title: Identification of pancreatic tumors in vivo with ligand-targeted, pH responsive mesoporous silica nanoparticles by multispectral optoacoustic tomography.
abstract: Despite significant efforts to translate nanotechnology for cancer application, lack of identification of biodistribution/accumulation of these nanovehicles in vivo remains a substantial barrier for successful implementation of theranostic nanoparticles in the clinic. The purpose of the study was to develop a tumor-targeted theranostic nanovehicle for pancreatic cancer detectable by multispectral optoacoustic tomography (MSOT). To improve the tumor specificity of our mesoporous silica nanoparticle (MSN), we utilized a dual targeting strategy: 1) an elevated tumor receptor, urokinase plasminogen activator receptor (UPAR), and 2) the acidic tumor microenvironment. The tumor specificity of the MSN particle was improved with the addition of both chitosan, targeting acidic pH, and urokinase plasminogen activator (UPA), targeting UPAR. Drug release assays confirmed pH responsive release of gemcitabine in vitro. The UPAR specific binding of MSN-UPA nanoparticles was confirmed by reduction in fluorescence signal following MSN-UPA nanoparticle treatment in UPAR positive cells blocked with a UPAR-blocking antibody. Based upon Indocyanine Green encapsulation within the nanoparticles, UPA ligand targeted MSNs demonstrated increased intensity compared to untargeted MSNs at both pH7.4 (7×) and 6.5 (20×); however the signal was much more pronounced at a pH of 6.5 using tissue phantoms (p<0.05). In vivo, MSN-UPA particles demonstrated orthotopic pancreatic tumor specific accumulation compared to liver or kidney as identified using multispectral optoacoustic tomography (p<0.05) and confirmed by ex vivo analysis. By tracking in vivo nanoparticle biodistribution with MSOT, it was shown that pH responsive, ligand targeted MSNs preferentially bind to pancreatic tumors for payload delivery.
authors.affiliation: Department of Radiation Oncology, University of Louisville, 529 S Jackson Street, Louisville, KY 40202, USA.
authors.forename: Marie K
authors.initials: MK
authors.lastname: Gurka
authors.affiliation: Department of Medicine, University of Louisville, 505 S Hancock, Louisville, KY 40202, USA.
authors.forename: Dillon
authors.initials: D
authors.lastname: Pender
authors.affiliation: Department of Medicine, University of Louisville, 505 S Hancock, Louisville, KY 40202, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Chuong
authors.affiliation: Department of Medicine, University of Louisville, 505 S Hancock, Louisville, KY 40202, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Fouts
authors.affiliation: Department of Medicine, University of Louisville, 505 S Hancock, Louisville, KY 40202, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sobelov
authors.affiliation: Department of Medicine, University of Louisville, 505 S Hancock, Louisville, KY 40202, USA.
authors.forename: Molly W
authors.initials: MW
authors.lastname: McNally
authors.affiliation: Department of Radiation Oncology, University of Louisville, 529 S Jackson Street, Louisville, KY 40202, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Mezera
authors.affiliation: Department of Radiation Oncology, University of Louisville, 529 S Jackson Street, Louisville, KY 40202, USA.
authors.forename: Shiao Y
authors.initials: SY
authors.lastname: Woo
authors.affiliation: Department of Medicine, University of Louisville, 505 S Hancock, Louisville, KY 40202, USA. Electronic address: lacey_mcnally@hotmail.com.
authors.forename: Lacey R
authors.initials: LR
authors.lastname: McNally
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D065546:Drug Liberation; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007208:Indocyanine Green / Q000737:chemistry; D008024:Ligands; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy; D010316:Particle Size; D061088:Photoacoustic Techniques / Q000379:methods; D016062:Porosity; D011923:Rats, Nude; D012822:Silicon Dioxide / Q000737:chemistry*; D013499:Surface Properties; D000068936:Theranostic Nanomedicine; D014018:Tissue Distribution; D014054:Tomography / Q000379:methods; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D008024:Ligands; D003841:Deoxycytidine; D012822:Silicon Dioxide; D048271:Chitosan; D014568:Urokinase-Type Plasminogen Activator; D007208:Indocyanine Green; D000093542:Gemcitabine
keywords: Mesoporous silica; Nanomedicine multispectral optoacoustic tomography; Pancreatic cancer; Theranostics