Perfluorocarbon Nanoemulsions for Combined Pulmonary siRNA Treatment of Lung Metastatic Osteosarcoma

Abstract

Lung metastatic osteosarcoma is a lethal disease afflicting children and adolescents, with a 5-year survival rate of less than 20%. The development of perfluorocarbon (PFC) nanoemulsions as systems for direct pulmonary delivery of combination drug/siRNA therapy is reported. Fluorinated polycation (F-PCX) with an inherent ability to inhibit C-X-C receptor type 4 (CXCR4) is synthesized and used as a surfactant in the preparation of F-PCX@PFC nanoemulsions. The nanoemulsions are loaded with siRNA against signal transducer and activator of transcription 3 (STAT3) for combined treatment of lung metastasis in osteosarcoma. Intratracheal instillation of the treatments significantly prolonged the survival of animals with established lung metastases. The treatment with F-PCX@PFC/siSTAT3 emulsion polyplexes decreased the number of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the tumors, while increasing CD8 + T cells infiltration andIFNγ secretion to overcome the immunosuppressive tumor microenvironment. The reported nanoemulsions represent a promising pulmonary treatment of lung metastatic osteosarcoma.

From Design to Clinic: Engineered Nanobiomaterials for Immune Normalization Therapy of Cancer

“…The nanocomplex reduced the activation of immunosuppressive cells (myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T regs )), which ultimately downregulated the expression of TGF-β and IL-10 while elicited the secretion of the proinflammatory cytokines, including interferon g (IFN-g) and tumor necrosis factor a (TNF-a) when it was combined with PD-L1 blockade. [35] IL-10 is associated with the overexpression of IL-12 and thus plays a key role in immunosuppression by blocking antitumor CTL responses. CXCL12 is the main factor that contributes to inhibiting T cell tumor infiltration.…”

Design of polymers for siRNA delivery: Recent progress and challenges

“…[101][102][103] To date, fluorination has successfully improved the siRNA delivery efficiency of various cationic polymers including branched PEI and PAMAM dendrimers. [104][105][106][107][108][109][110][111][112][113][114] For example, a series of fluorinated oligoethylenimines (fOEIs) were developed for siRNA-mediated gene therapy (Figure 4A). [115] The fOEIs could assemble into vesicle-like nanostructures with the fluorous segments densely embedded in the bilayers.…”

Increased Survival by Pulmonary Treatment of Established Lung Metastases with Dual STAT3/CXCR4 Inhibition by siRNA Nanoemulsions

“…We used FM as a stabilizer at the surface and perfluorodecalin as an emulsion core following a similar approach described in our recent studies. 26 The approach utilizes the high-affinity fluorous interactions between PFC and the heptafluorobutyryl moieties in FM for coating and stabilization of the FM@PFC. The hydrodynamic diameter of the prepared FM@PFC was $200 nm with a polydispersity index of 0.109 (Figure 2A).…”

“…The FM@PFC was prepared using the method as previously reported. 26 Briefly, FM (5 mg) was dissolved in diethyl pyrocarbonate-treated water (2 mL) and 20 mL PFC was added. The mixture was sonicated twice with a probe-type sonicator (35% amplitude, 1.5 s power on, 2 s power off) for 35 min in ice-water bath and refrigerated until use.…”

“…of CXCR4 and STAT3 combined inhibitors achieved good anti-lung metastasis efficacy in osteosarcoma. 26 Here, we further expanded the use of this treatment strat- egy to pulmonary metastases of different origin (breast cancer) and conducted direct head-tohead comparison of p.d. with intravenous (i.v.)…”