Paclitaxel is one of the most commonly used first-line drug for treating a variety of cancers in
clinical chemotherapy. However, its poor water solubility restricts its direct clinical
applications. More importantly, paclitaxel does not explicitly discriminate between cancer cells
and normal cells and frequently leads to serious undesirable side effects. Attaching to tumor
recognition elements has been proven beneficial for selective delivery of anti-cancer
compounds to tumor cells, however few tumor-targeting elements was proved to be successful.
Therefore, it is highly desirable to develop water-soluble paclitaxel derivatives with tumortargeting
Nucleic acid aptamers are small single-stranded DNA or RNA oligonucleotide segments,
which binds to their targets such as proteins with high affinity and specificity by unique threedimensional
structure. Aptamers have been widely used as tumor recognition elements. As one
of the most successful tumor-targeted aptamers, an anti-nucleolin aptamer (AS1411) is now in
phase II trial (NCT00740441) for treating metastatic renal cell carcinoma with confirmed
tumor targeting property and exceptional safety. The nucleolin aptamer targets nucleolin
protein on the cell surface. Nucleolin normally locates in the nucleus, however in many types
of cancer, it is also found expressing on the cell surface, including ovarian cancer. Hence, the
nucleolin aptamer could be a promising tumor targeting element for developing paclitaxel
Recently, our group reported a synthesized nucleolin aptamer-paclitaxel conjugate (NucAPTX).
The nucleolin aptamer conferred NucA-PTX with high water solubility. Paclitaxel and
the nucleolin aptamer were connected via a cathepsin B-sensitive dipeptide bond. Cathepsin B
is an intracellular enzyme, and is overexpressed in cancer cells such as ovarian cancer. The
conjugate remained stable and inactive in human plasma, and released paclitaxel after entering
ovarian cancer cells in the presence of cathepsin B enzyme. Both three-dimensional interaction
modeling and experimental data suggested that paclitaxel conjugation did not considerably
affect the binding affinity between the nucleolin aptamer and nucleolin protein. The cellular
uptake of NucA-PTX was in a nucleolin expression-dependent manner, and the cytotoxicity of
the conjugate was related to the uptake. Compared to normal cells, increased uptake and
improved cytotoxicity of NucA-PTX were observed for ovarian cancer cells due to higher
surface nucleolin expression. In a heterotopic xenograft mouse model of ovarian cancer
(subcutaneously inoculated with a human ovarian cancer cell line SKOV3), we observed
selective distribution of NucA-PTX in tumor tissue, enhanced antitumor activity and
diminished toxicity. To further evaluate the translational value of this aptamer-drug conjugate,
we hypothesis that in an orthotopic patient-derived xenografted (PDX) mouse model of
ovarian cancer (orthotopically transplanted with a tumor tissue fragment collected from
ovarian cancer patients), our NucA-PTX could also selectively accumulate in the tumor
tissue, improve the antitumor efficacy and reduce toxicity.
We will test our hypothesis using a orthotopic PDX mouse model of ovarian cancer.
This project is supported by the Research Grants Council (RGC), Hong Kong SAR, China (Project 12102518).
For further information on this research topic, please contact Prof. Aiping LU.