Abstract 1739: Cell-specific cargo delivery using synthetic bacterial spores

Abstract

Abstract The overexpression of the cell surface receptor “HER-2” is a common marker for many breast and ovarian cancers. New treatments for these cancers involve the use of monoclonal antibodies directed against HER2. SSHELs are synthetic bacterial spore-like particles wherein the spore’s cell surface is partially reconstituted around 1 µm-diameter silica beads. Via a unique cysteine engineered protein, the surface of SSHELs may be covalently decorated with molecules of interest. We showed that SSHELs decorated with anti-HER2 affibodies (SSHELs∝HER2) specifically bound to target cells and were internalized. Doxorubicin loaded SSHELs (Dox-SSHELs∝HER2) were internalized and trafficked to lysosomes, whereupon the cargo was released in a pH-dependent manner. Dox-SSHELs∝HER2 reduce tumor growth with lower toxicity in a mouse tumor xenograft model when compared to the free drug. Further, when compared to an FDA approved liposome-encased doxorubicin (AD), Dox-SSHELs∝HER2 showed similar efficacy in reducing tumor growth, but without any of the typical side effects correlated with AD injections (including weight loss, tumor ulceration, skin descaling). SKOV3 and SKBR3 cells’ targeting by SSHELs∝HER2 was evaluated by flow cytometry and confocal microscopy. Dox-SSHELs∝HER2 anti-tumor effect was evaluated in vitro by flow cytometry and caspase assay. HER2- cells were used as a control. Dox-SSHELs∝HER2’s efficacy was tested in vivo using athymic nude mice injected with SKOV3 cells and then treated for up to 40 days. SSHELs∝HER2 preferentially target cancer cells proportionally to their concentration, as flow cytometry showed. Additional analysis showed the inability of SSHELs∝HER2 to bind HER2+ cells if the receptor was previously blocked. Delivery-mechanism and co-localization analysis showed that SSHELs∝HER2 are preferentially taken up using macropinocytosis and that they undergo a lysosomal pathway where acidic pH contributes to release the cargo. Dox-SSHELs∝HER2 reduce the viability of the treated samples inducing DNA damages and triggering caspases with increase efficiency towards HER2+ cells. In vivo, we demonstrated that Dox-SSHELs∝HER2 can reduce SKOV3 tumor growth up to 75% when compared to the free drug. Additionally, the doxorubicin delivered by SSHELs∝HER2 did not lead to any side effect compared to the free drug or AD. Although new therapies are rising and becoming available for cancer treatments, limited options are still available. We suggest that SSHELs provide several unique benefits and that they may be used as an additional strategy for this purpose. With a facile, reproducible manufacturing process that allows for straightforward targeting towards specific cell types, pH driven cargo release, and lower overall toxicity compared to a leading treatment, we suggest that SSHELs may represent a versatile strategy opening new research avenues for targeted drug delivery treatment of breast and ovarian cancer. Citation Format: Domenico D'Atri, Minsuk Kong, Maria Teresa Bilotta, Kandice Tanner, David J. Fitzgerald, Kumaran S. Ramamurthi. Cell-specific cargo delivery using synthetic bacterial spores [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1739.