Development of Platinum (IV) Anticancer Prodrugs with Enhanced Selectivity, Elevated Tumor Accumulation and Accelerated Reduction


Student thesis: Doctoral Thesis

View graph of relations


Related Research Unit(s)


Awarding Institution
Award date2 Sep 2021


Platinum drugs, including cisplatin, carboplatin, and oxaliplatin, are widely and globally used in clinics to treat various types of cancer. However, the lack of cancer-cell selectivity is one of the leading causes that induce severe side effects of platinum drugs in normal tissues. In addition, the short half-life and low accumulation level of platinum drugs in tumors restrict their efficiency to kill cancer cells. Attaching moieties with biological properties such as cancer-cell targeting and improved tumor accumulation at the axial positions of platinum(IV) prodrugs is a promising strategy to solve these problems. The platinum(IV) complexes are regarded as prodrugs because once inside the cancer cells, they will be reduced or photoactivated to form the original active platinum(II) species. The aim of this thesis is to develop platinum(Ⅳ) prodrugs with enhanced selectivity, elevated tumor accumulation, and accelerated reduction to improve the anticancer effect of platinum drugs while reducing the side effects.

The lack of cancer-cell selectivity is one of the major problems that lead to side effects of platinum drugs in normal tissues. Luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in many types of cancer cells but rarely presented in normal cells, making LHRH receptor a good candidate for cancer targeting. In the first part of this thesis, we report the synthesis and cytotoxic study of a novel platinum(IV) anticancer prodrug functionalized with LHRH peptide at the axial position. Cytotoxic study reveals that the prodrug selectively targets LHRH receptor-positive cancer cell lines with the cytotoxicity 5−8 times higher than those in LHRH receptor-negative cell lines. In addition, the introduction of LHRH peptide enhances the cellular accumulation in a manner of receptor-mediated endocytosis. Moreover, the LHRH−platinum(IV) prodrug is proved to kill cancer cells by binding to the genomic DNA, inducing apoptosis, and arresting the cell cycle at the G2/M phase.

The short circulatory half-life in vivo and low accumulation in the tumor limit the efficiency of platinum drugs and contribute to serious side effects. In the second part of the thesis, we report the synthesis and antitumor study of a novel platinum(IV) anticancer prodrug that has enhanced circulation and tumor accumulation. The complex, designated as ERY1-Pt(IV), can bind to the erythrocytes efficiently and stably. As a consequence, the circulatory half-life of ERY1-Pt(IV) is examined to be 12 times longer than that of carboplatin in mice. This elongated circulation subsequently makes platinum accumulates more and stays longer in the tumors of mice. Moreover, the ERY1-Pt(IV) complex is shown to have enhanced antitumor activity and reduced side effects than carboplatin. Collectively, our study highlights an efficient strategy to utilize intrinsic erythrocytes as auto-binding carriers to enhance the tumor accumulation of platinum drugs.

Some of the platinum(IV) prodrugs, such as carboplatin-based tetracarboxylatoplatinum(IV) prodrugs, are not easily reduced to active platinum(II) species, leading to their low cytotoxicity. In the third part of the thesis, we report the design and synthesis of a carboplatin-based platinum(IV) prodrug functionalized with a boron dipyrromethene (BODIPY) ligand at the axial position, and the ligand acts as a photoabsorber to photoactivate the platinum(IV) prodrug. This complex, designated as BODI-Pt, is highly stable in the dark but quickly activated under irradiation to release carboplatin and the axial ligands. A cytotoxic study reveals that BODI-Pt is effective under irradiation, with cytotoxicity 11 times higher than that in the dark and 39 times higher than that of carboplatin in MCF-7 cells. Moreover, BODI-Pt has been proven to kill cancer cells by binding to the genomic DNA, arresting the cell cycle at the G2/M phase, inducing oncosis, and generating ROS upon irradiation.

Furthermore, the influence of the axial ligands on the photoactivation rate of platinum center and the subsequent biological activity are still unknown. In the fourth part of this thesis, we reported the design and synthesis of a series of carboplatin-based photoactivable platinum(IV) prodrugs containing BODIPY axial ligands with different lengths. The resulting BODIPY-conjugated platinum(IV) prodrugs OH2C-OH8C bearing hydroxido ligands at the opposite axial position are slightly less stable in the dark than the corresponding prodrugs AC2C-AC8C containing acetato ligands. The prodrugs OH3C-OH8C can be photoactivated under irradiation in eight minutes, and the photoactivation rate is further improved in prodrugs AC3C-AC8C where only twenty seconds are needed. Moreover, the prodrug AC3C, which has a proper length of the linker between the BODIPY photoabsorber and the platinum center, is photoactivated the quickest among the acetylated prodrugs AC2C-AC8C. Finally, the high cellular accumulation may contribute more to the moderate photocytotoxicity of these prodrugs. Our research highlights the way to promote the photoactivation of BODIPY-conjugated platinum(IV) anticancer prodrugs by optimization of axial ligands and may contribute to the future rational design of photoactivable platinum-based anticancer prodrugs.

Finally, it is still a debate on the intracellular components that are responsible for the reduction of platinum(IV) prodrugs. In this study, we report the design and synthesis of a platinum(IV)-based fluorescent sensor that is functionalized with a boron dipyrromethene (BODIPY) ligand at the axial position, with an aim to investigate the reduction of platinum(IV) prodrugs. In this sensor, the fluorescence of the BODIPY ligand is quenched by the heavy metal effect from platinum, and the fluorescence restores along with the reduction of platinum(IV) and the release of BODIPY ligand. Importantly, the increased fold of fluorescence intensity has a linear relationship with the reduction ratio of the platinum(IV)-based sensor. This sensor is then applied to demonstrate that it is the proteins with high molecular weight rather than the reducing agents with low molecular weight that contribute more to the reduction of the platinum(IV) prodrugs in cell extracts. Finally, the cytotoxicity of the sensor was related to both the reduction rate and the cellular accumulation level of the sensor. This work highlights a fluorescence “turn on” sensor that can be applied to quantify the reduction ratio of platinum(IV) prodrugs by simply monitoring the fluorescence intensity.