Codelivery of small molecule hedgehog inhibitor and miRNA for treating pancreatic cancer

Virender Kumar, Goutam Mondal, Paige Slavik, Satyanarayana Rachagani, Surinder Kumar Batra, Ram I Mahato

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1289-1298
Number of pages10
JournalMolecular Pharmaceutics
Volume12
Issue number4
DOIs
StatePublished - Apr 6 2015

Fingerprint

HhAntag691
MicroRNAs
Pancreatic Neoplasms
Hedgehogs
Micelles
Adenocarcinoma
pentamine
Neoplasms
Nude Mice
Triethylenephosphoramide
Dodecanol
Transplants
Ethylene Glycol
Growth
Down-Regulation
Cell Proliferation
Apoptosis
Neoplasm Metastasis
Drug Therapy

Keywords

  • GDC-0449
  • Hh signaling
  • K-RAS
  • miR-let7b
  • micelles
  • pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Codelivery of small molecule hedgehog inhibitor and miRNA for treating pancreatic cancer. / Kumar, Virender; Mondal, Goutam; Slavik, Paige; Rachagani, Satyanarayana; Batra, Surinder Kumar; Mahato, Ram I.

In: Molecular Pharmaceutics, Vol. 12, No. 4, 06.04.2015, p. 1289-1298.

Research output: Contribution to journalArticle

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