Nanomediated anticancer drug delivery

1. NANOMEDIATED ANTICANCER DRUG DELIVERY
Ms. Richa
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2. WHAT IS NANOTECHNOLOGY?
 Nanotechnology the science and engineering involved in the
design, synthesis, characterization and application of materials
and devices whose smallest functional organization in at least
one dimension is on the nanometer scale (one-billionth of a
meter) .
 This technology is being applied to almost every field imaginable,
including electronics, magnetics, optics, information technology,
materials development, and biomedicine. Because of their small
size, nanoscale materials and devices can interact readily with
biomolecules both on the surface of cells and inside them. As a
result, such materials and devices have the potential to detect
disease and deliver treatment in ways unimagined before now.
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3. APPLICATIONS OF NANOTECHNOLOGY
 Energy
 Cosmetics
 tissue engineering
 agriculture industry
 Environmental technology
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4. NANOTECHNOLOGY AND CANCER
Nanotechnology has many potential which is being used in cancer
research. In particular this technology facilitates research and
improve molecular imaging, early detection, prevention, and treatment
of cancer.
 Facilitating research
 Molecular imaging and early detection
 Prevention and control
 Therapeutics
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5. NANOTECHNOLOGY IN DRUG DELIVERY
 To achieve efficient drug delivery, it is important to understand
the interactions of nanomaterials with the biological
environment, targeting cell-surface receptors, drug release,
multiple drug administration, stability of therapeutic agents and
molecular mechanisms of cell signalling involved in
pathobiology of the disease under consideration.
 In nanoparticles therapeutics, the particles which are used typically
are comprised of therapeutic entities. i.e., they have potential
medicinal properties. The therapeutic entities described here are small
molecule drug, peptides, proteins and nucleic acids, and components
that assemble with the therapeutic entities such as lipids and
polymers, to form nanoparticles.
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6. SIZE AND SURFACE PROPERTIES OF NANOPARTICLES
Important factors determining the life span and fate of nanoparticles during circulation
relating to their capture by macrophages a size and surface characteristics.
 Size The size of nanoparticles used in a drug delivery system should be large
enough to prevent their rapid leakage into blood capillaries but small enough to
escape capture by fixed macrophages that are lodged in the reticuloendothelial
system, such as the liver and spleen.
 Surface characteristics Nanoparticles should ideally have a hydrophilic surface to
escape macrophage capture (38). This can be achieved in two ways: coating the
surface of nanoparticles with a hydrophilic polymer, such as PEG, protects them
from opsonization by repelling plasma proteins; alternatively, nanoparticles can be
formed from block copolymers with hydrophilic and hydrophobic domains (13, 39).
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7. TYPES OF NANOPARTICLES USED IN DRUG DELIVERY
On the basis of various drug delivery systems NANOPARTICLES can
be subdivided into four groups:
 metal based nanoparticles
 Lipid based nanoparticles
 Polymer based nanoparticles
 Biological based nanoparticles
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9.  Metal based nanoparticle
Metallic nanoshells, generally composed of inert metals such
as gold or titanium, have been used for controlled release of
chemotherapy (15). They typically have a silicon core which is
sealed in an outer metallic cover. Each of these platforms has
unique properties. Although these metal particles are inert and
biocompatible, a significant fraction of the particles is retained
in the body after administration, and accumulation of metal
particles after repeated administration can lead to toxicity.
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10.  Lipid based nanoparticle
Lipid-based nanoparticles, can be regarded as alternative carrier
system to traditional colloidal systems, such as emulsions,
liposomes. Lipid-based carriers have attractive biological properties,
including general biocompatibility, biodegradability, isolation of
drugs from the surrounding environment, and the ability to entrap
both hydrophilic and hydrophobic drugs. Through the addition of
agents to the lipid membrane or by the alteration of the surface
chemistry, properties of lipid-based carriers, such as their size,
charge, and surface functionality, can easily be modified.
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11.  Liposomes
Liposomes are spherical vesicles with an aqueous
core and a vesicle shell. They contain a single or
multiple bilayered membrane structure composed
of natural or synthetic lipids .
