nano technology is impacting the way medicine is developing ... · web viewtargeting of...
TRANSCRIPT
![Page 1: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/1.jpg)
Nano Curcumin: Making it useful for human therapy
Sitabja Mukherjee1, Gopesh Ray2, Puneet Gandhi3, Santosh K. Kar2
1School of Biotechnology, KIIT deemed to be University, Bhubaneswar, Odisha, India
2Nano Herb Research Laboratory, KIIT Technology Business Incubator, KIIT deemed to be
University, Bhubaneswar, Odisha, India
3Department of Research and Training, Bhopal Memorial Hospital and Research Centre, Bhopal,
India
Corresponding author:
Professor Santosh K. Kar,
Nano Herb Research Laboratory, KIIT Technology Business Incubator,
Kalinga Institute of Industrial Technology (Deemed University),
Bhubaneswar-751024, Odisha, India
e-mail : [email protected],
Phone : +919937085111
![Page 2: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/2.jpg)
Abstract:
Curcumin, the polyphenolic pigment from turmeric has excellent therapeutic potential but due to
poor aqueous solubility and metabolic instability it has not yet been possible to use it as a drug.
Structure-activity relationship studies have revealed that curcumin can remain in keto-enol
tautomeric forms depending upon the pH of the milleu in which it exists. The keto form is
generated at acidic pH and due to the presence of β-diketone domain in the molecule it has an
active methylene group which is responsible for its anti-oxidative properties. The enol form
becomes a planar molecule due to extensive delocalization of electron from one aromatic ring
to the other through the pi orbital of C=C bonds in the heptadione linkage. It gets degraded to
smaller molecules which have been shown to have therapeutic activity. Molecular interaction
studies have identified the methylene group, the methoxy group and phenol hydroxyl group on
the aromatic rings to be the contact points of curcumin molecule with enzymes and signaling
molecules for inactivating them. The bioavailable forms of curcumin which has been cited in this
review have been formulated using curcumin entrapped or bound to organic nanoparticles,
liposome, phospholipid complexes, nanoemulsions, or polymeric micelles and have been tested
against chronic inflammatory conditions in animal models with remarkable success. As an
alternative approach, we also have prepared nanocurcumin of 200 nm size using anti solvent
precipitation method and observed it to be effective in animal models of cancer, tuberculosis and
hypoxic conditions.
Introduction:
Turmeric prepared from the rhizome of Curcuma longa plant has been used in Indian traditional
system of medicine for centuries for healing wounds, reducing pain and as an anti bacterial
![Page 3: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/3.jpg)
agent. But no one had any idea about the component of turmeric which gave it this medicinal
properties till the yellow pigment responsible for the bioactivity was isolated by Vogel Jr in 1842
and it’s chemical structure was identified by Milobedzka and Lampe (1). Subsequently careful
fractionation by Srinivasan in 1953 showed that it consisted of three different molecules namely
curcumin, demethoxy curcumin and bis-demethoxy curcumin (2). Recently a fourth molecule
called cyclocurcumin has been added to this list (Fig. 1) (3).
Development of sensitive methods of separation and mass spectroscopic analysis has now
revealed that turmeric has many more molecules with potential therapeutic use. Except for very
few of them none of those molecules has been studied extensively (4). Once the methods for
isolation of Curcumin from curcuma longa extract was established it became commercially
available and many laboratories from different parts of the world got involved in evaluating its
potential as a therapeutic agent against bacteria, parasites and cancer cells in culture or in animal
models. This generated a large body of interesting data. Knowing that Curcumin has the
potential to reduce inflammation, efforts were made to find out whether Curcumin can be
developed into an adjunct drug to be used in chronic inflammatory diseases like Cancer,
Neurodegenerative diseases and arthritis in humans. It would require testing of the natural
curcumin for determination of its pharmacokinetics and short term as well as long term toxicity
in animals so that clinical trial in humans could be started and if found safe it could be used. Till
date more than 200 clinical trials have been conducted using natural curcumin and it has been
declared as “Generally Recognised as Safe”( GRAS). It was found that an individual can take at
least 12 grams of natural curcumin per day without any toxicity (5). But curcumin is very poorly
soluble in water (400ng/ml) and is metabolically unstable (6) Therefore it could not fulfil the
pharmaceutical requirement of proper absorption, distribution,metabolism,excretion and toxicity
![Page 4: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/4.jpg)
( ADMET ) to be developed into a drug. Therefore efforts to make curcumin bioavailable with
greater metabolic stability were taken up on a mission mode (7).
This review will therefore discuss briefly about Curcumin as a molecule and it’s pharmacology
and would highlight efforts that has gone into making it into nano form with better
bioavailability and its activity using cell lines and animal models. We would also point out how
it could be developed into a formulation which can be useful to humans. Since literature is vast
and many excellent reviews have been published recently we would mostly focus on preparation
of nano formulations with improved bioavailability which has been used with some success in
disease models involving cell lines and animal models. We would also mention about the
structural features of Curcumin which makes it an unique molecule, it’s pharmacological
properties and the role the degradation products may be playing in it’s therapeutic activity. We
would highlight our approach where pure curcumin has been used to make nano curcumin of 200
nm size without any carrier which has been used in animal models with equal efficacy and have
better chance of being developed as a therapeutic agent for chronic inflammatory diseases in
humans.
Curcumin the molecule: structure activity relationship
Curcumin,(1,7-bis (4'-hydroxy-3'-methoxyphenyl) hepta-1,6-diene-3,5-dione), the orange yellow
crystalline powder with a molecular weight of 368.38 kDa is an interesting molecule which has
a bis-α,β-unsaturated β-diketone form which exists in equilibrium with its enol tautomer (8). One
form or the other predominates depending upon the pH of the tissue in which it is present (Fig 2).
