Biomedical Engineering Reference
In-Depth Information
6.1 INTRODUCTION
Although the pharmaceutical industry has been successful in discovering many new cytotoxic drugs
that are potential candidates for cancer treatment, cancer remains a leading cause of death and is
a serious threat to human health. Current anticancer drug therapy results in systemic side effects
due to nonspecifi c uptake by normal, healthy, noncancerous tissues. Many anticancer drugs have
marginal selectivity for malignant cells because they target the replicative apparatus in cells with
high proliferation rates. Thus, anticancer drugs having the same mechanism of action also have high
toxicity against rapidly dividing normal cells [1,2]. Additionally, the side effects associated with che-
motherapy limit the dose or cumulative doses that can be administered to patients, which can lead to
relapse of the tumor and often to the development of drug resistance [1,2]. Therefore, there have been
numerous investigations aimed at developing more effi cient systems that improve selective toxicities
against cancer cells, that is, therapies that increase effi cacy and decrease side effects, resulting in an
increase in the therapeutic indices of the anticancer drugs. A successful approach is to use particulate
drug carriers to alter the pharmacokinetics and biodistribution of anticancer drugs. Nanoparticle
drug carriers can be delivered to specifi c sites by size-dependent passive targeting or active target-
ing. Recently, tumor-targeted delivery systems using nanoparticles have become increasingly used in
chemotherapeutic engineering of cancer treatments. In the fi rst part of this chapter, we present a short
introduction of nanoparticle systems as drug carriers. This review also provides current approaches
used in design and optimization of tumor-specifi c drug delivery systems.
6.2 CHEMOTHERAPY
6.2.1 T
UMOR
T
ISSUES
Current anticancer therapy can only prolong the patient's life but does not cure malignant diseases.
Although research efforts to improve anticancer technology have improved patient's survival, cancer
remains a leading cause of death. To achieve effective chemotherapy, it is important to recognize the
morphological and physiological differences between normal and malignant tissues [1-12]. Cancer
is caused by uncontrolled growth and spreading of abnormal cells. Cancerous cells, which can be
formed due to external factors (e.g., smoking, chemicals, and infections) or internal factors (e.g.,
inherited metabolism mutations, hormones, and immune conditions), replicate at a higher rate than
other healthy cells, placing strain on nutrient supply and metabolic waste product elimination [2].
Tumor cells will displace healthy cells until the tumor reaches a diffusion-limited maximum size.
To grow beyond this size, the tumor must recruit blood vessels to provide the necessary nutrients to
fuel continued expansion. Cells at the outer edge of the tumor mass have the best access to nutrients,
while cells on the inside that rely on diffusion to deliver nutrients and eliminate waste products
die, creating a necrotic core. Thus, tumors exhibit not only densely vascularized regions to acquire
adequate supply of nutrients for rapid growth but also necrotic regions or hemorrhages [13].
Additionally, tumor blood vessels show several abnormalities. Tumors develop a tortuous, chaotic
capillary network with a hierarchical branching pattern that is distinguishable from normal vascula-
ture. The capillary vasculature in tumors is often accompanied by occlusions, caused by rapidly prolif-
erating cancer cells. Compression of the vasculature causes hypoxia and eventually necrosis of viable
tumor cells. In addition, tumor vasculature exhibits aberrant basement membranes as well as a high
proportion of proliferating endothelial cells. Since the fast-growing tumor requires a large amount of
oxygen and nutrients, tumor blood vessels show 3-10 times higher permeability [1-5]. The interstitial
compartment of a tumor contains a collagen and elastic fi ber network, which is immersed in hyaluro-
nate and proteoglycan-containing fl uid. The interstitial pressure within the tumor tissue is elevated
due to the lack of a lymphatic drainage system. Increased pressure and rapid aberrant cell growth are
believed to be responsible for the compression and occlusion of blood and lymphatic vessels in solid
tumors and for hindering the extravasations and accumulation of drugs in the tumor tissue [1,2].
