Ferroptosis is crucial for many physiological and pathological processes, and hence it has been employed for treating a plethora of (resistant) tumors. On-demand iron delivery or modulation of iron metabolism is a typical approach for ferroptosis induction or sensitization. However, the tumor-specific delivery of Fe2+ is highly challenging. The emergence of ferrocene as a mechanophore offers a new solution for such purpose, but this nececcitates the design and synthesis of polymers featured with an ultra-high molecular weight (MW). These ferrocene-bearing high MW polymers often show limited aqueous dispersibility, limiting their biomedical and pharmaceutical application.
A project led by Prof. Yanjun Zhao and Prof. Zheng Wang at SPST has designed a smart appoach to address the above problem (Figure 1). They discover that the mechano-responsiveness of ferrocene polymers can be finely tuned at the presence of hydrogen peroxide that is a typical feature of tumor cells, which opens new avenues of ultrasound-aided drug delivery, ferroptosis manipulation and anti-tumor therapy.
In this project, the ferrocence-conjugated low-MW copolymers can self-assemble into nanoscale micelles wherein a model sonosensitizer, protoporphyrin IX (PpIX) is physically encapsulated. Upon triggering, the mechano-responsive micelles produce both singlet oxygen and hydroxyl radical for apoptotic cell death in a model murine breast cancer cell line (4T1). The reactive oxygen species also deplete intracellular glutathione and thioredoxin, which together with the heightened Fe2+ level boosts lipid peroxidation and hence ferroptotic cell death. The interactive apoptosis and ferroptosis induction and sensitization is further demonstrated in a 4T1 tumor-bearing mice model with negligible adverse effects. The current work provides a novel approach to simultaneously sensitize ferroptosis and/or apoptosis for efficient on-demand cancer therapy.
Fig 1. Mechano-responsive polymers for tailor on-deand iron and cargo delivery.