final draft for part 2

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aj 2019-11-18 19:10:06 +00:00
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@ -1780,11 +1780,11 @@ noprefix "false"
\end_layout \end_layout
\begin_layout Part \begin_layout Part
Application of Nanomaterials Application of Nanomaterials - Abraxane
\end_layout \end_layout
\begin_layout Standard \begin_layout Standard
The use of albumin protein nanoparticlces has provided a new delivery method The use of albumin protein nanoparticles has provided a new delivery aid
for the highly effective chemotherapy drug, paclitaxel, in turn reducing for the highly effective chemotherapy drug, paclitaxel, in turn reducing
side effects and toxicity caused by previous delivery schemes and increasing side effects and toxicity caused by previous delivery schemes and increasing
circulation half life around the body. circulation half life around the body.
@ -1797,15 +1797,22 @@ Paclitaxel
\begin_layout Standard \begin_layout Standard
Paclitaxel is a chemotherapy drug in the taxane family which function as Paclitaxel is a chemotherapy drug in the taxane family which function as
mitotic inhibitors. mitotic inhibitors.
This involves the suppression of mitosis or cell division which is effective This involves the suppression of mitosis or cell division by preventing
in treating cancer as constant cell mitosis is how cancer spreads throughout the breakdown of the microtubules helping provide structure to cells.
the body.
\end_layout \end_layout
\begin_layout Standard \begin_layout Standard
While taxanes are an effective cancer treatment, their use has proved difficult This is effective in treating cancer as constant, unmitigated cell mitosis
as they are not particularly soluble in water requiring a delivery vehicle is how cancer spreads throughout the body, blocking this process causes
in order to allow intraveneous application. it to die without reproducing.
\end_layout
\begin_layout Standard
While taxanes are an effective cancer treatment, their use is made less
efficacious due to their particularly insolubility in water requiring additiona
l chemcials to act as a delivery vehicle in order to allow a solution to
be created for intraveneous application.
\end_layout \end_layout
\begin_layout Standard \begin_layout Standard
@ -1836,10 +1843,6 @@ Chemical structure for paclitaxel
\end_inset \end_inset
\end_layout
\begin_layout Plain Layout
\end_layout \end_layout
\end_inset \end_inset
@ -1856,8 +1859,9 @@ As a result of the poor water solubility of taxanes and paclitaxel, a method
for delivering a solution was required. for delivering a solution was required.
Polyethoxylated castor oil (commercially known as Kolliphor EL, formerly Polyethoxylated castor oil (commercially known as Kolliphor EL, formerly
Cremophor EL [CrEL]) combined with dehydrated ethanol provides a suitable Cremophor EL [CrEL]) combined with dehydrated ethanol provides a suitable
formulation vehicle for many poorly water soluble and has been the standard formulation vehicle for many poorly water soluble and lipophilic drugs
for many forms of commercially available paclitaxel such as Taxol. and has been the standard for many forms of commercially available paclitaxel
such as Taxol.
\end_layout \end_layout
\begin_layout Standard \begin_layout Standard
@ -1901,12 +1905,11 @@ literal "false"
\end_inset \end_inset
and is part of the albumin family of proteins. and is part of the albumin protein family.
HSA is produced by the liver and performs important functions such as maintaini HSA is produced by the liver and performs important functions such as maintaini
ng oncotic pressure in the blood vessels, ensuring the right levels of fluids ng oncotic pressure in the blood vessels, ensuring the right levels of fluids
are found between blood vessels and body tissues, and transporting hormones are found between blood vessels and body tissues, and transporting hormones
and fatty acids around the body. and fatty acids around the body.
\end_layout \end_layout
\begin_layout Standard \begin_layout Standard
@ -1945,10 +1948,6 @@ literal "false"
\end_inset \end_inset
\end_layout
\begin_layout Plain Layout
\end_layout \end_layout
\end_inset \end_inset
@ -1968,7 +1967,7 @@ literal "false"
\end_inset \end_inset
. .
