Download lymph-directing prodrugs

MONASH
INNOVATION
LYMPH-DIRECTING PRODRUGS
Offering enhanced oral bioavailability immune cell targeting
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A novel technology to enhance drug
targeting to the intestinal lymphatics
Based on a modified lipid-mimetic
prodrug with novel approaches to
drug conjugation and release
In vivo proof of mechanism,
demonstrating stable transport of the
drug to the intestinal lymph and ready
reversion to the active parent agent
These components are subsequently
absorbed into enterocytes, where they are
re-esterified to triglycerides. The
triglycerides are assembled into intestinal
lipoproteins and subsequently gain
preferential access to the intestinal
lymphatics. Within the lymphatics, these
lipoproteins enter into systemic circulation
where they are preferentially and efficiently
taken up by adipose tissue, the liver and
potentially certain types of tumour tissues.
THE TECHNOLOGY
THE CHALLENGE
The lymphatic system plays a number of key
roles in immune response, fluid balance,
nutrient absorption, lipid homeostasis, and
tumour metastasis. Due to the unique
anatomical and physiological characteristics
of the lymphatic system, targeted delivery of
drugs to and through the lymphatic system
offers the potential to improve both
pharmacokinetic and pharmacodynamic
profiles. For instance, lymphatic drug
transport has the potential to:
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enhance oral bioavailability through
avoidance of first pass metabolism;
alter systemic drug disposition (e.g. to
enhance drug deposition in adipose
tissue and potentially in certain
tumours); and
enhance efficacy against lymph- or
lymphocyte-mediated pathologies such
as autoimmune disease, transplant
rejection and lymphatic tumour
metastasis.
Dietary lipids such as triglycerides use a
unique metabolic pathway to gain access to
the lymph and ultimately, the systemic
circulation. Following ingestion, dietary
triglycerides are hydrolysed by luminal lipases
to release a monoglyceride and fatty acids.
Researchers from the Monash Institute of
Pharmaceutical Sciences have developed a
proprietary lipidated prodrug technology
that is stable in the gastrointestinal tract,
promotes transport to the intestinal lymph
and ultimately, promotes release of the
active drug. By altering the composition of
the linker that is used to conjugate the drug
in the sn-2 position of the glyceride
backbone, the pharmacokinetic profile of
the drug can be optimised.
The researchers have completed in vivo
evaluations of a series of testosterone
prodrugs. When compared with
commercially available testosterone
undecanoate, the Monash testosterone
prodrugs demonstrated significantly
enhanced (>10 fold) lymphatic transport
(Fig.1) and significantly improved (up to >
50 fold) systemic exposure (Fig.2).
P2
30
25
P1
20
15
10
5
TU
0
Figure 1. Administration of lymph directing prodrugs (P1P2) to mesenteric lymph cannulated rats leads to
significantly enhanced lymphatic transport of total
testosterone when compared to the current commercial
product, testosterone undecanoate (TU)
Dose normalised plasma concentration of
f ree testosterone (n mol/L)

Cumulative % of drug dose
transported into lymph
A novel lymph-directing prodrug technology based on the structure of natural triglyceride.
The prodrug promotes transport to the intestinal lymph and offers potential to enhance
oral bioavailability by avoiding first pass hepatic metabolism and to target lymph or
lymphocyte-mediated pathologies. In vivo proof of mechanism has been demonstrated.
50 0
40 0
30 0
20 0
10 0
0
0246
Time (h)
Figure 2. Oral administration of lymph directing
prodrugs (P1-P3) to female rats leads to significantly
enhanced testosterone plasma exposure when
compared to the current commercial product,
testosterone undecanoate (TU).
THE OPPORTUNITY
Monash seeks partners with drugs that
would benefit from delivery with this lymphdirecting prodrug technology. The
researchers, together with the Faculty of
Pharmacy and Pharmaceutical Sciences,
have extensive academic and industrial
experience in drug absorption, lymphatic
transport and drug discovery.
KEY CONTACT
Joy Hewitt
Director, Business Development
Monash Institute of Pharmaceutical
Sciences
T: +61 3 9903 9054
E: [email protected]
CRICOS provider: Monash University 00008C
Produced by Monash Innovation: June 2016