title: Tumor-Priming Smoothened Inhibitor Enhances Deposition and Efficacy of Cytotoxic Nanoparticles in a Pancreatic Cancer Model.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York. Department of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Tista
authors.initials: T
authors.lastname: Roy Chaudhuri
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York.
authors.forename: Ninfa L
authors.initials: NL
authors.lastname: Straubinger
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Rosemarie F
authors.initials: RF
authors.lastname: Pitoniak
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Hylander
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Repasky
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York. Department of Molecular and Cellular Biophysics and Biochemistry, Roswell Park Cancer Institute, Buffalo, New York. Department of Cancer Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York. New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York. rms@Buffalo.edu.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Straubinger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002199:Capillary Permeability / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D004337:Drug Carriers; D006801:Humans; D008081:Liposomes; D051379:Mice; D053758:Nanoparticles; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D000072086:Smoothened Receptor; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin