Amphiphilic Block Copolymer Based Nanocarriers for Drug and Gene Delivery - Intracellular Delivery: Fundamentals and Applications - page 270

Transferrin - Human transferrin is a relatively large serum glycoprotein (80 KDa).
Transferrin receptors are known to be elevated in various types of cancer cells. The
level of elevation in transferrin receptor is also known to correlate with the prolif-
erative ability of the tumor cells. Kabanov et al. proposed delivery of phosphoro-
thioateoligonucleotides(SODNs)byPICmicellesformedwithtransferrin-conjugated
PEO-polyethylenimine (PEO-PEI). Compared to unmodified micelles, fluores-
cent-labeled transferrin-micelles showed a significantly higher accumulation in
resistant human oral epidermoid carcinoma (KBv) cells. Delivery of antisense
SODNs against expression of P-glycoprotein (P-gp) human mdr1- mRNA by
transferrin-PEO-PEI nano-carriers exhibited a significantly higher inhibition of
P-gp efflux system in resistant MCF-7/ADR cells that over-expresses P-gp com-
pared to unmodified micelles (Vinogradov et al. 1999 ). Complexes were generated
by mixing of plasmid DNA, linear PEI, PEO-PEI, and transferrin-PEO-PEI to
provide a ligand for receptor-mediated cell uptake (Kursa et al. 2003 ). For com-
plexes containing the luciferase reporter gene the highest expression was found in
tumor tissue of mice. An optimum formulation for in vivo application containing
plasmid DNA encoding for the tumor necrosis factor (TNF-a), inhibited tumor
growth in three murine tumor models.

2.4 Multifunctional Polymeric Micelles

Multifunctional polymeric micelles are designed to bear a combination of structural
components required for various targeting strategies on an individual carrier in
order to enhance the selectivity of the incorporated drug for the target site (Torchilin
2006 ). Development of multifunctional polymeric micelles having cancer specific
targeting ligands on the surface and anticancer drug conjugated through acid-
cleavable bond in the core, i.e., folate-PEO-p(Asp-Hyd-DOX), was reported by
Kataoka et al. (Bae et al. 2005a ). The folate-bound micelles can be guided to cancer
cells and get internalized through receptor mediated endocytosis. After micellar
entry to the cells, hydrazone bonds are cleaved by endosomal acidic environment
(pH 5-6).
The development of multidrug resistance (MDR) and severe side effects of
anticancer drugs require custom-designed targeted carriers to improve the cancer
chemotherapeutic efficacy. The high affinity of anthracyclines (e.g. DOX) towards
chromosomal DNA has been the main mechanism for their antitumor activity
against sensitive tumors, while highly lipophilic and unaminated anthracyclines
led to selective accumulation in cytoplasm, and demonstrated the ability to cir-
cumvent MDR which are most likely associated with their ability to reduce
P-glycoprotein (P-gp) recognition, to localize in cytoplasm, to affect subcellular
targets other than nuclear DNA, or to act as self modulators of MDR (Lampidis
et al. 1997 ; Guillemard and Uri Saragovi 2004 ). Bearing these in mind, our group
used PEO-PCL based polymer to design multifunctional polymeric micelles
which have peptide-decorated shell for tumor targeting and pH-sensitive core for