DOI: 10.1002/cmdc.201600270
Communications
Poly Ethoxy Ethyl Glycinamide (PEE-G) Dendrimers:
Dendrimers Specifically Designed for Pharmaceutical
Applications
Steven Toms,[b] Susan M. Carnachan,[a] Ian F. Hermans,[c] Keryn D. Johnson,[b]
Poly ethoxy ethyl glycinamide (PEE-G) dendrimers have been
specifically designed and synthesized with the aim of provid-
ing a readily available dendrimer scaffold that can be used to
make products that can meet the stringent requirements of
pharmaceutical applications. The synthesis has been refined to
produce dendrimers that are of high HPLC purity. The suitabili-
ty of PEE-G dendrimers for their designed use has been veri-
fied by subsequent measurements to demonstrate that they
are of high stability, high aqueous solubility, low cytotoxicity,
low immunogenicity and with low in vivo toxicity in an escalat-
ing-dose rat study. PEE-G dendrimers therefore provide
a useful scaffold for researchers wanting to develop dendri-
mer-based drug candidates.
the ability to consistently produce material with reproducible
characteristics. If material cannot be made with the same or
higher purity than previously, then safety data from toxicity
trials can be of little value.
Robust measurement of the purity of dendrimers is chal-
lenging.[5] Mass spectrometric data are useful for showing the
presence of impurities if a good method has been developed
that shows a strong resolved molecular ion, but is not a good
tool to accurately quantify impurities.[6] While size-exclusion
chromatography is more quantitative, it is not a good method
to detect subtle structural imperfections, for example, where
one terminal arm of the dendrimer is miss-capped. These im-
purities will be of very similar size to the product and so are
unlikely to be resolved. Because of the highly repetitive struc-
ture of dendrimers, NMR is not good for purity evaluation
when considering product-like impurities and is not a very sen-
sitive method for detecting low-level impurities, especially for
larger-generation dendrimers.
Dendrimers have been developed for many uses since the first
reports,[1] including for use in the pharmaceutical field.[2] De-
spite the many efforts in this area, there have only been a few
dendrimer products that have entered clinical trials,[3] and even
fewer have reached the market. We have developed a new
dendrimer scaffold that has been specifically designed to meet
the stringent requirements of pharmaceutical applications.
Of the polymeric or macromolecular materials available, den-
drimers are favorable for drug development because of their
discrete definable structure. However, to progress through the
regulatory process, regulators require demonstration of control
over the synthetic chemistry process backed up by informative
analytical methods.[4] Lack of control in the synthetic chemistry
can lead to variable efficacy and toxicity of the product. Lack
of ability to show purity and more importantly the level and
nature of impurities leads to concerns by the regulators over
HPLC is the key method for the measurement of purity of
dendrimer substances and should be used throughout the syn-
thesis to verify control of the chemical process. There are only
limited examples[7] of HPLC being used to measure dendrimer
product purity. Reymond et al. regularly synthesize peptide
dendrimers via solid-phase chemistry which they isolate to
high purity using preparative HPLC.[8]
We felt that there is a need for a readily available dendrimer
scaffold that fulfills the requirements for pharmaceutical appli-
cations and that can be made on scale.[3,9] This scaffold could
then be used in drug discovery with the knowledge that the
underlying dendrimer is suitable and unlikely to raise hurdles
when measuring the purity, stability, and toxicity properties of
the resulting active pharmaceutical ingredients (APIs). We
therefore report herein a new dendrimer scaffold that we have
specifically designed, synthesized, and evaluated as a tool for
researchers carrying out dendrimer-based drug discovery.
The criteria that we gave ourselves for a dendrimer scaffold
to be of use as a tool to make therapeutic drugs were that it
must have: low toxicity to allow for a suitable, safe dosing
window; high stability with measurable degradation, not pro-
ducing degradants likely to be toxic; low cost of goods and to
be able to be made by an efficient, scalable synthesis; high
HPLC-measurable purity; suitable solubility in biologically rele-
vant media; and amine or carboxylic acid termini available for
convenient further modification by subsequent coupling reac-
tions.
[a] Dr. S. M. Carnachan, Dr. P. M. Rendle
Victoria University of Wellington,
PO Box 33436, Petone 5046 (New Zealand)
[b] Dr. S. Toms, Dr. K. D. Johnson, Dr. A. A. Khan
Callaghan Innovation, PO Box 31310, Lower Hutt 5040 (New Zealand)
[c] Dr. I. F. Hermans, Dr. C.-W. Tang
Malaghan Institute of Medical Research,
PO Box 7060, Wellington 6242 (New Zealand)
[d] Dr. S. E. O’Hagan
Centre for Integrated Preclinical Drug Development,
Faculty of Medicine and Biomedical Sciences,
The University of Queensland, St. Lucia Campus, QLD 4072 (Australia)
Supporting information and the ORCID identification number(s) for the
ChemMedChem 2016, 11, 1 – 5
1
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