Biomedical Engineering Reference
In-Depth Information
6.5
TARGETED DRUG DELIVERY FOR CHEMOTHERAPY
6.5.1 D
RUG
T
ARGETING
Targeted drug delivery by an engineered system is said to be achieved when the time profi le of
the drug at the target site is optimized, and the burden of drug to other tissues is minimized. This
defi nition assumes that both the activity and toxicity are related to the time profi le of t he i nt act d r ug at
the target and toxic sites, respectively. The assessment of targeting can be determined by comparing
dose-response curves of the targeted system with the conventional or non-targeted system [48].
Targeted drug delivery has gained recognition in modern therapies, and attempts are being
made to explore the potentials of cellular biology-related bioevents in the development of specifi c,
programmed, and target-oriented systems [14-19]. Using nanoparticles to specifi cally deliver drugs
to tumors offers the attractive possibility of avoiding obstacles that occur during conventional,
systemic drug administration. Through several targeting strategies, nanoparticles can be selectively
accumulated in malignant tissues as opposed to healthy tissues [19-26]. Principal schemes of drug
targeting currently being investigated in various experimental and clinical settings include (1) direct
application of the drug to the affected sites (organs, tissues); (2) passive accumulation of the drug
through leaky vasculature (tumors, infarcts, infl ammation); (3) physical targeting of the drug based
on abnormal pH and temperature in the target site (tumor, infl ammation) and magnetic targeting
under the action of an external magnetic fi eld; and (4) use of vector molecules possessing high
specifi c affi nity toward the affected site [18].
6.5.2 P
ASSIVE
T
ARGETING
Functional and morphological differences exist between normal and diseased vasculature, offering
therapeutic opportunities and windows for the delivery of therapeutic agents. Rapidly growing
cancer cells require quick formation of new blood vessels. The tumor vasculature has many defects,
which allows large molecules to easily enter the tumor extravascular space. On the other hand, the
lymphatic drainage in cancer cells is undeveloped such that large molecules cannot be released
from the tumor [1-5]. Following systemic administration, drugs must be transported through blood
vessels across the vascular wall into the surrounding tissues and through the interstitial space. Fluid
movement accompanies the extravasation of molecules across leaky vessels by passive diffusion or
convection, depending on the hydrostatic and osmotic pressure differences between the blood and
interstitial space. As a result of the increased permeability of endothelial barriers in tumor blood
vessels and the lack of effective lymphatic drainage from the tumor, passive targeting results in the
selective extravasation and accumulation of particulates or other macromolecules in tumor tissues.
This phenomenon, termed as the EPR effect, was fi rst described by Maeda et al. in 1986, and it has
been confi rmed in numerous cases [1-5,14-19].
Passive targeting can result in severalfold increases in drug concentrations within solid tumors
relative to concentrations obtained with free drugs. Surface-modifi ed nanoparticles engineered to
display an overall positive charge facilitated adhesion to negatively charged arterial walls and have
shown about 7-10-fold greater arterial localized drug levels compared with unmodifi ed nanoparticles
in different models. Rexin-G, a targeted nanoparticle vector system with a proprietary mutant
cell-cycle control gene, has been approved for clinical trials for stage IV metastatic pancreatic
cancers [14]. Passive targeting with nanoparticulate drug carriers includes manipulation of the size,
hydrophobicity, or other physicochemical properties [15-20].
6.5.3 A
CTIVE
T
ARGETING
Active targeting relies on the expression of disease-selective molecular markers, mainly peptide or
glycoside receptors and transporters, by either diseased cells or disease-associated cells such as the
neoangiogenic endothelium of cancer tissue [14-18]. To achieve active targeting, it is necessary to
