LAUSR

Treatment of metastatic Triple-Negative Breast Cancer (TNBC) remains a challenge despite an increasing number of newer drugs being approved in recent years. The major challenge for improved treatment outcomes for metastatic cancer originates from the fact that the drugs are unable to reach the targeted site and hence are not able to elicit the desired response. Recently, natural mesenchymal stem cells (MSC) cells and their exosomes have been shown to have tumor-homing properties. By exploiting these homing properties, we propose the development of an exosome-polymeric hybrid nanosystem (EPHN) by using exosomes for their targeting ability to enhance the targetability and thus the therapeutic efficacy of the drug against TNBC. In this study, we bioengineered MSC exosome-coated drug-loaded polymeric nanoparticles to deliver our chemotherapeutic drug in a targeted fashion. To isolate the MSC exosomes, we grew the cells in exosome-free media and used the ultracentrifugation standard method. The MSC exosomes had a size of approximately 70 ± 5 nm and a PDI of 0.3. Our exosome sample was positive for exosomal proteins and negative for all other extracellular vesicles. The optimal doxorubicin-loaded PLGA nanoparticles were prepared using a microfluidics method resulting in a higher entrapment efficiency of 42 ± 3% and a smaller size of 70 ± 3 nm and a PDI of 0.2. To make the exosome-coated NPs, we used the extrusion method. After extrusion, the zeta potential of our EPHN was closer to -11mV compared to PLGA NPs (-50mV), which demonstrates that our NPs were coated with an exosomal membrane. We were able to make MSC exosome-coated drug-loaded polymeric nanoparticles and show that they were stable and uniform in size. Microfluidics-assisted doxorubicin-loaded PLGA nanoparticles show uniform size and higher entrapment efficiency. Release kinetics showed a strong burst phase release over the first 8 hours and subsequent sustained release up to 72 hours. In vivo biodistribution of EPHN shows better tumor accumulation compared to PLGA NP. The next stage in this project is in vivo tumor efficacy testing in breast cancer tumor models. This targeted NP system can serve as a novel therapeutic platform for developing improved treatments for metastatic TNBC. Citation Format: Rohan Joshi, Jana Lampe, Jamboor K. Vishwanatha, Amalendu P. Ranjan. Exosome-based hybrid nanosystem for targeted TNBC therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 832.