A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy

Ovarian cancer(OC)is one of the most common and recurring malignancies in gynecology.Patients with relapsed OC always develop"cascade drug resistance"(CDR)under repeated chemotherapy,leading to subsequent failure of chemotherapy.To overcome this challenge,amphiphiles(P1)carrying a nitric oxide(NO)donor(Isosorbide 5-mononitrate,ISMN)and high-density disulfide are synthesized for encapsulatingmitochondria-targeted tetravalent platinum prodrug(TPt)to construct a nanocomposite(INP@TPt).Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum,depleting glutathione,and preventing apoptosis escape through generating highly toxic peroxynitrite anion(ONOO−).To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor,an OC patient-derived tumor xenograft(PDXOC)model in BALB/c nude mice was established.INP@TPt showed the best therapeutic effects in the PDXOC model.The corresponding tumor tissues contained high ONOO−levels,which were attributed to the simultaneous release of O_(2)^(·−)and NO in tumor tissues.Taken together,INP@TPtbased systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR,providing practical applications for ovarian therapy.

COX-2 blocking therapy in cisplatin chemosensitization of ovarian cancer:An allicin-based nanomedicine approach

Recently,the utilization of nonsteroidal anti-inflammatory drugs(NSAIDs)to sensitize cisplatin(CDDP)has gained substantial traction in the treatment of ovarian cancer(OC).However,even widely employed NSAIDs such as celecoxib and naproxen carry an elevated risk of cardiovascular events,notably throm-bosis.Furthermore,the diminished sensitivity to CDDP therapy in OC is multifactorial,rendering the ap-plication of NSAIDs only partially effective due to their cyclooxygenase-2(COX-2)inhibiting mechanism.Hence,in this study,reactive oxygen species(ROS)-responsive composite nano-hydrangeas loaded with the Chinese medicine small molecule allicin and platinum(IV)prodrug(DTP@AP NPs)were prepared to achieve comprehensive chemosensitization.On one front,allicin achieved COX-2 blocking therapy,en-compassing the inhibition of proliferation,angiogenesis and endothelial mesenchymal transition(EMT),thereby mitigating the adverse impacts of CDDP chemotherapy.Simultaneously,synergistic chemosensi-tization was achieved from multifaceted mechanisms by decreasing CDDP inactivation,damaging mito-chondria and inhibiting DNA repair.In essence,these findings provided an optimized approach for syner-gizing CDDP with COX-2 inhibitors,offering a promising avenue for enhancing OC treatment outcomes.