1 CHAPTER 1 NANOPARTICLES IN TARGETED DRUG DELIVERY SYSTEMS: SURFACE MODIFICATION AND TOXICITY 1.1 INTRODUCTION Nanomedicine, the application of nanotechnology in medicine, aims to overcome problems related to diseases at the nano scale where most of the biological molecules exist and operate. It is an emerging field with wide range of applications from diagnosis to therapy, which includes targeted delivery and regenerative medicine. The role of nanotechnology in cancer is quite significant, enhancing the earlier crude procedures with modern diagnosis and therapeutic strategies. Nanoparticles are molecular assemblies that overcome biological barriers (bio-barriers) through their functional chemistry, and accumulate preferentially in tumors and specifically target the single cancer cell for detection and treatment. Cancer nanotechnology is an interdisciplinary field of research that is based in biology, chemistry, engineering and medicine, and is aiming at a giant leap in cancer diagnosis and treatment (Wang and Thanou 2010). 1.2 TARGETED DRUG DELIVERY Targeted drug delivery is a method of delivering the medicine to a patient in a manner that increases concentration at the diseased parts of the body. Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication
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CHAPTER 1
NANOPARTICLES IN TARGETED DRUG DELIVERY
SYSTEMS: SURFACE MODIFICATION AND TOXICITY
1.1 INTRODUCTION
Nanomedicine, the application of nanotechnology in medicine,
aims to overcome problems related to diseases at the nano scale where most
of the biological molecules exist and operate. It is an emerging field with
wide range of applications from diagnosis to therapy, which includes targeted
delivery and regenerative medicine. The role of nanotechnology in cancer is
quite significant, enhancing the earlier crude procedures with modern
diagnosis and therapeutic strategies. Nanoparticles are molecular assemblies
that overcome biological barriers (bio-barriers) through their functional
chemistry, and accumulate preferentially in tumors and specifically target the
single cancer cell for detection and treatment. Cancer nanotechnology is an
interdisciplinary field of research that is based in biology, chemistry,
engineering and medicine, and is aiming at a giant leap in cancer diagnosis
and treatment (Wang and Thanou 2010).
1.2 TARGETED DRUG DELIVERY
Targeted drug delivery is a method of delivering the medicine to a
patient in a manner that increases concentration at the diseased parts of the
body. Targeted drug delivery seeks to concentrate the medication in the
tissues of interest while reducing the relative concentration of the medication
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in the surrounding tissues. This improves the efficacy of the drug while
reducing side effects. Drug targeting delivers drugs exclusively to receptors,
organs, or any other specific part of the body to which one wishes to deliver
them. Multi functionalized single walled carbon nanotubes were used for
targeting biological transporters (Yang et al 2008).
The drug’s therapeutic index, as measured by its pharmacological
response and safety, relies in the access and specific introduction of the drug
with its candidate receptor, whilst minimizing its interaction with non –target
tissue. With desired differential distribution of the drug, its targeted delivery
spares the rest of the body and thus significantly reduces the overall toxicity
to the normal cell, while maintaining the drug’s therapeutic benefits. The
targeted or site-specific delivery of the drug is indeed a very attractive goal
because it may to improve the therapeutic index of the drug (Manish and
Vimukta 2011). A schematic diagram of a targeted drug delivery system is
given in Figure 1.1.
Figure 1.1 Schematic diagram of targeted drug delivery system
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1.2.1 Types of Drug Targeting
Drug targeting may be classified into two general methods:
1) Active targeting
2) Passive targeting
1.2.1.1 Active Targeting
Active targeting refers to the delivery of drugs to a target through
the use of specific interactions at the target site where a drug’s
pharmacological activities are required. These interactions include antigen–
antibody and ligand–receptor binding. Alternatively, physical signals such as
magnetic fields and thermal energy that are externally applied to the target
sites may be utilized for active targeting. Active targeting involves the use of
peripherally conjugated targeting moieties for enhanced delivery of
nanoparticle systems. The targeting moieties are important to the mechanism
of cellular uptake. For example doxorubicin, an anticancer drug, is targeted to
cancer cells by entrapping it in folate conjugated liposomes (Lee and Low
1995).
Long circulation times will allow for effective transport of the
nanoparticles to the tumor site through the enhanced permeability retention
(EPR) effect, and the targeting molecule can increase the endocytosis of these
nanoparticles. The internalization of nanoparticle drug delivery systems has
shown an increased therapeutic effect (Kirpotin et al 2006). If the
nanoparticle attaches to vascular endothelial cells via a non-internalizing
epitope, high local concentrations of the drug will be available on the outer
surface of the target cell. Although this has a higher efficiency than free drug
released into circulation, only a fraction of the released drug will be delivered
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to the target cell. In most cases, internalization of the nanoparticle is
important for effective delivery of some anticancer drugs, especially in gene
delivery, gene silencing, and other biotherapeutics (Atobe et al 2007). The
schematic representation of active targeting is given in Figure 1.2.
Figure 1.2 Schematic representation of active targeting
1.2.1.2 Passive targeting
Passive targeting is defined as a method whereby the physical and
chemical properties of carrier systems increase the target/non-target ratio of
the quantity of the drug delivered by adjusting these properties to the
physiological and the histological characteristics of the target and non-target
tissues, organs, and cells. Carriers included in this category are synthetic
polymers, some natural polymers such as albumin, liposomes, micro (or nano)
particles, and polymeric micelles. Influential characteristics of passive
targeting are (1) chemical factors such as hydrophilicity/hydrophobicity and
positive/negative charge and (2) physical factors such as size and mass.
Passive targeting can be achieved by minimizing both nonspecific interactions
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and delivery with/to non-target organs, tissues,
and cells, as well as through the maximization of delivery to the target
(Yokoyama 2005). The schematic representation of passive targeting is given
in Figure 1.3.
Figure 1.3 Schematic representation of passive targeting
1.3 NANOPARTICLES IN TARGETED DRUG DELIVERY
1.3.1 Inorganic Nanoparticles
Ceramic nanoparticles are typically composed of inorganic
compounds like silica or alumina. However, the nanoparticle core is not
limited to just these two materials; rather, metals, metal oxides and metal
sulphides can be used to produce a myriad of nanostructures with varying
size, shape, and porosity. Generally, inorganic nanoparticles may be
engineered to evade the reticuloendothelial system by varying size and
surface composition. Moreover, nanocarriers may be porous, and provide a
physical encasement a molecular payload (drug) from degradation or
denaturization. Several functional groups can be introduced onto the surface
of inorganic nanoparticles, ranging from saturated and unsaturated
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hydrocarbons to carboxylic acids, thiols, amines, and alcohols. Inorganic
nanoparticles are relatively stable over broad ranges of temperature and pH,
yet their lack of biodegradation and slow dissolution raises safety questions,
especially for long- term administration.
1.3.2 Polymeric Nanoparticles
Polymeric nanoparticles are biodegradable and biocompatible, and
have been adopted as a preferred method for nanomaterial drug delivery.
They also exhibit a good potential for surface modification via chemical
transformations, provide excellent pharmacokinetic control, and are suitable
for the entrapment and delivery of a wide range of therapeutic agents.
Pertinent nanoparticle formulations include those made from gelatins,