Photoactivatable and Organelle - Targeted Platinum (IV) Anticancer Prodrugs to Overcome Platinum Resistance

構建細胞器靶向的光控活化型四價鉑前藥用於剋服鉑類抗腫瘤藥物耐藥性的研究

Student thesis: Doctoral Thesis

View graph of relations

Author(s)

Related Research Unit(s)

Detail(s)

Awarding Institution
Supervisors/Advisors
Award date2 Sep 2021

Abstract

Platinum-based drugs are the most widely used anticancer drugs in the clinic. As the milestone of chemotherapeutic drugs, platinum-based anticancer drugs have greatly improved the survival rates of cancer patients in the last decades. The therapeutic outcome of platinum drugs, however, is limited by the various side effects from their uncontrollable property and drug resistance of cancer cells. To address these limitations, developing clinical Pt drug-based Pt(IV) prodrugs that can be specifically and controllably activated in target regions of cancer cells is a promising strategy. In this thesis, we designed and synthesized several clinical drug-based photoactivatable and organelle-targeted Pt(IV) prodrugs. Compared with the conventional Pt drugs, these prodrugs are non-toxic in the dark but can be effectively converted to clinical drugs through visible or NIR light irradiation. Such kind of Pt(IV) prodrugs dramatically decreased the “off-target” effect and reduced the side effects. In addition, accumulating and activating these prodrugs in certain organelles improve the efficiency of Pt drugs to kill cancer cells and exhibit mechanisms of action distinct from the original clinical Pt drugs to overcome the drug resistance.

In Chapter II, we report a new class of photoactivatable Pt(IV) prodrugs based on clinical Pt(II) drugs, designated as rhodaplatins. Rhodaplatins bear an internal photoswitch to realize efficient accumulation, significant co-localization, and subsequent effective photoactivation in cancer cells. Compared with the conventional platform of “external photocatalyst plus substrate”, rhodaplatins presented up to 4.8 × 104-fold increased photoconversion efficiency in converting inert Pt(IV) prodrugs to active Pt(II) species under physiological conditions, due to the increased proximity and covalent bond between the photoswitch and Pt(IV) substrate. Intriguingly, rhodaplatin 2 efficiently accumulated in the mitochondria and induced apoptosis without causing genomic DNA damage to overcome drug resistance. This work presents a new approach to develop highly effective prodrugs containing intramolecular photoswitches for potential medical applications.

In Chapter III, we report coumaplatin, an oxaliplatin-based and photocaged Pt(IV) prodrug, to realize nuclear accumulation along with “on-demand” activation. This prodrug is based on a Pt(IV) complex that can be efficiently photoactivated via water oxidation without the requirement of reducing agents. After photoactivation, the fluorescence of coumaplatin increases 101-fold, which could be used to monitor the intracellular activation and localization of this prodrug. Coumaplatin accumulates very efficiently in the nucleoli, and upon photoactivation, this prodrug exhibits a level of photocytotoxicity up to two orders of magnitude higher than that of oxaliplatin. Unexpectedly, this prodrug presents strikingly enhanced tumor penetration ability and utilizes a distinct action mode to overcome drug resistance, i.e., coumaplatin but not oxaliplatin induces cell senescence, p53-independent cell death, and immunogenic cell death along with T cell activation. Our findings not only provide a novel strategy for the rational design of controllably-activated and nucleolus-targeted Pt(IV) anticancer prodrugs but also demonstrate that accumulating conventional platinum drugs to the nucleus is a practical way to change its canonical mechanism of action and to achieve reduced resistance.

In Chapters IV and V, we develop a class of clinical drugs-based Pt(IV) photooxidants, which can be activated by NIR light. These Pt(IV) complexes are stable in the dark; upon NIR irradiation at 880 nm, these complexes could be excited in two-photon excitation (TPE) fashion and converted to strong oxidants. These photooxidants could robustly oxidize various intracellular biomolecules and then reduce to clinical Pt(II) drugs. Compared with the conventional cancer therapeutic photosensitizers which are activated by visible light, the NIR-activatable property of this type of Pt(IV) photooxidants brings better tissue penetration ability, which expands their potential applications. More importantly, the activation of these Pt(IV) photooxidants is independent of oxygen, and the photooxidants could maintain their anticancer efficiency in the hypoxic tumor microenvironment to address the main limitation for conventional photosensitizers.

In Chapter IV, we report the first example of near-infrared (NIR) light-activated Pt(IV) photooxidants that can effectively eliminate cancer cells by oxidizing intracellular biomolecules and modulating the intracellular environment in an oxygen-independent manner. Intriguingly, these photooxidants accumulated in the endoplasmic reticulum (ER), and upon irradiation with NIR light, they robustly oxidized intracellular components, induced intense oxidative stress, disrupted intracellular homeostasis, and initiated an unprecedented cell death mode. In vivo experiments proved that the leading photooxidant could effectively inhibit tumor growth, block metastasis, and activate the immune system after photoactivation. This study provides a novel strategy to develop NIR-light activatable Pt(IV) anticancer photooxidants and suggests that developing such photooxidants might be a new direction for effective metal-based anticancer complexes.

In Chapter V, we examine the anticancer activities of Pt(IV) photooxidants that could specifically accumulate on the cell membrane of cancer cells. Compared with the intracellular environment, the cell membrane containing fewer biomolecules that could reduce Pt(IV) complexes, which enables the membrane-targeted Pt(IV) complexes higher stability in the dark. Upon activation by NIR light, these Pt(IV) photooxidants rapidly oxidized the membrane components to induce cell membrane damage, resulted in the leakage of intracellular content and thus, killed the cancer cells. The in vitro experiments indicated that the cell membrane-targeting strategy bypassed the intracellular resistance pathways and successfully overcame drug resistance.