Ultrasound-Mediated Destruction of LHRHa-Targeted and Paclitaxel-Loaded Lipid Microbubbles Induces Proliferation Inhibition and Apoptosis in Ovarian Cancer Cells

Abstract

Although paclitaxel (PTX) is used with platinum as the first line chemotherapy regimen for ovarian cancer, its clinical efficacy is often limited by severe adverse effects. Ultrasound targeted microbubble destruction (UTMD) technique holds a great promise in minimizing the side effects and maximizing the therapeutic efficacy. However, the technique typically uses non-targeted microbubbles with suboptimal efficiency. We synthesized targeted and PTX-loaded microbubbles (MBs) for UTMD mediated chemotherapy in ovarian cancer cells. PTX-loaded lipid MBs were coated with a luteinizing hormone-releasing hormone analogue (LHRHa) through a biotin-avidin linkage to target the ovarian cancer A2780/DDP cells that express the LHRH receptor. In the cell culture studies, PTX-loaded and LHRHa targeted MBs (TPLMBs) in combination with ultrasound (300 kHz, 0.5 W/cm2, 30 seconds) demonstrated anti-proliferative activities of 41.30 ± 3.93%, 67.76 ± 2.45%, and 75.93 ± 2.81% at 24 hours, 48 hours, and 72 hours after the treatment, respectively. The cell apoptosis ratio at 24 hours after the treatment is 32.6 ± 0.79 %, which is significantly higher than other treatment groups such as PTX only and no-targeted PTX-loaded MBs (NPLMBs) with or without ultrasound mediation. Our experiment verifies the hypothesis that ultrasound mediation of ovarian cancer targeted and drug loaded MBs will enhance the PTX therapeutic efficiency.

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

“…tUCA vs. non-tUCA for enhanced drug delivery Strikingly, when tUCAs for drug delivery are directly compared with their non-targeted UCA counterparts, tUCAs are more efficient both in vitro [184,185,188,189,192] (up to 7.7-fold higher [189]) and in vivo [186,187,190,191] (up to 5-fold higher [186]), regardless of whether the drug was coadministered with the tUCAs or whether the drug was loaded on/in the tUCAs. Although the reasons for this higher efficiency have not yet been investigated, several could be possible.…”

Ultrasound-mediated destruction of oxygen and paclitaxel loaded lipid microbubbles for combination therapy in hypoxic ovarian cancer cells

“…PLMBs were fabricated as described previously [27]. OPLMBs were fabricated by a modified emulsification process [27,28].…”

“…OPLMBs were fabricated by a modified emulsification process [27,28]. Five milligrams of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (Avanti Polar Lipids Inc., Alabaster, AL, USA), two milligrams of 1,2-distearoyl-sn-glycero-3- The PTX loaded MBs (PLMBs) were prepared by replacing oxygen and perfluoropropane gas with perfluoropropane gas only in the above recipe.…”

“…Several oxygen-loaded MBs and nanobubbles have been previously fabricated for UTMD-mediated oxygen delivery [24][25][26]. We have previously demonstrated the enhanced therapeutic efficacy in ovarian cancer cells and cancer xenograft mice by ultrasound-mediated delivery of PTX therapy [27,28]. We have further observed in an ovarian cancer xenograft model that systemic delivery of oxygen and drug-loaded microbubbles followed by ultrasound mediation is able to enhance the anticancer effect [29].…”

Ultrasound mediated destruction of multifunctional microbubbles for image guided delivery of oxygen and drugs

“…We have encapsulated perflourocarbon compounds (PFC) in liposome MBs and loaded the MBs with paclitaxel (PTX) for UTMD-mediated drug delivery. Our previous in vitro and in vivo studies have demonstrated that the UTMD process can effectively enhance the PTX deposition at the disease site and improve the therapeutic outcome [14,15]. We have also delivered oxygen and PTX simultaneously for combination therapy in hypoxic ovarian cancer cells.…”