title: Codelivery of small molecule hedgehog inhibitor and miRNA for treating pancreatic cancer.
abstract: Successful treatment of pancreatic ductal adenocarcinoma (PDAC) remains a challenge due to the desmoplastic microenvironment that promotes both tumor growth and metastasis and forms a barrier to chemotherapy. Hedgehog (Hh) signaling is implicated in initiation and progression of PDAC and also contributes to desmoplasia. While Hh levels are increased in pancreatic cancer cells, levels of tumor suppressor miR-let7b, which targets several genes involved in PDAC pathogenesis, is downregulated. Therefore, our overall objective was to inhibit Hh pathway and restore miR-let7b simultaneously for synergistically treating PDAC. miR-let7b and Hh inhibitor GDC-0449 could inhibit the proliferation of human pancreatic cancer cells (Capan-1, HPAF-II, T3M4, and MIA PaCa-2), and there was synergistic effect when miR-let7b and GDC-0449 were coformulated into micelles using methoxy poly(ethylene glycol)-block-poly(2-methyl- 2-carboxyl-propylenecarbonate-graft-dodecanol-graft-tetraethylene-pentamine) (mPEG-b-PCC-g-DC-g-TEPA). This copolymer self-assembled into micelles of <100 nm and encapsulated hydrophobic GDC-0449 into its core with 5% w/w drug loading and allowed complex formation between miR-let7b and its cationic pendant chains. Complete polyplex formation with miRNA was observed at the N/P ratio of 16/1. Almost 80% of GDC-0449 was released from the polyplex in a sustained manner in 2 days. miRNA in the micelle formulation was stable for up to 24 h in the presence of serum and high uptake efficiency was achieved with low cytotoxicity. This combination therapy effectively inhibited tumor growth when injected to athymic nude mice bearing ectopic tumor generated using MIA PaCa-2 cells compared to micelles carrying GDC-0449 or miR-let7b alone. Immunohistochemical analysis revealed decreased tumor cell proliferation with increased apoptosis in the animals treated with miR-let7b and GDC-0449 combination.
authors: †Departments of Pharmaceutical Sciences and ‡Biochemistry and Molecular Biology, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors: Virender
authors: V
authors: Kumar
authors: †Departments of Pharmaceutical Sciences and ‡Biochemistry and Molecular Biology, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors: Goutam
authors: G
authors: Mondal
authors: †Departments of Pharmaceutical Sciences and ‡Biochemistry and Molecular Biology, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors: Paige
authors: P
authors: Slavik
authors: †Departments of Pharmaceutical Sciences and ‡Biochemistry and Molecular Biology, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors: Satyanarayna
authors: S
authors: Rachagani
authors: †Departments of Pharmaceutical Sciences and ‡Biochemistry and Molecular Biology, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors: Surinder K
authors: SK
authors: Batra
authors: †Departments of Pharmaceutical Sciences and ‡Biochemistry and Molecular Biology, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors: Ram I
authors: RI
authors: Mahato
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000475:Alkenes / Q000737:chemistry; D000813:Anilides / Q000737:chemistry; D000818:Animals; D002254:Carbonates / Q000737:chemistry; D002412:Cations; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D007851:Dodecanol / Q000737:chemistry; D004337:Drug Carriers; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism; D005029:Ethylenediamines / Q000737:chemistry; D053823:Hedgehog Proteins / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D035683:MicroRNAs / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D000475:Alkenes; D000813:Anilides; D002254:Carbonates; D002412:Cations; D004337:Drug Carriers; D005029:Ethylenediamines; D053823:Hedgehog Proteins; C538724:HhAntag691; D008823:Micelles; D035683:MicroRNAs; D011108:Polymers; D011725:Pyridines; D007851:Dodecanol; D011092:Polyethylene Glycols; C013658:propylene; C034269:tetraethylenepentamine
keywords: GDC-0449; Hh signaling; K-RAS; miR-let7b; micelles; pancreatic ductal adenocarcinoma