Paclitaxel-loaded hybrid exosome for targeted chemotherapy of triple-negative breast cancer

Abstract

Abstract Background: Triple-negative breast cancer (TNBC) is a highly invasive malignant tumor with bleak prognosis.Paclitaxel (PTX) is the first-line chemotherapeutic drug for TNBC management. It is of great significance to develop carriers for targeted delivery of PTX to enhance the anti-tumor efficacy and reduce the side effects for TNBC management. Exosomes are small extracellular vesicles and emerging competent nanocarriers for targeted drug delivery. However, the application of exosomes has been challenged by the production, drug loading and quality control. The introduction of synthetic nanomaterials may help to overcome the limitations of exosomes and generate alternatives. Herein, we performed a biohybrid approach to fuse exosomeswith liposomes to produce hybrid exosome (HE) with improved PTX loading capacity and enhanced tumor-targeting ability for TNBC chemotherapy. Methods:HE and PTX-loaded HE (PTX-HE) were prepared by co-extrusion of exosomes with liposome (lipo) or PTX-loaded liposome (PTX-lipo) respectively. The size distribution of HE was measured by nanoparticle tracking analysis (NTA) and dynamic laser-light scattering (DLS). The morphology was observed by transmission electron microscopy (TEM). The protein profile of HE was determined by western blot and Coomassie Blue staining. Drug loading capacity and encapsulation efficiency were measured by high-performance liquid chromatography (HPLC). Cellular uptake, tumor cell killing effect and anti-migration ability of PTX-HE were evaluated in vitro. Biodistribution, anti-tumor therapeutic efficacy and safety of PTX-HE were evaluated in orthotopic TNBC mice models. Results:The characterization results manifested HE was spherical structure with uniform size distribution (157.28 nm). HE had improved loading capacity (6.20 ± 0.79%) and higher encapsulation efficiency (86.79 ± 11.07%) of PTX than lipo. More importantly, PTX-HE possessed higher cellular uptake efficiency, lower IC50 (4.32 ± 0.48 μg/mL) and stronger anti-migration ability (cell mobility: 16%) as compared with PTX-lipo. In TNBC-bearing mice, PTX-HE accumulated at tumor sites and suppressed tumor growth (tumor inhibition rate: 60%) with minimal systemic toxicity. Conclusions: HE exhibits improved drug loading capacity, targeting ability and cancer cell-killing effect. Overall, HE developed by fusing exosomes with liposomes provides a promising strategy for the large-scale generation of exosome alternatives as drug carriers for targeted chemotherapy.