Development of nano-encapsulated zinc and copper-diethyldithiocarbamate as novel immunomodulatory and cancer stem cell targeting medicine for multiple myeloma treatment

Supervisory Team: Professor Weiguang Wang, Professor Basu Supratik, Dr Vinodh Kannappan

Background: Multiple myeloma (MM) is the second most common blood cancer. Current best therapeutic options involve combining a proteasome inhibitor with one of the immunomodulatory imide drugs (IMiDs, lenalidamide or pomalidomide). All MM patients are ultimately relapsed. MM contains cancer stem cells (CSCs) commonly located in poorly vascularised regions. CSCs are typically associated with resistance to chemotherapy. Therefore, development of new drugs with immunomodulatory and CSC-targeting effect is of clinical urgency. Disulfiram (DS), an anti-alcoholism drug, demonstrates excellent activity against a wide range of cancers without toxicity to normal cells. DS chelates copper and zinc to form copper-diethyldithiocarbamate (Cu-DDC) and zinc-diethyldithiocarbamate (Zn-DDC) which are the active anticancer compounds. The anticancer activity of DS, Cu-DDC and Zn-DDC has been known for more than three decades. Its application in cancer clinic is limited by the very short half-life of these compounds in the bloodstream (< 4 min) and insolubility. Our team developed nanoparticles encapsulated DS, Cu-DDC and Zn-DDC which are injectable with long half-life (7 hours) showing strong anticancer efficacy in numerous cancer animal models. In our pilot studies, PEGylated liposome encapsulated Zn-DDC had stronger immunomodulatory and anti-MM effect than currently available IMiDs. It also reverses CSC-induced resistance and synergistically enhances the anti-MM activity of IMiDs.

Methodologies: 1. Using high-pressure homogenizer to generate PEG-Lipo/Zn-DDC and Cu-DDC. 2. Using MTT cytotoxicity to test the anti-MM activity. 3. Investigating the effect of PEG-Lipo/Zn-DDC and Cu-DDC on IKZF1/3-IRF4-cMYC-IL2 immunomodulatory pathway. 4. Examining the effect on CSCs.

Outcomes: 1. Development of PEG-Lipo/Zn-DDC and Cu-DDC; 2. Examination of the anti-MM effect of PEG-Lipo/Zn-DDC and Cu-DDC; 3. Elucidation of anti-MM mechanisms.

For further information regarding the project or an informal discussion please contact Director of Studies, Prof Weiguang Wang  [Email Address Removed]

Applications

To apply for the PhD Research Studentship applicants must hold a first class/distinction at Master and/or Bachelor level of study.

Applications to include one identified project, a full CV (including 2 referee names and contact details), transcripts and a letter of application outlining the motivation for applying (maximum of 2 pages). Applicants from outside UK must provide evidence of English Language requirement as stated in https://www.wlv.ac.uk/research/research-degrees/

Application submission deadline is 10:00am BST 19 June 2023 to [Email Address Removed]

A shortlist of candidates will be prepared from the pool of applicants, in line with Faculty of Science and Engineering Post Graduate Research (PGR) studentship selection criteria, who will be invited to attend an interview with a panel of academic staff, week commencing 26 June 2023.

Following this process all successful candidates will be notified to enrol in July 2023 on a PhD degree programme. The studentship award will include tuition fees at home level for the first three years of full-time study including any write-up period fees and research support fees.

For further information on fees https://www.wlv.ac.uk/apply/funding-costs-fees-and-support/fees-and-costs/research-fees/

Informal enquiries are welcome and should be directed to individual Director of Studies mentioned above.