Download Biomedical applications of polymer-based pharmaceuticals

Biomedical applications of
polymer-based pharmaceuticals
Biomedical Engineering – Group XII
Almeida, Diogo1; Balthazar, Lucas2; Ribeiro, Filipe3
1
[email protected]; [email protected]; [email protected]
Abstract
The medical use of polymer-based pharmaceuticals is a new hope to healthcare. Polymerdrug conjugates and polymer-protein conjugates gave nanomedicine a whole new meaning, as
their application is showing new kinds of treatment for diseases such as cancer and hepatitis C.
Judging from the current research, their role will be even more significant in the near future.
In this report we will explore natural and synthetic polymers, giving an extra relevance to
polymer-drug conjugates, namely its therapeutic benefits.
Keywords
Polymer-drug conjugate, polymer-protein conjugate, chitosan, hyaluronic acid, dextran,
gellan, HPMA, PGA
Contents
1. Introduction
2. State of the art
3. Methods and Results
3.1. Polymer-protein conjugates
3.2. Polymer-drug conjugates
3.2.1. Mechanism of action of polymer-drug conjugates
3.2.2. HPMA and PGA as polymers: Brief description
3.2.3. Clinical Results
4. Polymer-drug conjugates: conclusions, challenges and opportunities
5. Natural Polymers
5.1. Chitosan
5.2. Hyaluronic acid
5.3. Dextran
5.4. Gellan
6. Conclusion
7. Acknowledgements
8. References
BIOMEDICAL APPLICATIONS OF POLYMER-BASED PHARMACEUTICALS 2008
1. Introduction
Over the past decades, research at the level of molecular biology has unveiled the
molecular basis for many diseases. New important technologies and concepts, such as
recombinant DNA and gene therapy, have provided tools for the creation of pharmaceuticals and
methods designed to specifically address such diseases. However, progress towards the
application of these medicines outside of the laboratory has been considerably slow, principally
due to the lack of effective drug delivery systems, that is, mechanisms that allow the release of the
drug into the appropriate body compartment, for the appropriate amount of time, without
seriously disrupting the rest of the organism functionality.
There has been a growing number of different approaches to counter this issue, each with
its own particular applications, given the pathophysiology of the disease. Polymers, and associated
nanomedicine technologies, constitute a relatively new and promising approach that has already
been proven effective in a wide range of applications.
The current work covers mainly two concepts subordinated to the named polymer
therapeutics: polymer-protein conjugates (Figure 1) and polymer-drug conjugates. Although both
include the binding of polymers to pharmacological substances, polymer-protein and polymerdrug conjugation are effectively different, principally in terms of their final applications and the
purpose behind conjugation.
It should also be noted that although our work will focus mainly in polymer-drug and
polymer-protein conjugation, synthetic and natural polymers are used widely as components of
new medical devices, for example, as rate-controlling coatings, of hydrogels or materials for the
topical administration of drugs, and as constructs for tissue engineering.
Besides the use of polymers as carriers for drug-delivery systems, certain natural polymers
such as dextran, gellan, chitosan and hyaluronic acid have very interesting properties, which
makes them particularly useful in a diverse spectrum of applications (including protein/drug
conjugation). As such, it is also our intention to explore these compounds, in a tentative to find
out why this is so.
Figure 1: Schematic representation showing the families of polymer constructs called polymer therapeutics.1
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2. State of the art
The use of polymers in the medical field is not a novelty - natural polymers have been used
as components of herbal remedies for centuries. When it comes to synthetic polymers, however,
the situation is very different. Because polymer science is a relatively recent area of research,
synthetic water-soluble polymers as macromolecular drugs or as part of drug delivery systems
related to inoculation can be considered a modern achievement.
Hermann Staudinger, Morawetz, Lehn and Ringsdorf are important names associated to
the birth of the polymer science field, which occurred in the 1920s. In 1953, Staudinger received
the first Nobel Prize related to this new area of research, about the same time Watson and Crick
revealed their theory on the structure of DNA. Such discoveries paved the way for more advanced
water-soluble synthetic polymers, which were starting to make an important contribution to
healthcare.