Hydrophilic ends of the globular bilayers point to
the water side, hydrophobic ends are oriented
bilateral to the outer of the layer. Since a liposome
can encapsulate an aqueous solution with a
hydrophobic outer memberanne, hydrophilic
solutes can’t pass through the lipids. So liposomes
can carry hydrophobic as well as hydrophilic
molecules by having its lipid bilayer fuse with the
bilayers of the cell memberane.
Depending on design, they can range in size from
tens of nanometers up to micrometers in size.
Their biocompatible and biodegradable
composition, as well as their unique ability to
encapsulate hydrophilic agents in their aqueous
core and hydrophobic agents within their lamellae,
makes liposomes excellent therapeutic carriers.
To improve their stability and circulation half-life,
liposomes can also be coated with polymers such
as polyethylene glycol (PEG).
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12. • Micelles
 Micelles are self assembling closed
lipid monolayer with a hydrophobic
core and a hydrophilic shell.
 They belong to a group of amphiphilic
colloid that can be formed
spontaneously under certain
concentrations and temperatures from
amphiphilic or surface active agents
(surfactants).
 Drug can be trapped in the core of a
micelle and transported at
concentrations even greater than their
intrinsic water solubility. A hydrophilic
shell can form around the micelle,
effectively protecting the contents.
They have been successfully used as
pharmaceutical carriers for water
insoluble drugs.
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13.  Polymer based nanoparticle
Many of the nanoparticles therapeutics includes polymeric
nanoparticles, which involves various natural or biocompatible
synthetic polymers.
Depending on the method of preparation the drug is either
physically entrapped in or covalently bound to the polymer
matrix (6) . The resulting compounds may have the structure
of capsules (polymeric nanaoparticles), amphiphillic core/shell
(polymeric micelles), or hyperbranched macromolecules(
dendrimers).
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14.  Dendrimers
Dendrimers are synthetic, branched nanometer sized polymer
macromolecules that form a tree like structure which have a high degree
of molecular uniformity, narrow molecular weight distribution, specific size
and shape characteristics and a highly functionalise terminal surface.
The core chemistry determines the solubilising properties of the cavity
within the core, whereas external chemical groups determine the solubility
and chemical behaviour of the dendrimers itself.
Targeting is achieved by attaching specific linkers to the external surface
of the dendrimers which enables it to bind to a diseased site.
Dendrimers are generally synthesised from either synthetic or natural
elements such as amino acids, sugars, and nucleotides.
In vivo delivery of dendrimer– methotrexate conjugates using multivalent
targeting results in a tenfold reduction in tumour size compared with that
achieved with the same molar concentration of free systemic
methotrexate22,46.
Although promising, dendrimers are more expensive than other
nanoparticles as it requires many repetitive steps for synthesis, posing a
challenge for large scale production.
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15.  Biological nanoparticles
The conjugation of biological molecules (peptides/proteins) and
synthetic polymers is an efficient means of improving control over
the nanoscale structure formation of synthetic polymers that can be
used as drug delivery systems.
The conjugation of suitable synthetic polymers to peptides or
proteins can reduce toxicity, prevent immunogenic or antigenic side
reactions, blood circulation times and improve drug solubility.
Modification of synthetic polymers with peptide sequences, which
can act as antibodies with peptide Sequences, which can act as
antibodies to specific epitodes, can also prevent random distribution
of drugs throughout Patient’s body by active targeting.
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16. WHAT IS CANCER?
 Cancer is a complex disease which arises due to a series of genetic changes related
to cell division and growth control.
 It is characterized by unrestricted proliferation of cells that are genetically modified to
have acquired the ability to metastasize to distant organ sites.
 In essence, cancer is a genetic disease arising from a stepwise accumulation of
genetic and epigenetic alterations that deregulate multiple complex regulatory
pathways of genes ,proteins and biochemical components affecting cellular growth,
division, migration and survival . These alterations arise at somatic level in sporadic
cancers or may be inherited through the germline in familiar cancers either
reactivating proto-oncogenes or inactivating tumour suppressor genes.