The keto form is found in acidic or neutral condition and is mostly found embedded into the lipid
bilayer of the cell membrane has the methylene group flanked by two keto groups as well as the
![Page 5: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/5.jpg)
phenolic OH groups on the aromatic rings which has been ascribed to make curcumin bioactive
and the enol form which is generated in alkaline condition is degraded fast. This keto-enol-
enolate equilibrium of curcumin determines its physicochemical and antioxidant properties. It is
interesting to note here that when curcumin is present in the enol form both the aromatic rings
present at either end of the molecule can interact with each other through extensive
delocalization of electrons. Due to these structural constraints the aromatic rings at either end of
the molecule will have to be in the same plane and the whole molecule will be planar. Such a
molecule will have the propensity to bind to a large number of proteins circulating in the blood
as it can just slip into the active site of the enzyme or even non specifically into a hydrophobic
cavity in the protein. The keto form will be flexible due to freedom of rotation of c-c bonds
present in the bis-α, β-unsaturated β-diketone form (Fig. 1). The two aromatic rings with
hydroxyl and o-methyl groups can be in different planes and can interact with other molecules
independent of each other. Therefore the keto form can have different physiological properties
than the enol form which has to be a planar molecule.
When curcumin in the native form is administered into the body either orally or by
intraperitoneal injection it is rapidly eliminated from the body due to its low solubility which
leads to diminished absorption and extensive systemic clearance due to its degradation or
metabolic conversion to more water soluble forms and rapid secretion. The curcumin is
enzymatically converted to more soluble forms like glucuronide and sulfate conjugates or
reduced to tetrahydrocurcumin and hexahydrocurcumin glucuronides in the gut of mice, rats or
humans (Fig. 3).
The basic antioxidant activity of curcumin is directly dependent on the presence of hydrogen on
the phenolic groups or on the central-methylene groups . A phenoxy radical can be generated
![Page 6: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/6.jpg)
from the phenolic groups present in the curcumin molecule by loss of a proton and similar
reactions can generate a carbon radical from the central methylene group. The stability of the
phenoxy-radical is higher than that of the carbon-radical, but experimental data where curcumin
has been used indicate that both the phenoxy radicals as well as the carbon radicals contribute to
the biological activity of curcumin. The phenoxy or the carbon radicals generated in the
curcumin molecules are resonance stabilized and could be inter-converted through extensive
conjugation. Therefore curcumin can act as a powerful scavenger of different reactive oxygen
species (ROS), such as the hydroxyl radicals, hydrogen peroxide, singlet oxygen, superoxide
anion etc., thereby preventing damage to macromolecules in circulation in the blood or present in
the tissue. Therefore phenolic groups or the active methylene groups are one of the most
important parts of the curcumin molecule. Confirmation of such statement comes from the fact
that after replacing the hydroxyl group by other functional groups, the ability of curcumin to
remove the free radicals is generally lost.
The pharmacology of curcumin molecule: role of degradation products
Curcumin is poorly bioavailable and unstable under the physiologic condition prevalent in the
tissue. So it is very likely that the degradation products of curcumin which are relatively more
water soluble may be responsible for the observed health benefits ascribed to curcumin.
Wang et al. found that 90% of curcumin degraded within 30 min in phosphate buffer at pH 7.4
into various products, identified as trans-6-(4`-hydroxy-3`- methoxyphenyl)-2,4-dioxo-5-hexenal,
ferulic aldehyde, ferulic acid, feruloyl methane, and vanillin (9) (Fig 3) In addition, it is not
clear how curcumin exerts inhibitory effects against so many enzymes, whose binding
pockets cannot bind to curcumin. By analyzing the similarities between the biological
![Page 7: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/7.jpg)
activities of curcumin and its degradation products against diseases such as Alzheimer’s
disease and cancer, as well as the preferential inhibition of some enzymes by these
products, it appears that the bioactive degradation products may contribute to the
pharmacological effects of curcumin. But when curcumin enters the body it binds to the
proteins like albumin and fibrinogen circulating in the blood and gets stabilized
(10).Therefore the degradation of curcumin which is observed in the absence of proteins
may not happen that rapidly in the tissue. This possibility should be examined in greater
details for elucidating the pharmacology of curcumin against various diseases.
Nanoformulations of Curcumin: How is it different?
Nano technology is impacting the way medicine is developing by combining nano science
with the technology of drug delivery. It tries to address poor bioavailabilty with targeted
delivery and reduction of organ toxicity. During the past two decades a large number of
methods have been developed to make nano formulations of curcumin. Out of these the
antisolvent precipitation method and ionic gelation methods are emerging to be the two most
efficient and superior techniques. Antisolvent precipitation method is a widely used
technique, where curcumin is dissolved in a solvent which is miscible with water and then
curcumin is precipitated from this solution by adding water while stirring the solution very
vigorously. Ionic gelation technique is based on the capability of polymers to crosslink in the
presence of counter ions. This technique emerged as one of the most promising systems by
using natural polymers that are non-toxic, biocompatible, and biodegradable like chitosan
and alginate. Several studies have described the potential use of such natural polymer
(chitosan/alginate) nanoparticles for oral delivery of curcumin. Literature review suggest that
the antisolvent precipitation-based methods and ionic gelation method resulted in the
![Page 8: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/8.jpg)
synthesis of curcumin nanoparticles with better solubility and stability compared to other
techniques. Many studies have reported that the antisolvent precipitation technique is
promising and cost-effective. It provides better solubility and stability of the curcumin
nanoparticles that are produced. This simple to operate technique is easy to apply for the
industrial scale production of drug nanoparticles.
