Invited Talk: Nanotechnology Strategy in Medicine Shahidan Radiman School of Applied Physics , Faculty of Science and Technology UKM Bangi 43600 , Selangor DE. E-mail: [email protected]www.ukm.my/fst Conference on Nano- and Bioresource Technology 2015 (NBT2015) , 28 -29 March 2015, Universiti Kebangsaan Malaysia
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Invited Talk:
Nanotechnology Strategy in Medicine Shahidan Radiman
School of Applied Physics , Faculty of Science and Technology UKM Bangi 43600 , Selangor DE. E-mail: [email protected]
w w w . u k m . m y / f s t
Conference on Nano- and Bioresource Technology 2015 (NBT2015) , 28 -29
March 2015, Universiti Kebangsaan Malaysia
Content of Talk 1. Background
2. Brief History of Nanoparticles in Medicines
3. Drug delivery mechanism for passing the Blood- Brain
Barrier
4. Some of our work in this area
5. New strategies to be developed
6. Conclusions
Possible Applications of Gold Nanorods
By combining terminal protection of small molecule (folate)-capped
DNA probes, exonuclease III signal amplification and gold
nanoparticles, a simple and label-free colorimetric assay were
develpoed for highly sensitive detection of folate receptor (FR). A
detection limit of 50 fM FR was obtained using UV-vis spectrometry and
10 pM FR could be visualized by the naked eye.
1.Background
Use of nanotechnologies in medicine is not new- has been
around for 30 years.
Today 44 nano-delivery products have received marhet
approval in the USA already ( it includes 18 pharmaceutical
products and 15 field imaging and diagnostics)
According to BCC Research Market report (2012) the global
nanomedicine market is expected to grow from $63.6 billion
in 2010 to $130.9 billion by 2016.
Intake of Nanoparticles
Petros and DeSimone , 2010
In general , NP are used for therapeutics applications
to achieve:
(i) precise delivery
(ii) improve solubility
(iii) extend half-life
(iv) improve therapeutic index ,
(v) reduce immunogenicity
(vi) enhanced multifunctionality
The first liposome- based therapeutic is liposome-
encapsulated doxorubicin (Doxil) approved by US FDA in
1995 for the treatment of HIV-related Kaposi sarcoma – it
showed reduced cardiotoxicity compared to free drug.
PEG (polyethylene glycol) can enhance the solubility and
plasma stability of proteind and reduce immunogenicity .
PEG- L-asparaginase was approved by FDA in 1994 for
treatment of acute lymphocytic leukemia. Other PEGlated
drugs follow suits namely PEG-interferon –alpha2a and
2b for hepatitis C and PEG-granulocyte colony-simulating
factor for neutropania.
In general PEG and other polymers act as steric brush and
prevent protein absorption on NP surface immediately after
contact in plasma called opsonization.
Later albumin-coated liposomes were shown to decrease
accumulation in liver, spleen and heart with increased
accumulation in tumour as well as longer retention time and
faster cell uptake using elongated particles.
Many types of cancer cells overexpress transferrin, folate
receptors making conjugation of transferrin , folic acid or
antibodies to these receptors successfully targeting approach.
For cell uptake ,ligands such as folic acids , albumin,
cholesterol have been shown to facilitate uptake through
which will ensure a sufficient supply of nutrients and oxygen to
tumor tissues for rapid growth. The EPR effect considers this
unique anatomical–pathophysiological nature of tumor blood
vessels that facilitates transport of macromolecules into tumor
tissues. Macromolecules larger than 40 kDa selectively leak out
from tumor vessels and accumulate in tumor tissues. In contrast,
this EPR effect-driven delivery does not occur in normal tissues .
This unique phenomenon in solid tumors— the EPR effect — is
thus considered to be a landmark principle in tumor-targeting
chemotherapy and is becoming an increasingly promising
paradigm for anticancer drug development.
