Optical diagnostic tool for disease detection
A novel technology that will allow transplant surgeons to obtain accurate measurements of liver fat content during donor surgeries has been developed. These results will be immediate and will guide the transplant surgeon in deciding whether the liver is safe to use for transplantation. This will lead to fewer discarded livers, reduce waitlists for liver transplantation and improve the quality of life for many individuals with end-stage liver disease.
A fiber optic Raman system developed by collaborator Dr. Haishan Zeng of the BC Cancer Agency (BCCA) has been applied towards a new use – an improved assessment of the fat content of livers. By applying multivariate statistical approaches with this probe, we have shown the technology improves both the speed and accuracy of the assessment of the hepatic fat content (Hewitt et al. Accurate assessment of liver steatosis in animal models using a high throughput Raman fiber optic probe. Analyst 140, 6602 – 6609 (2015)). A provisional patent was filed on this technology in June 2015, and a PCT application on June 16, 2016.
During PoC studies funded by Springboard we found the Raman
technology developed by BCCA could be re-envisioned into a robust, more cost
effective, and simple to use product.
The new design still uses the BCCA fibre optic bundle but now a simpler
light collection system and more appropriate laser that prevents the salient
features in the scattered light from being obscured has been incorporated into
our alpha version (as funded by Innovacorp ESCF). The new instrument is still retains IP
protection because of the broad patent scope that was initially filed. These
technology enhancements and simplification reduces the cost by a factor of 5
and the resulting retail price from $65,000 to
$18,000.
We are refining the alpha version of our probe using Springboard funding, to build and test the beta prototype of this new technology to consistently meet customer and regulatory (ISO and IEC standards) requirements. Commercialization could take several different forms including a licensing agreement to large pharma, a license to a smaller, already existing BC start-up or our own spin-off company. Providing clinicians access to a tool to rapidly (1 sec), and robustly assess, at the site of retrieval, the suitability of donor livers for transplantation would be widely and positively received in the transplantation community.
bionanophotonics for cancer
Nanomedicines are proving to be versatile delivery systems that facilitate the selective distribution of a wide variety of compounds in vivo, with many applications, from imaging to therapeutics.
Nanomedicines increase the localization of therapeutic compounds, including imaging agents and photosensitizers, targeting tissues such as solid tumors. The successful use of nanomedicines in vivo, requires a clear understanding of how the properties of the carriers (composition, size, physical structure, drug release rates, etc.), and the associated compounds (solubility, size, shape, mechanism of action, etc.), affect their pharmacokinetics, biodistribution and the optimal rates for in vivo bioavailability.
Weissleder (2006) identified four hallmarks of effective imaging agents. They (i) display exquisite affinity for their molecular/biological targets, (ii) efficiently gain access to these targets, (iii) show minimal nonspecific uptake or retention (a major factor contributing to low target-to-background ratios) and (iv) have sufficiently long half-lives to be detectible/functional at trace concentrations.
We have developed a nanocarrier that targets the Epidermal Growth Factor receptor (EGFR/HER1), a membrane receptor tyrosine kinase that mediates cell growth, proliferation and differentiation.
Overexpression of EGFR family members is a hallmark of many cancers and pre-cancers, including those of the skin, lung , brain, breast, neck and bladder. HER1 overexpression is associated with poor prognosis, manifested by a short overall survival and disease-free interval, high metastatic potential and negative oestrogen receptor (ER) status.
HER2/ErbB2 is one of the best studies oncogenes involved in breast cancer and is overexpressed in 25% of invasive breast cancers; more specifically in high grade ductal carcinoma in situ and c-myc at 15- 25%. Since ErbB2 does not have a natural ligand, it must dimerize with other ErbB-family members. As such, ErbB2 when dimerized with other ErbB-family members elicits strong catalytic activity.
When ErbB2 forms a dimer with ErbB1 or ErbB3 in response to ligand binding, the dimer activates the mitogen-activated protein kinase (MAPK) cascade and the phosphoinositide 3- kinase (PI3K), respectively, leading to signal transduction events. Dimerization of HER1 and HER2 has an adverse
synergistic effect on both prognosis and metastasis and is present in 37% of breast cancers.
Therapies that target these receptors have been successful for the treatment of HER2 breast cancer, specifically the mono-clonal antibody Herceptin is currently the standard of care. However, the treatment is also associated with toxic side effects including cardiac arrest.
Antibodies for EGFR tagged with fluorescent probes and gold nanoparticles have been used as optical contrast agents to image EGFR overexpression [32-33], but with at most a 10:1 intensity contrast. An earlier version of the nanocarrier we developed provide an order of magnitude improvement in optical contrast with existing techniques and detection at tens of picomolar concentrations. The nanocarriers are based on gold or silver nanoparticles bound to EGF, and Anti-EGFR antibodies.
Gold and silver nanoparticles have also been described for use as cancer imaging agents and in selective photothermal therapy. Photothermal effects are due to the conversion of light to thermal energy in the particle. The enhanced electric field created by exciting a plasmon resonance in the gold nanoparticle can also produce an intense electric field large enough to break bonds.
We have demonstrated that the EGF version of our probes (i) display exquisite sensitivity for HER1, and are not sequestered in organs of immune competent mice – an indication of the lack of non-specific uptake. It remains to be shown that these nanoprobes accumulate in HER2+ breast cancer cells. In pursuit of this objective, this study will assess the biodistribution (using Computed Tomography, Inductively Coupled Plasma mass spectroscopy) of our nanoprobes in mice, bred by our collaborator Dr. Paola Marignani, to spontaneously produce HER2+ breast cancer.
If we can confirm that the nanoprobes accumulate in the target tissue at detectable levels, and in no other organ/tissue, it would provide proof of principle, introducing a novel nanomedicine for diagnosis and treatment of cancers which co-overexpress HER1 and HER2. Because of the poor clinical prognosis of these types of breast cancers the nanoprobe would offer improved diagnostic approaches and therapeutic outcomes for those at greatest risk.