Nanoparticles
Nanoparticles are usually defined as particles of approximately 1–100 nm in diameter which
possess unique physical, chemical, and biological properties which can be used for drug delivery.
Even particles of slightly bigger size can be considered as long as they are suitable for both
controlled and targeted drug delivery purposes. If a drug can be made into such a nano particle it
is excellent but otherwise the intended drug can be encapsulated inside nanoparticles which
can enhance the pharmacokinetics and solubility of the drug, help in targeted delivery and
controlled release of the drugs. In recent times, there has been increase in approved nano-based
pharmaceutical products which are the therapeutic agents themselves, or which act as
vehicles to carry different active pharmaceutical agents into specific parts of the body.
Liposomes
Liposomes are vesicular structures consisting of an aqueous core surrounded with single or multiple
phospholipid bilayers. They may vary in their charge, dimensions, and composition which
arises due to presence of different types of phospholipids. They can be
multilamellar consisting of several concentric bilayers of phospholipids or unilamellar
consisting of only one phospholipid bilayer. Liposomes can be ideal delivery systems for
![Page 9: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/9.jpg)
biologically active substances. Targeting of liposome-encapsulated drugs to particular cells
or tissues can be achieved by covalent attachment of monoclonal antibodies. Many studies
have shown that liposome solubilizes curcumin in the phospholipidic bilayer and allows
curcumin to be distributed over the aqueous medium so that it can be delivered into the
target cell after fusion of the liposome with the cell. Extensive studies showed that liposomal
curcumin was the most suitable vehicle to treat various cancer diseases.
Micelles
Ampipathic molecules like lipids and detergents having both polar and non polar regions
spontaneously aggregate in an aqueous solution above a critical concentration to form micelles.
While forming the micelles the polar region of the ampipathic molecule form the outer layer
and remains in contact with water and non polar tails are sequestered in the interior and in this
process they can trap hydrophobic molecules inside. The nature and length of the non polar
tail,the nature and size of the polar head, the temperature at which the aggregates are formed,
the salt concentration and the pH of the aqueous suspension determines what kind of
aggregates will be formed.
Micelles therefore can trap hydrophobic drugs inside and move them across hydrophilic
environment. It has been used to deliver poorly water-soluble drugs like curcumin into the
tissue. The carrying ability of micelles can be altered if parameters determining their size and
shape are changed.
Solid Dispersions
![Page 10: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/10.jpg)
Poor aqueous solubility of drugs leading to low bioavailability is the main problem of making
effective drug formulations for therapy. Solid dispersion have become an attractive way to
tackle this problem where a hydrophilic matrix is used to disperse a hydrophobic drug at solid
state to improve its bioavailability. Solid dispersions are usually made through fusion and melt
or solvent-based methods and the bound drugs are released by making nano range colloidal
particles from the solid dispersion in an aqueous media which improves the oral biodistribution
of the drug. Therefore suitable solid dispersions can be used for oral delivery of curcumin.
Conjugates
Use of hydrophilic polymers to disperse a drug molecule to improve bioavailability of the drug
which is known as solid dispersion is quite popular in pharmaceutical industry. But the methods
of making hydrophilic–hydrophobic polymer nanoconjugates and hydrophobic drug-
hydrophilic polymer nanoconjugates have been developed to have alternate strategy for drug
development. The conjugation process induces formation of structures where in aqueous
environment the poorly water-soluble drugs is reduced to nanosize leading to enhanced
bioavailability.
It has been shown that conjugation of curcumin to small molecules or hydrophilic polymers
increase its solubility and oral bioavailability. Therefore curcumin conjugates will be quite
effective in delivering the drug to the target site.
Nanospheres and Microcapsules
As another alternative to solid dispersion or conjugates, polymer-based nanocapsules have
been widely studied as a potential drug delivery system for hydrophobic drugs with poor
![Page 11: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/11.jpg)
bioavailability. Nanocapsules provide a unique nanostructure, consisting of a liquid/solid core
and a polymeric shell which will have important role in drug delivery applications. Using
curcumin it has been shown to be quite effective.
Miscellaneous Nanoformulations
Besides what we have discussed till now other nano formulations like nanogels and metallo-
complexes of curcumin can be used to enhance curcumin’s biological activities. A nanogel is
formed by either physical or chemical cross-linking of curcumin with a polymers under
controlled conditions. It can become a structure for storing curcumin and protecting it from
degradation. Curcumin can be released slowly and therefore can be effective.
