12:00 – 12:30 Camilla Pegoraro
Novel polypeptide-based drug delivery systems for precise mitochondria targeting
In today’s pharmaceutical era, many emerging therapies rely on releasing therapeutics at a subcellular level. Given the role of mitochondrial dysfunctions in diseases such as cancer, there is a particular focus on developing systems targeting mitochondria specifically. However, it is challenging to deliver therapies to this organelle due to its compartmentalized and difficult-to-penetrate membranes, as well as the need to bypass the cell membrane and ensure cytosolic delivery. Polypeptide-based systems offer a promising solution for delivering therapeutics in a controlled and targeted manner.
In this context, within my Ph.D. thesis being performed as part of the Marie Curie International Training Network (ITN) Biomolmacs, we have designed, synthesized and characterized two different polyornithine (PLO)-based systems with a high propensity for mitochondria. In the first platform, a complex system based on PLO and TPP was designed to ensure cytosolic release after endocytosis and mitochondria targeting. In the second design, PLO-based diblock copolymers were developed to target the mitochondria after direct cell membrane permeation. Internalization studies by confocal fluorescence microscopy and extensive studies with model membrane systems (GUVs and SUVs) were applied to confirm the mitochondria affinity. To test the effectiveness of the diblock copolymer carrier, we covalently linked two drugs that target mitochondria, lonidamine and α-tocopherol succinate (TOS), and evaluated their activity by analyzing the mitochondria membrane potential with the JC-1 assay and measuring the mitochondria respiration using Seahorse Analytics. Moreover, the mitochondria targeting vector was covalently coupled to a molecular motor to test the hybrid system’s effectiveness in enhancing membrane permeation. In conclusion, we designed, characterized and extensively tested in vitro novel mitochondria-targeted platforms and their derivatives with promising features as a subcellular cancer therapy.
12:30 – 13:00 Francesca de Angelis
HAPLN1 is a driver for peritoneal carcinomatosis in PDAC
Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Despite the cancer cell intrinsic features, a key regulator of metastasis is the microenvironment that tumor cells are facing during their metastatic journey. Here, we show that a protein of the extracellular matrix, HAPLN1, which crosslinks Hyaluronan (HA) and proteoglycan, is associated with worse overall patient survival. Its presence in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis in the peritoneal cavity. Mechanistically, we observed that HAPLN1 promotes upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. As such, we identified HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC.
