Biomedical Engineering Reference
In-Depth Information
One of the major advantages of nanoparticles is their small size, which allows access to capillaries
and provides increased resistance to macrophage uptake of the reticuloendothelial system (RES).
Another advantage is that therapeutic agents can often be encapsulated, dispersed, or dissolved at
a high density within these nanoparticles and engineered to yield different properties and release
characteristics for delivery of the required drug concentration [27-32]. When a drug molecule is
administered with a carrier, drug clearance decreases (half-life increases), volume of distribution
decreases, and the area under the time versus concentration curve increases [27-30].
Due to the versatility of the chemistries and preparations of these systems, nanoparticles can
be fabricated to incorporate surface functionalities, which can facilitate attractive properties, such
as the attachment of shielding ligands to prolong the circulation of the nanoparticles in the blood-
stream or the targeting of ligands for interaction with specifi c cells or tissues [14].
Nanoparticles have the potential to improve cancer drug delivery, and they provide the following
advantages [2,5]: (1) decreased immunogenicity, (2) protection from alteration and inactivation of
the active drug, (3) altered biodistribution to reduce systemic toxicity, (4) elimination of multidrug
resistance, (5) increased tumor cytotoxicity, (6) passive targeting by enhanced permeability and
retention (EPR), and (7) site-specifi c delivery of drugs by active targeting.
6.3.2 L
IPOSOMES
Liposomes, the most intensively investigated family of particulate carriers, are lipid molecules,
highly ordered in a lamellar arrangement that encapsulates a fraction of the solvent in which they
are suspended [42-47]. Liposomes are considered attractive, harmless drug carriers that can circu-
late in the bloodstream for an extended time because they are natural materials [11,39]. They may be
formulated into small structures to encapsulate hydrophilic drugs in the aqueous interior or hydro-
phobic drugs within the bilayer [14]. Liposomes can be engineered to yield different properties
depending upon the lipid [42-44]. In addition, the liposome surface can be engineered to improve
properties. To date, the most noteworthy surface modifi cation is the incorporation of polyethylene
glycol (PEG). PEG-modifi ed liposomes show a longer blood circulation period (
T
1/2
>
48 h) than
that of polymeric micelles (
T
1/2
<
24 h). Also, some liposomal formulations, such as Doxil (Alza
Co.) and Visudyne (Novartis Co.), have already been approved for clinical use. However, the treat-
ment with Doxil sometimes induces the side effects of the hand-foot syndrome as well as infusion-
related reactions. Thus, the patients need to be pretreated with antihistamine or anti-infl ammatory
agents before the administration of Doxil [27].
PEG can serve as a barrier, preventing interactions with plasma proteins and thus retarding
recognition by the RES and enhancing lifetime circulation of the liposome [14]. Liposomes used
as particulate drug carriers are homogeneous, unilamellar, and 50-150 nm diameter vesicles [42].
However, there have been major drawbacks to the use of liposomes for targeted drug delivery, most
notably due to poor control over drug release from the liposome (i.e., the potential for leakage of the
drug into the blood), low encapsulation effi ciency and manufacturability at the industrial scale, and
poor storage stability [14]. For the liposome to act as a useful drug carrier, it should be able to retain
an encapsulated drug for a suffi ciently long time after its administration in order to appropriately
alter the pharmacokinetics of the drug [48].
TAT or penetratin peptides conjugated to lipid constituents of liposomes have been shown to
dramatically improve cellular delivery
in vitro
and to have some potential
in vivo
for gene therapy
[3]. Recently, a multicomponent liposomal drug delivery system consisting of doxorubicin and
antisense oligonucleotides targeted to MRP1 mRNA and BCL2 mRNA to suppress pump resis-
tance and nonpump resistance, respectively, has been developed. This liposomal system success-
fully delivered the antisense oligonucleotides and doxorubicin to cell nuclei of multidrug-resistant
human lung cancer cells and substantially increased the potential anticancer action of doxorubicin
by stimulating the caspase-dependent apoptosis pathway [23,45].
