Cancers feed on lipid and protein to support their anabolic requirements of growth, aggressiveness, and spread. To do this they feed on Lipoprotein particles from the blood stream and bring in these "food particles" into their cells by increasing the number of receptors on the cells and, we think, blood vessels. 

Earlier this year we published a new paper (1) that got written up in the press including Neuroscience News.  It showed widespread Low Density Lipoprotein Receptor (LDLR) expression in microscopic slides of adult and pediatric brain tumor samples.  The images to the left show how, while normal liver expresses receptors for these lipoprotein particles, both paediatric  Astrocytoma and GMB tumors are loaded with increased density of the receptors around all the blood vessels (brown coloration associated with detection-antibodies that bind to them).  

Thus, in a new realization, this feeding mechanism could enable a new diagnostic tool, where the appearance of the "food-receptors" is identified as soon as the tumors start expressing them, thereby catching them earlier in their development, and could be especially important for metastatic tumors if they can be shown to also over-express these receptors.

Here we are looking to team up with molecular diagnostic labs, with probably antibody-radio-imaging capabilities to generate LDLR-radio-labelled PET or SPECT imageable antibodies that can detect the up-regulation of LDLRs, that bring in the cancer's food, and so detect the cancers as they start their initial growth.

(1)  Adekeye, A.O., D. Needham, and R. Rahman, Low-Density Lipoprotein Pathway Is a Ubiquitous Metabolic Vulnerability in High Grade Glioma Amenable for Nanotherapeutic Delivery. Pharmaceutics, 2023. 15(2): p. 599.

This same up-regulation of Low Density and Very Low Density Lipoproteins (LDLs and VLDLs) are made in the liver and circulate in the blood stream around the body to support normal nutritional tissue requirements.  As above, it seems that many if not all cancers need these particles to support their metabolic reprogramming. Given this propensity to feed on natural LDL and VLDL nanoparticles from the blood stream, David, in his Niels Bohr Professorship in Denmark (2013-2020) and then with colleagues at Duke University have been exploring if and to what extent we could deliver anti-cancer drugs to tumors by "making the drug look like the cancer's food",

This approach has already  has shown promise using specially designed prodrug therapeutic particles in a mouse model of lung metastatic osteosarcoma (1) and has actually cured three dogs in a small feasibility canine trial (2) that would otherwise have succumbed to lung metastatic disease. This, "Trojan Horse approach" was featured in a @scienceft.engineering4000 2021 media video.  (Prof. David Needham fights cancer with his Trojan Horse).

While these particles may well accumulate in "regular" tumors by simply leaking out of the blood stream, in the brain tumor setting, it seems the blood brain barrier is so tight that there are no gaps big enough for such transport.  However, here, the brain tumor's vasculature facilitates the uptake of these all-important Lipoproteins by shuttling them across the blood vessel lining into the tumor itself.  And so we envision a project where we modify the already established prodrug therapeutic particles to utilize this brain-specific crossing-mechanism, and so deliver therapeutics that would not normally cross the BBB but do so now via this trojan horse approach.

Here we would like to collaborate with pharmaceutics labs that can fabricate the nanoparticles to our existing formulation and preclinical labs for initial cell and animal testing.

(1) Reddy, G., B., et al., Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) shows efficacy against Osteosarcoma. Molecular Cancer Therapeutics, 2020. 19(7): p. 1448.

(2) Manuscripts in preparation

(3) Zhang, Z. and C. Zhan, 5 - Receptor-mediated transportation through BBB, in Brain Targeted Drug Delivery System, H. Gao and X. Gao, Editors. 2019, Academic Press. p. 105-128.

(4) Calabrese, C., et al., A Perivascular Niche for Brain Tumor Stem Cells. Cancer Cell, 2007. 11(1): p. 69-82.

This, "Make the drug look like the cancer's food" or what might be called a "Trojan Horse" approach was featured in a @scienceft.engineering4000 2021 media video.  (Prof. David Needham fights cancer with his Trojan Horse)made by some media students while he was in Denmark on his Niels Bohr Professorship. The video is a n interesting juxtaposition of David's music (playing one of his other inventions --the "Snardhran" (A metal snare attached to the back of an Irish drum called a Bodhran) and his description of this new anti-cancer drug delivery approach.

Primary GBM is usually, already, 5 - 6cm diameter upon initial diagnosis and so is rapidly scheduled for surgical resection (craniotomy).  Unfortunately, relapse is common due to even just a few remaining infiltrating tumor cells that were not able to be surgically removed.   Furthermore, as found by researchers at UNC Chapel Hill (1),  "removing a brain tumor causes any cancer left behind to grow 75 percent faster than the original tumor". 

Thus, in this project we thought we would expand on the LTSL-Dox application and bring it to an earlier intervention, -- to post resection treatment while still open. As shown in the schematic, with the cavity and parenchyma surface fresh and still accessible, infra-red heating could, in principle, warm at least 1mm (and possibly more depending on the wattage and wavelength),  into the remaining parenchyma.  This could then release doxorubicin from i.v.-LTSL-Dox in the blood vessels feeding those difficult- or impossible-to-remove cells, that are likely to generate a relapse.  

Here, we are looking to team up with hyperthermia engineers and clinicians to adapt and evaluate already-available torch-like  heating systems, and preclinical translational researchers who could test initial prototypes in animal studies.

(1) Okolie, O., et al., Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model. Neuro-Oncology, 2016. 18(12): p. 1622-1633.

Following the work of Rahman et al, (1) this idea focuses on trying to  combat the disease at a stage of low residual tumor burden immediately post-surgery.  We propose a localized drug delivery system comprising a niclosamide formulation in a gel like matrix that is designed to be administered directly into brain parenchyma adjacent to the surgical cavity.   The idea is that the drug could diffuse into the un-resected parenchyma and reach and treat residual cells remaining, that are a source for relapse.  

This project requires detailed analyses and in vivo measurement of drug transport as a function of the particular parenchyma and tumor tissue architecture, and drug properties including, solubility, hydrophobicity, and membrane partitioning.  And so here we are looking to collaborate with transport engineers and pharmaceutical scientists, as well as preclinical labs to test this niclosamide formulation and also a range of drugs and scaffolds.

(1) McCrorie, P., et al., Etoposide and olaparib polymer-coated nanoparticles within a bioadhesive sprayable hydrogel for post-surgical localised delivery to brain tumours. Eur J Pharm Biopharm, 2020. 157: p. 108-120.