PEGylated Liposomes and the Accelerated Blood Clearance (ABC) Phenomenon: Implications for Drug Delivery

Grafting PEG to long chained lipids onto liposomes grants them stealth-like properties that prolong their half-life in circulation. The PEG coating was thought to hinder antibody and complement protein binding, known as opsonins, that elicit phagocytosis of foreign entities they identify. However, many studies have challenged the notion that PEGylated liposomes are inert to opsonins and thus non-immunogenic. One type of immunogenic response leads to rapid clearance of PEGylated drug delivery systems upon repeated injections. This effect, called the 'accelerated blood clearance (ABC) phenomenon', is mediated by antibodies raised against the foreign drug delivery system after the first injection. The ABC phenomenon has been observed across animal species. Factors that affect ABC clearance of PEGylated liposomes are dose (in a reciprocal way), time interval between injections, and liposomal physicochemical properties including lipid composition, size, surface charge, and drug cargo. However, the ABC phenomenon has not seriously impacted the clinical use of PEGylated liposomal anticancer drug formulations such as Doxil. Such anticancer drugs may impair anti-PEG antibody production in B-cells. Yet rapid clearance as in the ABC phenomenon could pose a challenge for the safety and efficacy of non-anticancer drugs loaded into PEGylated drug delivery systems. Besin et al. showed in mice studies that LNPs can trigger ABC and that this immune response is based on production of both anti-phosphatidylcholine and anti-PEG antibodies.