RNA‐Peptide nanoplexes drug DNA damage pathways in high‐grade serous ovarian tumors

Abstract

DNA damaging chemotherapy is a cornerstone of current front‐line treatments for advanced ovarian cancer (OC). Despite the fact that a majority of these patients initially respond to therapy, most will relapse with chemo‐resistant disease; therefore, adjuvant treatments that synergize with DNA‐damaging chemotherapy could improve treatment outcomes and survival in patients with this deadly disease. Here, we report the development of a nanoscale peptide‐nucleic acid complex that facilitates tumor‐specific RNA interference therapy to chemosensitize advanced ovarian tumors to frontline platinum/taxane therapy. We found that the nanoplex‐mediated silencing of the protein kinase, MK2, profoundly sensitized mouse models of high‐grade serous OC to cytotoxic chemotherapy by blocking p38/MK2‐dependent cell cycle checkpoint maintenance. Combined RNAi therapy improved overall survival by 37% compared with platinum/taxane chemotherapy alone and decreased metastatic spread to the lungs without observable toxic side effects. These findings suggest (a) that peptide nanoplexes can serve as safe and effective delivery vectors for siRNA and (b) that combined inhibition of MK2 could improve treatment outcomes in patients currently receiving frontline chemotherapy for advanced OC.

Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints

“…interfering RNAs (siRNAs) to tumors 38 , in order to deliver siR-NAs against MK2 (Fig. 3a) or to simultaneously co-deliver siR-NAs against both MK2 and XPA ( Fig.…”

“…3a; Supplementary Fig. 3A; "Methods") 38 . Nanoplexes containing fluorescently tagged siRNAs form punctate foci in cells at early time points, consistent with endosomal/lysosomal cellular uptake (Supplementary Fig.…”

“…3B). These steps are followed by gradual endosomal escape and release of siRNA to the cytoplasm 38 . When the nanoplexes were used to deliver siRNA to cells in vitro, single and combined target knockdown efficiencies at least as effective as those obtained using conventional cationic lipids were observed (Fig.…”

Bioengineering & Translational Medicine: Year 2020 in review

“…Consistent with general literature trends, a significant number of recent papers were focused on nanomedicine. Topics included translatable mouse models for cancer, 13 new designs of nanoparticles, 14,15 and scalable synthesis methods for nanoparticles 16,17 . Translationally focused reports, for example, novel tumor models for nanomedicine and scalable synthesis methods, represent a particular need of time and we look forward to receiving more similar translationally focused nanomedicine manuscripts in future.…”

Editorial: The launch phase of Bioengineering & Translational Medicine

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