Tumor-priming smoothened inhibitor enhances deposition and efficacy of cytotoxic nanoparticles in a pancreatic cancer model

Tista Roy Chaudhuri, Ninfa L. Straubinger, Rosemarie F. Pitoniak, Bonnie L. Hylander, Elizabeth A. Repasky, Wen Wee Ma, Robert M. Straubinger

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Most pancreatic adenocarcinoma patients present with unresectable disease and benefit little from chemotherapy. Poor tumor perfusion and vascular permeability limit drug deposition. Previous work showed that Smoothened inhibitors of hedgehog signaling (sHHI) promote neovascularization in spontaneous mouse models of pancreatic cancer (PaCA) and enhance tumor permeability to low-molecular weight compounds. Here, we tested the hypothesis that sHHI can enhance tumor deposition and efficacy of drug-containing nanoparticles consisting of 80 to 100 nm sterically-stabilized liposomes (SSL) containing doxorubicin (SSL-DXR). SCID mice bearing low-passage patient-derived PaCA xenografts (PDX) were pretreated p.o. for 10 days with 40 mg/kg/d NVP-LDE225 (erismodegib), followed by i.v. SSL-DXR. Microvessel density, permeability, perfusion, and morphology were compared with untreated controls, as was SSL deposition and therapeutic efficacy. The sHHI alone affected tumor growth minimally, but markedly increased extravasation of nanoparticles into adenocarcinoma cell-enriched regions of the tumor. Immunostaining showed that sHHI treatment decreased pericyte coverage (α-SMA+) of CD31+ vascular endothelium structures, and increased the abundance of endothelium-poor (CD31-) basement membrane structures (collagen IV+), suggesting increased immature microvessels. SSL-DXR (15 mg/kg) administered after sHHI pretreatment arrested tumor volume progression and decreased tumor perfusion/permeability, suggesting an initial vascular pruning response. Compared with controls, one cycle of 10-day sHHI pretreatment followed by 6 mg/kg SSL-DXR doubled median tumor progression time. Three cycles of treatment with sHHI and SSL-DXR, with a 10-day between-cycle drug holiday, nearly tripled median tumor progression time. Based upon these data, short-term sHHI treatment sequenced with nanoparticulate drug carriers constitutes a potential strategy to enhance efficacy of pancreatic cancer therapy.

Original languageEnglish (US)
Pages (from-to)84-93
Number of pages10
JournalMolecular Cancer Therapeutics
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Nanoparticles
Liposomes
Neoplasms
Permeability
Perfusion
Microvessels
Adenocarcinoma
Pharmaceutical Preparations
Therapeutics
Pericytes
Holidays
Drug Carriers
SCID Mice
Hedgehogs
Vascular Endothelium
Capillary Permeability
Cerebral Palsy
Tumor Burden
Basement Membrane

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tumor-priming smoothened inhibitor enhances deposition and efficacy of cytotoxic nanoparticles in a pancreatic cancer model. / Chaudhuri, Tista Roy; Straubinger, Ninfa L.; Pitoniak, Rosemarie F.; Hylander, Bonnie L.; Repasky, Elizabeth A.; Ma, Wen Wee; Straubinger, Robert M.

In: Molecular Cancer Therapeutics, Vol. 15, No. 1, 01.01.2016, p. 84-93.

Research output: Contribution to journalArticle

Chaudhuri, Tista Roy ; Straubinger, Ninfa L. ; Pitoniak, Rosemarie F. ; Hylander, Bonnie L. ; Repasky, Elizabeth A. ; Ma, Wen Wee ; Straubinger, Robert M. / Tumor-priming smoothened inhibitor enhances deposition and efficacy of cytotoxic nanoparticles in a pancreatic cancer model. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 1. pp. 84-93.
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