Anticancer therapeutic research aims to improve clinical management of the disease through the development
of strategies that involve currently-relevant treatment options and targeted delivery. Tumour-specific and -targeted delivery
of compounds to the site of malignancy allows for enhanced cellular uptake, increased therapeutic benefit with high
intratumoural drug concentrations, and decreased systemic exposure. Due to the upregulation of transferrin receptor expression
in a wide variety of cancers, its function and its highly efficient recycling pathway, strategies involving the selective
targeting of the receptor are well documented. Direct conjugation and immunotoxin studies using the transferrin peptide
or anti-transferrin receptor antibodies as the targeting moiety have established the capacity to enhance cellular uptake,
cross the blood brain barrier, limit systemic toxicity and reverse multi-drug resistance. Limitations in direct conjugation,
including the difficulty in linking an adequate amount of therapeutic compound to the ligand or antibody have identified
the requirement to develop novel delivery methods. The application of nanoparticulate theory in the development of functional
drug delivery systems has proven to be most promising, with the ability to selectively modify size-dependent properties
and surface chemistry. The transferrin modification on a range of nanoparticle formulations enhances selective cellular
uptake through transferrin-mediated processes, and increases therapeutic benefit through the ability to encapsulate
high concentrations of relevant drug to the tumour site. Although ineffective in crossing the blood brain barrier in its free
form, chemotherapeutic compounds including doxorubicin, may be loaded into transferrin-conjugated nanocarriers and
impart cytotoxic effects in glioma cells in vitro and in vivo. Additionally, transferrin-targeted nanoparticles may be used in
selective diagnostic applications with enhanced selectivity and sensitivity. Four transferrin-modified nano-based drug delivery
systems are currently in early phases of human clinical trials. Despite the collective promise, inconsistencies in
some studies have exposed some limitations in current formulations and the difficulty in translating preliminary studies
into clinically-relevant therapeutic options. The main objective of this review is to investigate the development of transferrin
targeted nano-based drug delivery systems in order to establish the use of transferrin as a cancer-targeted moiety, and
to ultimately evaluate the progression of cancer therapeutic strategies for future research.
Cancer therapy, nanoparticles, transferrin, transferrin receptor, targeted therapy.
Epigenomic Medicine. BakerIDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, Australia.