Critically HSA has been shown to be nontoxic, non-immunogenic (provokes Critically HSA has been shown to be nontoxic, non-immunogenic (provoking
little response from the immune system), biocompatible and biodegradable little response from the immune system), biocompatible and biodegradable
\begin_inset CommandInset citation \begin_inset CommandInset citation
LatexCommand cite LatexCommand cite
@ -1977,7 +1976,23 @@ literal "false"
\end_inset \end_inset
providing many advantages over Cremophor EL delivery. providing many theoretical advantages over Cremophor EL delivery as a result
of using a native biological subtance.
\end_layout
\begin_layout Standard
The nanoparticles are biodegradable as nano particles of the sizes 10-100nm
can be shown to enter the capillaries and be expelled as part of normal
cell clearance.
\end_layout
\begin_layout Standard
While HSA is frequently used due to it's native presence in the body reducing
the chances of an immunologic response, suitable albumin can also be found
in egg whites (ovalbumin [OVA]) and bovine serum (bovine serum albumin
[BSA]) where abundance and low cost are advantages.
Many of the advantages provided by using albumin can be attributed to using
a biological protein.
\end_layout \end_layout
\begin_layout Section \begin_layout Section
@ -1985,7 +2000,172 @@ NAB-Paclitaxel
\end_layout \end_layout
\begin_layout Standard \begin_layout Standard
Word Count: While there are many ways to produce albumin nanoparticles including desolvation
, emulsification and thermal gelation, an albumin specific technology was
developed in order to capture lipophilic (tending to dissolve in lipids
or fats) drugs in albumin nanoparticles known as NAB-technology where NAB
refers to nanoparticle albumin-bound.
\end_layout
\begin_layout Standard
The formulation process involves the drug in question being mixed in an
aqueous solution with HSA before being passed through a high pressure jet.
This forms nanoparticles of sizes between 100nm and 200nm
\begin_inset CommandInset citation
LatexCommand cite
key "wos000301045400002"
literal "false"
\end_inset
.
\end_layout
\begin_layout Standard
The solubility in water of the final product is increased as operating at
the nano-scale increases the surface area of the particles and increases
the dissolution of the formulation.
This protein based delivery solution also has the benefit of allowing higher
doses of paclitaxel than is deemed safe when delivered in combination with
Cremophor.
\end_layout
\begin_layout Section
Abraxane
\end_layout
\begin_layout Standard
Abraxane is a NAB-paclitaxel drug sold by Celgene, a biotechnology company
developing drugs for cancer and inflammoatory diseases.
Abraxane is made up of nanoparticles roughly 130nm in size and represents
the first FDA approved use of a nanotechnology chemotherapy for metastatic
breast cancer
\begin_inset CommandInset citation
LatexCommand cite
key "wos000301045400002"
literal "false"
\end_inset
.
The European Medicines Agency lists three applications for Abraxane
\begin_inset CommandInset citation
LatexCommand cite
key "epar_summary_for_the_public-abraxane_2015"
literal "false"
\end_inset
:
\end_layout
\begin_layout Itemize
Metastatic breast cancer
\end_layout
\begin_deeper
\begin_layout Itemize
Following failure of an initial treatment
\end_layout
\begin_layout Itemize
When a standard treatment including an 'anthracycline' drug is not suitable
\end_layout
\end_deeper
\begin_layout Itemize
Metastatic adenocarcinoma of the pancreas
\end_layout
\begin_deeper
\begin_layout Itemize
In combination with the drug gemcitabine
\end_layout
\end_deeper
\begin_layout Itemize
Non-small cell lung cancer
\end_layout
\begin_deeper
\begin_layout Itemize
In combination with the drug carboplatin
\end_layout
\begin_layout Itemize
When surgery or radiotherapy is not suitable
\end_layout
\end_deeper
\begin_layout Section
Efficacy
\end_layout
\begin_layout Standard
The efficacy of abraxane can be measured by comparing the treatment results
of this nanoparticle based approach with the alternative solvent based
method.
