Lipid-Polymer Bilaminar Oxygen Nanobubbles for Enhanced Photodynamic Therapy of Cancer

Hypoxia in solid tumors may be a hindrance to effective treatments of tumors in achieving their therapeutic potential, especially for photodynamic therapy (PDT) which requires oxygen as the supplement substrate. Oxygen delivery using perfluorocarbon emulsions or lipid oxygen microbubbles has been developed as the agents to supply endogenous oxygen to fuel singlet oxygen generation in PDT. However, such methods suffer from premature oxygen release and storage issues. To address these limitations, we designed lipid-polymer bilaminar oxygen nanobubbles with chlorin e6 (Ce6) conjugated to the polymer shell as a novel oxygen self-supplement agent for PDT. The resultant nanobubbles possessed excellent stability to reduce the risk of premature oxygen release and were stored as freeze-dried powders to avoid shelf storage issues. In vitro and in vivo experimental results demonstrated that the nanobubbles exhibited much higher cellular uptake rates and tumor targeting efficiency compared to free Ce6. Using the oxygen nanobubbles for PDT, a significant enhancement of therapeutic efficacy and survival rates was achieved on a C6 glioma-bearing mice model with no noticeable side effects, owing to the greatly enhanced singlet oxygen generation powered by oxygen encapsulated nanobubbles

Controllable Formation of Monodisperse Polymer Microbubbles as Ultrasound Contrast Agents

Microbubbles have been widely used as ultrasound contrast agents in clinical diagnosis and hold great potential for ultrasound-mediated therapy. However, polydispersed population and short half-life time (<10 min) of the microbubbles still limit their applications in imaging and therapy. To tackle these problems, we develop a microfluidic flow-focusing approach to produce monodisperse microbubbles stabilized by Poly­(lactic-co-glycolic acid) (PLGA) as the polymer shell. The size of PLGA microbubbles can be tightly controlled from ∼600 nm to ∼7 μm with a coefficient of variation less than 4% in size distribution for ensuring highly homogeneous echogenic behavior of PLGA polymer microbubbles in ultrasound fields. Both in vitro and in vivo experiments showed that the monodisperse PLGA microbubbles had excellent echogenicity and elongated sonographic duration time (>3 times) for ultrasound imaging in comparison with the commercial lipid microbubbles