Abstract
Only a small number of promising drugs target pancreatic cancer, which is the fourth leading cause of cancer deaths with a 5-year survival of less than 5%. Our goal is to develop a new biotherapeutic agent in which a lysosomal protein (saposin C, SapC) and a phospholipid (dioleoylphosphatidylserine, DOPS) are assembled into nanovesicles (SapC-DOPS) for treating pancreatic cancer. A distinguishing feature of SapC-DOPS nanovesicles is their high affinity for phosphatidylserine (PS) rich microdomains, which are abnormally exposed on the membrane surface of human pancreatic tumor cells. To evaluate the role of external cell PS, in vitro assays were used to correlate PS exposure and the cytotoxic effect of SapC-DOPS in human tumor and nontumorigenic pancreatic cells. Next, pancreatic tumor xenografts (orthotopic and subcutaneous models) were used for tumor targeting and therapeutic efficacy studies with systemic SapC-DOPS treatment. We observed that the nanovesicles selectively killed human pancreatic cancer cells in vitro by inducing apoptotic death, whereas untransformed cells remained unaffected. This in vitro cytotoxic effect correlated to the surface exposure level of PS on the tumor cells. Using xenografts, animals treated with SapC-DOPS showed clear survival benefits and their tumors shrank or disappeared. Furthermore, using a double-tracking method in live mice, we showed that the nanovesicles were specifically targeted to orthotopically-implanted, bioluminescent pancreatic tumors. These data suggest that the acidic phospholipid PS is a biomarker for pancreatic cancer that can be effectively targeted for therapy utilizing cancer-selective SapC-DOPS nanovesicles. This study provides convincing evidence in support of developing a new therapeutic approach to pancreatic cancer.
Highlights
Pancreatic cancer is the fourth leading cause of cancer deaths, with a 5-year survival of less than 5% [1,2,3]
We found that the optimal molar ratio of SapC and DOPS was from 1:3 to 1:10 for maximal cytotoxic effect against human neuroblastoma and skin cancer cells [36,37]
When the three pancreatic adenocarcinoma cell lines and Human pancreatic ductal epithelium (HPDE) cells were treated with SapC-DOPS, most of the tumor cells died, while the HPDE cells remained viable (Figure 1B)
Summary
Pancreatic cancer is the fourth leading cause of cancer deaths, with a 5-year survival of less than 5% [1,2,3]. It is usually asymptomatic in the early stages, while frequently invading regional lymph nodes and liver, and less often the lungs and visceral organs. Current multi-modal strategies, including surgery, chemotherapy, and radiation therapy, have failed to improve longterm survival. The current standard of treatment, the nucleoside analog gemcitabine [4], prolongs survival by only several months. Experimental therapeutic strategies include small and large molecule inhibitors of oncogenic pathways, anti-angiogenic agents, vaccination/immunotherapy, gene therapies, and many others, but no clearly superior therapies have emerged
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