Our fourth webinar in the MDC Connects Series 2021 | A Guide to Complex Medicines. This slide deck takes a closer look at precision drug delivery with therapeutic microbubbles and the promise that they bring. Louise Coletta, University of Leeds

1. Louise Coletta
Leeds Institute of Medical Research
St James’s University Hospital
“Bursting with Promise”
precision drug delivery with
Therapeutic Microbubbles

2. The whys and wherefores of
Improving
Cancer Drug Delivery

3. 2-8 μm MB allows safe navigation
within blood vessels and capillaries
Contrast enhanced ultrasound Therapeutic Microbubbles:
the concept
Targeted, Ultrasound-triggered drug delivery
Targeting
Receptors
PAYLOAD
Ultrasound Destruction Pulse
Diseased Tissue
Blood stream
Ultrasound
better therapeutic index with less off-site toxicity

4. MB fabrication and
Characterization
Drug loading
MB response to US
US mediated drug
release and uptake
MB targeting
Drug release
PK/PD response

5. 1 - 3 um
Gas core
low solubility
Lipid Shell
resistance to gas diffusion
biocompatibility
PEG layer
improved biocompatibility
longer persistence time
Targeting Ligand
Antibody, aptamers, peptides
target MBs
C4F10
2.5 nm

6. Streptavidin
Lipid shell
Drug
50
nm
• Liposomes made by extrusion
• average of 200 nm in diameter
• 3.5 x 1012 Liposomes / mL
• 5% biotinylated PEG2000 for
attachment protocols
Luciferin
Irinotecan
SN38
Streptavidin
Lipid shell
Drug
200
nm
• Lipid coated oil nanodroplets (LONDS)
• average of 50 nm in diameter
• 1 x 1012 LONDS / mL
• 5% biotinylated PEG2000 for attachment
• Charalambous et al., 2021
Combretastatin A4

7. drug
Gas
Core
Gas Core
Liposome
~400 liposomes per MB
Targeting antibodies
Liposome loaded MB Drug loaded liposome

8. On-chip production of microbubbles prod
(WO Patent 2,013,001,309, 2013)
Microspray regime
[MB] = ~109 MB/
ml
F= 0.5 – 2.5 µm
Lab on Chip, 2012, 12, 4544
‘Plug and play’ design
Gas
MBs
multiplexing
x4, x8, x16

9. 200 nm
Therapeutic concs. 109
bubbles/mL
Antibody targeted
Encapsulating:,
irinotecan, SN38
Gas
Lipid + liposomes
antibodies

10. VEGFR2 is a Targeting
Biomarker in human CRC
Isotype Control Targeted to VEGFR2
S. A. Peyman et al, Lab on a Chip, 2012, 12, 4544
In vitro flow assays assess MB binding to
murine endothelial cells.
CD31
VEGFR2

11. 0 minutes 16 minutes
n=3

12. 0 7
inoculate
HFUS and
randomise
Rx 1 Rx 2 Rx 3 Rx 4 Rx 5
HFUS HFUS HFUS tissue
collection
Day 14
Therapeutic microbubbles enhance tumour responses to low
dose irinotecan
Targeting ligand: Anti-VEGFR2
antibodies
Drug: irinotecan-loaded liposome
Release: was triggered at the
tumor site using an ultrasound
destruction pulse

13. I
r
i
S
N
3
8
I
r
i
S
N
3
8
I
r
i
S
N
3
8
I
r
i
S
N
3
8
1
10
100
1000
LOD
Concentration
(ng/g)
thMBs + T
Biodistribution (72 h)
Liver Kidney Spleen Colon
I
r
i
S
N
3
8
I
r
i
S
N
3
8
I
r
i
S
N
3
8
I
r
i
S
N
3
8
1
10
100
1000
LOD
Concentration
(ng/g)
Tumour
Vehicle Free thMBs
- T
thMBs
+ T
All < LOD
**
Tumour Drug Metabolism Tissue Biodistribution

14. 0 10 20 30
0
2
4
6
8
10
Days post-tumour inoculation
HFUS
tumour
volume
(Ratio
to
day
0)
thMBs + T
Vehicle + T
*
*
Tumour Volume
hMBs improve the therapeutic index of
cytotoxic drugs
by increasing
%ID reaching the tumour and limiting
bioavailability in normal tissues

16. Ultrasound-triggered, therapeutic microbubbles
enhance cytotoxic drug efficacy by increasing
tumour drug accumulation, prolonging survival in
the circulation and limiting bioavailability in normal
tissues Theranostics (2020( 10(24):10973-10992
Ingram N1*, McVeigh LE1*, Abou-Saleh RH2, Maynard J3, Peyman SA2,
McLaughlan JR4, Fairclough M5, Marston G1, Valleley EMA 1, Jimenez-Macias
JL1, Charalambous A1, Townley W3, Haddrick M3, Wierzbicki A6, Wright A1,
Volpato M1, Simpson PB3, Treanor DE1, Thomson NH7, Loadman PM6, Bushby
RJ2, Johnson BRG2, Jones PF1, Evans JA1, Freear S4, Markham AF1, Evans SD2 &
Coletta PL1
1 Leeds Institute for Medical Research, Wellcome Trust Brenner Building, St James University Hospital,
Leeds, LS9 7TF, United Kingdom
2 Molecular and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, Leeds,
LS2 9JT, United Kingdom
3 Medicines Discovery Catapult, Mereside, Alderley Park, Cheshire, SK10 4TG, United Kingdom
4 Faculty of Electronic and Electrical Engineering, University of Leeds, Leeds, LS2 9JT, United Kingdom
5 Wolfson Molecular Imaging Centre, Palatine Road, Manchester, M20 3JJ, United Kingdom
6 Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, United Kingdom
7 School of Dentistry, Wellcome Trust Brenner Building, St. James’s University Hospital, Leeds, LS9 7TF,
United Kingdom