Biomedical Engineering Reference
In-Depth Information
effectiveness in vitro against five human monolayer tumor cell lines. Namely
MCF7 (breast carcinoma), HEPG(2) (liver carcinoma), U-251 (glioma),
HCT116 (colon carcinoma), and H-460 (lung carcinoma). Recent evalu-
ation has been undertaken of the potential antitumor activity of NK012,
a 7-ethyl-10-hydroxycamptothecin (SN-38) micellar formulation, and
bevacizumab in human lung cancers [110]. Nude mice bearing PC-14 or
A549 lung adenocarcinoma xenografts show evidence of significant tumor
growth inhibition compared to saline controls. B-lapachone (b-lap) is a
novel anticancer agent, whose cell-killing effect is activated by the enzyme
NADPH-quinone oxidoreductase 1 (NQO1), a flavoprotein overexpressed
in breast, prostate, and lung cancer [111]. In cancer cells where NQO1 is
over-expressed, the agent undergoes futile cycling, resulting in the genera-
tion of reactive oxygen species (ROS). Experimental studies have demon-
strated that growth inhibition occurs in cells over-expressing NQO1, while
cells in which NQO1 is absent are unaffected at equivalent concentrations.
Antitumor efficacy was examined in female nude mice bearing subcutaneous
A549 lung tumors and orthotopic Lewis lung carcinoma. Following intrave-
nous administration of b-lap micelles, A549 tumor growth suppression was
evidenced. In the Lewis lung carcinoma model a doubling of survival was
observed (16 days compared to 8 days in controls) [112]. Another target
for molecular cancer therapy is heat shock protein 90 (HSP90), a molecular
chaperone, which under normal conditions is responsible for prevention of
protein aggregation [113]. HSP90 becomes over-expressed under condi-
tions of stress, resulting in tumorigenesis and increased proliferation in a
variety of cancers including lung, prostate, and breast. Tanespimycin, a de-
rivative of the HSP90 inhibitor geldanamycin, has been explored clinically
for chemotherapeutic purposes. The mechanism of action of tanespimycin
involves the degradation of oncogenic signaling proteins, inducing cell death
via apoptosis. In patients with multiple myeloma, treated with tanespimy-
cin, disease stabilization was observed [114].
5.3 Liposomes
Liposomes (Figure 2-2) are vesicles made up of a lipid bilayer, resembling a
cell membrane. The lipids form a bilayer based on hydrophobic interactions
in continuous parallel packing, with the hydrophilic head groups positioned
towards the aqueous environment. They possess advantages of carrying hy-
drophilic, lipophilic, as well as amphoteric drug molecules, either entrapped
inside it or on its micellar surface. The brain distribution of long circulating
liposomes can be modulated by conjugation of appropriate targeting vectors.
Examples of brain targeting vectors include monoclonal antibody (mAbto
anti-transferrin receptor, mAb to insulin receptor), cationized proteins (cat-
ionized human serum albumin), endogenous peptides or plasma proteins.
The basic mechanism by which these liposomes achieve brain concentration
by crossing the BBB is by coupling with brain drug transport vector through