Therapeutic use of Nanocurcumin in different disease models
Cardiovascular Diseases
Wang et al. (11) designed a self-assembled amphiphilic carbomethylhexanol chitosan (CHC)
nanomatrix with demethoxycurcumin (DMC), with an approach to inhibit the proliferation and
migration of vascular smooth muscle cells (VSMCs); a process that is associated with response
to vascular injury and atherogenesis. In this approach DMC and CHC were solubilized in an
organic solvent::aqueous mixture, from which the organic solvent was slowly removed under
reduced pressure using a rotary vacuum evaporator at room temperature. The modified
amphiphilic chitosan used in the preparation demonstrated the ability to self-associate in contact
with aqueous media to form polymeric nanoparticles and hydrogels and encapsulating the DMC
present in the solution. The drug encapsulated nanomatrix prepared this way was then tested and
![Page 12: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/12.jpg)
found to be successful in manipulating the cellular internalization and exerting a controlled
cytotoxic effect on the growth and migration of VSMCs. Carlson et al. (12) demonstrated the
preparation of a polymeric micellar delivery system of curcumin which could mitigate the severe
cardiotoxicity that is associated with Doxorubicin hydrochloride (DOX) treatment, by reducing
apoptosis and reactive oxygen species (ROS) levels in vitro. Pramanik et al. (13) further
confirmed that the curcumin entrapped nano-micellar formulation not only led to amelioration of
doxorubicin-associated cardiomyopathy but also successfully aided in overcoming multidrug
resistance in cancer cells. The mitigation of cardiopathy observed in this study was attributed to
the reduction of DOX induced intracellular oxidative stress in cardiac tissue brought about by the
activity of curcumin present in the nanoformulation. In another study, a preparation comprising
curcumin loaded onto poly(ester amine) nanoparticles was tested by Ding et al. for enhancement
of hydrophilic characteristics and improvement of therapeutic efficacy against angiogenesis in a
transgenic zebrafish model. The study demonstrated the effectiveness of poly(ester amine)
nanoparticles as a suitable curcumin delivery system for efficient anti-angiogenesis therapy (14).
Neurodegenerative diseases
The dysfunctioning of the central nervous system (CNS), brain, or the spinal cord is at the root of
several complex diseases that are observed in humans. Drug delivery at these anatomical sites for
effective therapy requires overcoming the complexity of the blood– brain barrier (BBB). Given
the neuroprotective benefits curcumin is known to exert, one of the more successful strategies in
the attempt for delivering curcumin across the BBB for therapeutic purposes has been to
synthesize apolipoprotein E (ApoE)-derived peptide nanoparticles and incorporate curcumin or
![Page 13: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/13.jpg)
suitable derivatives of curcumin onto the synthesized peptide nanoparticles as demonstrated by
Re et al.(15). Curcumin is a molecule that has been studied to possess anti-amyloid-β activities,
which can help prevent the pathological manifestations associated with the development of
Alzheimer’s disease (AD). As a result, successful delivery of curcumin to targeted sites received
great focus and attention. In this context, Sihem et al. attempted to encapsulate curcumin into
biodegradable PLGA–nanoparticles and deliver it to neuronal cells to facilitate internalization of
the molecule inside the cellular environment. The formulation was observed to exert neuro-
protective effects against H2O2- induced elevation of ROS. The curcumin encapsulated PLGA
nanoparticles used in this study was demonstrated to be able to prevent Nrf2 induction in the
presence of H2O2, thereby conferring protection against oxidative damage (16). Apart from
PLGA, curcumin has been formulated using biotin coupling poly(ethylene glycol)ylated
(PEGylated), biodegradable poly(alkyl cyanoacrylate) (17), PEG liposomes with the anti-
transferrin (18), lipid conjugate liposome (19), nanoliposomes (20), PEG–polylactic acid block
co-polymer (20), and click-chemistry-based nanoliposomes (21) and demonstrated to inhibit
aggregation of Aβ and Aβ associated cytotoxicities observable in AD.
Inflammatory Diseases
Inflammatory diseases include a vast array of disorders and conditions that are characterized by
inflammation. Curcumin, for a long time, has been regarded as a strong anti-inflammatory agent
and hence several attempts have been made to develop it into a suitable formulation that can be
employed to treat a variety of inflammation related ailments. In a rat model of inflammation,
gold nanoparticle formulated curcumin was demonstrated to successfully suppress
lipopolysaccharide (LPS)-induced inflammation and cytotoxicity(22). In another study curcumin
![Page 14: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/14.jpg)
loaded onto PLGA-Eudragit(®) S100-based nanoformulations was observed to significantly
reduce TNF-α secretion by LPS-activated macrophages (J774 cells) (23). Shukla et al. (24)
showed that treatment with nanoemulsion of curcumin inhibited LPS-induced lung- and liver-
associated injury by minimizing neutrophil migration, TNF-α levels and oxidative stress in rats.
Sun et al. demonstrated exosome-mediated delivery as an approach for delivering curcumin
efficiently to activated myeloid cells for reducing inflammatory damage in vivo, as awell as in a
lipopolysaccharide (LPS)- induced septic shock mouse model) (25). Curcumin-loaded solid lipid
nanoparticles were observed to be beneficial in the treatment for sepsis (26) and for providing
hepatoprotection (27). Arora et al. (28) established an effective curcumin-loaded solid lipid
nanoparticle utility in complete Freund’s adjuvant-induced arthritis rat model. The results in
arthritic rat model showed that treatment with curcumin loaded solid lipid nanoparticles
significantly ameliorated several symptoms that are associated with arthritis in rats which
support the protective effects exerted by this particular form of curcumin nanoformulation.
Nehra et al. (29) demonstrated the therapeutic efficacy of pure nanotized curcumin particles (200
nm average size) in ameliorating hyperbaric hypoxia induced lung injury by modulation of the
Akt/Erk signalling pathway in rat lungs.