For example, Doxil, which is a PEGylated (polyethylene
glycol-coated) liposome-encapsulated formulation of
doxorubicin, was approved for treatment of Kaposi
sarcoma and other cancers.
Many other polymeric or micellar drugs are in clinical
stage development (phases I and II) . Compared with
conventional anticancer drugs, most of which are small
molecular drugs, these macromolecular drugs have
superior in vivo pharmacokinetics (e.g., a prolonged
plasma half-life) and, more important, greater tumor
selectivity, so that they produce improved antitumor
effects with no or less adverse reactions .
Bertrand et al Adv Drug
Delivery Rev , 2013
Theranostic mechanism of functionalised QD at
cellular level Xu et al , Frontiers in Phamacology
2013
3. Drug delivery mechanism passing the blood brain barrier A number of obstacles present substantial challenges when
attempting to treat CNS disorders. For example, systemically
delivered products must pass through the blood–brain barrier
(BBB), and substances delivered intracranially must withstand
the substantial dynamic force of cerebrospinal fluid (CSF) flow
in the brain interstitium. In addition, the complex cellular
organization of the brain and spinal cord complicates the
targeted treatment of specific cell populations.
Nanotechnology presents a potential solution to these
problems.The scale of nanoengineered materials enables the
structures to interact with biological substrates at a molecular
level, providing these materials with the potential to effect
change in biological systems in unprecedented ways.
BBB limits the brain penetration of most CNS drug
candidates
Neurological disorders such as HIV-associated
encephalopathy has significant morbidity and
mortality.
Of more than 7000 drugs in the comprehensive
medicinal chemistry database only 5 % can be used
for CNS treatment , only 12 % are active in the CNS
and only 1 % are active in the brain.
The Blood-Brain Barrier
•To be BBB permeable , molecules need to be lipid soluble and less than 400 Da in size.
•Larger biomolecules can pass if they are transported by receptor-mediated transcytosis (RMT) using ligands that bind to specific BBB receptor.
• Some of the attempted delivery systems include transcranial brain drug delivery, trans-nasal brain drug delivery , BBB disruption and small molecule lipidisation.
. One can use the circulating phagocytic cells such as monocytes or macrophages as Tojan horse to deliver drug molecules into the brain . In the human brain there are about 100 billion capillaries providing a combined length of brain capillary endothelium of approximately 650 km and total surface area of ca. 20 m**2. Any molecules entry into the brain is strictly controlled by Blood-Brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) .The chief anatomical and functional site of the BBB is the brain endothelium. Physiologically in addition to brain capillary endothelilal cells, extracellular base membrane , adjoining pericytes , astrocytes and microglia are all integral part of BBB supporting system.
A feature of the BBB is its low and selective permeabilities attributed to its unqique biological characteristics : (i) The presence of tight junction (TJ) between adjacent
endothelial cells formed by intricate complex transmembrane proteins which are linked to the actin cytoskeleton forming the most intimate cell-to-cell connection
(ii)The expression of various transporters including glucose carrier (GLUT 1) , amino acid carrier (LAT1) , transferring receptors , insulin receptors , lipoprotein receptors and ATP family of efflux transporters.
(iii)The synergistic inductive functions and upregulating of BBB features by astrocytes , astrocytic perivascular endfeet , pericytes , perivascular macrophage and neurons ( as suggested from cell culture studies) (iv)The lack of lymphatic damage and absence of major histocompatibility complex antigens. The BBB has a strict limit for the passage of immune cells especially lymphocytes and its immune barrier is made by the association between BBB endothelial cells and perivascular macrophages and mast cells. This immune barrier is reinforced by local microglial cells.
