Intrinsic antibacterial and osteoinductive sterosomes promote infected bone healing.

Open fractures and internal fixation implants are often accompanied by bacterial infection, leading to osteomyelitis, characterized by intractable bone infection and sequestrum formation, and can result in lifelong disability or fatal sepsis. As common clinical treatment strategies, high-dose antibiotic application and autologous bone transplantation face the risk of recurrence and donor site injury. Herein, we designed and prepared a novel drug delivery system by rational selection of the antibacterial single-chain amphiphile (cetylpyridinium chloride, CPC) and osteoinductive sterol (20S-hydroxycholesterol, Oxy) to formulate CPC/Oxy sterosomes. We demonstrate their excellent biocompatibility and antibacterial ability through 2D and 3D settings in vitro. In addition, the osteogenic differentiation of bone marrow mesenchymal stem cells was investigated in cell monolayers and a hydrogel environment. Moreover, a rat infected critical-sized calvarial defect model was employed to illustrate the effects of antibacterial and osteogenic CPC/Oxy sterosomes in vivo. Our results showed that CPC/Oxy sterosomes not only exterminated bacterial infections, but also enhanced calvarial healing without additional antibiotics, bone formation promoters or exogenous cells. This research provides a promising and effective multifunctional sterosomal platform for the treatment of infected bone defects, with the potential to be combined with therapeutic genes, and small molecule drugs.

Synergistic effect of the anti-PD-1 antibody with blood stable and reduction sensitive curcumin micelles on colon cancer.

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a potent anticancer drug with versatile biological activities, while the clinical translation of curcumin is severely limited due to its hydrophobicity, rapid elimination, and metabolism in the blood circulation. Herein, we aim to unravel the potential of curcumin as a synergistic agent with immunotherapy in the treatment of cancers. In an effort to minimize premature release and improve the systemic bioavailability, a superior blood stable and reduction sensitive curcumin micellar formulation, of which the release can be triggered by cancer cells, is rationally designed. We have synthesized a telodendrimer (mPEG-PLA-(LA)4) capable of forming reversible disulfide crosslinked micelles (DCMs). The curcumin loaded DCMs (Cur/DCMs) are spherical with a uniform size of 24.6 nm. The in vitro release profile demonstrates that curcumin releases significantly slower from DCMs than that from non-crosslinked micelles (NCMs), while the release can be accelerated with the increasing concentration of reducing agent glutathione (GSH). Intravenous administration of Cur/DCMs stably retains curcumin in the bloodstream and efficiently improves the systemic bioavailability. Furthermore, Cur/DCMs exhibit synergistic anticancer efficacy when combined with the anti-PD-1 antibody in an MC-38 colon cancer xenograft model. Our results potentiate the integration of blood stable curcumin nanoformulation and immunotherapy for cancer treatment.