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| Fullerenes in Medicine; Will it ever Occur? |
| Chris Kepley* |
| Associate Professor, Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro, North Carolina, 27401, USA |
| *Corresponding author: |
Chris Kepley, PhD
Associate Professor
Joint School of
Nanoscience and Nanoengineering
University of North Carolina at Greensboro
North
Carolina, 27401, USA
E-mail: clkepley@uncg.edu |
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| Received July 09, 2012; Accepted July 09, 2012; Published July 11, 2012 |
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| Citation: Kepley C (2012) Fullerenes in Medicine; Will it ever Occur? J Nanomed
Nanotechol 3:e111. doi:10.4172/2157-7439.1000e111 |
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| Copyright: © 2012 Kepley C. This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited. |
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| Fullerenes represent a group of compounds having unique
properties that make them attractive candidates for use as a platform
for developing new medical applications. The carbon cage (usually
C60 and C70) of empty cage fullerenes (Figure 1-left/middle) are being
developed as therapeutics for disease processes such as multiple
sclerosis, neurodegeneration, HIV infection, cancer, radiation exposure,
ischemia, allergic disease, infectious disease, and general inflammation.
Metallo-fullerenes (Figure 1-right; that have metals enclosed within
the carbon cage) are being developed into new biomarker homing,
diagnostic contrast agents for MRI. Lastly, a new class of theranostics
are being developed that combine cell targeting capabilities/imaging
with a therapeutic payload. Their inherent properties combined with
their ability to be derivatized with side chains results in almost limitless
new chemical structures making them ideal platform molecules for
new solutions to basic biological problems. However, one of the biggest
obstacles that have kept this class of compounds from potentially
improving human health and reducing health care costs is the concern
about toxicity. This has been due, in part, to the lack of standard
structural relationships that affect biological outcomes of Fullerene
Derivatives (FD). |
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Figure 1: Representative fullerene structures. |
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| Of course, toxicity considerations are implicit when contemplating
human use for novel compounds such as fullerenes. To this end there
have been a number of studies examining the toxicity using a myriad
of fullerene preparations. However, the results of most of these studies
are conflicting, inconclusive, and the subject of much debate. One of
the most “damaging” fullerene studies (that was subsequently proven
to be unfounded) exposed juvenile bass to un-derivatized C60, which
is insoluble in water [1]. Unfortunately the authors did not include
a control that provided insights into whether the observed effects
were simply due to large aggregated particles/THF contaminants or
whether they were specific to the chemical nature of C60. Yet there was
widespread publicity that concluded fullerenes as a class could be toxic
[2]. A more recent publication by the same group (without publicity)
demonstrated that the originally observed “toxicity” was due to
impurities in the sample [3]. Even more recently these original studies
were “formally” debunked by a follow-up publication which stated that
the original Oberdorster studies where “compromised by experimental
artifacts” [4]. On the opposite end of the spectrum, studies in mice
demonstrate that similar C60 preparations significantly increase the
lifespan of mice [5]. Thus, it is difficult for researchers, and the general
public, to determine if fullerenes are dangerous nanostructures that
should be banned or a potential novel platform for developing new
fountain-of-youth medicines. How can a class of compounds be
simultaneously toxic and lifespan extenders? |
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| Contributing to the confusion is that few studies examining
toxicity use well characterized and highly purified material that are
not mixtures of many isomers, aggregate sizes, and impurities. Most
studies in which fullerenes are deemed to be toxic use starting material
with little or no characterization (DLS, zeta potential, FTIR, etc.). In
addition, no studies have compared differences in cage sizes (C60 vs.
C70 vs. C80); the latter two are much more likely to become US Food
and Drug Administration (FDA) approved products due to their size
being conducive to fewer numbers of isomers when adding side chain
moieties. The FDA requires that every new chemical entity (NCE)
must be evaluated separately; extrapolating toxicity (or non-toxicity)
by categorizing compound mixtures and making generalizations
about classes of compounds (as is the case with fullerenes) with
many different isomers is not acceptable to the FDA. Anyone with a
high school-level understanding of basic chemistry is aware that even
extremely similar molecules can have different biologic activities.
