Cancer Cell Membrane Wrapped Nanoparticles for the Delivery of a Bcl-2 Inhibitor to Triple-Negative Breast Cancer

Overexpression of the antiapoptoticprotein B-cell lymphoma 2 (Bcl-2)is correlated with poor survival outcomes in triple-negative breastcancer (TNBC), making Bcl-2 inhibition a promising strategy to treatthis aggressive disease. Unfortunately, Bcl-2 inhibitors developedto date have limited clinical success against solid tumors, owingto poor bioavailability, insufficient tumor delivery, and off-targettoxicity. To circumvent these problems, we loaded the Bcl-2 inhibitorABT-737 in poly(lactic-co-glycolic acid) (PLGA) nanoparticles(NPs) that were wrapped with phospholipid membranes derived from 4T1murine mammary cancer cells, which mimic the growth and metastasisof human TNBC. We show that the biomimetic cancer cell membrane coatingenabled the NPs to preferentially target 4T1 TNBC cells over noncancerousmammary epithelial cells in vitro and significantlyincreased NP accumulation in orthotopic 4T1 tumors in mice after intravenousinjection by over 2-fold compared to poly(ethylene glycol)-poly(lactide-co-glycolic) (PEG-PLGA) copolymer NPs. Congruently,the ABT-737 loaded, cancer cell membrane-wrapped PLGA NPs (ABT CCNPs)induced higher levels of apoptosis in TNBC cells in vitro than ABT-737 delivered freely or in PEG-PLGA NPs. When testedin a syngeneic spontaneous metastasis model, the ABT CCNPs significantlyincreased apoptosis (evidenced by elevated active caspase-3 and decreasedBcl-2 staining) and decreased proliferation (denoted by reduced Ki67staining) throughout tumors compared with saline or ABT-loaded PEG-PLGANP controls. Moreover, the ABT CCNPs did not alter animal weight orblood composition, suggesting that the specificity afforded by theTNBC cell membrane coating mitigated the off-target adverse effectstypically associated with ABT-737. Despite these promising results,the low dose of ABT CCNPs administered only modestly reduced primarytumor growth and metastatic nodule formation in the lungs relativeto controls. We posit that increasing the dose of ABT CCNPs, alteringthe treatment schedule, or encapsulating a more potent Bcl-2 inhibitormay yield more robust effects on tumor growth and metastasis. Withfurther development, drug-loaded biomimetic NPs may safely treat solidtumors such as TNBC that are characterized by Bcl-2 overexpression.