The first polymer-drug conjugates appeared around 1955, being mescaline-Nvinylpyrolidine conjugate one of the first. This conjugate had a drug attached by non-degradable
or enzymatically degradable side chains, quite like many polymer-drug conjugates tested today. In
the following years, many others biologically active polymeric drugs followed, as their clinical
importance started to increase. In the 1960s, divinylether-maleic anhydride copolymer (pyran
copolymer) was clinically tested as an anticancer agent, but the early trials failed due to its severe
toxicity, later discovered to be caused by minor differences in the polymer molecular weight (and
thus in the chain length).
About ten years later Frank Davis and
Abraham Abuchowski were able to foresee the
potential of conjugating poly(ethylene glycol)
(PEG) to proteins, causing the birth of a
technique called PEGylation. PEGylation consists
in the covalent bond of poly(ethylene glycol)
polymer chains to another molecule, usually a
drug or a protein with therapeutic effects (Figure
2). This covalent attachment is able to disguise
the drug or the therapeutic protein from the
immune system of the host, reducing its
stimulation (immunogenicity) and increasing the
size of the agent in solution, which on its turn
increases the conjugate’s circulatory time.
Figure 2: Schematic of PEG polymer-protein conjugation. 2
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In the early 1990s, the clinical use of the first PEGylated proteins was approved. At this
time, PEGylation became a process widely known and it was crucial for the development of
localized therapeutics. As it increases the molecular weight of a molecule, this process improves
drug solubility and stability, extending its circulating time, therefore reducing dosage frequency
with potentially reduced toxicity, and boosting protection from proteolytic degradation.
By the time the first PEGylated medicines were approved, a new phenomenon was
discovered in Japan. It was the passive tumour targeting phenomenon now known as the EPR
effect (Enhanced Permeability and Retention effect), which consists in the passive accumulation of
substances, usually liposomes or macromolecular drugs, in tumour tissue (because of the lack of
effective tumour lymphatic drainage), and in the hyperpermeability of the blood vessels towards
the same kind of molecules referred above (due to the angiogenic tumour vasculature, which has
a discontinuous endothelium).
Also in the 1990s, many interesting polymeric drugs were created. Those synthetic
products were designed to treat different pathologies, such as multiple sclerosis (treated with
synthetic random copolymer of L-alanine, L-lysine, L-glutamic acid and L-tyrosine administered
subcutaneously) and HIV-1 (treated with dextrin-2-sulfate given orally).
In 1994, the first synthetic polymer-drug conjugate designed to treat cancer was clinically
tested. It consisted on an HPMA (N-(2-hydroxypropyl)methacrylamide) copolymer conjugate of
doxorubicin. Targeted release of anticancer agents can also be made using block copolymer
micelles, which have the ability to entrap the drug or to covalently link to it. By that time, HPMA
copolymer micelles were clinically tested for the first time.
In the 2000s, two polymer-protein conjugates, PEG-interferon-α (an antiviral drug intended
to treat chronic hepatitis C and hepatitis B) and PEG-GCSF (PEG granulocyte colony-stimulating
factor) were placed in the market, and five years later the first therapeutic nanoparticleI (albuminentrapped paclitaxel) was approved as a treatment for metastatic breast cancer.
All the above achievements and researches were the core elements that led to the
development of polymer-based pharmaceuticals, namely polymeric drugs, polymer-drug
conjugates and polymer-protein conjugates. The clinical trials of these new technologies
eventually lead to the resolution of many other unexpected challenges that quickly appeared, such
as the manufacturing of the polymers at an industrial scale and the quick and total solubilization of
the pharmaceuticals for safe inoculation. The optimization of these clinical tests (in terms of
dosage and frequency) is still being evaluated today for a large variety of products.3, 4
I A nanoparticle is a small particle (usually of 20-500 nm dimensions) produced from natural or synthetic
polymers, which are used, as mentioned before, to capture drugs for drug targeting and controlled release.
