Poly(ethylene glycol) (PEG)–coated liposomes are widely used as drug delivery carriers because PEGylation prolongs circulation and enhances accumulation at pathological sites. However, repeated dosing can trigger the accelerated blood clearance (ABC) phenomenon driven by induction of anti-PEG antibodies (APAs). ABC reduces the effectiveness of PEGylated formulations by increasing immune recognition, uptake by immune cells, and nonspecific hepatic accumulation, thereby limiting repeated administration and long-term efficacy.
The authors evaluated a zwitterionic PEGylation approach that grafts short glutamic acid–lysine (EK) peptides onto PEGylated phospholipid derivatives to create modified liposomes (referred to as EK-Lip). The strategy retains a PEG backbone while introducing a zwitterionic peptide motif at the surface to alter hydration and interfacial properties. The modification was applied to assemble liposome-based drug delivery systems and compared with conventional PEGylated liposomes (Lip) in head-to-head experiments reported in the source.
Small-angle neutron scattering (SANS) analysis demonstrated that EK modification significantly enhanced liposome hydration relative to conventional PEGylation. The increased hydration of the EK-decorated surface correlated with a marked reduction in protein adsorption: EK-Lip exhibited approximately a 40-fold reduction in protein adsorption compared with standard PEGylated liposomes. The authors link the improved hydration and suppressed protein binding as a mechanistic basis for downstream reductions in immune recognition.
Reduction in protein adsorption for EK-Lip translated into lower interaction with immune cells. The EK modification decreased immune cell uptake and reduced the induction of anti-PEG antibodies. In vivo, EK-Lip also showed decreased nonspecific hepatic accumulation compared with conventional PEGylated formulations. Together these observations indicate that surface zwitterionic modification can lower the immunogenic footprint of otherwise PEGylated liposomes.
A central finding reported is that EK-Lip mitigated the ABC phenomenon. Even in the presence of preexisting anti-PEG antibodies, EK-Lip attenuated accelerated clearance seen with repeated administration of conventional PEGylated liposomes. Specifically, after multiple injections, EK-Lip produced an approximately twofold increase in the area under the curve (AUC) of the pharmacokinetic profile compared with conventional PEGylated liposomes. These data suggest the zwitterionic EK surface reduces APA-driven clearance and improves systemic exposure across repeated dosing.
The study evaluated therapeutic performance by loading EK-Lip with doxorubicin and comparing outcomes with conventional formulations. EK-Lip loaded with doxorubicin retained the immune-sparing advantages: lower immunogenicity and reduced ABC-associated effects. In tumor models reported by the authors, doxorubicin-loaded EK-Lip demonstrated superior antitumor efficacy relative to conventional PEGylated doxorubicin liposomes. This indicates the EK modification can both preserve and enhance the therapeutic effectiveness of an established cytotoxic payload when immune-mediated clearance is a limiting factor.
Grafting EK zwitterionic peptides onto PEGylated phospholipid derivatives produced liposomes with enhanced surface hydration, dramatically reduced protein adsorption, and diminished immune recognition. These surface-chemistry changes decreased immune cell uptake, lowered anti-PEG antibody induction, limited nonspecific hepatic accumulation, and mitigated the ABC effect, including in the presence of preexisting APAs. Functionally, EK-Lip achieved roughly a twofold higher AUC after multiple injections and improved antitumor efficacy when delivering doxorubicin.
The work offers a practical surface-modification approach to address APA-mediated limitations of PEGylated liposomes. By reducing protein adsorption and immunogenicity while preserving favorable pharmacokinetics and therapeutic activity, zwitterionic PEGylation using EK peptides provides a promising strategy to improve repeated-dose performance of liposomal drug carriers.
Keywords reported in the source include: accelerated blood clearance; anti-PEG antibodies; liposomes; poly(ethylene glycol); zwitterionic modification. The DOI reported for the full study is 10.1021/acsami.6c12129 and the PubMed identifier is 42680140.