Biomedical Engineering Reference
In-Depth Information
3.4.1.2.2
Active targeting: ligand targeting
Sigma receptor, a well-known membrane-bound protein, is
overexpressed in various types of human tumors, including prostate
cancer, melanoma, non-small cell lung carcinoma, and breast
tumors, as well as in normal tissues. However, the physiological
role of this receptor has not yet been elucidated.
98-104
The
105
98
neuroleptics
such as anisamide, are
known to have a high affinity to the sigma receptor. Huang
and benzamide derivatives,
106
first demonstrated that anisamide, with its small molecular weight,
can be successfully used as a ligand to target anticancer drugs to
tumors that overexpress sigma receptor. Anisamide is conjugated
to the end of PEG lipid and this unique lipid, DSPE-PEG-AA, has
been utilized as an active tumor-targeting ligand for LPD NPs
(LPD-PEG-AA).
et al.
studies showed that the delivery efficiency
of LPD-PEG-AA for both antisense oligodeoxynucleotide (AS-
ODN)
In vitro
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95, 107
and siRNA
was 4-7-fold greater than that of LPD-PEG,
which has no anisamide ligand but is sterically stabilized by
PEGylation, in sigma receptor expressing cells, H1299. Also,
when free haloperidol, a well-known high affinity ligand for sigma
receptor, is co-treated, it shows partially competitive inhibition
in LPD-PEG-AA particles but not in LPD-PEG, confirming that the
delivery of AS-ODN or siRNA to H1299 cells by LPD-PEG-AA is
mediated by sigma receptor-dependent endocytosis.
The effect of targeting ligand, anisamide, on the enhanced
delivery efficiency in H1299 cells has been further supported by
the strong silencing effect on target genes, the inhibition of tumor
cell growth, and the sensitization of tumor cells to anticancer drugs.
95
The silencing activity of the targeted LPD NPs (LPD-PEG-AA) in a
B16F10 lung metastatic tumor mouse model has been found to be
significantly higher (70-80% gene silencing) than other formulations,
including free siRNA, non-targeted LPD, and control siRNA in the
targeted LPD, which appears to be consistent with the
in vitro
observation. This enhanced activity of the LPD-PEG-AA comes mainly
from the significantly improved intracellular (cytosolic) delivery, not
just from the increased tumor uptake.
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In another study using a
more aggressive lung cancer cell line, NCI-H460, the xenograft tumor
mouse model also demonstrated that only the targeted NPs had a
significant cytosolic delivery of siRNA. Non-targeted NPs in this
study showed less intracellular delivery efficiency, regardless of the
comparable amount of accumulation in the tumor (70-80 ID%/g).
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