Objective
The method by which a drug is
delivered can have a significant effect on its efficacy. All drugs have an
optimum concentration range in which maximum benefit is achieved and there is a
real need for multi-disciplinary approaches to optimise the delivery of a
therapeutic to its target tissue.
The Medicines Discovery Catapult
(MDC) have partnered
with the University of Leeds to develop a therapeutic microbubble (ThMb) platform
as an innovative drug delivery system.
The platform has the potential to selectively deliver drugs, thereby
increasing the therapeutic window. It is
hypothesised that the ThMb platform will enable higher concentrations of drugs
to reach their target, thereby increasing efficacy whilst minimising toxicity.
Our ThMb platform consists of µm-sized
gas filled phospholipid bubbles that form the core of a therapeutic microbubble
drug complex. Targeting molecules and drug payload are attached to the
microbubbles and injected into the body. An ultrasound trigger causes the
therapeutic drug complex to release its drug payload and cause localised
release of drug.
MDC are conducting studies to prove
and differentiate the ThMb delivery platform as a superior method to
conventional formulation techniques. Our initial focus is on a therapeutic
intervention for colorectal carcinoma and uses liposome encapsulated SN38
(LE-SN38). SN38 is a very potent drug and cannot be given via conventional
formulation.
In this study we aimed to
understand the pharmacokinetic distribution and dynamic time-course of LE-SN38
using the radioactive label zirconium (89Zr) as a marker of
accumulation. We wanted to understand
the pharmacokinetic profile changes once incorporated into microbubbles and
show superiority against conventional liposome formulation and understand the
physical mechanism of controlled drug release with our ultrasound platform.
89Zr labelled liposome PET
scans were performed in CD1 nude mice in the SW480 (colorectal cancer cell
line) xenograft model. Mice were injected with either 89Zr LE-SN38
alone, 89Zr LE-SN38 ThMb complex with an ultrasound destruction pulse
applied or 89Zr LE-SN38 ThMb’s without the ultrasound destruction pulse
applied. Mice were imaged longitudinally 1hr, 24hr and 72hr post 89Zr
injection. At each imaging time point a satellite group of animals were
euthanised and a series of organs taken for biodistribution analysis.
Results showed that distribution
and degradation of LE-SN38 was through the reticuloendothelial system (RES).
Greatest accumulation of 89Zr LE-SN38 was in the liver and spleen.
Results were expressed as %ID/g. %ID/g in all other organs was <2%. 89Zr
LE-SN38 tumour accumulation was also measureable and was observed to be 0.83 ±
0.13; 0.96 ±
0.21 and 0.73 ± 0.14 %ID/g at each imaging time point respectively. A
2-fold increase in tumour accumulation was observed following administration of
ThMb SN38 loaded liposomes with significantly increased accumulation in the
blood at 1 hour post administration. In addition, application of the ultrasound
in combination with the ThMbs caused transient and localised permeability to
the tumour tissues with a significant difference in tumour uptake at 1 hour
post treatment when ultrasound was applied.
We showed that 89Zr
labelled LE-SN38 can be reproducibly tracked in a series of body organs across
time. We showed that ThMB’s demonstrated greater accumulation than liposomal
formulation alone, thus overcoming the caveat of liposome formulations of an
inability to get sufficiently high enough dose of therapeutic compound to achieve
efficacious effect in the target organ. Following successful validation we will now
investigate where this platform could be
beneficial with other candidate compou
