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Smart Drug Delivery Systems – Futuristic Window in Cancer Therapy
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Chapter 2
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Nanomedicine for Targeted Drug
Delivery in Cancer Chemotherapy
Niladri ShekharDey, Ramesh KumariDasgupta
a
nd Saumendu DebRoy
Abstract
Cancer is the uncontrolled proliferation of cells which subsequent spread of other
organs of the human body (metastasis). The major therapeutic approaches of cancer
chemotherapy are to deliver the correct amount of drug molecule in the desired site
(malignant cells) for longer duration of action. Nanomedicine basically by passive as
well as active targeting has been implemented for recognition, diagnosis and treatment for cancer and widely accepted in the modern field of oncology. Nanomedicine
such as nanoliposomes and polymer based nanoparticles combine with genetic
materials administered to the target cells for cancer chemotherapy. The advancement
of nanomedicine will improve the therapeutic index of anticancer drug via modulation of pharmacokinetics parameters and tissue distribution to targeted sites. Ligand
molecule can be tagged with this nanodevices for recognize the malignant cells via
active targeting purposes and drug can be release at the site of specific target area
followed by pre-programmed or predictable manner. This novel strategy of drug
delivery technology is also applicable for conventional chemotherapy as well as metastatic state of the cancer patients. Targeting of neoplastic cells by nanocarriers play a
vital role in novel drug delivery by protecting healthy normal cells from cytotoxicity
as well as helpful for preventing the angiogenesis (neovascularization).
Keywords: nanomedicine, metastasis, target cells, ligand molecule, cytotoxicity,
angiogenesis
. Introduction
Cancer is one of the serious and devastating illnesses of human beings in all over
the world. It is an abnormal growth of cell division where apoptosis is generally
disappeared and need very complex for long term treatment [1]. The treatment for
cancer in the field of oncology is that surgical removal, radiation, hormone therapy
and chemotherapy. Chemotherapy is applied by the use of anticancer drugs loaded
formulations at the disease site for recovery of patients. Conventional chemotherapy
cannot achieve proper selectively to target the cancerous cells and showed the
unwanted or adverse effect for the patient during the chemotherapy [2]. Conventional
chemotherapy worked by destroying abnormal proliferated cells and due to its
cytotoxic nature it also damages the normal healthy cells. Common side effects are
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shown alopecia (hair loss), nausea or vomiting, organ dysfunction, anemia, thrombocytopenia, myelosuppression and mucositis [3]. As per therapeutic drug monitory
the strategies of modern chemotherapy are preferentially destroying malignant cells
without having any harmful toxic effects of the normal healthy cells [4]. Nowadays,
in the modern field of oncology anticancer drug loaded nanocarriers or nanomedicine
were implemented for detection, diagnosis and recovery of critical illness of the
patients. The various nanodevices are designed or fabricated for a major role of treatment of neoplastic diseases via passive or active targeting purposes [5]. Anticancer
drug loaded nanodevices can also attack the malignant cells through passive targeting
where leaky blood vessels are there due to basement membrane abnormalities [6].
Antibody or ligand conjugated anticancer drug loaded nanodevices are fabricated for
active targeting is specially based on molecular recognition [7]. In the modern field of
nanotechnology, ligand molecules which are conjugated with the surface of nanocarriers may benefit for active targeting purposes.
Our major focus is to application of nanodevices in the modern field of cancer
chemotherapy by avoiding cytotoxicity of normal healthy cells and also discussion of
cellular uptake of malignant cells of different organs of the human body by various
anticancer drug loaded nanocarriers.
. Global prevalence of cancer and the side effects of few anticancer drugs
Cancer is the devastating disease which ranked as a leading cause of death in all
over world. WHO estimate that cancer is the first or second leading cause of death
before the age of 70years (Figure ) [8]. The substances that cause abnormal proliferation of cells (malignant cells) known as carcinogens. The change of genetic material in
the cells may occur spontaneously as a random event or may be modulation of genetic
material [9]. This incident occurs due to an external exposure to a substance (carcinogens) which develops the neoplastic cells as well as promote neovascularization i.e. new
Figure 1.
Global cancer incidence in present scenario.
Nanomedicine for Targeted Drug Delivery in Cancer Chemotherapy
DOI: http://ITexLi.114066
blood vessel formation for survive the malignant cells. Carcinogens include radiations,
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tobacco, chemical or may be viruses also. Few ionizing radiation like X-rays, nuclear
power plants and atomic bomb explosions can cause various malignancies particularly
sarcomas, leukemia, thyroid, cancer or breast cancer [10].
Common side effects of chemotherapy include fatigue, hair loss, pain, nerve
damage, mouth and throat sores, diarrhea, constipation, nausea & vomiting, blood
disorders, loss appetite, heart problem and fertility problem also [11].
. Application of nanomedicine
Cancer is a complicated biological disorder in the human body where abnormal
proliferation occurs in malignant cells. The main focus of modern treatment of cancer
chemotherapy is to damage the neoplastic cells or control of growth rate and also
avoiding cytotoxicity i.e. not to produce any harmful effect in normal healthy cells.
