Dextran-modified Quercetin-Cu(II)/hyaluronic acid nanomedicine with natural poly(ADP-ribose) polymerase inhibitor and dual targeting for programmed synthetic lethal therapy in triple-negative breast cancer

Serious side effects from chemotherapies are the main problem with cancer treatments. To solve these issues, precision cancer nanomedicine based on natural therapeutic materials is developed, which enables specifically apoptosis by interacting with genetic mutation in cancer cells, while leaving normal cells unaffected. Here, we report a novel nanomedicine (CuQDA/IO@HA) composed of hyaluronic acid (HA) / copper ion (Cu(II))-chelated dextran-aldehyde (DA)-quercetin (Q) with dual targeting for synthetic lethal therapy. The CuQDA/IO@HA prepared using a ratio of metal/Q at 0.5:1 resulted in a stable particle structure with uniform particle distribution. The CuQDA/IO@HA can specifically target and induce specific cytotoxicity in BRCA-mutant cancer cells in vitro. Combination treatment with CuQDA/IO@HA and magnetic navigation can induce poly (ADP-ribose) polymerase (PARP) inhibition and DNA damage in BRCA-mutant triple-negative breast cancer (TNBC) via CD44 targeting. The dual-targeting CuQDA/IO@HA can extend the median survival of the BRCA-mutant xenograft mice from 34 to 61 days in comparison to Q treatment alone in vivo, which is attributed to the significant increase in γH2AX, leading to significant apoptosis. More importantly, the CuQDA/IO@HA displayed biocompatibility and no obvious side-effect in normal organs. These results demonstrate the promising potential of integrating natural and metal ions into a nanomedicine that can provide precision medicine through synthetic lethality. A new nanomedicine based on the natural material was constructed for synthetic lethal therapy with dual targeting in triple-negative breast cancer. [Display omitted] •A novel nanomedicine composed of natural material without loading chemotherapeutics was developed for programmed synthetic lethal therapy.•The nanomedicine enhanced the tumor accumulation and targeting with IO and HA to reduce side-effect using low dose.•The dual targeting nanomedicine exhibited precision medicine therapy in BRCA-mutated triple-negative breast cancer.