title: A Computational/Experimental Assessment of Antitumor Activity of Polymer Nanoassemblies for pH-Controlled Drug Delivery to Primary and Metastatic Tumors.
abstract: Polymer nanoassemblies (PNAs) with drug release fine-tuned to occur in acidic tumor regions (pH < 7) while sparing normal tissues (pH = 7.4) were previously shown to hold promise as nanoparticle drug carriers to effectively suppress tumor growth with reduced systemic toxicity. However, therapeutic benefits of pH-controlled drug delivery remain elusive due to complex interactions between the drug carriers, tumor cells with varying drug sensitivity, and the tumor microenvironment.
  
  
  
  We implement a combined computational and experimental approach to evaluate the in vivo antitumor activity of acid-sensitive PNAs controlling drug release in pH 5 ~ 7.4 at different rates [PNA1 (fastest) > PNA2 > PNA3 (slowest)].
  
  
  
  Computational simulations projecting the transport, drug release, and antitumor activity of PNAs in primary and metastatic tumor models of colorectal cancer correspond well with experimental observations in vivo. The simulations also reveal that all PNAs could reach peak drug concentrations in tumors at 11 h post injection, while PNAs with slower drug release (PNA2 and PNA3) reduced tumor size more effectively than fast drug releasing PNA1 (24.5 and 20.3 vs 7.5%, respectively, as fraction of untreated control).
  
  
  
  A combined computational/experimental approach may help to evaluate pH-controlled drug delivery targeting aggressive tumors that have substantial acidity.
authors.affiliation: Department of Bioengineering, University of Louisville, Lutz Hall 419, Louisville, Kentucky, 40208, USA.
authors.forename: Louis T
authors.initials: LT
authors.lastname: Curtis
authors.affiliation: Markey Cancer Center and Department of Surgery, University of Kentucky, 741 South Limestone,, Lexington, Kentucky, 40506, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Rychahou
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone,, Lexington, Kentucky, 40536, USA. younsoo.bae@uky.edu.
authors.forename: Younsoo
authors.initials: Y
authors.lastname: Bae
authors.affiliation: Department of Bioengineering, University of Louisville, Lutz Hall 419, Louisville, Kentucky, 40208, USA. hbfrie01@louisville.edu.|Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA. hbfrie01@louisville.edu.|James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA. hbfrie01@louisville.edu.
authors.forename: Hermann B
authors.initials: HB
authors.lastname: Frieboes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods*; D019073:HT29 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism; D011108:Polymers / Q000008:administration & dosage* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers
keywords: cancer nanotherapy; computational simulation; mathematical modeling; nanoparticles; pH-controlled release; polymer micelles