Infectious Diseases
Curcumin has been used in several investigations for demonstrating anti microbial activities
against different types of bacteria, fungi, viruses and parasites. Parenteral administration of lipid-
based curcumin nanoparticles in an in vivo model was demonstrated to result in a 2- fold
increase in anti-malarial activity over free curcumin (30). Furthermore, a novel PEGylated
liposome-based curcumin nanoformulation was observed to provide therapeutic benefit in
![Page 15: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/15.jpg)
Plasmodium berghei NK-65-infected mice (31). Curcumin bound to chitosan nanoparticles was
demonstrated to be able to inhibit hemozoin synthesis indicating its potential to be developed as
a potent anti-malarial compound. One of the major complications of malaria in humans is the
development of cerebral malaria which results in severe neurological impairments, coma and
death. The pathophysiology of human cerebral malaria is largely reflected in murine models of
cerebral malaria. The efficacy of curcumin in being able to prevent cerebral malaria in mice was
demonstrated by Dende et al. Dende et al. further showed that entrapping curcumin into PLGA
nanoparticles and orally administering into mice infected with P. berghei ANKA enables
prevention of disease pathology in infected mice at fifteen fold lower concentration as compared
to free curcumin owing to the improvement in the bioavilability of curcumin when formulated
into PLGA nanoparticles. Gandapu et al. (32) developed apotransferrin tagged curcumin
nanoparticles by sol–oil chemistry for improved uptake in T cells through transferrin-mediated
endocytosis, which showed a higher anti HIV activity of nanocurcumin (IC(50). Tousif et al.
(33) demonstrated the preparation of nanoparticles of pure curcumin of 200 nm size and its
application in reducing hepatotoxicity associated with isoniazid treatment in M.tb infected mice.
Ahmed et al. (34) demonstrated the use of the same formulation in enhancing the capacity of
BCG to induce central memory T cells of Th1 and Th17 lineages that result in augmentation of
host protective responses against TB infection.
Cancer
Cancer is one of the leading causes of death in human. The most commonly used treatment
options include surgery, chemotherapy, radiation therapy, targeted therapy, immunotherapy,
hyperthermia, photothermic therapy, and other alternative therapies. For solid and metastatic
tumors chemotherapy is the usual choice of treatment but is associated with adverse effects to
![Page 16: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/16.jpg)
healthy tissues, leading to organ damage. Use of curcumin and its nanoformulations therefore
play a significant role in enhancing the effectiveness of anti cancer drugs by chemosensitization
of cancer cells. Curcumin nanoformulations significantly internalize inside cancer cells through
endocytosis or receptor-mediated and release curcumin in active form in order to induce its
biological effects (35, 36). Dextran–CCM nanoparticles have been demonstrated to be
significantly taken up in HeLa cells in a selective manner. Maitra et al. have engineered a
curcumin nanoformulation (NanoCurc™) (37–39), developed by a random copolymerization of
N-isopropylacrylamide with N-vinyl-2-pyrrolidone, poly(ethylene glycol)–monoacrylate in the
presence of N,N′-methylenebisacrylamide, ammonium persulfate, ferrous ammonium sulfate,
and tetramethylethylenediamine. This formulation produced micellar aggregates of 50 nm
amphiphilic polymers which release 40% of curcumin at physiological pH. NanoCurc
formulation was demonstrated to possess high systemic bioavailability in plasma and tissues over
free curcumin (37–39). This formulation was demonstrated to inhibit tumor growth by
significantly reducing activation of nuclear factor kappa B (NF-κB), inhibiting the expression of
matrix metalloproteinase-9 (MMP-9) and cyclin D1 I animal models (40-43). Newer approaches
for delivery of curcumin with augmented activity include layer-by-layer deposition of
polyelectrolytes (polystyrene sulfonate/polyallylamine hydrochloride, polyglutamic acid/poly-l-
lysine, dextran sulfate/protamine sulfate, and carboxymethyl cellulose/gelatin loaded with
curcumin formulations) which successfully blocks the hepatocyte growth factor induced
signaling in the breast cancer cell line, MDA-MB-231 (44). Curcumin encapsulation in Eudragit
S100 polymer nanoparticles, which dissolves at colonic pH, was shown to influence cellular
uptake and exhibit a two-fold superior anti-cancer potential in HT-29 human colorectal cell line
(45). Hossain et al. demonstrated that nanoparticles of pure curcumin prepared by a modified
![Page 17: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/17.jpg)
solvent co-precipitation method exhibit better bioavailability as compared to ordinary curcumin
and reverses tumour-shed TGF- β-induced Treg cell augmentation in tumour micro environment
(46).
Summary
Even though anti solvent precipation method could produce stable nanocurcumin particles,
numerous attempts to develop delivery strategies involving preparation of curcumin formulations
comprising of organic nanoparticles, liposome, phospholipid complexes, nanoemulsions, or
polymeric micelles which has been referred to as “Nanocurcumin” has been made and tested
against chronic inflammatory conditions in animal models with remarkable success. One issue
which has not received enough attendtion is the role of the degradation products of curcumin in
bringing abaout therapeutic efficacy. This needs to be tested using appropriate models.
As an alternative approach to preparing curcumin bound or entrapped to polymeric nanoparticles
we have prepared pure nano curcumin particles of 200 nm size using anti solvent precipation
method which has been patented and published. Our formulation has enhanced the
bioavailability of curcumin by about 4 to 5 folds without the need of embedding or entrapping
into any carrier matrix but still showing efficacy in animal models. Use of nanoparticles of pure
curcumin provides a better control over Cmax and T1/2 of curcumin in the blood which
determines the therapeutic efficacy of the formulation. The use of nano formulations of
curcumin for therapeutic purposes needs further attention.
![Page 18: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/18.jpg)
References :
1. Gupta SC, Patchva S, Koh W, Aggarwal BB. Discovery of curcumin, a component of
golden spice, and its miraculous biological activities. Clin Exp Pharmacol Physiol. 2012
Mar;39(3):283-99. doi: 10.1111/j.1440-1681.2011.05648.x.
2. Srinivasan KR. A chromatographic study of the curcuminoids in Curcuma longa, L. J
Pharm Pharmacol. 1953 Jul;5(7):448-57. doi: 10.1111/j.2042-7158.1953.tb14007.x.
