Abstract:
Chemotherapy is a traditional method in clinical cancer treatment. As a malignant solid tumor caused by abnormal proliferation of trophoblastic cells, choriocarcinoma can be cured by chemotherapy for preserving patients’ fertility potential. But at present the biggest hurdle in cancer treatment is insufficient delivery of chemotherapeutics to solid tumors leading to serious side effects and drug resistance. The development of nanomedicine provides a new idea to solve the dilemma and have shown great potential in the application of tumor therapy. Biomimetic metal-organic framework loaded with antineoplastic drugs can achieve targeted drug delivery, which enriches drugs at tumor sites and reduces the toxic side effects in normal tissues. Therefore, we developed a biomimetic nanoreactor derived from cancer cell membrane coated metal-organic frameworks encapsulating methotrexate to achieve maximum therapeutic effects and minimum adverse side-effects.
In this work, the biomimetic nanoreactor (MMC NPs) are built from methotrexate (MTX)-loaded iron-based metal-organic framework (Fe-MOFs) and cancer cell membrane camouflage (MMC NPs). The successful preparation of biomimetic nanoreactor was proved by a series of characterization methods, including transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, UV-visible spectrophotometer and western blotting. The biomimetic nanoreactor could be specifically targeted to the tumor site and accumulated in the tumor in biodistribution studies. There were potentiated anti-cancer effects of MMC NPs on JEG-3 cells, including an antiproliferative effect by G0/G1 phase cell cycle arrest and a reduction in endocrine activity and migration ability. Furthermore, the overproduction of highly toxic •OH by Fenton reaction led to excellent chemodynamic therapy (CDT) effect, glutathione (GSH) scavenging caused intracellular redox dyshomeostasis, and lipid peroxidation resulted in cell death by concurrent apoptosis and ferroptosis. A subcutaneous xenograft tumor model of choriocarcinoma demonstrated that the biomimetic nanoreactor showed excellent tumor targeting and achieved satisfactory tumor inhibition effects without appreciable systemic toxicity. Further transcriptomics analysis showed that the specific mechanism of the MMC NPs is through apoptosis and ferroptosis. These elaborately synthesized nanoparticles are promising as multifunctional platforms for cancer therapy due to their excellent biocompatibility and easy preparation.
In summary, this nanoreactor caused obvious tumor cells apoptosis by Chemotherapy (MTX) and ferroptosis by GSH depletion-enhanced CDT (MIL-100 NPs). This new strategy for the cooperative combination of chemotherapy and chemodynamic therapy provides a reference for cancer therapy due to their excellent performance.
Audience take Away Notes:
- JEG-3 membrane camouflage could deliver MTX to the tumor site, lessen the drug dosage and reduce side effects incidentally. Cooperation with CDT effect generating by Fenton reaction, the therapeutic efficiency of MMC NPs is further amplified basing on highly toxic •OH, glutathione scavenging and lipid peroxidation. In vivo and in vitro experimental results clearly illustrate the ability of kill tumor cells and satisfactory biological safety of this nanoplatform
- This elaborately synthesized multifunctional nanoreactor could achieve accurate targeting oncotherapy by easy preparation, taking full advantage of nanomedicine to the cancer treatment
- Biomimetics have excellent tumor targeting ability which extract different cancer cell membrane from different cancer cells which preserve homologous targeting to recognize tumor site
- Biomimetic nanoreactor loading first-line chemotherapeutics methotrexate maybe a new method to treat choriocarcinoma patients with excellent tumor killing ability and little side effects, thereby avoiding hysterectomy and preserving patients’ fertility potential
- As the mechanism of tumor treatment is interrelated in some way, the achievements of our work could also be applied in other pathological types of tumors or molecular biology in future research. Other faculty can use biomimetic strategy from this research to expand their research about other cancer
