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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, 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”.
Acknowledgements
We would like to acknowledge very helpful discussions with and clinical motivation for these studies from several clinicians, clinical scientists and researchers, including:
Duke University Medical Center: Neil Spector MD, Medical Oncology; Kim Lyerly, MD, Surgery; Donald McDonnell PhD, Pharmacology and Cancer Biology; Dan George MD, Medical Oncology; Andy Armstrong MD, Medical Oncology; Mike Harrison MD, Medical Oncology, Mark Dewhirst, PhD DVM, Radiation Oncology.
Odense University Hospital: Peter Bjørn Licht MD PhD, Cardiac, Pulmonary and Vascular Surgery; Karen Ege Olsen Consultant, dr.med, Pathology.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Funding
David Needham would also like to acknowledge funding from the Danish National Research Foundation, Denmark, in the form of a Niels Bohr Professorship 2013–2018, 10.13039/501100001732, DNRF grant project no. 232149 and co financing from SDU.
Notes
2 The LDL actually could be more of a discoid shape.
3 Niclosamide has varying reported solubilities. It could be up to 25–40 µm for presumably amorphous material [Citation64]. The Pesticide Manual-A World Compendium. 8th edition, Thornton Heath, UK, The British Crop Protection Council., or as a hydrated crystal at 2–4 µM, [Citation65]. The Pesticide Manual – World Compendium. 10th ed, Surrey, UK, The British Crop Protection Council.
4 Liposomes are thin sheets of the bilayers, where the van der Waals attraction (0.01 ergs/cm2, or 1 × 10−5 J/m2) measured between GUVs is now only interacting over square nanometers for such small single-bilayer liposomes, and so is estimated to be on the order of kT. Liposomes would not aggregate due to van der Waals attraction alone! – and they appear not to do; but nanoparticles would, and do.
5 For our DLS (Delsamax Pro, Beckman Coulter) we have two modes: cumulant fit and regularization fit, and the diameter we are reporting is determined from the cumulant fit of the autocorrelation function, which is based on the intensity distribution.
6 hydrophobic drugs could still work orally if entry from the gut into lymphatics is optimized, by using say a “fat-chaser”, which is probably how Lapatinib etc, get into the blood stream in the first place!
7 Echinoderm Microtubule-associated protein-Like 4 (EML4) and Anaplastic Lymphoma Kinase (ALK).
8 Epidermal Growth Factor Receptor.
9 T describes the size of the original (primary) tumor and whether it has invaded nearby tissue; N describes nearby (regional) lymph nodes that are involved; M describes distant metastasis (spread of cancer from one part of the body to another).
10 It was my colleague and close collaborator, Poul Flemming Høilund-Carlsen, Professor, and Head of Research Unit, Clinical Physiology and Nuclear Medicine, Odense University Hospital (OUH), that coined the phrase, “Diapeutics”, because as he and we all know, diagnosis comes before therapy, …. and that’s the point.