3. Fu M, Chen L, Zhang L, Yu X, Yang Q. Cyclocurcumin, a curcumin derivative, exhibits
immune-modulating ability and is a potential compound for the treatment of rheumatoid
arthritis as predicted by the MM-PBSA method. Int J Mol Med. 2017 May;39(5):1164-
1172. doi: 10.3892/ijmm.2017.2926.
4. Dosoky NS, Setzer WN. Chemical Composition and Biological Activities of Essential
Oils of Curcuma Species. Nutrients. 2018 Sep 1;10(9):1196. doi: 10.3390/nu10091196.
5. Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from
clinical trials. AAPS J. 2013 Jan;15(1):195-218. doi: 10.1208/s12248-012-9432-8.
6. Modasiya MK ,Patel VM. Solubility of curcumin in water. Int. J. of Pharm. & Life Sci.
(IJPLS), Vol. 3, Issue 3: March: 2012, 1490-1497.
7. Yu H, Huang Q. Improving the oral bioavailability of curcumin using novel organogel-
based nanoemulsions. J Agric Food Chem. 2012 May 30;60(21):5373-9. doi:
10.1021/jf300609p.
8. Rega. SA, Arya M, Momin SA. Structure activity relationship of tautomers of curcumin:
A review. Ukrainian Food Technology.2019. DOI: 10.24263/2304- 974X-2019-8-1-6
![Page 19: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/19.jpg)
9. Jankun J, Wyganowska-Świątkowska M, Dettlaff K, Jelińska A, Surdacka A, Wątróbska-
Świetlikowska D, Skrzypczak-Jankun E. Determining whether curcumin
degradation/condensation is actually bioactivation (Review). Int J Mol Med. 2016
May;37(5):1151-8. doi: 10.3892/ijmm.2016.2524.
10. Leung MH, Kee TW. Effective stabilization of curcumin by association to plasma
proteins: human serum albumin and fibrinogen. Langmuir. 2009 May 19;25(10):5773-7.
doi: 10.1021/la804215v.
11. Wang YJ, Lin HY, Wu CH, Liu DM. Forming of demethoxycurcumin nanocrystallite-
chitosan nanocarrier for controlled low dose cellular release for inhibition of the migration of
vascular smooth muscle cells. Mol Pharm. 2012 Aug 6;9(8):2268-79. doi:
10.1021/mp300150q
12. Carlson LJ, Cote B, Alani AW, Rao DA. Polymeric micellar co-delivery of resveratrol
and curcumin to mitigate in vitro doxorubicin-induced cardiotoxicity. J Pharm Sci. 2014
Aug;103(8):2315-22. doi: 10.1002/jps.24042.
13. Pramanik D, Campbell NR, Das S, Gupta S, Chenna V, Bisht S, Sysa-Shah P, Bedja D,
Karikari C, Steenbergen C, Gabrielson KL, Maitra A, Maitra A. A composite polymer
nanoparticle overcomes multidrug resistance and ameliorates doxorubicin-associated
cardiomyopathy. Oncotarget. 2012 Jun;3(6):640-50. doi: 10.18632/oncotarget.543.
14. Ding Q, Niu T, Yang Y, Guo Q, Luo F, Qian Z. Preparation of curcumin-loaded
poly(ester amine) nanoparticles for the treatment of anti-angiogenesis. J Biomed
Nanotechnol. 2014 Apr;10(4):632-41. doi: 10.1166/jbn.2014.1829.
![Page 20: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/20.jpg)
15. Re F, Cambianica I, Zona C, Sesana S, Gregori M, Rigolio R, La Ferla B, Nicotra F,
Forloni G, Cagnotto A, Salmona M, Masserini M, Sancini G. Functionalization of liposomes
with ApoE-derived peptides at different density affects cellular uptake and drug transport
across a blood-brain barrier model. Nanomedicine. 2011 Oct;7(5):551-9. doi:
10.1016/j.nano.2011.05.004.
16. Doggui S, Sahni JK, Arseneault M, Dao L, Ramassamy C. Neuronal uptake and
neuroprotective effect of curcumin-loaded PLGA nanoparticles on the human SK-N-SH cell
line. J Alzheimers Dis. 2012;30(2):377-92. doi: 10.3233/JAD-2012-112141.
17. Le Droumaguet B, Nicolas J, Brambilla D, Mura S, Maksimenko A, De Kimpe L, Salvati
E, Zona C, Airoldi C, Canovi M, Gobbi M, Magali N, La Ferla B, Nicotra F, Scheper W,
Flores O, Masserini M, Andrieux K, Couvreur P. Versatile and efficient targeting using a
single nanoparticulate platform: application to cancer and Alzheimer's disease. ACS Nano.
2012 Jul 24;6(7):5866-79. doi: 10.1021/nn3004372.
18. Mourtas S, Lazar AN, Markoutsa E, Duyckaerts C, Antimisiaris SG. Multifunctional
nanoliposomes with curcumin-lipid derivative and brain targeting functionality with potential
applications for Alzheimer disease. Eur J Med Chem. 2014 Jun 10;80:175-83. doi:
10.1016/j.ejmech.2014.04.050.
19. Taylor M, Moore S, Mourtas S, Niarakis A, Re F, Zona C, La Ferla B, Nicotra F,
Masserini M, Antimisiaris SG, Gregori M, Allsop D. Effect of curcumin-associated and lipid
ligand-functionalized nanoliposomes on aggregation of the Alzheimer's Aβ peptide.
Nanomedicine. 2011 Oct;7(5):541-50. doi: 10.1016/j.nano.2011.06.015.