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3. Methods and Results
3.1 Polymer-protein conjugates
Polymer-protein conjugation can be seen as an approach to increase the efficiency of
protein, peptide and antibody based drugs, given the vast range of these medicines that are being
created as a result from genomics and proteomics research, associated with new technologies
such as recombinant DNA and monoclonal antibodies. Their limitations often include a short
plasma half-life, poor stability, and, especially in the case of proteins, immunogenicity.3 Research
done in the 1970’s foresaw the potential of binding the polymer PEG (polyethylene glycol) to
proteins and since then a great progress was achieved. Nowadays, the advantages of this
technique have become evident. It is used in a wide variety of products, including enzymes,
cytokines and monoclonal antibody fragments. PEGylation has been proven to provide among
other things, increased protein solubility and stability, reduce receptor-mediated protein uptake
by cells of the reticuloendothelial systemII, reduce protein immunogenicity, prevent the rapid
renal clearance of small proteins, and prolonging plasma half-lifeIII, thus requiring less frequent
dosing, which is of great patient benefit.1
The first polymer-protein conjugate to enter the market was PEG-adenosine deaminase in
1990. Since then, others have followed (Table A). PEG-L-asparaginase, for instance, is used as a
treatment for acute lymphoblastic leukaemia, with the advantage of reduced hypersensitivity
reactions when compared to the native enzyme. Other PEGylated protein compounds includes
PEG-G-CSF (G-CFS stands for a recombinant methionyl human granulocyte colony-stimulating
factorIV), which is used to prevent cancer chemotherapy induced neutropaeniaV, with the
advantage of requiring less frequent dosing when compared to free G-CSF. In addition to proteins,
PEG has also been used to produce a number of polymer-cytokines conjugates. Two PEGinterferon-α conjugates, which have shown better activity in vivo compared to IFN-α, have been
approved as treatments for hepatitis C.
Despite the possibility of using other polymers for polymer-protein conjugation, PEG has
been more widely used due to a number of reasons. Firstly, it has a number of other uses apart
from serving as a polymeric carrier, and is known to be non-toxic and non immunogenic. Secondly,
it’s flexible, highly water-soluble chain provides a hydrodynamic radiusVI up to 10 times greater
than a globular protein of equivalent molecular weight, and in addition to that, it is high degree of
hydration means it effectively has a water shell, which helps to mask the protein to which it is
II
The reticuloendothelial system is a part of the immune system, which consists in the phagocytic cells, primarily monocytes and
macrophages.
III
Plasma half-life can be defined as the time a certain substance takes to lose half its pharmacological or physiological activity.
IV
Granulocyte colony-stimulating factor is a substance that stimulate the bone marrow to produce granulocytes and stem cells.
V
Neutropaenia is an abnormal condition characterized by a low number of neutrophils in the blood.
VI
The hydrodynamic radius is a mathematically defined quantity that arises from the study of the dynamics of polymers moving in a
solvent. Here it can be seen as a measure of the easiness a polymer can move in water.
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bound. And thirdly, the fact that PEG can be prepared with a single reactive group at one terminal
end aids site specific conjugation and prevents protein crosslinkingVII during this process.
Table A: Examples of polymer-protein conjugates in clinical use or development.
Compound
Status
Indications
PEG-adenosine-deaminase
Market
Hepatocellular carcinoma
PEG-l-asparaginase
Market
Acute lymphoblastic leukaemia
PEG-GCSF
Market
Prevention of neutropaenia associated with
cancer chemotherapy
PEG-IFNα2a
Market / Phase I/II
Hepatitis B and C / Melanoma, chronic myeloid
leukaemia and renal-cell carcinoma
PEG-IFNα2b
Market / Phase I/II
Hepatitis C / Melanoma, multiple myeloma and
renal-cell carcinoma
PEG-arginine deiminase
Phase I
Hepatocellular carcinoma
3.2 Polymer-drug conjugates
Polymer-drug conjugation has been explored so far mainly as a means of targeted drugdelivery for anti-cancer drugs. Most of the anti-cancer polymer-drug conjugates designed rely on
the EPR effect for passive targeting. Although extracellular drug-delivery can account for some
anti-cancer activity, a main concept behind polymer-drug conjugation is that of lysosomotropic
and endosomotropic drug delivery, that is, the liberation of the drug inside lysosomes and
endosomes, respectively. As of 2006VIII, quite a few polymer-drug conjugates were under clinical
evaluation as shown in Table B. Their clinical performance will be discussed below.
