Publication

Protease-Responsive Targeted Delivery of Chemotherapeutics Holds Great Promise for the Treatment of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest common cancer, with only 8% of patients surviving for five years. One reason for this poor outcome is that current chemotherapy treatments are highly toxic, often leaving patients too sick to receive treatment or forcing doctors to lower the dose or stop treatment altogether. Targeting the cancer cells directly without harming healthy cells could reduce toxicity and could improve therapy efficacy. This could, in turn, increase survival, improve patients' quality of life, and reduce healthcare costs.

Author

E.J. Slapak, M. el Mandili, M.S. Ten Brink, A. Kros, M.F. Bijlsma, C.A. Spek

Date

28 May 2024

Links

Full publication

Our published study aimed to obtain proof of principle that the targeted delivery of chemotherapeutics to pancreatic cancer cells without affecting healthy tissue using drug loaded mesoporous silica nanoparticles (MSNs) could be a valuable approach.

Certain proteins called proteases, which cut other proteins, are more or less abundant in pancreatic cancer compared to healthy tissue. We identified various proteases with increased abundance in PDAC, including a protease called Calpain 2 (CAPN2). Using this information, we designed MSNs equipped with ‘locks’ that can only be opened by this specific protease. After loading the MSNs with chemotherapy drugs, they remain tightly sealed until they encounter CAPN2 inside PDAC cells, which act as ‘keys’ to open the locks and release the drug.

In cell lines, we proved that paclitaxel-loaded CAPN2-responsive MSNs very efficiently killed PDAC cells, with greatly limited toxicity towards healthy nerve and white blood cells, which are typically affected by paclitaxel in patients. Finally, we showed that, in two mouse models that mimic human disease, the CAPN2-responsive MSNs showed improved efficacy over free paclitaxel, as evidenced by a smaller tumor volume, decreased cell cycle progression, and increased regulated cell death (apoptosis). Of note, and of particular importance, side effects were reduced in CAPN2-MSNs treated mice as compared to free paclitaxel treated mice.

In conclusion, our study shows that paclitaxel-loaded nanoparticles equipped with a protease-dependent lock kill cancer cells more effectively with fewer side effects than the traditional untargeted paclitaxel treatment. While this is an early-stage study and more research is needed, it provides promising evidence that protease-responsive targeted delivery of chemotherapeutics could one day benefit PDAC patients, especially those who are too weak for current treatments.