Our team at The
Nanomedicine Lab within the Centre for Drug Delivery Research wants to generate and
disseminate fundamental knowledge in the emerging field of nanomedicine by
bringing together biomedical engineering, pharmacology and nanotechnology and
their translation to advanced, clinically-relevant therapeutics and
Our aim is the development of novel, viable and effective therapeutics based
on the transformation of nanotechnology tools and materials and their use as
either the 'drug' or the 'delivery system'. Such components include DNA, RNA,
viruses, stem cells, radionuclides, liposomes, carbon nanomaterials and other
nanomaterials (quantum dots, fullerenes, carbon nanohorns).
The research efforts taking place within The Nanomedicine Lab
are bridging the gap between fundamental nanomaterials engineering and
pharmaceutical development towards the realisation of advanced therapeutic and
imaging modalities. Our mission is to pioneer the cutting-edge and emerging
discipline of nanomedicine. Some examples of what systems we have developed
Dendrimeric Nanocontainers that block Angiogenesis in Cancer
Lab recently demonstrated for the first time that poly-L-lysine (PLL)
dendrimers can exhibit anti-angiogenic activity and block the formation of newly
formed blood vessels in developing tumours. This has led to tumour growth delay
of an aggressive murine melanoma model and significantly reduced tumour
volume1. Dendrimers are three dimensional nanometer
scale hyper-branched polymers that have been described by Don Tomalia in the mid
1980's. Dendrimers have mainly been used as nanocontainers for small drugs,
therapeutic macromolecules and MRI imaging agents.
|PLL-dendrimer structure and tumor vasculature
treated with control (left) and the PLL-dendrimer (right)1.
A number of dendrimers have been studied pre-clinically to show
anti-angiogenic activity, but this inherent activity had not been shown
previously in vivo or after systemic administration. In this study, the
therapeutic activity was achieved after intravenous injection of the dendrimer
without the need to include drugs or other therapeutic agents. Only two
intravenous injections of the PLL dendrimer were sufficient to retard tumour
growth with no systemic toxicity observed in the liver, spleen and kidneys.
illustrates that new-generation nanocontainers may offer inherent biological
activities whenever required and at the right location, such as in aggressive
tumours that require high vascularisation for growth.
Nanotubes as Nanoneedles for Cells
Chemically modified carbon nanotubes with different functional groups were
discovered to be able to internalise in a variety of cell types, including human
cells. Carbon nanotubes have shown potential as new-age delivery systems and it
is the chemical functionalisation that is critical in this transformation as it
allows them to become water soluble, and therefore able to be used in biological
fluids. Chemically functionalised nanotubes were able to easily cross cell
barriers in mammalian, bacterial and fungal cells without causing cell death,
and were even able to enter cells under conditions which would usually hinder
this process2. Nanotubes capable of acting as
cell-penetrating materials will have tremendous advantages. The potential of
functionalised carbon nanotubes to act as nanoneedles that pierce plasma
membranes and translocate directly into cytoplasm without causing cell damage or
death is significant for a variety of biomedical and biotechnology applications.
While the actual mechanism by which the functionalised nanotubes are taken up
by cells is still unclear, the hypothesis that the team is working with is that
they simply pierce the cell and move within. Some types of functionalisation
prompted a greater uptake, but it was by no means a prerequisite. All
functionalised nanotubes were taken up to a significant extent. The Nanomedicine Lab,
in collaboration with the laboratories of Dr.A.Bianco at the CNRS in Strasbourg,
France and Prof.M.Prato in Trieste, Italy, have experimented with attempts to
intracellularly deliver small molecules, nucleic acids and imaging agents. If
the research team's working hypothesis regarding the uptake of functionalised
carbon nanotubes proves correct, the technique could offer significant
advantages over current drug delivery technologies. Traditional delivery methods
(using liposomes for example) usually exploit endocytosis, but stop before
reaching the cytoplasm leaving other barriers for the drug to fight through. By
piercing plasma membranes and heading straight to the cytoplasm, the
functionalised carbon nanotube encounters fewer biological barriers and delivers
the drug more directly.
Nanoengineering Artificial Viral Envelopes
Gene therapy involves the delivery of a functional gene by a vector into
target cells, resulting in a desired therapeutic effect. Adenovirus (Ad) has
shown great promise in gene therapy, however clinical and in vivo studies have
reported severe immunogenic responses and an overwhelming accumulation and gene
expression in the liver resulting in significant hepatotoxicity. We are
attempting to overcome these limitations by engineering artificial envelopes
around non-enveloped viruses by allowing the self-assembly of a variety of lipid
molecules (zwitterionic, anionic, cationic, responsive) around viral
Such exercises in nanoscale engineering of viral gene therapy vectors are
thought to offer significant improvements in their safety profile by allowing
also re-targeting and tissue-specific gene transfer. New generation vectors for
genetic therapies and vaccines are currently under development.
Liposome-Quantum Dot Hybrids for Combinatory Therapeutic & Diagnostic
Quantum dots (QD) are being explored in biomedicine as fluorescent probes of
intracellular compartments and for cell labelling and tracking in vivo.
Lab has developed two novel types of lipid-quantum dot hybrid vesicle
systems to achieve improved biocompatibility and the opportunity to develop
nanoparticles for combinatory imaging (quantum dot component) and therapeutic
(vesicle component) capabilities. The first liposome-QD hybrid system was
engineered by allowing small (less than 5nm in diameter), hydrophobic CdSe/ZnS
core/shell QD to be embedded within the vesicle lipid bilayers (L-QD)5. The second type consists of larger (20-40nm in diameter),
hydrophilic, surface functionalized QD encapsulated at the inner liposome
aqueous phase (f-QD-L)6. Both types of lipid-quantum
dot hybrids were shown to successfully label tumor cells in vitro and in vivo.
We believe that liposome-nanoparticle hybrids of this type using a variety of
nanoparticles (gold, silver, iron, gadolinium) can provide a wide range of
new-age liposome-based delivery systems for therapeutic or diagnostic purposes.
1. Al-Jamal KT, Al-Jamal WT, Akerman S, Podesta JE, Yilmazer A,
Turton JA, Bianco A, Vargesson N, Kanthou C, Florence AT, Tozer GM, Kostarelos
K., Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays
tumor growth. Proc Natl Acad Sci U S A. 2010,
2. Kostarelos K, Lacerda L, Pastorin G,
Wu W, Wieckowski S, Luangsivilay J, Godefroy S, Pantarotto D, Briand JP, Muller
S, Prato M, Bianco A., Cellular uptake of functionalized carbon nanotubes is
independent of functional group and cell type. Nature Nanotechnology
3. Singh R, Al-Jamal KT, Lacerda L,
Kostarelos K., Nanoengineering artificial lipid envelopes around adenovirus by
self-assembly. ACS Nano 2008, 2(5):1040-50.
Singh R, Tian B, Kostarelos K., Artificial envelopment of nonenveloped viruses:
enhancing adenovirus tumor targeting in vivo. FASEB J. 2008,
5. Al-Jamal WT, Al-Jamal KT, Tian B,
Lacerda L, Bomans PH, Frederik PM, Kostarelos K., Lipid-quantum dot bilayer
vesicles enhance tumor cell uptake and retention in vitro and in vivo. ACS
Nano, 2008, 2(3):408-18
6. Al-Jamal WT, Al-Jamal KT,
Bomans PH, Frederik PM, Kostarelos K., Functionalized-quantum-dot-liposome
hybrids as multimodal nanoparticles for cancer. Small 2008, 4(9):1406-15.
Copyright AZoNano.com, Professor Kostas Kostarelos (University
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