Mechanism of action of polymer-drug conjugates
Polymer-drug conjugates mechanism of action is based on two main aspects: EPRmediated targeting and endocellular drug-delivery through the endocytic pathway. The following
image (Figure 3) summarizes the current understanding of the mechanism of action of polymerdrug conjugates.
VII
A cross-link is a link between two polymers (in this case, proteins). Cross-links are normally formed by chemical reactions
initiated by heat, pressure or radiation.
VIII
The results presented here are all based on 2006 studies.
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Figure 3: A. After intravenous administration of the conjugate, the increased leakiness of the tumour angiogenic
vasculature would lead to a preferential accumulation of the drug in the tumour interstitium, by the EPR effect (a and
b). The addition of cell specific targeting ligands (as in the case of HPMA copolymer-doxorubicin-galactosamine, see
below) could increase the targeting effect. B. After arrival in the tumour tissue, the molecule would be internalized
either by fluid-phase pinocytosis, non-specific receptor-mediated pinocytosis or ligand-receptor docking. Lysosomal
proteases (such as cathepsin B, which is more expressed in tumoural cells) or the decrease in pH inside
endosomes/lysosomes would lead to either the cleavage of the polymer-drug linker or the polymer itself (as in the
case of PGA-paclitaxel, see below), releasing the drug inside the cell. Such a system of delivery could, in theory, bypass
certain resistance mechanisms, namely those associated with membrane efflux pumps as in the case with MRP
(multidrug resistant protein) and p-glycoprotein. Note that if the polymeric carrier is non-biodegradable, its size must
be limited in order to assure renal elimination and preventing polymer-associated unwanted toxic effects.3
Table B: Examples of polymer-drug conjugates in clinical development.3
Polymer-drug conjugates
Compound name
Status
Indications
HPMA copolymer-doxorubicin
Phase II
Various cancers, particularly lung and breast cancer
HPMA copolymer-doxorubicingalactosamine
Phase
I/II
Particularly hepatocellular carcinoma.
HPMA copolymer-camptothecin
Phase I
Various cancers.
HPMA copolymer-paclitaxel
Phase I
Various cancers.
HPMA copolymer-carboplatin
platinate
Phase
I/II
Various cancers.
HPMA copolymer-DACH-platinate
Phase
I/II
Various cancers.
PGA-paclitaxel
Phase III
Various cancers, particularly non-small cell lung cancer;
ovarian cancer
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Polymer-drug conjugates
PGA-camptothecin
Phase
I/II
Various cancers.
Dextran-doxorubicin
Phase I
Various cancers.
Modified dextran-camptothecin
Phase I
Various cancers.
PEG-camptothecin
Phase II
Various cancers.
HPMA and PGA as polymers: Brief description
HPMA (N-(2-hydroxypropyl)methacrylamide) homopolymer was initially designed for use
as a plasma substitute, and doxorubicin is a drug from the family of the anthracyclinesIX. HPMA
copolymer-doxorubicin uses a Gly-Phe-Leu-Gly tetrapeptide as a linker, which is degraded by the
lysosomal protease chatepsin B after cellular uptake of the conjugate, following the
lysosomotropic model. HPMA copolymer-doxorubicin-galactosamine has a similar structure,
except for the addition of galactosamine, which is intended to work as a targeting ligand for the
asialoglycoprotein receptor present in hepatocytesX, thus increasing hepatocyte-associated drug
concentrations.
PGA (polyglutamate), unlike HPMA, is a biodegradable polymer. Therefore, PGA polymerdrug conjugates release drug through hydrolysis during systemic circulation, but most of the drug
is released inside the cells, after cleavage of the polymer backbone by the protease chatepsin B.
