Chemistry for Life/Chemistry for Medicine Seminar

Abstract

Introduction: The discovery of cisplatin as a (Pt)-based anti-cancer drug in 1965 was an important milestone. Nowadays, cisplatin and its analogues, all acting at the nuclear DNA as their biological target, are still used in 40% of all chemotherapy treatments. However, these drugs have toxic side effects (e.g. kidney dysfunction). Hence, we have conceived a novel dual-targeting platform to ensure strategic delivery of dual-action Pt prodrugs.

Materials & methods: The first targeting was established by liposomal nanoencapsulation of Pt complexes (including cisplatin and mitochondrial sensitizers) to attain high accumulation [1] at the tumor site. After the release of the Pt prodrug inside cancer cells, a second stage of targeting directed the Pt prodrugs to the mitochondria [2]. Upon intracellular reduction, these Pt prodrugs released two bioactive molecules [3], acting on the mitochondrial and on the nuclear DNA [4].

Results: Our Pt system showed excellent activity, characterized by low micromolar cytotoxicity and complete tumor remission in vivo, accompanied by reduced kidney toxicity [3].

Conclusion: The research findings provide insights into the potential of nanomedicine to reach the diseased area, protect the incorporated bioactive molecules from premature deactivation and enhance delivery of drugs at the mitochondria while decreasing their side effects.

References:

1. Sia Lee Yoong, Bin Sheng Wong, Qi Lin Zhou, Chee Fei Chin, Jian Li, Thirumalai Venky Venkatesan, Han Kiat Ho, Victor Chun Kong Yu, Wee Han Ang*, Giorgia Pastorin*. Enhanced Cytotoxicity to Cancer Cells by Mitochondria-targeting MWCNTs Containing Platinum(IV) Prodrug of Cisplatin. Biomaterials, 2014, 35(2), 748–759.

2. Sia Lee Yoong, Wei Liang Lau, Ang Yu Liu, D’Arcy Prendergast, Han Kiat Ho, Victor Chun Kong Yu, Chengkuo Lee, Wee Han Ang,* and Giorgia Pastorin*. Mitochondria-acting Hexokinase II Peptide Carried by Short-length Carbon Nanotubes with Increased Cellular Uptake, Endosomal Evasion, and Enhanced Bioactivity Against Cancer Cells. Nanoscale, 2015, 7, 13907 – 13917.

3. Chee Fei Chin, Siew Qi Yap, Jian Li, Giorgia Pastorin* and Wee Han Ang*. Ratiometric Delivery of Cisplatin and Doxorubicin using Tumour-Targeting Carbon-Nanotubes Entrapping Platinum(IV) Prodrugs. Chemical Science, 2014, 5, 2265-2270.

4. Maria V. Babak, Yang Zhi, Bertrand Czarny, Tan Boon Toh, Lissa Hooi, Edward Kai-Hua Chow, Wee Han Ang,* Dan Gibson* and Giorgia Pastorin*. Dual-targeting Dual-action Platinum(IV) Platform for Enhanced Anticancer Activity and Reduced Nephrotoxicity. Angew. Chemie Int. Ed., 2019, 58, 1-7.

Also presenting is Dr. Daniel Whitaker (UCL Departmental of Chemistry) who will speak about the plausibility of prebiotic aminonucleotide formation