Biomedical Engineering Reference
In-Depth Information
6.2.2 P
ROBLEMS
OF
C
HEMOTHERAPY
Problems of chemotherapy are the high toxicity and lack of tumor specifi city of currently used
chemotherapeutic drugs. Many anticancer drugs have marginal selectivity for malignant cells
because they target the replicative apparatus in cells with high proliferation rates. Thus, anticancer
drugs that target the replicating apparatus also have high toxicity against rapidly dividing normal
cells, which leads to systemic toxicity causing undesirable severe side effects such as hair loss, and
damage to the liver, kidney, and bone marrow. In addition, the dense packing of tumor cells limits
the movement of molecules from the vessel into the interstitial compartment [2-5].
The effi cacy of anticancer drugs may decrease at times when it is not possible to increase
chemotherapeutic dosages or when patients in relapse do not respond to the drug due to an acquired
resistance. The lack of tumor response to a drug, drug resistance, can be due to poorly vascularized
regions and insuffi cient accumulation of the drug to a therapeutically effective concentration [10].
While rapid drug internalization by passive diffusion across the plasma membrane produces
a suffi cient concentration, effl ux pumps, which actively pump out a large spectrum of structurally
unrelated drugs, counteract the diffusion [5]. Some tumor cells are able to expel intracellular drugs
into the external medium, thereby attaining resistance from drug action. This mechanism, called
multidrug resistance, is related to the overexpression of transporters from the adenosine triphosphate
(ATP)-binding cassette family, including the P-glycoprotein (Pgp) transporter and multidrug
resistance protein (MDRP). These transmembrane proteins are capable of pumping out many of the
anticancer drugs that diffuse into the plasma membrane [14]. Thus, it is very diffi cult to achieve and
maintain the required effective therapeutic drug concentration in the tumor tissue. Nanoparticles,
however, appear to be useful for overcoming certain kinds of drug resistance. Internalized particles
bypass the transporter mechanism that recognizes drugs in the plasma membrane, and they are able
to release drugs within the cytoplasm or endosomal vesicles, thereby increasing the effectiveness of
the drug [14-16]. Several strategies may be employed to achieve drug targeting in tumors, and the
method is chosen depending on the tumor type and tissue characteristics, the drug chemical and
biological properties, and the rate and time-course of drug application [14-26].
6.3
NANOPARTICLES IN CANCER THERAPY
6.3.1 P
ARTICULATE
D
RUG
C
ARRIERS
An approach that overcomes the limitation of chemotherapeutic agents is the targeting of tumors
with particulate drug carriers. Particulate drug carriers have become an important area of drug
delivery applications due to their ability to deliver a wide range of drugs to varying areas of the
body for sustained periods of time [27-40]. Nanoparticles can be defi ned as colloidal systems with
a diameter smaller than 1000 nm. Nanoparticles may or may not be biodegradable and can be
defi ned as solid colloidal particles containing an active substance that are produced by mechani-
cal or chemical means. Nanoparticles are a collective name for nanospheres and nanocapsules.
Nanospheres have a matrix-type structure. Drugs may be absorbed at their surface, or entrapped or
dissolved within the particle. Nanocapsules are vesicular systems in which the drug is confi ned to a
cavity or inner liquid core surrounded by a membrane. In this case the drugs are usually dissolved
in the inner core but may also be adsorbed at their surface [41].
These particles can enter cells, including nuclear compartments, allowing for interaction with
DNA and cellular proteins [27]. In addition, nanoparticles can be prepared with different sizes and
surface modifi cations, which will determine their properties in biological systems. Recently, many
therapeutic agents including small molecules, proteins, DNAs, and peptides have been combined
to form potent and complex agents. Various nanoparticle drug delivery systems, listed in Table 6.1,
have been developed using a variety of materials (polymers, liposomes, metals, ceramics, etc.) with
unique architectures [27,28,39].
