Biomedical Engineering Reference
In-Depth Information
(
T
1/2
: 140 and 30 min, respectively). In addition, the block copolymeric nanoparticles delivered an
increased amount of doxorubicin to the tumor when compared with free DOX [108].
Research performed by Dagor et al. indicated that vasoactive intestinal peptide-targeted
liposomes achieve signifi cantly higher intratumoral accumulation than nontargeted counterparts,
suggesting that levels of intratumoral accumulation of actively targeted particulates are infl uenced by
the choice of the ligand and by the microenvironment of the individual tumor type. It remains to be
established whether noninternalizing ligands will also yield improved therapeutic effi cacy compared
with passively targeted particulates under conditions of higher intratumoral accumulation [109].
In spite of the limitations in targeting tumor cells in solid tumors, a particulate drug carrier for
active targeting has entered clinical trials. MCC465 is a sterically stabilized liposomes containing
doxorubicin that selectively targets stomach cancer cells using f(ab
)
2
human IgG Mab fragment and
is currently in Phase I clinical trials [110]. MCC465 demonstrated clinical effi cacy and considerably
reduced side effects relative to other therapies. Furthermore, an anti-HER2, doxorubicin-
incorporating SSL formulation is about to enter clinical development trials [111].
Foarokhzad et al. developed poly(d,l-lactide-
co
-glycolide)-PEG block copolymer nanoparticles
conjugated with the A10 RNA aptamer (Apt) that binds to the prostate-specifi c membrane antigen
(PSMA), and they investigated the biodistribution of Apt-conjugated nanoparticle drug carriers in a
LNCaP (PSMA
′
) xenograft mouse model of prostate cancer. The surface functionalization of nanopar-
ticles with the A10 PSMA Apt signifi cantly enhanced delivery of nanoparticles to tumors compared
with equivalent nanoparticles lacking the A10 PSMA Apt (a 3.77-fold increase at 24 h) [35].
+
6.6 CONCLUSIONS
Traditional cancer chemotherapy relies on the premise that rapidly proliferating cancer cells are
more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or
no specifi city, which lead to systemic toxicity, causing severe, undesirable side effects. The current
focus in pharmaceuticals is shifting to a “smart drug” paradigm, in which increased effi cacy and
decreased toxicity are the motivating factors. An attractive strategy to enhance the therapeutic
index of drugs is to specifi cally deliver these agents to the defi ned target cells, thereby keeping them
away from healthy cells, which are sensitive to the toxic effects of the drugs. Many attempts are
being made to explore the potential of specifi c and target-oriented delivery systems. New nanopar-
ticle structures, materials, and new encapsulation methods are continuously being reported. With
these dedicated efforts, it seems that the synergistic future of a nanoparticle delivery system holds
substantial promise. Engineering the drug loading of nanoparticle drug carriers, controlling the
drug release profi le, and guiding nanoparticle systems to the desired target are among other chal-
lenges that are currently being evaluated. Specifi cally, ligand receptor-medicated delivery systems
have received major attention in the past few years due to the potential of nonimmunogenic, site-
specifi c targeting to ligand-specifi c sites of the naturally existing ligands and their receptors. There
is no doubt that molecularly targeted therapies will revolutionize the treatment of cancer and other
diseases. Although major advances have been made in the delivery of cancer chemotherapeutics,
much work lies ahead. To accomplish the desired goals of this innovative system, further clinical
trials need to be performed as they are the key to the realization and success of the next generation
of therapy.
REFERENCES
1. A. El-Aneed, An overview of current delivery systems in cancer gene therapy,
Journal of Controlled
Release
94 (2004) 1-14.
2. C. Leuschner and C. Kumar, Nanoparticles for cancer drug delivery, in
Nanofabrication Towards
Biomedical Applications
(Eds.) C. Kumar, J. Hormes, and C. Leuschner, 2005 Wiley-VCH Verlag
GmbH & Co., KGaA, Weinheim, Germany, pp. 289-326.