![Page 21: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/21.jpg)
20. Lazar AN, Mourtas S, Youssef I, Parizot C, Dauphin A, Delatour B, Antimisiaris SG,
Duyckaerts C. Curcumin-conjugated nanoliposomes with high affinity for Aβ deposits:
possible applications to Alzheimer disease. Nanomedicine. 2013 Jul;9(5):712-21. doi:
10.1016/j.nano.2012.11.004.
21. Mourtas S, Canovi M, Zona C, Aurilia D, Niarakis A, La Ferla B, Salmona M, Nicotra F,
Gobbi M, Antimisiaris SG. Curcumin-decorated nanoliposomes with very high affinity for
amyloid-β1-42 peptide. Biomaterials. 2011 Feb;32(6):1635-45. doi:
10.1016/j.biomaterials.2010.10.027.
22. Singh AK, Jiang Y, Gupta S, Younus M, Ramzan M. Anti-inflammatory potency of
nano-formulated puerarin and curcumin in rats subjected to the lipopolysaccharide-induced
inflammation. J Med Food. 2013 Oct;16(10):899-911. doi: 10.1089/jmf.2012.0049.
23. Beloqui A, Coco R, Memvanga PB, Ucakar B, des Rieux A, Préat V. pH-sensitive
nanoparticles for colonic delivery of curcumin in inflammatory bowel disease. Int J Pharm.
2014 Oct 1;473(1-2):203-12. doi: 10.1016/j.ijpharm.2014.07.009.
24. Shukla P, Dwivedi P, Gupta PK, Mishra PR. Optimization of novel tocopheryl acetate
nanoemulsions for parenteral delivery of curcumin for therapeutic intervention of sepsis.
Expert Opin Drug Deliv. 2014 Nov;11(11):1697-712. doi: 10.1517/17425247.2014.932769.
25. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D,
Zhang HG. A novel nanoparticle drug delivery system: the anti-inflammatory activity of
curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010 Sep;18(9):1606-14.
doi: 10.1038/mt.2010.105.
![Page 22: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/22.jpg)
26. Wang J, Wang H, Zhu R, Liu Q, Fei J, Wang S. Anti-inflammatory activity of curcumin-
loaded solid lipid nanoparticles in IL-1β transgenic mice subjected to the lipopolysaccharide-
induced sepsis. Biomaterials. 2015 Mar;53:475-83. doi: 10.1016/j.biomaterials.2015.02.116.
27. Singh N, Khullar N, Kakkar V, Kaur IP. Attenuation of carbon tetrachloride-induced
hepatic injury with curcumin-loaded solid lipid nanoparticles. BioDrugs. 2014
Jun;28(3):297-312. doi: 10.1007/s40259-014-0086-1.
28. Arora R, Kuhad A, Kaur IP, Chopra K. Curcumin loaded solid lipid nanoparticles
ameliorate adjuvant-induced arthritis in rats. Eur J Pain. 2015 Aug;19(7):940-52. doi:
10.1002/ejp.620.
29. Nehra S, Bhardwaj V, Bansal A, Saraswat D. Nanocurcumin accords protection against
acute hypobaric hypoxia induced lung injury in rats. J Physiol Biochem. 2016
Dec;72(4):763-779. doi: 10.1007/s13105-016-0515-3.
30. Nayak AP, Tiyaboonchai W, Patankar S, Madhusudhan B, Souto EB. Curcuminoids-
loaded lipid nanoparticles: novel approach towards malaria treatment. Colloids Surf B
Biointerfaces. 2010 Nov 1;81(1):263-73. doi: 10.1016/j.colsurfb.2010.07.020.
31. Isacchi B, Bergonzi MC, Grazioso M, Righeschi C, Pietretti A, Severini C, Bilia AR.
Artemisinin and artemisinin plus curcumin liposomal formulations: enhanced antimalarial
efficacy against Plasmodium berghei-infected mice. Eur J Pharm Biopharm. 2012
Apr;80(3):528-34. doi: 10.1016/j.ejpb.2011.11.015.
![Page 23: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/23.jpg)
32. Gandapu U, Chaitanya RK, Kishore G, Reddy RC, Kondapi AK. Curcumin-loaded
apotransferrin nanoparticles provide efficient cellular uptake and effectively inhibit HIV-1
replication in vitro. PLoS One. 2011;6(8):e23388. doi: 10.1371/journal.pone.0023388.
33. Tousif S, Singh DK, Mukherjee S, Ahmad S, Arya R, Nanda R, Ranganathan A,
Bhattacharyya M, Van Kaer L, Kar SK, Das G. Nanoparticle-Formulated Curcumin Prevents
Posttherapeutic Disease Reactivation and Reinfection with Mycobacterium
tuberculosis following Isoniazid Therapy. Front Immunol. 2017 Jun 30;8:739. doi:
10.3389/fimmu.2017.00739.
34. Ahmad S, Bhattacharya D, Kar S, Ranganathan A, Van Kaer L, Das G. Curcumin
Nanoparticles Enhance Mycobacterium bovis BCG Vaccine Efficacy by Modulating Host
Immune Responses. Infect Immun. 2019 Oct 18;87(11):e00291-19. doi: 10.1128/IAI.00291-
19.
35. Yallapu MM, Khan S, Maher DM, Ebeling MC, Sundram V, Chauhan N, Ganju A,
Balakrishna S, Gupta BK, Zafar N, Jaggi M, Chauhan SC. Anti-cancer activity of curcumin
loaded nanoparticles in prostate cancer. Biomaterials. 2014 Oct;35(30):8635-48. doi:
10.1016/j.biomaterials.2014.06.040.
