Effect of PEG Pairing on the Efficiency of Cancer-Targeting Liposomes

Abstract

Standardized poly(ethylene glycol)-modified (PEGylated) liposomes, which have been widely used in research as well as in pre-clinical and clinical studies, are typically constructed using PEG with a molecular weight of 2000 Da (PEG2000). Targeting ligands are also generally conjugated using various functionalized PEG2000. However, although standardized protocols have routinely used PEG2000, it is not because this molecular weight PEG has been optimized to enhance tumor uptake of nanoparticles. Herein, we investigated the effect of various PEG lipid pairings—that is, PEG lipids for targeting-ligand conjugation and PEG lipids for achieving 'stealth' function—on in vitro cancer cell- and in vivo tumor-targeting efficacy. A class of high-affinity peptides (aptides) specific to extra domain B of fibronectin (APTEDB) was used as a representative model for a cancer-targeting ligand. We synthesized a set of aptide-conjugated PEGylated phospholipids (APTEDB‑PEG2000‑DSPE and APTEDB‑PEG1000‑DSPE) and then paired them with methoxy-capped PEGylated phospholipids with diverse molecular weights (PEG2000, PEG1000, PEG550, and PEG350) to construct various aptide-conjugated PEGylated liposomes. The liposomes with APTEDB‑PEG2000/PEG1000 and APTEDB‑PEG1000/PEG550 pairings had the highest uptake in EDB-positive cancer cells. Furthermore, in a U87MG xenograft model, APTEDB‑PEG2000/PEG1000 liposomes retarded tumor growth to the greatest extent, followed closely by APTEDB‑PEG1000/PEG550 liposomes. Among the PEGylated liposomes tested, pairs in which the methoxy-capped PEG length was about half that of the targeting ligand-displaying PEG exhibited the best performance, suggesting that PEG pairing is a key consideration in the design of drug-delivery vehicles.

Immune cell impact of three differently coated lipid nanocapsules: pluronic, chitosan and polyethylene glycol

“…The PEG mediated action on internalization is still under discussion due to its well-known stealth property 20 . However, other recent studies evidenced how a specific PEG coating can enhance the nanoparticle uptake, such as in the case of cancer cells 39 40 . On the other hand, the chosen time point (24 h) might be also responsible for the no PEG mediated uptake inhibition, as it was also reported in the study of Sheng Y et al 41 .…”

Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr−/− Mice

“…However, it is also important to choose the right density and length of the PEG-coating molecules in designing targeted NPs with optimal binding specificity, as PEG interferes with the binding of the targeting ligand to its target [23]. The biorecognition of targeted liposomes and inorganic NPs was maximized when the length of the PEG-coating molecules was properly shortened relative to the ligand linker [23–26]. On the other hand, the optimal length of targeted lipid-polymer hybrid NPs was not yet been identified.…”

“…In contrast, no binding was observed in Col IV-NPs(2000), in which the length of the PEG-coating molecules (DSPE-mPEG2000) used to construct the NPs was similar to that of the targeting ligand displaying lipid-PEG (Col IV-DSPE-PEG2000), as well as in non-targeting NPs(1000) and NPs(2000) (Figure S3B–D). These results suggest that the PEG conjugated with the Col IV targeting ligand should be longer than the PEG coated on the surface of lipid-polymer hybrid NPs, similar to the PEGylated liposomal or inorganic targeted NPs [23,26]. Consequently, the Col IV-NPs(1000) surrounded by a lipid layer of DSPE-mPEG1000/DLPC/Col IV-DSPE-PEG2000 were considered optimal and suitable for further use in cell culture and in vivo studies.…”

Folic acid-functionalized graphene oxide nanosheets via plasma etching as a platform to combine NIR anticancer phototherapy and targeted drug delivery

“…[36] [37] Whereas PEG 2000 was selected because it is a discrete high mobile macromolecule that generates large volume exclusion that limits unspecific protein adsorption in vivo and proven able to allow specific recognition of targeting agents introduced as end-chain. [38] The alkyne-terminated PEG-Fol was exploited to functionalize both faces of GO-N 3 by the click reaction between azides of GO-N 3 and alkyne end chain of Fol-PEG-CC, while the amine-teminated PEG was introduced at the GO perimeter by the coupling reaction between carboxyl groups of GO-N 3 and the amine function of the PEG chains.…”