Abstract
Chemoresistance is the major impediment for treating pancreatic cancer. Herb-derived compound triptolide (TP) can inhibit proliferation of chemo-resistant pancreatic cancer (CPC) cell lines through multiple mechanisms, which exhibited superior anticancer efficacy compared with gemcitabine. However, toxicity due to non-specific exposure to healthy tissues hindered its clinical translation. Herein we successfully achieved targeting CPC cells and avoiding exposure to healthy tissues for TP by nucleolin-specific aptamer (AS1411) mediated polymeric nanocarrier. We conjugated AS1411 aptamer to carboxy terminated poly(ethylene glycol)–block–poly(d, l-lactide) (HOOC-PEG-PDLLA), then prepared AS1411-PEG-PDLLA micelle loading TP (AS-PPT) through solid dispersion technique. AS-PPT showed more antitumor activity than TP and equivalent specific binding ability with gemcitabine-resistant human pancreatic cancer cell (MIA PaCa-2) to AS1411 aptamer in vitro. Furthermore, we studied the distribution of AS-PPT (Cy3-labed TP) at tissue and cellular levels using biophotonic imaging technology. The results showed AS1411 facilitated TP selectively accumulating in tumor tissues and targeting CPC cells. The lifetime of the MIA PaCa-2 cell-bearing mice administrated with AS-PPT was efficiently prolonged than that of the mice subjected to the clinical anticancer drug Gemzar® in vivo. Such work provides a new strategy for overcoming the drug resistance of pancreatic cancer.
Highlights
Pancreatic cancer (PC) is one of the most aggressive human malignancies with a historically dismal long-term prognosis, which accounts for 2% of all cancers but 6% of cancer deaths worldwide [1]
Triptolide (TP, Figure 1 is the structure of Triptolide) is a major active compound of Tripterygium wilfordii Hook F, which can inhibit proliferation of chemo-resistant pancreatic cancer cells (CPC) through multiple pathways, such as inhibition of P-glycoprotein, Heat Shock Protein 70 (HSP70), NF- κB, Bax gene and angiogenesis, etc, which exhibited superior anticancer efficacy compared to gemcitabine and taxanes in vitro [6, 10,11,12,13,14,15,16,17]
AS1411 aptamer, HOOC-PEG-PDLLA and AS- PP polymer were characterized by mass spectrometry (MS), 1H-NMR and polyacrylamide gel electroporesis (PAGE) respectively
Summary
Pancreatic cancer (PC) is one of the most aggressive human malignancies with a historically dismal long-term prognosis, which accounts for 2% of all cancers but 6% of cancer deaths worldwide [1]. Chemoresistance in PC is triggered by various molecular mechanisms including aberrant gene expression, mutations, deregulation of key signaling pathways (such as NF-κB, Akt, and apoptosis pathways), epithelial-mesenchymal transition (EMT) and the presence of stroma cells, highly resistant cells and stem cells [2,3,4,5]. Each of those mechanisms contributes to drug resistance in pancreatic cancer from different aspects, and www.impactjournals.com/oncotarget recommends different therapeutic targets. Realizing TP selectively targeting PC tissues or cells to enhance uptake and simultaneouly reduce side effect may be practical to reverse DR with longer survival time
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