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Bottom up design of nanoparticles for anti-cancer diapeutics: "put the drug in the cancer's food".

Publication ,  Journal Article
Needham, D; Arslanagic, A; Glud, K; Hervella, P; Karimi, L; Høeilund-Carlsen, P-F; Kinoshita, K; Mollenhauer, J; Parra, E; Utoft, A; Walke, P
Published in: Journal of drug targeting
November 2016

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, requiring 18FDG detection of metastatic lesions, functional imaging of a protein target (e.g. Fatty Acid Synthase) using 11C 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".

Duke Scholars

Published In

Journal of drug targeting

DOI

EISSN

1029-2330

ISSN

1061-186X

Publication Date

November 2016

Volume

24

Issue

9

Start / End Page

836 / 856

Related Subject Headings

  • Pharmacology & Pharmacy
  • Neoplasms
  • Nanoparticles
  • Lipids
  • Hydrophobic and Hydrophilic Interactions
  • Humans
  • Drug Delivery Systems
  • Chemistry, Pharmaceutical
  • Antineoplastic Agents
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Needham, D., Arslanagic, A., Glud, K., Hervella, P., Karimi, L., Høeilund-Carlsen, P.-F., … Walke, P. (2016). Bottom up design of nanoparticles for anti-cancer diapeutics: "put the drug in the cancer's food". Journal of Drug Targeting, 24(9), 836–856. https://doi.org/10.1080/1061186x.2016.1238092
Needham, David, Amina Arslanagic, Kasper Glud, Pablo Hervella, Leena Karimi, Poul-Flemming Høeilund-Carlsen, Koji Kinoshita, et al. “Bottom up design of nanoparticles for anti-cancer diapeutics: "put the drug in the cancer's food".Journal of Drug Targeting 24, no. 9 (November 2016): 836–56. https://doi.org/10.1080/1061186x.2016.1238092.
Needham D, Arslanagic A, Glud K, Hervella P, Karimi L, Høeilund-Carlsen P-F, et al. Bottom up design of nanoparticles for anti-cancer diapeutics: "put the drug in the cancer's food". Journal of drug targeting. 2016 Nov;24(9):836–56.
Needham, David, et al. “Bottom up design of nanoparticles for anti-cancer diapeutics: "put the drug in the cancer's food".Journal of Drug Targeting, vol. 24, no. 9, Nov. 2016, pp. 836–56. Epmc, doi:10.1080/1061186x.2016.1238092.
Needham D, Arslanagic A, Glud K, Hervella P, Karimi L, Høeilund-Carlsen P-F, Kinoshita K, Mollenhauer J, Parra E, Utoft A, Walke P. Bottom up design of nanoparticles for anti-cancer diapeutics: "put the drug in the cancer's food". Journal of drug targeting. 2016 Nov;24(9):836–856.

Published In

Journal of drug targeting

DOI

EISSN

1029-2330

ISSN

1061-186X

Publication Date

November 2016

Volume

24

Issue

9

Start / End Page

836 / 856

Related Subject Headings

  • Pharmacology & Pharmacy
  • Neoplasms
  • Nanoparticles
  • Lipids
  • Hydrophobic and Hydrophilic Interactions
  • Humans
  • Drug Delivery Systems
  • Chemistry, Pharmaceutical
  • Antineoplastic Agents
  • Animals