Light and X-ray triggered liposomal gene/drug delivery system for cancer therapy

Transcription

1 Light and X-ray triggered liposomal gene/drug delivery system for cancer therapy Wei Deng, 1 Wenjie Chen, 2 Sandhya Clement, 1 Anna Guller, 1 Alexander Engel, 3 Ewa Goldys 1 1 The Graduate School of Biomedical Engineering, UNSW 2 ARC Centre of Excellence for Nanoscale Biophotonics, Macquarie University 3 Sydney Medical School, University of Sydney wei.deng@unsw.edu.au

2 Introduction Liposomes are simple microscopic vesicles in which an aqueous volume is entirely enclosed of phospholipid molecule. The structure of the phospholipid molecule generally consists of two hydrophobic tails and a hydrophilic head. Water soluble drugs The arrangement of phospholipid molecules that make up a lipid bilayer The scheme of a liposome formed by phospholipids

3 Introduction Applications of liposomes Chelation therapy for treatment of heavy metal poisoning Enzyme replacement Diagnostic imaging of tumours Cosmetics Study of membranes Drug/gene delivery

4 Current research focus of liposomes Controlled release Changes in ph Enzymes Heat Ultrasound Direct light X-ray radiation Specific site-targeting Targeting ligands Peptides Monoclonal antibodies

5 Light-triggered liposome delivery system Features: Clinically approved compounds Temporal and spatial release control Stability Robust liposomal gene carrier Efficient release of genetic materials Minimal off-target effect Applications: Gene therapy opportunity Anti-cancer drug delivery Journal of Materials Chemistry B, 2018, DOI: /C8TB00994E

6 Specifications of light-triggered liposomes Liposome formulation DOTAP/DSPE-PEG/DOPE/Chol Size 150 nm Zeta potential +12 mv Genetic materials Plasmid and CRISPR RNP Stability Less than 10% content release within 6 days in physiological environment Light source LED Photosensitive molecules Verteporfin in the lipid bilayer Excitation wavelength 690 nm Illumination time 4 min Power density (mw/cm 2 ) 15 Gene transfection efficiencies 2-time increase in protein expression Toxicity More than 80% cells are alive after incubation with liposomes at 100 μg/ml

7 CLSM images (A-F) of EGFP expression in HCT 116 cells after 48 hr of transfection with and without light illumination. (H) transfection efficiencies of different groups

8 X-ray triggered liposome system Features: Safety nanocarrier Controlled drug/gene release Localised treatment-reduced side effects to healthy tissues Neoadjuvant treatment of deep-seated tumour Applications: Neo-adjuvant cancer treatment (photodynamic therapy and immunotherapy) Targeted anti-cancer drug delivery Targeted gene therapy opportunity Nature Communications 9:2713, 2018

9 Targeted liposomes: conjugation of liposomes with targeting molecules Schematic presentation of the formation of liposome-peg-fa

10 Cellular uptake of liposome-folic acid conjugates Confocal laser scanning microscopy images of HCT116 cells (colorectal cancer cells, top panel) and CCD 841 CoN cells (normal colon cells, bottom panel) incubated with targeted liposomes for 1 h

11 In vitro cell killing effect of X-ray triggered liposomes IC 50 was achieved at 1.6 microm of Dox loaded inside liposomes and triggered by X-ray radiation Only about 10% of cancer cells was killed at the same concentration without X-ray radiation

12 Mice bearing HCT 116 cells was injected (i.t.) with liposomes prior to X-ray radiation Mice were radiated with X-ray at 4 Gy

13 In vivo tumour control effect of X-ray triggered liposomes a b c (a and b) Changes of tumours and body weight of mice after various treatments indicated. (c) The structural components of treated tumour. (d) Morphometric analysis of the effect of the experimental treatments on the structural composition of the tumours

14 Prof. Ewa M Goldys Prof. Alexander Engel Dr Wenjie Chen Dr Sandhya Clement Dr Anna Guller Dr Zhenjun Zhao Dr Vaughan Moutrie Dr Daniel Santos Acknowledgement