Tailored Membrane
Permeation
IonoChem
Attrition rates of drugs are still extremely high, and this is mainly due to lack of efficacy or for reason of toxicity.
Arguably these issues are mainly substantiated by the fact that drug candidates are typically isolated on the
basis of their potency in a screen against a molecular target, and only subsequently are they tested in
organisms in vivo. Considering that most modern targets have enjoyed a rather high degree of validation, it is
likely that the issue of ostensible potency in vitro but lack of efficacy in vivo is not so much with the target but with
the ability of drugs to reach and thereby interact with their target.
Since most drugs address intracellular targets they have to cross cellular membranes. These lipophilic barriers
are especially for hydrophilic compounds an intractable obstacle leading not only to a poor bioavailability but
also a too short biological half-life of Active Pharmaceutical Ingredients (APIs).
IonoChem Application Note 01
IonoChem addresses these issues and offers various methods to improve membrane permeation capabilities
of APIs. One approach is the design and formulation of lipid based compounds, another an equivalent prodrug
concept (below). Common ground is a selective derivatisation of APIs with a broad spectrum of lipohilic
moieties, which are covalently coupled to the metabolic active structure. These penetration enhancers
comprise mono- and double-tailed natural and (semi-)synthetic lipids, that can be introduced into various
positions of therapeutic molecules.
IonoChem offers a broad spectrum of lipids for the lipophilisation of APIs. It comprises various classes of lipids
ranging from natural plant origin like isoprenoids to functionalised mono- and double tailed natural or (semi-)
synthetic lipids.
O
C18 H37
2
C 18H37
2
OH
N
b
C 18H37
2
O
C18 H37
2
C18H37
2
OH
N
C18 H37
2
D
C 18H37
2
Br
N
C 18H37
2
C18H37
2
N
C18H37
2
hH
H2
C C
C
D D
D
OH
N
hH
H2
C Cl
OH
O
/
H2
18 37
C
N
C
OH
CH
C H2
18 37
CH
N
H
O
O
OH
OH
C18 H37
2
C H2
N
18 37
N
With its substantial Lipid Tool Box IonoChem addresses a
multitude of therapeutic molecules, i.e.
H
H
OH
C H2
18 37
N
C
CH
 Small Molecules
 Nucleic Acid Therapeutics (NATs)
Ionovation GmbH • Westerbreite 7 • 49084 Osnabrück, Germany Phone +49 (541) 9778-660 • Fax +49 (541) 9778-666
www.ionovation.com • [email protected]
Tailored Membrane
Permeation
5-FU: Improved membrane permeation through lipophilisation
Cytostatic chemotherapies play a key role in cancer treatment with nucleoside analogues and nucleobases
being important agents. However, these hydrophilic molecules encounter severe difficulties to cross cell
membranes which leads to poor pharmacokinetic properties and a low bioavailability. The two antimetabolites
5-fluorouracile (5-FU) and its ß-D-ribonucleoside 5-fluorouridine (5-FUrd) show a broad activity against
different types of cancer, but not only due to a lack of lipophilicity also some undesired properties like
O
O
 Severe side effects, as e.g.
 bone marrow suppression
 damage the heart or ZNS
F
F
NH
N
H
NH
O
 Low bioavailability with
 short half-life in the plasma
 frequent application of high doses
 low response rates (10 - 30%)
N
O
HO
O
H
H
OH
OH
H
H
5-fluorouracile
 resistance formation
5-fluorouridine
O
O
O
N
O
O
HN
F
O
O
N
H
O
O
H
O
O
H
O
H
O
N
O
O
O
N
O
O
O
O
O
5-Fluorouridine (5-FUrd) conjugated with three
lipophilic Atto 425 molecules
Ionovation Explorer: Membranes in Focus
A series of confocal images in the xz-plane was acquired to visualize the translocation of lipophilised 5-FUrd
across an artificial lipid bilayer (POPC/POPE/POPS, 8/1/1). 5 µl of the lipohilised and fluorescently labeled 5FUrd was added at a concentration of 1 µM into a side port of the Ionovation Bilayer Slide. Slow diffusion of
the 5-FUrd derivative into the upper compartment leads to an immediate brightness increase that is followed by
a delayed fluorescence increase in the lower compartment(right).
Left: control image; Middle: lipophilised 5-FUrd enters the chamber from the right side (upper compartment) and accumulates in
the bilayer membrane; Right: end concentration (1 µM) of the 5-FUrd on the right side and high accumulation in the membrane.
Release of 5-FUrd from the membrane into the left (lower) compartment is obvious.
Ionovation GmbH • Westerbreite 7 • 49084 Osnabrück, Germany Phone +49 (541) 9778-660 • Fax +49 (541) 9778-666
www.ionovation.com • [email protected]
IonoChem Application Note 01
In order to increase the membrane permeability and thus the efficacy of 5-FUrd the nucleoside was lipophilised
with three molecules of ATTO 425, a coumarin based, non-ionic, and lipophilic fluorescent dye. The interaction
of the lipophilised pharmaceutical compound and the lipid membrane was studied using an Ionovation
Explorer mounted onto a standard inverted laser scanning microscope.