Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity.
Fulvestrant, a selective
estrogen receptor degrader, is commonly used for treating patients with
estrogen receptor (ER)-positive
breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously
injectable, hydrophilic NP that encapsulates
fulvestrant to facilitate its delivery via the bloodstream to
tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with
abemaciclib, an inhibitor of
cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term
fulvestrant treatment. Targeting
peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the
tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient
tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive
breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of
fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive
breast cancer.
SIGNIFICANCE: A smart nanomedicine encapsulating
fulvestrant to improve its half-life, bioavailability, and
tumor-targeting and coloaded with CDK4/6 inhibitor
abemaciclib to block resistance is a safe and effective
therapy for ER-positive
breast cancer.