolerated because of its poor solubility in water and systemic immune activation. In order to address these limitations, we developed an intravenously-injectable formulation with R848 using thermosensitive liposomes (TSLs) as a delivery vehicle. R848 was remotely loaded into TSLs composed of DPPC: DSPC: DSPE-PEG2K (85:10:5, mol%) with 100 mM FeSO4 as the trapping agent inside. The final R848 to lipid ratio of the optimized R848-loaded TSLs (R848-TSLs) was 0.09 (w/w), 10-fold higher than the previously-reported values. R848-TSLs released 80% of R848 within 5 mM at 42 degrees C. These TSLs were then combined with aPD-1, an immune checkpoint inhibitor, and ultrasound-mediated hyperthermia in a neu deletion (NDL) mouse mammary carcinoma model (Her2(+), ER/PR negative). Combined with alpha PD-1, local injection of R848-TSLs showed superior efficacy with complete NDL tumor regression in both treated and abscopal sites achieved in 8 of 11 tumor bearing mice over 100 days. Immunohistochemistry confirmed enhanced CD8(+) T cell infiltration and accumulation by R848-TSLs. Systemic delivery of R848-TSLs, combined with local hyperthermia and alpha PD-1, inhibited tumor growth and extended median survival from 28 days (nontreatment control) to 94 days. Upon re-challenge with reinjection of tumor cells, none of the previously cured mice developed tumors, as compared with 100% of age-matched control mice. The dose of R848 (10 mu g for intratumoral injection or 6 mg/kg for intravenous injection delivered up to 4 times) was well-tolerated without weight loss or organ hypertrophy. In summary, we developed R848-TSLs that can be administered locally or systematically, resulting in tumor regression and enhanced survival when combined with alpha PD-1 in mouse models of breast cancer.
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