Abstract 1800: BL0175: An intramuscular nano-conjugate of fulvestrant, exhibits superior tumor distribution and antitumor efficacy compared to fulvestrant injection in MCF-7 xenograft mouse model

Background: Breast cancer (BC) was the most commonly diagnosed cancer and the second leading cause of cancer death among women worldwide. Fulvestrant injection was the first approved SERD (selective estrogen receptor degrader) for metastatic/advanced HR positive (HR+) breast cancer. Although the clinical efficacy of fulvestrant has been defined, its higher efficacy has not been achieved due to several inherent disadvantages, such as low solubility, poor pharmacokinetics (PK), injection site pain with oil-based concentrate formulation. To overcome these drawbacks, we developed a novel nano-conjugate candidate BL0175 for targeted delivery of fulvestrant. BL0175 is highly water-soluble and has a low viscosity intramuscular formulation with high drug loading, which can result in improved efficacy along patient compliance compared to original formulation·of fulvestrant. In this preclinical study, we evaluated the efficacy as well as PK/PD properties of BL0175 in MCF-7 xenograft model. Methods: PK/PD study was performed in MCF-7 xenograft model in a 336 h-period. The drug of fulvestrant concentration was determined in plasma and tumor tissue at different time points. MCF-7 (human BC) tumor fragments were implanted subcutaneously in NOD/SCID mice. Three doses of BL0175 (containing 25, 50 and 100 mg/kg of fulvestrant) or fulvestrant injection(100 mg/kg) were administered subcutaneously (s.c.) weekly for 3 weeks. Results: In the PK/PD experiments, BL0175 showed excellent pharmacokinetic properties. The 336-h tumor AUC of released fulvestrant from BL0175 was 140 times higher than fulvestrant injection in tumor tissue. The tumor-accumulation efficiency (AUCTumor/AUCPlasma) of fulvestrant released from BL0175 was 210, which was 21 times higher than that of fulvestrant injection. In the MCF-7 xenograft model, BL0175 had much better efficacy than fulvestrant injection as monotherapy. All three treatment groups of BL0175 showed strong efficacy (TGI 75.1% at 25 mg/kg, 81.0% at 50 mg/kg, 87.3% at 100 mg/kg, p < 0.001) compared to fulvestrant injection (TGI 36.7% at 100 mg/kg, p < 0.001) on day 28. Furthermore, BL0175 was safe and well tolerated without sign of clinical toxicity and body weight loss. Conclusions: BL0175 is a unique preclinical nano-drug candidate that exhibited remarkedly enhanced tumor retention and excellent pharmacokinetic properties compared to fulvestrant injection. Furthermore, BL0175 demonstrated superior anti-tumor efficacy against fulvestrant injection in breast cancer. The pre-clinical efficacy and safety studies supported its further development in the clinical stage for HR+ breast cancer therapy. Citation Format: Haoyuan Jiang, Xianjie Chen, Yuxiang Shao, Fuyao Zhang. BL0175: An intramuscular nano-conjugate of fulvestrant, exhibits superior tumor distribution and antitumor efficacy compared to fulvestrant injection in MCF-7 xenograft mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1800.