Biomedical Engineering Reference
In-Depth Information
(B) Poly(ethylene glycol)
(PEG)
(A) Traditional
nanoparticles
(C) Antibodies
(G) Oligonucleotides
Chemotherapeutic
agents
(F) Carbohydrates
(D) Ligands
(E) Peptides
FIGURE 6.3
Schematic representation of nanoparticulate drug carrier structure with site-directing ligands
for targeting approaches. Several classes of ligands have been used for targeted chemotherapy: (A) traditional
“plain” nanoparticles, (B) long-circulating nanoparticles with surface protecting PEG chain, (C) monoclonal
antibody, (D) tumor-specifi c ligands to cell surface receptor (folate), (E) peptides (RGD, YIGSR, cell membrane-
penetrating peptides, etc.), (F) carbohydrates (hyaluronic acid, galactose, etc.), and (G) oligonucleotide
aptamers.
Target mAbs were fi rst shown to bind to specifi c tumor antigens in 1975 [13]. The discovery
of antigens that are particularly overexpressed on the cancer cell surface suggests that by using
certain antibodies to selectively mark tumor cells, malignant tissues could be distinguished from
normal tissues. Monoclonal antibodies that have shown high binding specifi city to tumor-specifi c
antigens could fulfi ll this task. These mAbs could be used as vehicles to selectively deliver cytotoxic
drugs to tumor cells. The mAb moiety then binds to the cancer cell antigen, and the conjugate is
internalized through receptor-mediated endocytosis followed by the release of the patient drug to
restore original activity [19,83-85]. Monoclonal antibodies are being used as imaging vehicles for
drug targeting, as drug carriers, and solely as the drug. Early mAb—drug conjugates used mAbs
derived from murine hybridomas. Kohler and Milstein described their pioneering work on mAbs by
hybridoma technology; however, the therapeutic effects were severely impaired due to the human
antimouse antibody (HAMA) response, resulting in the rapid clearance of the immunoconjugates
from the bloodstream [86]. Consequently, a recombinant DNA protocol was developed, which
produced generations of humanized mAbs generated by grafting the complementary determining
region (CDR) from a mouse mAb into a human [19]. In 2000, Mylotarg (gemtuzumab-ozogamicin)
was approved by the FDA for the treatment of acute myelogenous leukemia, providing the fi rst in
clinic mAb—drug immunoconjugate for the treatment of cancer [19,83-86]. Currently, there are at
least nine FDA-approved antibodies for clinical use in cancer, and approximately 20 more are being
evaluated in clinical trials (Table 6.2) [6,83-86].
6.5.3.1.2
Transferrin
The Tf family of iron-binding proteins has been the subject of intense investigation since serum
transferring was discovered more than 40 years ago. A considerable number of reviews have
provided a wide range of functional properties, structures, metal-binding properties, and metal