Clinical Results
Both HPMA-doxorubicin and HPMA-doxorubicin-galactosamine have displayed, in some
areas, significative clinical improvement when compared to their non-conjugated counterparts.
HPMA-doxorubicin showed a maximum tolerated dose of 320 mg/m2, which represents a five-fold
increase compared to free doxorubicin. Maximum dose associated toxicity was typical of the
anthracyclines (mucositisXI and neutropaenia), with the notable exception of cardiotoxicity. During
phase I trials, anti-cancer activity was observed in patients with non-small-cell-lung cancer,
colorectal cancer and anthracycline-resistant breast cancer. However, during phase II trials, no
activity was observed from colorectal cancer patients.3
HPMA-doxorubicin-galactosamine was designed as a treatment for primary liver cancer. A
maximum tolerated dose of 160 mg/m2 was observed during phase I/II trials, and maximum
tolerated toxicities were again typical of the anthracyclines. Of the 23 patients treated, two
displayed partial responses, one displayed a reduction in tumour size, and eleven had stable
IX
Anthracyclines are a class of drugs widely used in cancer treatment. Their mechanism of action involves the
inhibition of topoisomerase II, an enzyme involved in DNA replication.
X
Hepatocytes are the main type of cells that constitute the liver.
XI
Mucositis is the painful inflammation of the mucous membranes lining the digestive tract.
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disease. However, hepatocyte-associated drug was 12-50-fold higher than what can be achieved
with free drug.3
First generation HPMA copolymer-conjugates contained anthracyclines, as these were the
most used anti-cancer drug at the time. Camptothecin and paclitaxel, once discovered, became
interesting candidates for polymer conjugation given their poor water solubility (and thus the
conjugation to a more soluble polymer could help to improve the drug biodistribution), and the
hypersensitivity reactions associated with free drug administration, in the case of paclitaxel.
However, HPMA copolymer-camptothecin and HPMA copolymer-paclitaxel early clinical trials
were disappointing.5 HPMA-camptothecin displayed no anti-tumour activity, whereas HPMApaclitaxel showed no improvement in therms of dose-limiting toxicity compared to free paclitaxel.
Both conjugates use a normal ester linkage between the drug and the polymer, and unexpected
excessive liberation of drug during systemic circulation and renal clearance could explain some of
the observations, namely, the lack of preferential EPR mediated tumour accumulation and severe
cystitisXII in the case of HPMA-camptothecin.
Partial successes resultant from PGA-paclitaxel phase I/II studies granted eligibility for
phase III studies. PGA-paclitaxel was compared with gemcitabineXIII or vinorelbine as a first-line
treatment for poor performance status non-small-cell lung cancer (NSCLC) patients.3 A significative
improvement in terms of survival was observed when compared with vinorelbine. Such an
increase was particularly high in pre-menopausal women treated with PGA-paclitaxel, which could
be related to the increased expression of cathepsin B due to greater oestrogen levels.3 A pivotal
trial is ongoing in order to compare PGA-paclitaxel with paclitaxel as a first line-treatment for
NSCLC in women.
4. Polymer-drug conjugates: conclusions, challenges and opportunities
The fact that both HPMA copolymer-doxorubicin conjugates showed a decrease in toxicity
when compared to the administration of free drug proves the feasibility of polymer-drug
conjugation as a means of decreasing chemotherapy-related general toxicity. On the other hand,
HPMA-camptothecin and HPMA-paclitaxel disappointing results make clear the need for careful
linkage selection, since the excessive unwanted release of the drug in the bloodstream can
seriously hazard anti-cancer activity, either by lowering EPR mediated targeting or increasing
general toxicity.3
Most of the conjugates have showed superior in vivo results when compared to their
parent drug, and there are some indications that HPMA-copolymer conjugates can circumvent
multi-drug resistance (MDR), which would be consistent with lysosomotropic delivery of the drug.
