A Clinically Translatable Ternary Platinum(IV) Prodrug for Synergistically Reversing Drug Resistance  

Abstract

Scalable production of a clinically translatable formulation with enhanced therapeutic efficacy against cisplatin-resistant tumors without the use of any clinically unapproved reagents and additional manipulation remains a challenge. For this purpose, we report herein the construction of TPP-Pt-acetal-CA based on all commercially available, clinically approved reagents consisting of a cinnamaldehyde (CA) unit for reactive oxygen species generation, a mitochondrially targeted triphenylphosphonium (TPP)-modified Pt(IV) moiety for mitochondrial dysfunction, and an intracellular acidic pH-cleavable acetal link between these two moieties. The resulting self-assembled, stabilized TPP-Pt-acetal-CA nanoparticles mediated an IC 50 value approximately 6-fold lower than that of cisplatin in A549/DDP cells and a tumor weight reduction 3.6-fold greater than that of cisplatin in A549/DDP tumor-bearing BALB/c mice with insignificant systematic toxicity due to the synergistic mitochondrial dysfunction and markedly amplified oxidative stress. Therefore, this study presents the first example of a clinically translatable Pt(IV) prodrug with enhanced efficiency for synergistically reversing drug resistance.

Ligustrazine-Derived Chalcones-Modified Platinum(IV) Complexes Intervene in Cisplatin Resistance in Pancreatic Cancer through Ferroptosis and Apoptosis

“…Thereafter, the mitochondria-dependent apoptosis-related proteins in the initiation and execution of apoptosis were verified via Western blotting assays. Results in Figure A,B revealed that 14a and combination group ( 14a + CDDP) up-regulated the expression of the pro-apoptotic protein Bax, but down-regulated that of anti-apoptotic protein Bcl-2, which subsequently promoted the release of cytoplasmic Cyt c. By comparison with untreated group, CDDP showed moderate effects on levels of Bax and Bcl-2, which was in accordance with our and others’ reports. ,, Especially, 16a demonstrated more effective than CDDP, 14a , or their combination in activating mitochondrial apoptotic pathway signaling transduction, as evidenced by higher expression levels of pro-apoptotic proteins and cleaved caspase-9 and -3. Furthermore, the severe DNA damage induced by 16a was validated by significant up-regulation of cleaved PARP, whereas CDDP only showed moderate effect as compared with control group (Figure A,B).…”

“…Previously, we and other researchers had proved that platinum-based anti-cancer agents could disrupt mitochondrial membrane depolarization (ΔΨm) and increase the intracellular ROS accumulation, which were thought to be beneficial for intervening cisplatin resistance. , Moreover, the elevated production of ROS would further promote the collapse of ΔΨm and activate apoptosis-related cascades. Besides, the drug resistance of CDDP in cancer cells frequently occurred along with the decreased effect on promoting ROS generation or regulating expression levels of apoptosis-related proteins. , Therefore, to further investigate whether 16a could initiate mitochondrial apoptotic signaling pathway, we first study the effect of 16a on the changes of intracellular ROS generation via 2′,7′-dichlorofluorescein diacetate (DCFH-DA) staining assays, using 14a , CDDP (5 μM), and combined group ( 14a + CDDP, 5 μM + 5 μM) as references. In line with our and others’ reports, ,, CDDP was not able to increase the production of ROS in PANC-1/CDDP cells as compared with untreated group (Figure A,B).…”

“…Besides, the drug resistance of CDDP in cancer cells frequently occurred along with the decreased effect on promoting ROS generation or regulating expression levels of apoptosis-related proteins. , Therefore, to further investigate whether 16a could initiate mitochondrial apoptotic signaling pathway, we first study the effect of 16a on the changes of intracellular ROS generation via 2′,7′-dichlorofluorescein diacetate (DCFH-DA) staining assays, using 14a , CDDP (5 μM), and combined group ( 14a + CDDP, 5 μM + 5 μM) as references. In line with our and others’ reports, ,, CDDP was not able to increase the production of ROS in PANC-1/CDDP cells as compared with untreated group (Figure A,B). Besides, ROS levels in 14a -treated group were 4.76-fold higher than those of the CDDP-treated group and were further elevated to 13.06-fold in the combined group, indicating that 14a and CDDP in combination were more potent to promote the ROS production.…”

“…Currently, the use of classical anti-neoplastics remains one of the effective therapeutic strategies in the clinic for PC treatment. Platinum­(II)-based anti-cancer agents, such as cisplatin (CDDP, Figure A) and its analogues, are important therapeutic tools used to treat various malignant tumors in the clinic, including PC. , However, CDDP is commonly hindered with undesirable moderate to severe toxicity toward various organs and resistance in its clinical application. , In general, a combination of drugs is usually used to intervene CDDP resistance, improve the efficacy, reduce toxicity, and so on but may fail to obtain expected clinical results owing to the unpredictable pharmacokinetic parameters and drug–drug interactions. − Therefore, it will be of great significance to develop novel platinum-based anti-cancer agents to delay or alleviate drug resistance in tandem with reduced toxicity in PC treatment.…”

Novel NF-κB Inhibitor-Conjugated Pt(IV) Prodrug to Enable Cancer Therapy through ROS/ER Stress and Mitochondrial Dysfunction and Overcome Multidrug Resistance

“…Many studies demonstrated that the loss of MMP is frequently accompanied by the generation of reactive oxygen species (ROS). 58,59 Additionally, a large amount of ROS accumulation in cells could remarkably cause mitochondrial damage, which subsequently leads to tumor cell death. In view of the important physiological functions of ROS, we investigated the ability of the Pt(IV) complex 9 to generate ROS in A549 cells using DCHF-DA staining assays for flow cytometric detection.…”