Abstract
Pancreatic cancer is a malignant disease with high mortality and poor prognosis due to lack of early diagnosis and low treatment efficiency after diagnosis. Although Gemcitabine (GEM) is used as the first-line chemotherapeutic drug, chemoresistance is still the major problem that limits its therapeutic efficacy. Here in this study, we developed a specific M1 macrophage-derived exosome (M1Exo)-based drug delivery system against GEM resistance in pancreatic cancer. In addition to GEM, Deferasirox (DFX) was also loaded into drug carrier, M1Exo, in order to inhibit ribonucleotide reductase regulatory subunit M2 (RRM2) expression via depleting iron, and thus increase chemosensitivity of GEM. The M1Exo nanoformulations combining both GEM and DFX significantly enhanced the therapeutic efficacy on the GEM-resistant PANC-1/GEM cells and 3D tumor spheroids by inhibiting cancer cell proliferation, cell attachment and migration, and chemoresistance to GEM. These data demonstrated that M1Exo loaded with GEM and DFX offered an efficient therapeutic strategy for drug-resistant pancreatic cancer.
Highlights
Pancreatic cancer is a lethal disease with poor survival rate and an increasing incidence due to lack of early diagnosis and low treatment efficiency after diagnosis [1]
The measurement of the spheroid roundness was compared, and we found that the tumor spheroids became granular and irregular on the periphery and broke into pieces when treated with M1Exo-GEM-DFX (Figure 6C)
Our results indicated that M1Exo-GEM-DFX effectively inhibited the formation and growth of PANC-1/GEM tumor spheroids compared with free drugs
Summary
Pancreatic cancer is a lethal disease with poor survival rate and an increasing incidence due to lack of early diagnosis and low treatment efficiency after diagnosis [1]. 20% of patients are suitable for resection, chemotherapy is still one of the main treatments for pancreatic cancer [2,3]. Current treatment strategies are still unsatisfactory and have failed to significantly increase the overall survival time of patients with pancreatic cancer over the last decade. Gemcitabine (GEM), a hydrophilic deoxycytidine analogue, is a first-line chemotherapeutic drug and is widely used in the treatment of unresectable pancreatic cancer. Chemoresistance is still the major problem that limits the therapeutic efficacy of GEM. The positive response rate for standard GEM treatment in pancreatic cancer patients is only
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