title: Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.
abstract: OBJECTIVE
  Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy.
  
  
  METHODS
  C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53(Null) orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg i.v. x1. Area under the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by IHC. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg i.v. weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed.
  
  
  RESULTS
  Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin was similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P < 0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and VEGF-a, greater vascular quantity, and decreased expression of VEGF-c compared with C3-TAg (P < 0.05). PLD was more efficacious compared with NL-doxo in both models.
  
  
  CONCLUSIONS
  The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small-molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Gina
authors.initials: G
authors.lastname: Song
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: David B
authors.initials: DB
authors.lastname: Darr
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. The Animal Studies Core, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Santos
authors.affiliation: The Animal Studies Core, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Mark
authors.initials: M
authors.lastname: Ross
authors.affiliation: The Animal Studies Core, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Alain
authors.initials: A
authors.lastname: Valdivia
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Jordan
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. Translational Pathology Lab, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Bentley R
authors.initials: BR
authors.lastname: Midkiff
authors.affiliation: Translational Pathology Lab, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cohen
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. Translational Pathology Lab, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Nana
authors.initials: N
authors.lastname: Nikolaishvili-Feinberg
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. Department of Pathology and Laboratory Medicine, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. Department of Medicine, Division of Rheumatology, Allergy, and Immunology and Thurston Arthritis Research Center, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Tarrant
authors.affiliation: Cummings School of Veterinary Medicine, Tufts University, Medford, Massachusetts.
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. Department of Cell and Molecular Physiology, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Dudley
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. Department of Pathology and Laboratory Medicine, UNC at Chapel Hill, Chapel Hill, North Carolina. Department of Genetics, UNC at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. Carolina Center of Cancer Nanotechnology Excellence, UNC at Chapel Hill, Chapel Hill, North Carolina. Center for Pharmacogenomics and Individualized Therapy, UNC at Chapel Hill, Chapel Hill, North Carolina. zamboni@email.unc.edu.
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000097:blood / Q000378:metabolism; D018946:Chemokine CCL5 / Q000097:blood / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018932:Chemokine CCL2; D018946:Chemokine CCL5; D042461:Vascular Endothelial Growth Factor A; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003094:Collagen