Malignant cells are able to proliferate in the human body through new blood vessels
generation for neoplastic cell growth formation (neovascularization) known as angiogenesis and lymphatic streams, causing metastasis by forming a secondary tumor
[12]. Anticancer drugs work in different ways: by killing the neoplastic cells through
direct exposure of chemical agent, by inducing apoptosis (suicide of malignant
cells) and arrest neovascularization i.e. (angiogenesis) [3]. The design of nanocarriers revealed a new avenue in the field of oncology such as solid lipid nanoparticles,
nanolipid vesicles such as nanoliposomes, carbon nanotubes, dendrimer, micelles,
quantum dots, mesoporous silica and protein based nanoparticles etc. which are
loaded with anticancer drugs. These nanodevices show potential activity and may
utilize for both active and passive targeting during chemotherapy.
. Dendrimers
Dendrimers are hyper branched nanodevices macromolecules which are three-
dimensional structure made up of polymer branching units by covalently attaching
with central core for organizing concentric layers [13]. These types of devices have the
ability to improve bioavailability as well as the solubility of hydrophobic drugs which
Figure 2.
Structure of dendrimer and its application.
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can be incorporated in to the intramolecular core of these nanodevices or tagged to
their surface of functional groups. By employing biocompatible components with
antineoplastic drugs, loaded dendrimers will modify therapeutic index and dosage
regimen also (Figure ) [14].
. Carbon nanotubes
Carbon nanotubes are built of single or more graphene sheets which are rolled
up into a cylindrical tube like single-walled (SW-CNT) or multiwalled (MW-CNT)
carbon nanotube structure. These carbon nanotubes are involved fullerenes group
(a third allotropic form of carbon) [15]. These nanodevices may assume the hollow
sphere, ellipsoid shape and also exists many other forms where the outer diameters
are typically in the range of 0.4–2nm for SW-CNT and 2–100nm for the MW-CNT
[16]. Water insoluble anticancer drugs can easily be incorporated into the hydrophobic hollow interior of carbon nanotubes [17]. Anti-neoplastic drug can be loaded into
carbon nanotube for passive as well as active targeting (Figure ).
Figure 3.
Schematic diagram of carbon nanotube and its application.
. Quantum dots
Quantum dots are fluorescent semiconducting inorganic nanocarriers. These nanocarriers are applying for several biomedical applications such as cellular imaging and
drug delivery [18]. For the synthesis of quantum dots, two common methods are there;
one is a bottom-up approach (by self-assembly processes in solution following chemical
reduction) and another one is by a top-down method (by means of molecular beam
epitaxy ion implantation, e-beam or X-ray lithography) [19, 20]. Most quantum dots are
constructed of three parts, an extremely small core (2–10nm in diameter) of a semiconductor component (e.g. CdSe) surrounded by another semiconductor material, such
as ZnS [21]. Finally, a cap made of different components encapsulates the double layer
structures of the QDs [22]. The inner semiconductor of CdSe coated with the outer shell
of ZnS for QDs revealed most important nanodevices for drug delivery (Figure ) [23].
Nanomedicine for Targeted Drug Delivery in Cancer Chemotherapy
DOI: http://ITexLi.114066
Figure 4.
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Internal structure of quantum dots and it’s fluorescence property.
. Nanoliposome or nanolipid vesicles
Liposomes are artificial microscopic bilayer of phospholipids vesicles. These
vesicles consist of natural or synthetic lipids represent as nanocarriers in the field of
modern drug delivery as well as applications for cancer chemotherapy [24]. Natural
phospholipid or synthetic i.e. conventional phospholipids are constructed with one or
more hydrophilic tails and hydrophilic head. The lipid bilayer vesicles i.e. liposomes in
aqueous solution depends on the different condition such as the method of preparation i.e. stirring, hydration, sonication, extrusion, and they microfluidification, or
electroformation (Figure ) [25, 26]. This nanodevices size ranges between 50 and
500nm and are available as unilamellar vesicles (<100nm), large unilamellar vesicles
(100–1000nm) or giant unilamellar vesicles (>1μm) [27].
The development of nanolipid vesicles or nanoliposomes is applicable for chemotherapy during treatment of cancer for their property having both controlled release
and targeted drug delivery at the disease site specific action [27]. Encapsulation of
chemotherapeutic agents or anticancer drugs within the lipid vesicles can enhance the
cellular uptake as well as improve the therapeutic index by systemic administration
during chemotherapy [28, 29]. The circulation-time of liposomes can be enhanced
and by conjugating stealth-imparting polymers to their surfaces poly-ethylene glycol
(PEG) their detection by the reticuloendothelial system (RES) can be reduced [30].
Nanolipid vesicles can penetrate preferentially on the malignant cells (due to the leaky
vasculature of tumor cells) by means of a passive targeting process via the enhanced
permeability and retention (EPR) effect [31, 32]. Ligand molecules may be attached
to the liposomal surface or vesicles for actively target to the cancer cells. Ligands such
as antibody or aptamer, proteins, peptides which are conjugated or tagged with the
lipid vesicles covalently or non-covalently can easily recognize the neoplastic cells
which are specific to the cancer cells or to the endothelial cells of the tumor vasculature (Figure and Table ) [33].
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