Design and In Situ Characterization of Lipid Containers with Enhanced Drug Retention

Drug delivery via liposomes has the potential to expand the therapeutic window by targeting and releasing drug at the disease site while minimizing drug concentrations elsewhere in the body.[1] In a liposome, a single bilayer defines the interior space, regulates release of the liposome contents, and protects the contents from the environment. However, finding a bilayer composition that provides the necessary physical integrity, drug retention, specific targeting and rapid contents release at the disease site has been problematic. Despite 40 years of research, only liposomal doxorubicin and amphotericin B are clinically available. Many drugs, including the antibiotic ciprofloxacin,[2,3] are retained in liposomes for weeks to months in buffer, but are released within minutes in serum.[1,4–9] Phospholipids and/or cholesterol can be removed from liposomes by high-density lipoproteins (HDL), leading to the formation of defects in the bilayer and release of small molecules.[5,9] Lipases and other enzymes can selectively break down lipids within the bilayer[7]. A possible solution is to protect the drug-encapsulating bilayer by surrounding it with a second, protective bilayer shell in a “vesosome”.[7,10] The second bilayer increases the serum half-life of ciprofloxacin from <10 minutes in liposomes to 6 hours in vesosomes. PEG-lipid coating prevents vesosome aggregation in blood, leading to a ~ 2 hour half-life in the circulation. The biodistribution of vesosomes is similar to unilamellar liposomes as shown by near-infrared full body images. The vesosome structure may be a viable alternative for targeted delivery of weakly basic drugs, such as ciprofloxacin, that leak too rapidly from liposomes.