Journal of Microscopy, Vol. 270, Issue 1 2018, pp. 92–97 doi: 10.1111/jmi.12659
Received 9 June 2017; accepted 26 September 2017
Observation of metal nanoparticles at atomic resolution in Pt-based
, A.M. VARAMBHIA
, R.A. FLECK†, S.J.L. FLATTERS‡ & P.D. NELLIST
Department of Materials, University of Oxford, Oxford, U.K
†Centre for Ultrastructural Imaging, Kings College London, London, U.K
‡Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, U.K
Key words. Annular dark field, atom imaging, atom weighing, platin
pharmaceuticals, scanning transmission electron microscopy.
The chemotherapeutics cisplatin and oxaliplatin are impor-
tant tools in the fight against cancer. Both compounds are
platinum complexes. Aberration-corrected scanning trans-
mission electron microscopy using the annular dark-field
imaging mode now routinely provides single-atom sensitivity
with atomic number contrast. Here, this imaging mode is used
to directly image the platinum within the two drugs in their
dried form on an amorphous carbon support film. The oxali-
platin is found to have wetted the supporting amorphous car-
bon, forming disordered clusters suggesting that the platinum
has remained within the complex. Conversely, the cisplatin
sample reveals 1.8-nm-diameter metallic platinum clusters.
The size and shape of the clusters do not appear to be depen-
dent on drying rate nor formed by beam damage, which may
suggest that they were present in the original drug solution.
The platinum-based antineoplastic family of chemotherapeu-
tics (colloquially termed platins) are used extensively as first-
line treatment for solid tumours. Over 50% (Johnstone et al.,
2014) of cancer treatment globally comprises, at least in part,
one or more of the four platinum-based drugs approved for
medical use in humans.
One such drug is cis-[PtCl
], or cisplatin. Although
this compound had been synthesized as early as 1845 un-
der the moniker of Peyrone’s salt, the anti-cancer potential of
cisplatin was not realized until 1965, in Rosenburg’s fortu-
itous experiments on the influence of current on cell division
of Escherichia coli (Rosenberg et al., 1965).
Correspondence to: A.A. Sheader. Department of Materials, University of Oxford,
Parks Road, Oxford, OX1 3PH, U.K. Tel: +44 1865 273657; fax: +44 1865 283333;
The unexpected changes observed to the shape of the E . coli
cells were at first thought to originate from the influence of the
electric field on cellular division. However, several additional
years of investigation revealed that the culprit was, in fact, the
platinum(IV) complex cis-[PtCl
], only present in the
experiment at all due to the serendipitous combination of am-
monium chloride buffer solution with the platinum electrodes.
Subsequent research into the effects of platinum complexes on
cells led swiftly to the idea that such compounds could be used
as chemotherapeutic agents, and to the subsequent develop-
ment of the first platinum-based chemotherapeutic, cisplatin.
Cisplatin is used to treat solid tumours of the bladder, cervix
and lung, amongst other cancers. It is especially effective
against testicular cancer, and is responsible for raising the
cure rate from 5% when the drug was first approved, to over
90% today Einhorn (2002).
A newer member of the platin family is oxalato(trans-l-
1,2-cyclohexanediamine)Pt(II), or oxaliplatin, borne from the
need for chemotherapeutics to treat cisplatin-resistant can-
cers (including both intrinsically resistant tumours, and those
which acquire resistance over multiple courses of chemother-
apy), and to reduce the extensive toxic side effects experienced
by patients (Alcindor & Beauger, 2011). Oxaliplatin is par-
ticularly effective against colorectal tumours, against which
cisplatin has no activity.
Both cisplatin and oxaliplatin share similar structures, as
shown in Figure 1. Both have square-planar Pt(II) centre, with
the primary difference between the two being in the replace-
ment of the monodentate chloride groups in cisplatin with
bidentate oxalate in oxaliplatin.
Annular dark-field scanning transmission electron microscopy
In the scanning transmission electron microscope (STEM),
a convergent electron beam is rastered across a specimen,
and the transmitted signal collected in a number of differ-
ent imaging modes. The power of STEM comes from the
2017 The Authors
Journal of Microscopy
2017 Royal Microscopical Society