b2815 Tissue Engineering and Nanotheranostics “9.61x6.69”
244 Tissue Engineering and Nanotheranostics
Proteins. The use of proteins as targeting ligands that can bind
to membrane bound receptors on cancer cells is available for active
targeting delivery. Transferrins are ironbinding blood plasma glyco
proteins that operate through transferrin receptormediated endocy
tosis, by adjusting the level of free iron in biological fluids. Cancer
cells have an overexpression of the transferrin receptor, approximately
two to tenfold compared to healthy cells, because they need more
iron during growth periods.^246 By utilizing the characteristic of trans
ferrins, Pang et al. used biodegradable polymersomes loaded with
DOX and conjugated with transferrin to demonstrate significant
enhancement of intracellular delivery of DOX in glioma and the
chemotherapeutic effect of DOX for glioma rats.^247 EGF is a growth
factor that stimulates cell growth, proliferation, and differentiation
through binding to its receptor EGFR. Ye et al. developed EGF
receptor targeted Fe3O4@TiO2 nanoparticles that use the native
intracellular trafficking of EGF receptor to improve internalization
and nuclear translocation in EGF receptorexpressing HeLa cells.^248
Prostatespecific membrane antigen (PSMA) is a glycoprotein enzyme
encoded in humans by the KLK3 gene. Mukherjee et al. established
a screening method based on humanized antiPSMA antibody conju
gated, silicacoated iron oxide nanoparticles for PSMAspecific cell
targeting.^249 Disadvantages of using proteins attached to nanomateri
als for active targeting consist of immunogenicity, rapid clearance, and
low recognition at target site.
Small Molecules. Compared to mAbs and proteins, advantages of
using small molecules linked with nanomaterials for active targeting
include rapid accumulation in solid tumors, nonimmunogenicity,
stability/shelf lives, and cheapness. Folic acid, a classic vitamin, is the
one that has been most frequently applied as a biomarker for tumor
targeted drug delivery.250–254 As we know, all living cells require vita
mins for their survival, but cancer cells need them in greater amounts
to sustain rapid growth, so vitamin uptake receptors tend to be over
expressed on cancer cells.255,256 Other than the folic acid receptor,
biotin also is a promising vitaminbased targeting ligand for active
targeting delivery of drugs or diagnostics.^2 57–259 Because biotin is
required for cell growth, and the biotin demand in tumors is higher