 Years of study has associated many internal factors (inherited mutations, hormonal
changes, change in immune conditions and metabolic problems) and externalfactors
(tobacco, radiation, different chemical carcinogene and infectious organisms) with
cancer. These factors may contribute to the accumulation of different abnormalities
by changing genetic or epigenetic composition of the genome, which may lead to
acquisition of many important traits by cancerous cells, including losing their control
on division, migration and invasion and even resistance to radio and chemotherapy.
cancer
Smoker’s lung
Image from national
Institute of cancer
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17. MECHANISM OF GROWTH OF TUMOUR
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18. CAUSES
 INFECTIOUS agents such as viruses, bacteria and parasitesare well-
accepted, bona fide etiological factors associated with specific human
cancers and account for almost 20%of the global cancer burden.
 It is estimated that up to 15% of all human tumours worldwide are
caused by viruses 3 The infectious nature of viruses distinguishes
them from other cancer-causing factors in that viruses establish
chronic infections in humans, where cancer development occurs by
the accumulation of multiple cooperating events . Such long-term
association with hosts provides them ample opportunities to mount
mutagenic onslaughts and initiate the cell transformation process
ultimately giving rise to malignant disease.
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19. MODERN VS CONVECTIONAL METHOD
 Conventional chemotherapeutic agents are distributed non-specifically in the body
where they affect both cancerous and normal cells, thereby limiting the dose
achievable within the tumour and also resulting in suboptimal treatment due to
excessive toxicities.
 Cancer therapy usually involves intrusive processes including surgery, radiotherapy
and chemotherapy depending on the type, location and stage of tumour.
 Surgical resection involves maximum possible removal of cancerous tissue. In
many cancers, surgery is followed by radiotherapy and or chemotherapy.
surgery
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20. Radiotherapy is given in the form of ionizing radiation, which works by damaging the DNA leading
to cell death.
radiotherapy
In addition to radiotherapy, high-grade tumours are also treated with different types of
chemotherapy, which includes treatment with single or multiple drugs. The purpose of
chemotherapy and radiation is to kill the tumour cells as these cells are more susceptible to the
actions of these drugs and methods because of their growth at much faster rate than healthy cells.
It would therefore be desirable to develop chemotherapeutics that can either passively or actively
target cancerous cells.
chemotherapy
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21. TARGETED DELIVERY NANOPARTICLE
 Ideally, for anticancer drugs to be effective in cancer treatment,
they should
 First, after administration, be able to reach the desired tumor
tissues through the penetration of barriers in the body with
minimal loss of their volume or activity in the blood circulation.
 Second, after reaching the tumor tissue, drugs should have the
ability to selectively kill tumor cells without affecting normal cells
with a controlled release mechanism of the active form.
Increasingly, nanoparticles seem to have the potential to satisfy
both of these requirements for effective drug carrier systems.
 There are two ways of targeted delivery of nanoparticles: active
and passive.
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22. PASSIVE TARGETING BY NANOPARTICLES
 It exploits the characteristic features of tumor biology that allow nanocarrier to
accumulate in the tumor by the enhanced permeability and retention (EPR) effect.
 Enhanced permeability and retention effect. Nanoparticles that satisfy the size
and surface characteristics requirements described above for escaping
ticuloendothelial system capture have the ability to circulate for longer times in the
bloodstream and a greater chance of reaching the targeted tumor tissues. The
unique pathophysiologic characteristics of tumor vessels enable macromolecules,
including nanoparticles, to selectively accumulate in tumor tissues . Fast-growing
cancer cells demand the recruitment of new vessels (neovascularization) or rerouting
of existing vessels near the tumor mass to supply themwith oxygen and nutrients .
The resulting imbalance of angiogenic regulators such as growth factors and matrix
metalloproteinases makes tumor vessels highly disorganized anddilated with
numerous pores showing enlarged gap junctions between endothelial cells and
compromised lymphatic drainage . These features are called the enhanced
permeability and retention effect, which constitutes an important mechanism by
which macromolecules, including nanoparticles, with a molecular weight above 50
kDa, can selectively accumulate inthe tumor interstitium.
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