Investigator
Dongguan Peoples Hospital
Epigenetic Metal‐Organic Framework Nanoagonist Overcomes Triple Defenses to Enable Effective Chemo‐Metalloimmunotherapy in Platinum‐Resistant Ovarian Cancer
ABSTRACT Platinum‐resistant ovarian cancer (PROC) responds poorly to platinum chemotherapy and evades immune surveillance by suppressing the cGAS‐STING pathway, leading to poor outcomes. Herein, we developed an epigenetic metal‐organic framework (MOF) nanoagonist (CMZ‐Pt‐SA@HA) that overcomes cisplatin (CisPt) resistance while restoring immune activation. The platform consists of Mn‐ZIF‐8 encapsulating CaO 2 and co‐loaded with CisPt and SAHA (a histone deacetylase inhibitor), then modified with hyaluronic acid to enable tumor targeting and controlled release. CMZ‐Pt‐SA@HA is multifunctional: SAHA downregulates resistance proteins epigenetically, CaO 2 triggers calcium overload and oxygen release, and Mn 2+ /Zn 2+ enhances oxidative stress and STING signaling, collectively strengthening chemo‐metalloimmunotherapy. These mechanisms intensify CisPt‐induced DNA damage and stimulate immune activation. CMZ‐Pt‐SA@HA applies a three‐step “POP” strategy to overcome PROC's triple defenses: (I) Pre‐targeting to enhance DNA‐CisPt adducts; (II) On‐targeting to block DNA repair; and (III) Post‐targeting to induce apoptosis by relieving hypoxia, arresting the cell cycle, damaging mitochondria, and activating cGAS‐STING. Whether used alone in subcutaneous tumors in preclinical ID8 and patient‐derived xenograft mouse models, or combined with anti‐PD‐L1 therapy in ascites metastasis models, CMZ‐Pt‐SA@HA consistently showed strong therapeutic efficacy. Its Mn 2+ ‐based magnetic resonance imaging (MRI) capability further supports image‐guided therapy and clinical translation.
Highly Efficient Synergistic Chemotherapy and Magnetic Resonance Imaging for Targeted Ovarian Cancer Therapy Using Hyaluronic Acid‐Coated Coordination Polymer Nanoparticles
AbstractThe diagnosis and treatment of ovarian cancer (OC) are still a grand challenge, more than 70% of patients are diagnosed at an advanced stage with a dismal prognosis. Magnetic resonance imaging (MRI) has shown superior results to other examinations in preoperative assessment, while cisplatin‐based chemotherapy is the first‐line treatment for OC. However, few previous studies have brought together the two rapidly expanding fields. Here a technique is presented using cisplatin prodrug (Pt‐COOH), Fe3+, and natural polyphenols (Gossypol) to construct the nanoparticles (HA@PFG NPs) that have a stable structure, controllable drug release behavior, and high drug loading capacity. The acidic pH values in tumor sites facilitate the release of Fe3+, Pt‐COOH, and Gossypol from HA@PFG NPs. Pt‐COOH with GSH consumption and cisplatin‐based chemotherapy plus Gossypol with pro‐apoptotic effects displays a synergistic effect for killing tumor cells. Furthermore, the release of Fe3+ at the tumor sites promotes ferroptosis and enables MRI imaging of OC. In the patient‐derived tumor xenograft (PDX) model, HA@PFG NPs alleviate the tumor activity. RNA sequencing analysis reveals that HA@PFG NPs ameliorate OC symptoms mainly through IL‐6 signal pathways. This work combines MRI imaging with cisplatin‐based chemotherapy, which holds great promise for OC diagnosis and synergistic therapy.
Amplification of cGAS-STING pathway with “single-molecule multitarget” nanoparticles for chemo-immunotherapy of ovarian cancer
With a low autoimmune risk and dedicated induction of type Ⅰ interferon production in immunotherapy, "STING therapy" holds broad prospects in the treatment of aggressive and metastatic cancers such as ovarian cancer (OC). Inducing pyroptosis constitutes a promising approach for activating the anti-tumor immune response. Nevertheless, compared to combination therapies, "single-molecule multitarget" drugs possess the merits of a lower interaction risk, more predictable pharmacokinetics and a lower cost of clinical trials. Therefore, the present study was conducted to construct a structurally stable nanoparticles (TPAQu-Pt@HA NPs) with controlled drug release behavior and active targeting ability based on a self-designed and synthesized photo-platinum compound (TPAQu-Pt) with aggregation-induced emission (AIE) effect without excipients. The NPs attained "single-molecule multitarget" effect via three mechanisms: 1) causing nuclear and mitochondrial DNA damage and cytoplasmic leakage of double-stranded DNA (dsDNA), effectively activating cGAS-STING pathway; 2) inducing pyroptosis benefited from the AIE effect conferring a stronger ROS-generating capacity; 3) photothermal therapy worsened mitochondrial dysfunction and intensified pyroptosis, amplifying activation of cGAS-STING pathway and the subsequent anti-tumor immune response. In conclusion, this study provided a scientific basis for the molecular modification of cisplatin, which was expected to improve the treatment status of OC.
Nano-assembly of ursolic acid with platinum prodrug overcomes multiple deactivation pathways in platinum-resistant ovarian cancer
A dual prodrug nano-assembled system for synergistic chemotherapy of platinum-resistant ovarian cancer.
