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Optimising the gold nanorod platform for effective cancer theranostics

PGR-P-713

Key facts

Type of research degree
PhD
Application deadline
Friday 17 April 2020
Project start date
Thursday 1 October 2020
Country eligibility
UK and EU
Funding
Competition funded
Source of funding
Research council
Supervisors
Dr James Mclaughlan and Professor Dejian Zhou
Additional supervisors
Dr Nicole Hondow
Schools
School of Chemistry, School of Electronic and Electrical Engineering
Research groups/institutes
Chemical Biology and Medicinal Chemistry
<h2 class="heading hide-accessible">Summary</h2>

Cancer is a leading cause of death worldwide, accounting for 9.6 million deaths in 2018 and &gt;US$1.16 trillion annual economic cost[1]. The current treatments all suffer from limitations such as strong invasiveness (surgery), lacking of targeting specificity and/or severe side-effects (radio-/chemo-therapy), making them ineffective in treating metastatic and multidrug resistance cancers.

<h2 class="heading hide-accessible">Full description</h2>

<p>On the other hand, nanoscale medicine can exploit tumour&rsquo;s own pathological conditions, <em>e.g.</em> the enhanced permeation and retention (EPR) effect, to increase tumour accumulation and therapeutic efficiency.<span class="superscript_text">2</span> Moreover, the unique size-/shape- dependent physical-/chemical properties of nanomaterials can be further integrated to offer imaging, diagnostic, and therapeutic functions, making them highly attractive for cancer theranostics.<span class="superscript_text">3</span> However, despite offering great promise, most nanomedicines remain non-optimal in terms of tumour targeting specificity, penetration depth, and therapeutic efficacy.</p> <p>In this project, we aim to drastically improve the theranostic potential of gold nanorod (GNR) based nanomedicine for treatment of lung cancer, which is responsible for the 2<span class="superscript_text">nd</span> most cancer deaths<span class="superscript_text">1</span>. GNR is highly attractive here owing to its excellent biocompatibility, robust gold-thiol surface chemistry, and strong photo-thermal and photoacoustic effects that allow for non-invasive imaging and therapy.<span class="superscript_text">4</span> However, its use is still limited by difficulties in achieving highly specific targeting, deep tumour penetration without trapping by the mononuclear phagocyte system (MPS) and long term toxicity. Here we plan to address this problem by optimising size, surface coating, targeting ligand and valency to effectively exploit multivalency effect. This project contains five objectives:&nbsp;</p> <ol> <li>To synthesise lipoic acid-poly(ethylene glycol)-based multifunctional ligands (<em>e.g.</em> LA-PEG-X, PEG molecular weight = 600, 1000, 2000, 5000; X = -OH, -OMe, -N<span class="subscript_text">3</span>, -Cyclooctyne) for stable GNR coating (<em>via</em> LA&rsquo;s dithiol group), high water solubility, stability and resisting non-specific cell uptake (<em>via</em> PEG modification) and efficient conjugation of targeting ligands (<em>via</em> -N<span class="subscript_text">3</span> and -cyclooctyne based copper-free click chemistry). The ligands will be fully characterised by MS, <span class="superscript_text">1</span>H and <span class="superscript_text">13</span>C NMRs and IR.</li> <li>To synthesise and characterise GNRs of varied size, aspect ratio, and LSPR absorption band using seed-medicated method in the presence of CTAB surfactant, AgNO<span class="subscript_text">3</span> and aromatic additives. By tuning growth solution pH and reducing agent, the GNR LSPR absorption band will be tuned to that required for photo-thermal/acoustic imaging (<em>e.g.</em> ~808 or 1064 nm). The GNR size, shape, and aspect ratio will be determined by TEM and DLS.</li> <li>To functionalise the GNRs with the LA-PEG-X ligands <em>via</em> a facile gold-thiol self-assembly process. They will be controllably conjugated with a varied number of ligands that specifically recognise over-expressed receptors on lung cancer cells (<em>via</em> anti-EGFR/VEGF aptamers, RGD peptides) and tumour associated macrophages (<em>via</em> mannose). Their hydrodynamic sizes (D<span class="subscript_text">h</span>s) and stability in PBS, cell culture media and serum will be optimised to ensure no aggregation and nonspecific adsorption with the aim of achieving small D<span class="subscript_text">h</span> sizes to benefit tumour penetration.</li> <li>To evaluate the GNR&rsquo;s theranostic specificity and potency at cellular level. Model lung cancer cells and control epithelial cells will be treated with the GNRs at different dose for 24 and 48 hrs. After washing, the amount of GNR cell uptake will be quantified by ICP-MS, and the GNR cellular location will be imaged by TEM and confocal microscopy (<em>via</em> tagged fluorophore) and the results will be correlated with MTT cytotoxicity assays. The selectivity of the GNR in lung cancer cell theranostic will be demonstrated using NIR 808 nm laser radiation. Combining these data will establish the optimal GNR format for high specific lung cancer cells targeting and theranostics.</li> <li>To evaluate the GNR&rsquo;s theranostic efficiency <em>in vivo</em>. The targeting GNRs and the control GNRs will be intravenously injected to lung cancer mouse models. Their blood circulation, bio-distribution and organ accumulation will be monitored by photoacoustic imaging and ICP-MS, allowing us to establish the correlation between the cellular and <em>in vivo</em> cancer targeting efficiency. Photo-thermal in combination with chemotherapy,<span class="superscript_text">[4b]</span> will be further applied to the mouse models, and the survival and potential toxicity will be monitored to reveal the correlation between tumour targeting and theranostic efficacy.</li> </ol> <p>In summary, this project may develop a highly specific, targeted gold nanorod platform for effective cancer theranostic, allowing us to overcome some major limitations facing cancer treatment. It will provide extensive multidisciplinary training for the student at the international forefront of cancer nanomedicine research development.&nbsp;&nbsp;&nbsp;</p> <h5>References</h5> <p>[1] World health organisation website: <a href="https://www.who.int/news-room/fact-sheets/detail/cancer">https://www.who.int/news-room/fact-sheets/detail/cancer</a></p> <p>[2] D. Peer<em> et al. Nature Nanotech. </em><strong>2007</strong>, <em>2</em>, 751.</p> <p>[3] R. van der Meel <em>et al.</em> <em>Nature</em> <em>Nanotech. </em><strong>2019,</strong><em> 14, </em>1007.</p> <p>[4]<span class="superscript_text"> a)</span> Y.S. Chen et al. <em>Nature</em> <em>Nanotech. </em><strong>2019,</strong><em> 14, </em>465; <span class="superscript_text">b)</span> Wang et al. <em>J. Control. Release</em> <strong>2016</strong>, <em>232</em>, 9.</p>

