Hong Kong Baptist University (HKBU) Research Cluster on Data Analytics and Artificial Intelligence in X

Toward the next generation of smart anti-tumor drugs: a highly water-soluble nucleolin aptamer-paclitaxel conjugate with a serum-stable linker for tumor-specific targeting in ovarian cancer
Principal Investigatgor: Prof. Aiping LU ( School of Chinese Medicine )

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 property.

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 derivatives.

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.


  • To validate the nucleolin aptamer-mediated distribution of NucA-PTX;
  • To study the pharmacokinetics parameters of NucA-PTX in circulation upon time;
  • To evaluate the nucleolin aptamer-mediated change in antitumor activity of NucA-PTX;
  • To examine the nucleolin aptamer-mediated change in toxicity of NucA-PTX;

Grant Support:

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.