title: Bottom up design of nanoparticles for anti-cancer diapeutics: "put the drug in the cancer's food".
abstract: The story starts in Basel at CLINAM in 2013, when I asked Pieter about making nanoparticles and he advised me to "try this solvent-exchange method we have developed for making limit sized particles". We are particularly interested in what are "limit size materials" because we want to test the feasibility of an idea: could we design, make, develop, and test the concept for treating metastatic cancer by, "Putting the Drug in the Cancer's Food? "Limit size" is the size of the cancer's food, ? the common Low Density Lipoprotein, (LDL) ~20 nm diameter. In this contribution to Pieter's LTAA we focus on the "bottom" (nucleation) and the "up" (growth) of "bottom-up design" as it applies to homogeneous nucleation of especially, hydrophobic drugs and the 8 physico-chemical stages and associated parameters that determine the initial size, and any subsequent coarsening, of a nanoparticle suspension. We show that, when made by the rapid solvent-exchange method, the same sized particles can be obtained without phospholipid. Furthermore, the obtained size follows the predictions of classic nucleation theory when the appropriate values for the parameters (surface tension and supersaturation) at nucleation are included. Calculations on dissolution time for nanoparticles reveal that a typical fewmicromolar-solubility, hydrophobic, anti-cancer drug (like Lapatinib, Niclosamide, Abiraterone, and Fulvestrant) of 500 nm diameter would take between 3?7 s to dissolve in an infinite sink like the blood stream; and a 50 nm particle would dissolve in less than a second! And so the nanoparticle design requires a highly water-insoluble drug, and a tight, encapsulating, impermeable lipid:cholesterol monolayer. While the "Y" junction can be used to mix an ethanolic solution with anti-solvent, we find that a "no-junction" can give equally good results. A series of nanoparticles (DiI-fluorescently labeled Triolein-cored and drug-cored nanoparticles of Orlistat) were then tested in well-characterized cell lines for uptake and efficacy as well as a PET-imageable nanoparticle in initial PET-imaging studies in animals for EPR uptake and tumor detection. We show that, while free-drug cannot be optimally administered in vivo, a nanoparticle formulation of orlistat could in principle represent a stable parenteral delivery system. The article ends with a brief discussion of what we see as the way forward in Individualized Medicine from the Diagnostic-Therapeutic ("Diapeutic") side, requiring18FDG detection of metastatic lesions, functional imaging of a protein target (e.g. Fatty Acid Synthase) using11C acetate, then a PET (or other)-imageable nanoparticle to demonstrate EPR accumulation, and then the administration of the pure-drug nanoparticle taken in by the most aggressive cancer cells in the perivascular space, as they would their "food".
authors.affiliation: a Department of Mechanical Engineering and Material Science , Duke University , Durham , NC , USA.|b Center for Single Particle Science and Engineering (SPSE) , University of Southern Denmark , Odense , Denmark.
authors.forename: David
authors.initials: D
authors.lastname: Needham
authors.affiliation: b Center for Single Particle Science and Engineering (SPSE) , University of Southern Denmark , Odense , Denmark.
authors.forename: Amina
authors.initials: A
authors.lastname: Arslanagic
authors.affiliation: b Center for Single Particle Science and Engineering (SPSE) , University of Southern Denmark , Odense , Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Glud
authors.affiliation: b Center for Single Particle Science and Engineering (SPSE) , University of Southern Denmark , Odense , Denmark.
authors.forename: Pablo
authors.initials: P
authors.lastname: Hervella
authors.affiliation: b Center for Single Particle Science and Engineering (SPSE) , University of Southern Denmark , Odense , Denmark.
authors.forename: Leena
authors.initials: L
authors.lastname: Karimi
authors.affiliation: c Research Unit, Clinical Physiology and Nuclear Medicine , Odense University Hospital (OUH) , Odense , Denmark.
authors.forename: Poul-Flemming
authors.initials: PF
authors.lastname: Høeilund-Carlsen
authors.affiliation: b Center for Single Particle Science and Engineering (SPSE) , University of Southern Denmark , Odense , Denmark.
authors.forename: Koji
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: d NanoCAN, Institute for Molecular Medicine (IMM), SUND , University of Southern Denmark , Odense , Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Mollenhauer
authors.affiliation: b Center for Single Particle Science and Engineering (SPSE) , University of Southern Denmark , Odense , Denmark.
authors.forename: Elisa
authors.initials: E
authors.lastname: Parra
authors.affiliation: b Center for Single Particle Science and Engineering (SPSE) , University of Southern Denmark , Odense , Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Utoft
authors.affiliation: b Center for Single Particle Science and Engineering (SPSE) , University of Southern Denmark , Odense , Denmark.
authors.forename: Prasad
authors.initials: P
authors.lastname: Walke
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000737:chemistry; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids
keywords: Solvent-shifting; cell viability; diapeutics; drug nanoparticle solubility; energetics of nucleation; hydrophobic sink; individualized medicine; microcrystals; microparticles; micropipette manipulation; nucleation and growth