Abstract
Systemic delivery of conventional chemotherapies can cause negative systemic toxicity, including reduced immunity and damage to organs such as the heart and kidneys—limiting the maximum dose that can be administered. Targeted therapies appear to address this problem by having a specific target while mitigating off-target effects. Biocompatible perfluorocarbon-based nanodroplet emulsions encapsulated by a phospholipid shell are in development for delivery of molecular compounds and hold promise as vehicles for targeted delivery of chemotherapeutics to tumors. When ultrasound is applied, perfluorocarbon will undergo a phase change—ultimately inducing transient perforation of the cell membrane when in close proximity, which is more commonly known as “sonoporation.” Sonoporation allows enhanced intracellular delivery of molecular compounds and will reseal to encapsulate the molecular compound intracellularly. In this study, we investigated delivery of thymoquinone (TQ), a natural hydrophobic phytochemical compound with bioactivity in cancer cells. In addition, we conjugated a G-quadruplex aptamer, ‘AS1411’, to TQ-loaded nanodroplets and explored their effects on multiple human cancer cell lines. AS1411 binds nucleolin, which is over-expressed on the surface of cancer cells, and in addition to its tumor-targeting properties AS1411 has also been shown to induce anti-cancer effects. Thymoquinone was loaded onto AS1411-conjugated nanodroplet emulsion to assess activity against cancer cells. Confocal microscopy indicated uptake of AS1411-conjugated nanodroplets by cancer cells. Furthermore, AS1411-conjugated nanoemulsions loaded with TQ significantly enhanced cytotoxicity in cancer cells compared to free compound. These results demonstrate that AS1411 can be conjugated onto nanodroplet emulsions for targeted delivery to human cancer cells. This novel formulation offers significant potential for targeted delivery of hydrophobic chemotherapeutics to tumors for cancer treatment.
Highlights
Standard clinical treatments for cancer patients include surgery, radiation, and chemotherapy
We report for the first time a novel nanoemulsion formulation consisting of thymoquinone-loaded perfluorocarbon nanodroplets conjugated with a tumor-targeting aptamer, AS1411
The thymoquinone concentration in the nanodroplet emulsion after extrusion and 5-fold dilution in phosphate buffered saline (PBS) was calculated to be ~1 mM following the procedure described in the Methods, indicating a loading efficiency of ~10%
Summary
Standard clinical treatments for cancer patients include surgery, radiation, and chemotherapy. Administration of chemotherapeutic drugs has been used for cancer treatment since the 1940s but targeted anti-cancer therapies have only recently been developed [1, 2]. The therapeutic window that can be administered is limited To address this problem, targeted delivery strategies are in development to increase the efficacy of chemotherapy while reducing negative systemic toxicity. To overcome limitations with systemic intravenous delivery of chemotherapeutic drugs, perfluorocarbon-based nanodroplet emulsions have been developed which consist of liquid nanodroplets with average diameters of 100–400 nm. The nanodroplets are composed of a biocompatible phospholipid shell encapsulating an inert, non-toxic perfluorocarbon such as perfluoropentane (PFP). The liquid perfluorocarbon in nanoemulsions can be vaporized into gas bubbles using ultrasound or light, which enhances molecular delivery to targeted cells. The inert perfluorocarbon is cleared through exhalation [11,12,13,14,15]
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