Microenvironmentally Responsive Chemotherapeutic Prodrugs and CHEK2 Inhibitors Self‐Assembled Micelles: Protecting Fertility and Enhancing Chemotherapy

Abstract

Chemotherapy is a widely used and effective adjuvant treatment for cancer, and it has unavoidable damage to female fertility, with statistics showing 38% of women who have received chemotherapy are infertile. How to reduce fertility toxicity while enhancing the oncologic chemotherapy is a clinical challenge. Herein, co‐delivery micelles (BML@PMP) are developed, which are composed of a reduction‐sensitive paclitaxel prodrug (PMP) for chemotherapy and a CHEK2 inhibitor (BML277) for both fertility protection and chemotherapy enhancement. BML@PMP achieves fertility protection through three actions: (1) Due to the enhanced permeability and retention (EPR) effect, BML@PMP is more enriched in the tumor, while very little in the ovary (about 1/10th of the tumor). (2) Glutathione (GSH) triggers the release of PTX, and with low levels of GSH in the ovary, the amount of PTX released in the ovary is correspondingly reduced. (3) BML277 inhibits oocyte apoptosis by inhibiting the CHEK2‐TAp63α pathway. Because of the different downstream targets of CHEK2 in tumor cells and oocytes, BML277 also enhances chemotherapeutic efficacy by reducing DNA damage repair which is activated through the CHEK2 pathway. This bidirectional effect of CHEK2 inhibitor‐based co‐delivery system represents a promising strategy for improving oncology treatment indices and preventing chemotherapy‐associated fertility damage.

Satellite‐Type Sulfur Atom Distribution in Trithiocarbonate Bond‐Bridged Dimeric Prodrug Nanoassemblies: Achieving Both Stability and Activatability

“…Apart from arresting mitosis via microtubule stabilization, PTX also exerted its antiproliferative effect by inducing up‐regulation of ROS levels. [ 15 ] Hence, the intracellular ROS level was analyzed using the ROS probe (Figure 4f; and Figure S23, Supporting Information). Notably, the group treated with PSC(S)SP NPs displayed a stronger fluorescence intensity than the Taxol group, suggesting the existence of underlying mechanisms contributing to ROS up‐regulation in addition to PTX release.…”

Microneedle Device Delivering Aggregation-Induced Emission Photosensitizers for Enhanced Metronomic Photodynamic Therapy of Cancer

“…However, the commonly used PSs, such as Ce6, have poor resistance to photobleaching, which leads to a significant decrease in ROS yield under prolonged light exposure. In this study, we introduced AIE PS in the mPDT system, which has the advantages of large Stoker’s shift, excellent photobleach resistance, low biological background, high signal-to-noise ratio, high sensitivity, and good specificity. ,− In contrast to conventional ACQ PSs, AIE PSs enhance ROS generation in the aggregated state with increasing fluorescence emission, whereas the ROS generation capacity of ACQ PSs decreases with increasing aggregation. − Meanwhile, a novel mPDT system (M-mPDT) was constructed by using microneedles for PS delivery and wireless LEDs to provide a stable light source. M-mPDT offers better therapeutic results in a variety of application scenarios, and its safety and convenience are guaranteed, which provides a new option for cancer treatment.…”

Advances and applications of nanoparticles in cancer therapy

“…619,620 Hence, researching and creating improved cancer chemotherapy techniques is a critical issue that requires immediate attention. NPs for cancer treatments are initially conceived as magic bullet, which are intended to enhance solubility, reduce elimination by MPS, reduce immunogenicity, 621 lengthen circulation half-life, 622,623 optimize biodistribution, 624,625 and promote cellular uptake. 626 Zeng et al 602 developed responsive programmed micelles (RNW) for the treatment of malignant gliomas.…”