Alantolactone-Loaded Pegylated Prodrug Nanocarriers for Synergistic Treatment of Cisplatin-Resistant Ovarian Cancer via Reactivating Mitochondrial Apoptotic Pathway

Abstract

Ovarian cancer (OV) seriously damages women’s health because of refractory OV and the development of platinum (Pt) resistance. New treatment strategies are urgently needed to deal with the treatment of cisplatin-resistant OV. Here, a reduction-sensitive pegylated Pt­(IV) prodrug was synthesized by amidation of methoxy polyethylene glycol amine (PEG750-NH2) with monocarboxylic Pt­(IV) prodrug (Pt­(IV)-COOH). Then alantolactone (AL) loaded PEG-Pt­(IV) nanocarriers (NP­(Pt)@AL) were prepared. In the cisplatin-resistant model of OV, cancer cells actively ingest NP­(Pt)@AL through endocytosis, and AL and Pt­(II) were disintegrated and released under high intracellular reductant condition. The activity of thioredoxin reductase 1 (TrxR1) inhibited by AL and the adducts of Pt­(II) with mitochondrial DNA (mDNA) can costimulate reactive oxygen species (ROS) and reactivate the mitochondrial pathway of apoptosis. Meanwhile, Pt­(II) binds with nuclear DNA (nDNA) to jointly promote cell apoptosis. Both in vitro and in vivo results demonstrated that NP­(Pt)@AL could effectively reverse the drug resistance and displayed excellent synergistic therapeutic efficacy on platinum-resistant OV with high safety. Therefore, reactivation of the mitochondrial pathway of apoptosis would be a potential strategy to improve the therapeutic effect of Pt-based chemotherapy and even reverse drug resistance.

Mitochondrial DNA-targeted therapy: A novel approach to combat cancer

“…For instance, nanocarriers have emerged as a promising tool for mtDNA targeting, as they offer an optimal platform for drug delivery and facilitate mitochondrial accumulation. They can physically encapsulate insoluble drugs to achieve controlled drug release, ultimately improving drug metabolism and reducing systemic drug toxicity ( Luo et al, 2022 ). Moreover, other molecule-based, polymer-based, lipid-based and peptide-based nano-carrier systems have also been applied in this field, contributing to the advancement of cancer therapy.…”

“… Cervical carcinoma and lung cancer 2022 Luo et al. ( Luo et al, 2022 ) Carrier system NP(Pt)@AL The activity of thioredoxin reductase 1 inhibited by AL and the adducts of Pt (II) with mtDNA can costimulate ROS and reactivate the mitochondrial pathway of apoptosis. Ovarian carcinoma 2022 Tsuji et al.…”