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"Target-and-release" nanoparticles for effective immunotherapy of metastatic ovarian cancer.

Ivan S PiresGil CovarrubiasVictoria F GomerdingerCoralie BacklundApoorv ShankerEzra GordonShengwei WuAndrew J PickeringMariane B MeloHeikyung SuhDarrell J IrvinePaula T Hammond
Published in: bioRxiv : the preprint server for biology (2024)
Immunotherapies such as checkpoint inhibitors (CPI) are effective in treating several advanced cancers, but these treatments have had limited success in metastatic ovarian cancer (OC). Here, we engineered liposomal nanoparticles (NPs) carrying a layer-by-layer (LbL) polymer coating that promotes their binding to the surface of OC cells. Covalent anchoring of the potent immunostimulatory cytokine interleukin-12 (IL-12) to phospholipid headgroups of the liposome core enabled the LbL particles to concentrate IL-12 in disseminated OC tumors following intraperitoneal administration. Shedding of the LbL coating and serum protein-mediated extraction of IL-12-conjugated lipids from the liposomal core over time enabled IL-12 to disseminate in the tumor bed following rapid NP localization in tumor nodules. Optimized IL-12 LbL-NPs promoted robust T cell accumulation in ascites and tumors in mouse models, extending survival compared to free IL-12 and remarkedly sensitizing tumors to CPI, leading to curative treatments and immune memory.
Keyphrases
  • squamous cell carcinoma
  • dna damage
  • cell cycle
  • fatty acid
  • cell death
  • binding protein
  • endoplasmic reticulum stress
  • amino acid