Elucidating the intra-cellular trafficking mechanisms to inform design of next generation nanomedicines

My major research activities have been focused on developing innovative strategies based on nanoscience to deliver therapeutics (small molecules, macromolecules) across physiological barriers to disease target, such as cancer cells. Among various nanostructures, liposomes have demonstrated the most successful clinical translation. These tiny lipid bubbles can accommodate both small and large molecules (single or multi drugs), protect the payload from metabolism, and preferentially ferry the payload to cancerous cells. Another liposome-like nanostructure that we are interested in are derived from cells, known as extracellular vesicles (exosomes, 30-100 nm). However, mounting evidence shows that ‘endosomal entrapment’ is a huge bottleneck in the effective intracellular drug delivery using conventional nanoparticles. Our approach is to engineer ‘smart’ nanomedicines (based liposomes or exosomes) with functions to target hallmarks of cancers (specific receptors, redox, low pH) to enhance cellular uptake by target cells followed by rapid cytoplasmic drug release (endosome escape). Continued from the research projects previously funded via Marsden Fund, NZ-China Research Alliance Programme, and Cancer Society of New Zealand, etc, this project aims to seek a better understanding of the mechanisms for intracellular trafficking of liposomes/exosomes and to identify influencing factors to promote cellular bioavailability of the payload (therapeutics).

The propose will shed light on intracellular delivery of DNA toxins, proteins, siRNA, and genes using nanoscience, addressing some key questions towards the development of next-generation nanomedicines.

Zimei-Wu
Zimei-Wu

Principal Investigator:  Assoc. Professor Zimei Wu

Contact email:  z.wu@auckland.ac.nz 

Collaborators: please include name and affiliation in brackets. Separate each collaborator with ;

We have established a wide collaboration with researchers across the University:

  • Distinguished Professor Bruce Baguley (retired); Professor William (Bill) Wilson; Assoc Professor Brian Palmer; Dr Euphemia Leung; Dr Stephen Jamieson (Auckland Cancer Society Research Centre);
  • Professor Larry Chamley; Professor Andrew Shelling; Professor Stefan Bohlander; Professor Alan Davidson; Assoc Professor Chris Hall; Assoc Professor Justin Dean et al (Faculty of Medical and Health Sciences);
  • Dr Viji Sarojini; Assoc Professor Geoffrey Waterhouse et al (Faculty of Sciences)

Internationally, we have long-term collaboration with

  • Professor Guangji Wang and Professor Jianping Liu (China Pharmaceutical University);
  • Professor Hongbo Wang and Professor Kaoxiang Sun (Yantai University) with extensive publications.

Status: Ongoing

Funding:  Faculty Research Development Fund (UoA); Auckland Medical Research Foundation

Publications: please provide reference list of papers, published conference proceedings

  1. Gao Y, Tang M, Leung E, Svirskis D, A Shelling, Wu Z. Dual or multiple drug loaded nanoparticles to target breast cancer stem cells. RSC Advances. 10, 19089-105. 2020
  1. Linnerz T, Kanamala M, Astin JW, Dalbeth N.  Wu Z* and Hall CJ*.  Targeting drugs to larval zebrafish macrophages by injecting drug-loaded liposomes. J Visualized Experiments. e60198, 2020
  2. Tang M, Svirskis D, Leung E, Wang H, Wu Z. Can intracellular drug delivery using hyaluronic acid functionalised pH-sensitive liposomes overcome gemcitabine resistance in pancreatic cancer? J Control Release. 305:89-100, 2019
  3. Kanamala M, Palmer BD, Jamieson SF, Wilson WR, Wu Z. Dual pH-sensitive liposomes with low pH triggered sheddable-PEG for enhanced tumor targeted drug delivery. Nanomedicine (Lond) 14(15):1971-89, 2019
  1. Feng S, Wu Z-X, Zhao Z, Sun K, Guo C, Wang H, Wu Z. Engineering of bone- and CD44-dual-targeting redox-sensitive liposomes for the treatment of orthotopic osteosarcoma. ACS Appl Mater Interfaces. 11(5): 4842-57, 2019
  1. Kanamala M, Palmer BD, Wilson WR, Wu Z. Characterization of a smart pH-cleavable PEG polymer towards the development of dual pH-sensitive liposomes. Int J Pharm. 548(1):288-29. 2018
  2. Kanamala M, Palmer DB, Ghandehari H, Wilson WR, Wu Z. PEG-benzaldehyde-hydrazone-lipid based PEG-sheddable pH-sensitive liposomes: abilities for endosomal escape and long circulation: Pharm Res. 31:35(8):154. 2018
  3. Chi Y, Yin, Sun K, Feng, Liu J, Chen D, C. Guo C, Wu Z. Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models. J Control Release, 261,113-25, 2017
  4. Yang M, Wilson RW, Wu Z. pH-Sensitive PEGylated liposomes for delivery of an acidic dinitrobenzamide mustard prodrug: Pathways of internalization, cellular trafficking and cytotoxicity to cancer cells. Int J Pharm. 516(1-2):323-33. 2017  
  5. Kanamala M, Wilson RW, Yang M, Palmer D, Wu Z. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery – a review. Biomaterials. 85:152-67. 2016
  6. Xu H, Paxton JW, Wu Z. Development of long-circulating pH-sensitive liposomes for the reversal of gemcitabine resistance in pancreatic cancer cells. Pharm Res. (2014 IF 4.7). 33(7):1628-37. 2016
  7. Xu H, Paxton JW, Wu Z. Enhanced pH-responsiveness, cellular trafficking, cytotoxicity and long-circulation of PEGylated liposomes with post-insertion technique using gemcitabine as a model drug. Pharm Res. 32(7):2428-38. 2015