Effective treatment of brain diseases is critically hindered by the blood-brain barrier (BBB), a highly selective endothelial interface that restricts nearly all macromolecular therapeutics from entering the brain. This project aims to design non-viral nanomedicines capable of safely and effectively crossing the BBB and delivering therapeutic agents directly to brain tissues.

Our group has already demonstrated that lactoferrin-bearing polypropylenimine dendrimers significantly enhance gene delivery to the brain after intravenous administration, with up to a 6.4-fold increase in brain gene expression and minimal off-target distribution. Lactoferrin and transferrin, whose receptors are overexpressed on brain capillary endothelial cells, offer promising strategies to mediate BBB crossing via receptor-mediated transcytosis.

This project will build upon these successful platforms to design and evaluate advanced nanocarriers, including dendrimers, zein-based nanoparticles, and hybrid lipid-polymer structures, for the intravenous delivery of therapeutic agents to the brain, tailored to your interests.

Core objectives

• synthesis, and characterisation of BBB-crossing nanomedicines (e.g. dendrimers, lipid-polymer hybrids, hydrogels, zein-based hybrids)
• functionalisation with BBB-specific ligands 
• encapsulation and delivery of therapeutic payloads, including small-molecule drugs, genetic materials (i.e.  plasmid DNA, siRNA, CRISPR-Cas9 systems)
• in vitro assessment using BBB models for uptake, transport, and expression
• in vivo studies to assess brain delivery, biodistribution, and therapeutic efficacy

Research significance

There is an urgent need for safe, non-invasive delivery systems that can carry drugs and genes across the BBB to treat brain pathologies. Current treatment options are severely limited by poor brain penetration, systemic toxicity, or lack of specificity. This project addresses a critical bottleneck in treating CNS diseases: safe and effective therapeutic access to the brain.

Techniques you will learn

• synthesis and physicochemical characterisation of nanomedicines (size, zeta potential, drug/gene loading, release profile)
• surface ligand conjugation and PEGylation
• in vitro cell culture, cytotoxicity assays, transfection studies, confocal microscopy, flow cytometry
• in vivo imaging and biodistribution, gene expression