<h2 class="heading">How to apply</h2>

<p>Formal applications for research degree study should be made online through the&nbsp;<a href="https://eps.leeds.ac.uk/chemistry-research-degrees/doc/apply">University&#39;s website</a>. Please state clearly in the research information section&nbsp;that the research degree you wish to be considered for is &ldquo;Optimising the gold nanorod platform for effective cancer theranostics&rdquo;&nbsp;as well as&nbsp;<a href="https://eps.leeds.ac.uk/chemistry/staff/4199/professor-dejian-zhou">Prof Dejian Zhou</a>&nbsp;as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p><em>We welcome applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates. All scholarships will be awarded on the basis of merit.</em></p>

<h2 class="heading heading--sm">Entry requirements</h2>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

<h2 class="heading heading--sm">English language requirements</h2>

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid.

<h2 class="heading">Funding on offer</h2>

<main id="main"> <p><strong>UK/EU</strong>&nbsp;&ndash;&nbsp;Engineering &amp; Physical Sciences Research Council Studentship&nbsp;for 3.5 years. A full standard studentship consists of academic fees (&pound;4,600 in Session 2020/21), together with a maintenance grant paid at standard Research Council rates (&pound;15,285 in Session 2020/21). UK applicants will be eligible for a full award paying tuition fees and maintenance. European Union applicants will be eligible for an award paying tuition fees only, except in exceptional circumstances, or where residency has been established for more than 3 years prior to the start of the course.&nbsp;Funding is awarded on a competitive basis.</p> </main>

<h2 class="heading">Contact details</h2>

<p>For further information regarding the application procedure, please contact Doctoral College Admissions<br /> e:&nbsp;<a href="mailto:maps.pgr.admissions@leeds.ac.uk">maps.pgr.admissions@leeds.ac.uk</a>, t: +44 (0)113 343 5057.</p>


<h3 class="heading heading--sm">Linked funding opportunities</h3>