It is not yet clear to what extent polymer-drug conjugates display EPR mediated targeting
when considering clinical metastatic cancer. Preliminary studies with HPMA copolymerdoxorubicin using rodent models indicated that variations in lysosomal thiol-protease activity
XII
Cystitis is the inflammation of the urinary bladder.
Gemcitabine is a nucleoside analog which replaces cytosine, preventing DNA replication and thus leading to cell
apoptosis; vinorelbine acts as an anti-mitotic drug.
XIII
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(such as cathepsin B) were more important in determining anti-cancer activity than the extent of
EPR mediated targeting.3 In addition, the fact that some patients displayed more EPR mediated
targeting than others means that certain individuals would benefit more from the administration
of conjugates than others, and thus a better understanding of the factors behind EPR-targeting
could provide a foundation for the selection of patients better suited for treatment with polymerdrug conjugates.3 Also, the tumour targeting of many polymer-based pharmaceuticals could be
improved by co-administration of agents that enhance vascular permeability, providing another
possibility for increased effectiveness of the EPR effect.
The possibility of administrating more than one drug, either as two different conjugates, or
the conjugation of more than one drug to the same polymer in combinatorial therapies is also
something that is worth being explored. An ongoing study is examining a combination of PGApaclitaxel and carboplatinXIV as a first-line therapy for ovarian cancer, and initial results showed a
positive response in 80 out of 82 patients.3 Another interesting approach has been the
administration of a polymer-drug and a polymer-protein conjugate, in a two-step prodrug therapy.
In this sense, HPMA copolymer-Gly-Phe-Leu-Gly-doxorubicin could be administrated followed by
an HPMA copolymer-chatepsin B, thus triggering a faster release of doxorubicin, after
accumulation in the tumour tissue by the EPR effect.
It should be noted that although the results of many researches have been satisfactory,
polymer-drug conjugation is a concept that allows a lot more of development. New polymer
technologies, such as graft polymers, star polymers, multivalent polymers, dendrimers, and
dendronized polymers (Figure 4) constitute new polymeric architectures that could (and this is the
current trend at the moment) be applied to the field of polymer conjugation, thus providing new
opportunities for clinical development.
Figure 4: New polymeric architectures that could provide interesting possibilities for polymer conjugation. Their
advantages include a more defined chemical composition, tailored surface multivalency, providing more possibilities
for conjugation, and a defined three dimensional architecture.1
XIV
Carboplatin is a chemotherapy drug used against some forms of cancer, namely ovarian carcinoma, lung, head and
neck cancers.
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5. Natural Polymers
5.1 Chitosan
Figure 5: Chitosan is derived from chitin by a process named alkaline deacetylation, which consists in treating chitin
with 50% of hydroxide for a few hours. 6
Chitosan (poly-D-glucosamine) is a natural polymer derived from chitin (Figure 5). After
cellulose, chitin is probably the most abundant polysaccharide in nature, whereas chitosan is a
very rare compound that only exists in some kinds of fungi. Comparisons drawn between chitosan
and chitin show that the former has a better chemical and biochemical reactivity. In addition to
that, chitosan is known to have a series of interesting properties: low toxicity, biocompatibility and
biodegradability.6
Chitosan is composed by glucosamine units with a free amino group located in the second
carbon. The aminogroup (rare in polysaccharides) is frequently used as the reactive side. There are
four polymorphic forms of chitosan, discovered from X-ray diffraction measurements, three in a
hydrated form and one anhydrous form. Because of its specific characteristics, explained by the
unique physicochemical proprieties of the polymer, chitosan has recently attracted more attention
over chitin, although the latter also has its uses in pharmaceutical and biomedical branches as a
bioactive agent.
Chitosan is known to possess an intrinsic antibacterial activity, even though the exact
reason for this isn’t fully known. It is believed that the positive amino group of glucosamine units
changes the barrier proprieties of the microbial cell membranes, interacting with their negative
charged components, either preventing the nutrients from entering the cell or causing the leakage
of intracellular contents.6 Another possible explanation for this is that the penetration of chitosan
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inside the cell and subsequent binding to DNA provokes the inhibition of RNA transcription and
consequently protein synthesis.7
Depending on molecular size, solubility and partial acetylation, chitosan may also have an
anti-tumoural activity, displayed specially by low weight forms of the polymer.