Further information

References

• S. Koppu, Y.J. Oh, R. Edrada-Ebel, D.R. Blatchford, L. Tetley, R. J. Tate, C. Dufès, Tumor regression after systemic administration of a novel tumor-targeted gene delivery system carrying a therapeutic plasmid DNA, Journal of Controlled Release, 143 (2010) 215-221
• S. Somani, D.R. Blatchford, O. Millington, M.L. Stevenson, C. Dufès, Transferrin-bearing polypropylenimine dendrimer for targeted gene delivery to the brain, Journal of Controlled Release, 188 (2014) 78-86
• L. Y. Lim, P.Y. Koh, S. Somani, M. Al Robaian, R. Karim, Y.L. Yean, J. Mitchell, R.J. Tate, R. Edrada-Ebel, D.R. Blatchford, M. Mullin, C. Dufès, Tumor regression following intravenous administration of lactoferrin- and lactoferricin-bearing dendriplexes, Nanomedicine: Nanotechnology, Biology and Medicine, 11 (2015) 1445-1454
• S. Somani, G. Robb, B. S. Pickard, C. Dufès, Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex, Journal of Controlled Release, 217 (2015) 235-242
• S. Somani, P. Laskar, N. Altwaijry, P. Kewcharoenvong, C. Irving, G. Robb, B.S. Pickard, C. Dufès, PEGylation of polypropylenimine dendrimers: effects on cytotoxicity, DNA condensation, gene delivery and expression in cancer cells, Scientific Reports, 8(1) (2018) 9410
• N. Altwaijry, S. Somani, J.A. Parkinson, R.J. Tate, P. Keating, M. Warzecha, G.R. Mackenzie, H.Y. Leung, C. Dufès, Regression of prostate tumors after intravenous administration of lactoferrin-bearing polypropylenimine dendriplexes encoding TNF-α, TRAIL and interleukin-12, Drug Delivery, 25(1) (2018) 679-689 
•  P. Laskar, S. Somani, N. Altwaijry, M. Mullin, D. Bowering, M. Warzecha, H.Y. Leung, C. Dufès, Redox-sensitive, cholesterol-bearing PEGylated poly(propyleneimine)-based dendrimersomes for drug and gene delivery to cancer cells, Nanoscale, 10 (2018) 22830-22847
• P. Laskar, S. Somani, S.J. Campbell, M. Mullin, P. Keating, R.J. Tate, C. Irving, H.Y. Leung, C. Dufès, Camptothecin-based dendrimersomes for gene delivery and redox-responsive drug delivery to cancer cells, Nanoscale, 11(42) (2019) 20058-20071
• Sakpakdeejaroen, S. Somani, P. Laskar, C. Irving, M. Mullin, C. Dufès, Anti-tumor activity of intravenously administered plumbagin entrapped in targeted nanoparticles (Journal of Biomedical Nanotechnology, 16(1) (2020) 85-100
• P. Laskar, S. Somani, M. Mullin, R. J. Tate, M. Warzecha, D. Bowering, P. Keating, C. Irving, H. Y. Leung, C. Dufès, Octadecyl chain-bearing PEGylated poly(propyleneimine)-based dendrimersomes: physicochemical studies, redox-responsiveness, DNA condensation, cytotoxicity and gene delivery to cancer cells, Biomaterials Science, 9(4) (2021) 1431-1448
• Sakpakdeejaroen, S. Somani, P. Laskar, M. Mullin, C. Dufès, Regression of melanoma following intravenous injection of plumbagin entrapped in transferrin-conjugated, lipid–polymer hybrid nanoparticles, International Journal of Nanomedicine, 16 (2021) 2615-2631
• J. Almowalad, S. Somani, P. Laskar, J. Meewan, R.J. Tate, M. Mullin, C. Dufès, Lactoferrin-bearing gold nanocages for gene delivery in prostate cancer cells in vitro, International Journal of Nanomedicine, 16 (2021) 4391-4407
• J. Meewan, S. Somani, P. Laskar, C. Irving, M. Mullin, C.W. Roberts, S. Woods, V.A. Ferro, A.R. Alzahrani, R. Burchmore, S. Weidt, S. McGill, C. Dufès, Limited impact of the protein corona on the cellular uptake of PEGylated zein micelles by melanoma cancer cells, Pharmaceutics, 14 (2) (2022) 429
• J. Almowalad, P. Laskar, S. Somani, J. Meewan, R.J. Tate, C. Dufès, Lactoferrin- and dendrimer-bearing gold nanocages for stimulus-free DNA delivery to prostate cancer cells, International Journal of Nanomedicine, 17 (2022) 1409-1421
• J. Meewan, S. Somani, J. Almowalad, P. Laskar, M. Mullin, G. MacKenzie, S. Khadke, Y. Perrie, C. Dufès, Preparation of zein-based nanoparticles: nanoprecipitation versus microfluidic-assisted manufacture, effects of PEGylation on nanoparticle characteristics and cellular uptake by melanoma cells, International Journal of Nanomedicine, 17 (2022) 2809-2822
• K. Maeyouf, I. Sakpakdeejaroen, S. Somani, J. Meewan, H. Ali-Jerman, P. Laskar, M. Mullin, G. MacKenzie, R. J. Tate, C. Dufès, Transferrin-bearing, zein-based hybrid lipid nanoparticles for drug and gene delivery to prostate cancer cells, Pharmaceutics, 15 (11) (2023) 2643
• H. Ali-Jerman, Z. Al-Quraishi, A. Muglikar, Y. Perrie, R. J. Tate, M. Mullin, G. McNeill, G. Mackenzie, C. Dufès, Enhancing transfection in glioma cells: comparison of microfluidic versus manual polypropylenimine dendriplex formation, International Journal of Nanomedicine, 19 (2024) 12189-12203