The European Medicines Agency list the results from clinical studies for
each of the cancers listed above
\begin_inset CommandInset citation
LatexCommand cite
key "epar_summary_for_the_public-abraxane_2015"
literal "false"
\end_inset
, with the effectiveness measure defined as whether tumours disappeared
or were reduced by at least 30%.
\end_layout
\begin_layout Standard
Abraxane was found to be 31% effective compared to 16% for the alternative
paclitaxel based treatment for metastatic breast cancer.
\end_layout
\begin_layout Standard
However, when considering only patients who had not previously received
treatment following a metastatic diagnosis, the effectiveness was the same
for both.
\end_layout
\begin_layout Standard
For non-small cell lung cancer it was found to be 33% effective as opposed
to 25% for the alternative.
\end_layout
\begin_layout Standard
With regards to the pancreatic study a combination of Abraxane and gemcitabine
increased overall survival to 8.7 months from 6.7 months with a treatment
of just gemcitabine.
\end_layout
\begin_layout Standard
This indicates that the drug performance is as good or better than alternatives
for all three, an encouraging result for a delivery method that also reduces
side effects and increases efficiency of delivery.
\end_layout
\begin_layout Section
Discussion
\end_layout
\begin_layout Standard
Considering these results the use of protein nanoparticles looks to represent
an effective alternative to solvent based methods in delivering lipophobic
drugs.
In doing so the side effects of the solvent based methods can be avoided.
\end_layout
\begin_layout Standard
The landscape is further broadening with research being completed into applying
NAB-technology to other taxanes such as docetaxel and macrolides such as
rapamycin.
\end_layout
\begin_layout Paragraph*
Part II Word Count:
\end_layout \end_layout
\begin_layout Standard \begin_layout Standard

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@ -149,4 +149,6 @@ keywords = "human serum albumin, misfolded states, downhill polymerization, nucl
abstract = "Protein misfolding and self-assembly of disease-related and disease-unrelated proteins and peptides into highly ordered β-sheet-rich amyloid fibrils converts this self-assembly pathway in a generic property of polypeptide chains. Hence, to gain a detailed knowledge about the underlying packing and fibrillation mechanisms of such a process the use of model proteins appears to be the key. Human serum albumin (HSA) appears to be an excellent candidate because it is highly abundant and plays fundamental biologic roles; it also displays a complex tertiary structure without any propensity to fibrillation in its native state. Thus, in this chapter, we first give a very brief summary of the main aspects of the origin of protein fibrillation. Subsequently, we describe how the various factor induce HSA fibrillation, and we also describe the possible aggregation pathways and the structure of the resulting fibrils." abstract = "Protein misfolding and self-assembly of disease-related and disease-unrelated proteins and peptides into highly ordered β-sheet-rich amyloid fibrils converts this self-assembly pathway in a generic property of polypeptide chains. Hence, to gain a detailed knowledge about the underlying packing and fibrillation mechanisms of such a process the use of model proteins appears to be the key. Human serum albumin (HSA) appears to be an excellent candidate because it is highly abundant and plays fundamental biologic roles; it also displays a complex tertiary structure without any propensity to fibrillation in its native state. Thus, in this chapter, we first give a very brief summary of the main aspects of the origin of protein fibrillation. Subsequently, we describe how the various factor induce HSA fibrillation, and we also describe the possible aggregation pathways and the structure of the resulting fibrils."
} }
@book{epar_summary_for_the_public-abraxane_2015,
title={European Public Assessment Report Summary - Abraxane}, url={https://www.ema.europa.eu/en/medicines/human/EPAR/abraxane}, journal={ European Medicines Agency}, publisher={ European Medicines Agency}, year={2008}, month={Jan}}