Biomedical Engineering Reference
In-Depth Information
various cell functions including nucleotide biosynthesis. The concentration of folate
receptors on the tumor cells has been shown to increase as the tumor progresses. This,
along with the inaccessibility of the receptor on normal epithelial cells has made it an
attractive target for designing tumor-specific drug delivery systems (Lu and Low
2002a ). Guo et al showed that liposomes conjugated with folic acid and non-conju-
gated liposomes accumulated at tumor sites similarly in vivo , although the targeted
liposomes were internalized by tumor cells more efficiently than their untargeted
counterparts (Guo et al. 2000 ). This indicates that the targeting moieties may not
directly affect the organ distribution of the nanocarriers, but rather enhance the parti-
tioning of the drug within the tumor tissue between cancer and adjacent normal cells.
The suggested mechanism of internalization for macromolecules conjugated to folic
acid involves a nondestructive (non-lysosomal) endocytic pathway (Leamon and Low
1991 ). A number of therapeutic and imaging agents conjugated to folate were devel-
oped and are currently in clinical trials. Among these are the imaging agents
111 In-DTPA (diethylene triamine pentaacetic acid)-folate (Siegel et al. 2003 ) and
EC20 (Endocyte20) (Fisher et al. 2008 ), as well as the therapeutic agents EC17 (Lu
and Low 2002b ) and EC145 (Vlahov et al. 2006 ).
Leutinizing hormone releasing hormone (LHRH) is a peptide that was used as a
targeting moiety by Dharap and Minko to deliver campothecin to various tumor
cells in vitro and human ovarian carcinoma xenograft tumors in vivo (Dharap et al.
2005 ). The receptors for LHRH are overexpressed in multiple hormone-dependent
tumors such as ovarian, breast and prostate cancers. The nanocarriers decorated
with the LHRH peptides were shown to accumulate in the tumors preferentially
with minimal to no accumulation in other organs and showed significant reduction
in tumor size when injected in human ovarian carcinoma xenograft containing mice
(Dharap et al. 2005 ).
Poloxamer 188 coated Poly(lactide-co-glycolide) (PLGA) nanoparticles use their
similarity to low density lipoproteins (LDL) and bind to LDL receptors on endothe-
lial cells, thereby inducing a receptor mediated endocytosis of these nanoparticles
into the brain blood vessel endothelial cells and across the blood brain barrier.
Intravenous injection of doxorubicin-loaded poloxamer 188 PLGA nanoparticles
showed a long-term remission (<100 days without tumor) in 40% of rats with intrac-
ranially transplanted glioblastomas, in comparison to non-treated control mice that
died in less than 20 days post tumor implantation (Gelperina et al. 2010 ).
Aptamers, nucleic acid ligands selected for target specificity, are promising
agents for homing drug delivery vehicles to the disease site. Aptamers have been
used both as targeting agents and as therapeutic agents. For example, aptamers for
Prostate Specific Membrane Antigen (PSMA) have been used to label PLGA-PEG
(polyethylene glycol) nanoparticles that are loaded with Cisplatin, a platinum-
based drug. The labeled nanoparticles were efficient in targeting and eliminating
prostate tumor cells, as compared to non-targeted nanoparticles (Dhar et al. 2008 ).
Another example is the conjugation of aptamers to siRNA (small interfering RNA).
Aptamers targeted to gp120 (HIV-1 BAL envelop glycoprotein) in conjugation with
dicer substrate siRNA demonstrated specific inhibition of HIV replication and
infectivity to T-cells in vitro (Zhou et al. 2009 ).
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