36. Nagahama K, Sano Y, Kumano T. Anticancer drug-based multifunctional nanogels
through self-assembly of dextran-curcumin conjugates toward cancer theranostics. Bioorg
Med Chem Lett. 2015 Jun 15;25(12):2519-22. doi: 10.1016/j.bmcl.2015.04.062.
37. Zou P, Helson L, Maitra A, Stern ST, McNeil SE. Polymeric curcumin nanoparticle
pharmacokinetics and metabolism in bile duct cannulated rats. Mol Pharm. 2013 May
6;10(5):1977-87. doi: 10.1021/mp4000019.
![Page 24: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/24.jpg)
38. Chiu SS, Lui E, Majeed M, Vishwanatha JK, Ranjan AP, Maitra A, Pramanik D, Smith
JA, Helson L. Differential distribution of intravenous curcumin formulations in the rat brain.
Anticancer Res. 2011 Mar;31(3):907-11. PMID: 21498712; PMCID: PMC3568517.
39. Bisht S, Feldmann G, Soni S, Ravi R, Karikar C, Maitra A, Maitra A. Polymeric
nanoparticle-encapsulated curcumin ("nanocurcumin"): a novel strategy for human cancer
therapy. J Nanobiotechnology. 2007 Apr 17;5:3. doi: 10.1186/1477-3155-5-3.
40. Lim KJ, Bisht S, Bar EE, Maitra A, Eberhart CG. A polymeric nanoparticle formulation
of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain
tumors. Cancer Biol Ther. 2011;11(5):464-473. doi:10.4161/cbt.11.5.14410
41. Chun YS, Bisht S, Chenna V, et al. Intraductal administration of a polymeric nanoparticle
formulation of curcumin (NanoCurc) significantly attenuates incidence of mammary tumors
in a rodent chemical carcinogenesis model: Implications for breast cancer chemoprevention
in at-risk populations. Carcinogenesis. 2012;33(11):2242-2249. doi:10.1093/carcin/bgs248
42. Bisht S, Mizuma M, Feldmann G, Ottenhof NA, Hong SM, Pramanik D, Chenna V,
Karikari C, Sharma R, Goggins MG, Rudek MA, Ravi R, Maitra A, Maitra A. Systemic
administration of polymeric nanoparticle-encapsulated curcumin (NanoCurc) blocks tumor
growth and metastases in preclinical models of pancreatic cancer. Mol Cancer Ther. 2010
Aug;9(8):2255-64. doi: 10.1158/1535-7163.MCT-10-0172.
43. Bisht S, Khan MA, Bekhit M, et al. A polymeric nanoparticle formulation of curcumin
(NanoCurc™) ameliorates CCl4-induced hepatic injury and fibrosis through reduction of
pro-inflammatory cytokines and stellate cell activation. Lab Invest. 2011;91(9):1383-1395.
doi:10.1038/labinvest.2011.86
![Page 25: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/25.jpg)
44. Shutava TG, Balkundi SS, Vangala P, Steffan JJ, Bigelow RL, Cardelli JA, O'Neal DP,
Lvov YM. Layer-by-Layer-Coated Gelatin Nanoparticles as a Vehicle for Delivery of
Natural Polyphenols. ACS Nano. 2009 Jul 28;3(7):1877-85. doi: 10.1021/nn900451a.
45. Prajakta D, Ratnesh J, Chandan K, Suresh S, Grace S, Meera V, Vandana P. Curcumin
loaded pH-sensitive nanoparticles for the treatment of colon cancer. J Biomed Nanotechnol.
2009 Oct;5(5):445-55. doi: 10.1166/jbn.2009.1038.
46. Hossain DM, Panda AK, Chakrabarty S, Bhattacharjee P, Kajal K, Mohanty S, Sarkar I,
Sarkar DK, Kar SK, Sa G. MEK inhibition prevents tumour-shed transforming growth
factor-β-induced T-regulatory cell augmentation in tumour milieu. Immunology. 2015
Apr;144(4):561-73. doi: 10.1111/imm.12397.
![Page 26: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/26.jpg)
Figures:
Figure 1. Molecules present in Curcumin. A) Curcumin B) Bisdemthoxycurcumin C) Demethoxycurcumin D) Cyclocurcumin
Adapted from Karthikeyan A, Senthil N, Min T. Nanocurcumin: A Promising Candidate for Therapeutic Applications. Front Pharmacol. 2020 May 1;11:487. doi: 10.3389/fphar.2020.00487. PMID: 32425772; PMCID: PMC7206872.
![Page 27: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/27.jpg)
Figure 2. Keto enol tautomerism of curcumin. Adapted from Stanić Z. Curcumin, a Compound from Natural Sources, a True Scientific Challenge - A Review. Plant Foods Hum Nutr. 2017 Mar;72(1):1-12. doi: 10.1007/s11130-016-0590-1. PMID: 27995378.
Keto- form of curcumin Enol- form of curcumin
![Page 28: Nano technology is impacting the way medicine is developing ... · Web viewTargeting of liposome-encapsulated drugs to particular cells or tissues can be achieved by covalent attachment](https://reader035.vdocument.in/reader035/viewer/2022071600/613d241184584d0a6f5b537c/html5/thumbnails/28.jpg)
Figure 3. Degradation products of curcumin. Adapted from Shen L, Ji HF. The pharmacology of curcumin: is it the degradation products? Trends Mol Med. 2012 Mar;18(3):138-44. doi: 10.1016/j.molmed.2012.01.004. Epub 2012 Mar 1. PMID: 22386732.