ArticleMolecular pharmaceutics2016
Micelle Mixtures for Coadministration of Gemcitabine and GDC-0449 To Treat Pancreatic Cancer.
Article in Molecular pharmaceutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 27 citations in OpenAlex.
- Article
- Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond.Current issues in molecular biology · 2023Review
- Polymeric nanomedicine for overcoming resistance mechanisms in hedgehog and Myc-amplified medulloblastoma.Biomaterials · 2021Article
- Design of Hedgehog pathway inhibitors for cancer treatment.Medicinal research reviews · 2019Review
- PEG-b-poly (carbonate)-derived nanocarrier platform with pH-responsive properties for pancreatic cancer combination therapy.Colloids and surfaces. B, Biointerfaces · 2019Article
- Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer.Scientific reports · 2017Article
- Biodistribution of Self-Assembling Polymer-Gemcitabine Conjugate after Systemic Administration into Orthotopic Pancreatic Tumor Bearing Mice.Molecular pharmaceutics · 2017Article
- Pharmacokinetics and Biodistribution of GDC-0449 Loaded Micelles in Normal and Liver Fibrotic Mice.Pharmaceutical research · 2017Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Hedgehog (Hh) signaling plays an important role in the development and metastasis of pancreatic ductal adenocarcinoma (PDAC). Although gemcitabine (GEM) has been used as a first-line therapy for PDAC, its rapid metabolism and short plasma half-life restrict its use as a single chemotherapy. Combination therapy with more than one drug is a promising approach for treating cancer. Herein, we report the use of methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate)-graft-dodecanol (mPEG-b-PCC-g-DC) copolymer for conjugating GEM and encapsulating a Hh inhibitor, vismodegib (GDC-0449), into its hydrophobic core for treating PDAC. Our objective was to determine whether the micelle mixtures of these two drugs could show better response in inhibiting Hh signaling pathway and restraining the proliferation and metastasis of pancreatic cancer. The in vivo stability of GEM significantly increased after conjugation, which resulted in its increased antitumor efficacy. Almost 80% of encapsulated GDC-0449 and 19% conjugated GEM were released in vitro at pH 5.5 in 48 h in a sustained manner. The invasion, migration, and colony forming features of MIA PaCa-2 cells were significantly inhibited by micelle mixture carrying GEM and GDC-0449. Remarkable increase in PARP cleavage and Bax proved increased apoptosis by this combination formulation compared to individual micelles. This combination therapy efficiently inhibited tumor growth, increased apoptosis, reduced Hh ligands PTCH-1 and Gli-1, and lowered EMT-activator ZEB-1 when injected to athymic nude mice bearing subcutaneous tumor generated using MIA PaCa-2 cells compared to monotherapy as observed from immunohistochemical analysis. In conclusion, micelle mixtures carrying GEM and GDC-0449 have the potential to treat pancreatic cancer.
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