There are many examples where two isomers that are very similar have
completely different biological behavior. For example, the tragedy of
the drug thalidomide, where one isoform was an effective sedative and
the mirror image isoform was teratogenic resulting in fetal defects,
changed the face of drug testing. This applies to the studies with
fullerenes where even extremely small changes in the core fullerene
structure (through the addition of side-chain moieties) can result in
the FD having completely different biological properties. This has been
demonstrated repeatedly by several laboratories which highlight the
difficulty in interpreting data gathered from extrapolating findings
between even very similar compounds. |
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| Complicating the task of bringing FD to the marketplace is the fact
that the FDA does not have specific guidelines for products containing
nanoscale materials. A report issued by the FDA Nanotechnology
Task Force (July 2007) recommends guidance by various centers
within the FDA for industries working with nanomaterials. Unlike
“standard” drug products it is increasingly evident that at least in
the area of characterization of nanomaterials used in drug products,
different standards apply. Applying small molecule principles and
methodologies to nanomaterials cannot be extrapolated in biological
settings. The study stressed that biodistribution analysis should be at
the core of any evaluation of products containing nanomaterials. These
biodistribution studies, as recommended by the FDA, provide valuable
information on where the nanoparticles are traveling and possibly
accumulating, therefore subjecting those sites to increased likelihood
of toxicological effects. It was also stressed in the 2007 report that most
studies (using nanomaterials) are limited in that they are short-term, and might leave long-term effects unevaluated, especially because the
long-term toxicity and effects for most nanoscale materials remain
unknown. Furthermore, appropriate endpoints for in vitro assays
are seen to be difficult to determine, as single cell types are often not
sufficient for evaluation on the function or health of organs or tissues
that are made up of multiple cell types, and given that numerous types
of tissues are exposed to in the body. The major recommendation was
that nanoscale material be characterized with respect to size (surface
area and size distribution), chemical composition (such as purity and
crystallinity), surface structure (surface reactivity, surface groups,
coatings, etc.), solubility, shape, and aggregation. The protocols
developed at the National Cancer Institute’s, Nanotechnology
Characterization Laboratories was recommended as being very useful
in helping to characterize nanoscale materials and to develop standards
and standardized methods for measuring nanoscale materials. |
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| The potential for using fullerene-based medicines is substantial
but concerns of toxicity have slowed the initial enthusiasm that
surrounded their discovery. Only those studies using well characterized,
single species “lead candidate” fullerene formulations can provide
meaningful information regarding potential toxicological effects.
Such studies are needed as the state of research today with fullerenes
is shaped by studies such as these that address the observation “that
extrapolation across similar nanoparticles will be dependent upon surface chemistry and concentration which may affect the degree of
agglomeration and thus biological effects” [6]. Thus, more thorough
studies will serve as a building block in developing a database that links
surface functionalization chemistry of fullerene compounds to biologic
function. |
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| References |
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- Oberdorster E (2004) Manufactured nanomaterials (fullerenes, C60) induce oxidative stress in the brain of juvenile largemouth bass. Environ Health Perspect 112: 1058-1062.
- Barnaby JF, New York Times2004.
- Zhu S, Oberdorster E, Haasch ML (2006) Toxicity of an engineered nanoparticle (fullerene, C60) in two aquatic species, Daphnia and fathead minnow. Mar Environ Res 62: Suppl: S5-S9.
- Henry TB, Petersen EJ, Compton RN (2011) Aqueous fullerene aggregates (nC60) generate minimal reactive oxygen species and are of low toxicity in fish: a revision of previous reports. Curr Opin Biotechnol 22: 533-537.
- Quick KL, Ali SS, Arch R, Xiong C, Wozniak D, et al. (2008) A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice. Neurobiol Aging 29: 117-128.
- Saathoff JG, Inman AO, Xia XR, Riviere JE, Monteiro-Riviere NA (2011) In vitro toxicity assessment of three hydroxylated fullerenes in human skin cells. Toxicol In Vitro 25: 2105-2112.
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