Chitooligosaccharide with six sugars, for example, can inhibit the proliferation of CT26 cells
inducing their apoptosis, whereas partially acetylated chitosan has been shown to inhibit the
growth of sarcoma180 tumour cells in a rodent experiment. In vitro tests with 293 cell lines and
HeLa Cells reveal that complexes with different cooper to chitosan ratios can be used as potential
anti-tumour agents.
Chitosan also has an important antioxidant activity. Antioxidants delay or inhibit the
oxidation of some cell substrates, helping the body to fight against the damage caused by reactive
oxygen species (ROS) and degenerative diseases. Free radicals of oxygen, produced for example by
ultraviolet light, are very unstable and react easily with the cell or tissue. Low molecular weight
partly deacetylated chitosan is known to be a natural antioxidant, and although the exact reason
for this isn’t yet known, it is thought to be due to the amino group and hydroxyl groups in C-2, C-3
and C-6 positions, which react with free radicals to form more stable macromolecular radicals.
Chitosan-based compounds have also been clinically tested as a polimeric carriers for anticancer drugs, such as camptothecin. Since a simple chitosan-camptothecin conjugation was known
to have a series of disadvantages, namely, scarce water-solubility and possible toxic side-effects,
aggregates of O-carboxymethylchitosan (OCMSC) were prepared.6 Other uses of chitosan in the
area of drug delivery systems includes the production of anti-cancer drug carrying microparticles
and as polimeric vectors for gene therapy.
5.2 Hyaluronic Acid
Hyaluronic acid (HA) is a natural polymer and a polysaccharide which is characterized by
having a high molecular mass and viscoelastic properties. It belongs to a group of substances
called glycosaminoglycans and is a linear polysaccharide composed of alternating D-glucuronic
acid and N-acetylglucosamine (Figure 6).7
Figure 6: Structure of the disaccharide repeating unit of hyaluronic acid.7
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HA is a component of many different kinds of biological tissues and fluids and is also
present in the capsules of some bacteria (e.g. strains of streptococci), but is absent in fungi, plants
and insects.7 It has important physiological roles in living organisms: in human body, for example,
we can find HA in synovial fluid, umbilical cords, vitreous humor of the eye and skin (mainly the
one located in intracellular space). HA is also a key element in the human body due to its role in
embryogenesis, signal transduction and cell motility and it is strongly linked with cancer
invasiveness and metastasis.
The intrinsic biocompatibility of HA makes it excellent for medicine. Some of its
applications are:
1. viscosurgery, protecting tissues and providing space during surgeries like in
ophthalmological surgery;
2. viscoaugmentation, filling and augmenting tissue spaces, as in vocal and pharyngeal
tissues;
3. viscoseparation, separating connective tissue surfaces that are traumatized to prevent
adhesions and excessive scar surfaces;
4. viscosupplementation, replacing tissue fluids, as the replacement of synovial fluid in
complicated cases of arthritis and to relieve pain;
5. viscoprotection, protecting tissue surfaces from dryness or dangerous environmental
agents, and promoting the healing of injured surfaces.
HA has an important role in infection scenarios, as it affects the infected cells and causes
the reduction of inflammation. The analgesic effects of the substance are widely known at the
moment. There is also a great variety of applications of HA in the targeted release of medicines.
This polymer has been used to create a cross-linked hydrogel for drug delivery, and nowadays
scientists can also directly conjugate HA to drugs or use the polymer to prepare microcapsules for
optimized drug delivery capsules.