Xu et al , Frontiers in Pharmacology 4(10), 2013
Blood –brain barrier
Transport route across the blood-brain barrier
Some BBB terms :
CMT – carrier mediated transport : provide a facilitated
mechanism for certain small molecules , nutrients and
hormones to passively cross the BBB following a concentration
gradient ( mediated by CMT proteins e.g large neutral amino
acid trasnporter (LAT1))
Trojan horse drugs can be designed to target specific CMT
systems ( glucose transporter, organic anion transporting
endothelial cells express receptor –mediated transport through
transcytosis. Receptors include transferrin , insulin, lipoprotein,
peptides called angiopeps .
Efflux transport system : Efflux transporters include P-gp,
breast-cancer resistance protein (BCRP), multidrug
resistance proteins (MRPs).
BBB disruption : breaking down of tight-junctions, osmotic
disruptions etc. Very risky even though transient (e.g of
disruptors are short-chain alkylglycerols and medium
chain fatty acid salt sodium caprate ). Phamacologic
disruptors include sildenafil (Viagra) and vardenafil (Levitra)
Cell-penetrating peptides (CPP) : They are also known as
protein-transduction domains . CPPs are oligocationic or
amphiphilic peptides sequence of 10-30 amino acids that
can transverse mammalian plasma membrane and BBB.
The mechanism of CPP transport is currently believed to be
through endocytotic uptake.
Yan Chen and Lihong Liu , Advaced Drug Delivery Reviews 64(2012), 640-665
Transport route across the blood-brain-barrier
Use of quantum dot-bioconjugates to pass the BBB
(Xu et al , Frontiers in Pharmacology 2013)
Yan Chen and Lihong Liu , Advaced Drug Delivery
Reviews 64(2012), 640-665
Problems Formulation of water soluble drug with lipidisation is difficult to execute successfully. Poor solubility and stability on physiological medium Possible solutions- Nanotech approach Improved bioavailability and site specific biotargeting Drug delivery nanoplatform can also be used for diagnostics at the same time (theranostics) e.g transferrin (an Fe-binding glycoprotein) are easily conjugated to NP for targeting BBB and facilitate the RMT process.
Srikanth and Kessler (2014)
Srikanth and Kessler (2014)
4. Some of our own work in drug delivery
Materials and Methods
Materials: - N-dimethylglycine Betaine with 35% active substance in H2O
(classifies as zwitterionic surfactant)
- 5-cholesten-3β-ol (Cholesterol, purity≥ 99%)
- 1-Decanol with purity ≥ 99%
- Deionized water
Materials was purchased from Fulka Co. and used as received without any further purification.
a) b)
Figure3: a) N-dimethylglycine betaine structure. b) Cholesterol
R. Elenaizi et al, JCIS submitted
Figure 1. Partial-Ternary phase diagram of Betaine/ Cholesterol/water system for short time period (~ 1 month).
Figure 2. Partial-Ternary phase diagram of Betaine/ Cholesterol/water system for long time period (~ 6 month).
Akter et al , Nature Sc. Report 1 (2011)
For topical application
Carrageenans are large, highly flexible molecules that curl forming helical
structures. This gives them the ability to form a variety of different gels at room
temperature. They are widely used in the food and other industries as
thickening and stabilizing agents.
All carrageenans are high-molecular-weight polysaccharides made up of
repeating galactose units and 3,6 anhydrogalactose (3,6-AG), both sulfated
and nonsulfated. The units are joined by alternating α-1,3 and β-1,4 glycosidic
linkages.
There are three main commercial classes of carrageenan:
Kappa forms strong, rigid gels in the presence of potassium ions; it reacts with
dairy proteins. It is sourced mainly from Kappaphycus alvarezii.
Iota forms soft gels in the presence of calcium ions. It is produced mainly from
Eucheuma denticulatum
Lambda does not gel, and is used to thicken dairy products.
The primary differences that influence the properties of kappa, iota, and
lambda carrageenan are the number and position of the ester sulfate groups
on the repeating galactose units. Higher levels of ester sulfate lower the
solubility temperature of the carrageenan and produce lower strength gels, or
contribute to gel inhibition (lambda carrageenan).