5.3 Dextran
Dextran is a polysaccharide synthesized from sucrose by lactic acid bacteria. It is a
component of the human body, being part of the dental plaque, for example. Since the polymer is
a natural compost, it has some important advantages, as biocompatibility, biodegradability and
low toxicity. Some of dextran’s clinical applications are the following:
 Decreasing of vascular thrombosis
 Lubricant agent in some eye drops
 Increasing blood sugar levels
 Replacement of blood loss
 Plasma substitution
 Volume expansion
 Rheological improvement
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Recent researches in mice indicate that it is possible to use dextran as a carrier in
anticancer therapy, which is an important discovery to the future of an efficient anticancer
treatment.
5.4 Gellan
Gellan is a high molecular weight exopolysaccharide (EPS) produced by bacteria like
Sphingomonas elodea. Gellan has important characteristics as a natural polymer and a large
variety of applications, particularly in the food, pharmaceutical and biomedical fields, as seen in
Table C.
Table C: Selected list of worldwide-issued and published patents covering the use of gellan gum categorized into
application fields.8
Application
Patent Title
Country / Patent nº
Gellan gum beverage and process for making a
US5,597,604
gelled beverage
Gelatin-free gummy confection using gellan gum
US6,586,032
and carrageenan
Calcium stable high acyl gellan gum for enhanced
CN101001538
colloidal stability in beverages
Food containing native gellan gum
JP2005253473
Gellan gum tablet film coating
Gellan gum based oral controlled release dosage
forms-a novel platform technology for gastric
retention
Liquid aqueous ophthalmic composition containing
gellan gum
Spray able wound care compositions comprising
gellan gum
Controlled release compositions comprising gellan
gum gels
PHB-free gellan gum broth
Mutant strain of Sphingomonas elodea which
produces nonacetylated gellan gum
US2004033261
Genetically purified gellan gum
US2006003051
Modified gellan gum and its production
JP11341955
US2006177497
NZ217662
NZ523126
WO9922768
US5300429
US2003100078
Cosmetic composition comprising gellan gum and
GB2384705
carrageenan
Oil-in-water emulsion comprising gellan and a
WO0078442
particular surfactant and uses
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BIOMEDICAL APPLICATIONS OF POLYMER-BASED PHARMACEUTICALS 2008
Composition of toothpaste having improved
physical properties and stability, comprising gellan KR20050023598
gum
Gellan seamless breakable capsule and process for
manufacturing thereof
WO2006136198
Process using gellan as a filtrate reducer for waterUS5744428
based drilling fluid
Paper coating composition comprising gellan
US6290814
gum/starch blend
Purification and use of gellan in electrophoresis
US2004168920
gels
Media and methods for promoting maturation of
US20050003415
conifer somatic embryos
a) Tissue culture gels, air freshener gels, paper coating, oil recovery, etc.
Due to gellan’s stability, biocompatibility and biodegradability, researchers began to
investigate the use of the polymer as a drug delivery vehicle.
6. Conclusion
Polymer-based pharmaceuticals are starting to be seen as key elements to treat many
lethal diseases that affect a great number of individuals, such as cancer or hepatitis C.
At the moment, the impact of the researches on polymers applied to nanomedicine is more
significant than it ever was, as new properties and applications of the polymer conjugates are
being found. Nonetheless, clinical testing is still an obstacle for many developments in the field, as
sometimes theory does not apply in its entirety to practice. There is still a need for the cautious
design of new conjugates and careful validation of the chemical characterization before clinical
trial.
The previously revised study shows many applications of some widely known natural
polymers and synthetic polymer-based medicines, which are being seen as crucial elements to
boost healthcare.
Further studies will surely be able to clarify some blurred concepts and if the obstacles
found in clinical trials are surpassed, biomedical applications of polymer-based pharmaceuticals
may overcome expectations.
7. Acknowledgements
The authors would like to show their gratitude towards Prof. Leonilde Moreira, who guided
us through the development of this report.
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BIOMEDICAL APPLICATIONS OF POLYMER-BASED PHARMACEUTICALS 2008
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Arsenio M. Fialho, Leonilde M. Moreira, Ana Teresa Granja, Alma O. Popescu, Karen Hoffmann and Isabel SáCorreia. 2008. Occurrence, production, and applications of gellan: current state and perspectives. Appl Microbiol
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