RT Journal Article
SR Electronic
T1 Unexpected accelerated blood clearance phenomenon in albumin coated liposome
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1265
OP 1265
VO 62
IS supplement 1
A1 Jeon, Miyeon
A1 Lee, Wooseung
A1 Im, Hyung-Jun
YR 2021
UL http://jnm.snmjournals.org/content/62/supplement_1/1265.abstract
AB 1265Purpose: Surface modification of nanomaterials with polyethylene glycol (PEG), or PEGylation, is a widely used strategy to stability and circulation half-life of nanomedicines. However, an accelerated blood clearance (ABC) phenomenon is observed during the repeated injection of PEGylated nanomaterials resulting in the decreased in vivo blood circulation. To overcome the ABC phenomenon of PEGylated liposome (PEG-lipo), recombinant human serum albumin (rHSA) coating can be considered because it is the most abundant protein in the body without immunogenicity. However, we observed unexpected ABC phenomenon after repeated injection of rHSA coated liposome (rHSA-lipo), which was worse than PEG-lipo. Methods: PEG-lipo and rHSA-lipo were prepared to investigate ABC phenomena (S1). Both PEG-lipo and maleimide-PEG-lipo (MAL-lipo) were prepared by thin-film hydration method with same molar ratio with DPSC:cholesterol:DSPE-PEG (or DSPE-PEG-MAL) = 15:5:2 followed by purification using a syringe filter and a PD-10 column. NOTA modified DSPE-PEG(2K) was added for radiolabeling. rHSA immobilization was conducted in pH 8 phosphate buffered saline (PBS) at 37℃ for 2 hours. Another purification was carried out to remove excess rHSA.64Cu labeling was conducted in pH 5 sodium acetate buffer. Biodistribution data of 64Cu labeled rHSA-lipo and PEG-lipo were obtained from positron emission tomography (PET) images with normal BALB/c mice via intravenous injection. 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) was incorporated to the liposome for an hour. DiR labeled rHSA-lipo and PEG-lipo were used for the observation of in vivo imaging system (IVIS) with 4T1 tumor bearing BALB/c mice via intravenous injection. Results: The hydrodynamic sizes of PEG-lipo, MAL-lipo and rHSA-lipo were 117.7 ± 35.26 nm, 113.8 ± 33.88 nm, and 144.2 ± 53.6 nm, respectively (S2a). The prepared rHSA-lipo in PBS and RPMI 1640 containing 10% FBS was stable showing no significant size changes for 7 days at room temperature (S2b, c). In the PET images of normal mice, both 64Cu labeled PEG-lipo, and 64Cu labeled rHSA-lipo showed good circulation at 1st injection. Both tracers showed significant ABC phenomenon upon repeated injection and unexpectedly the ABC phenomenon was more severe in 64Cu labeled rHSA-lipo than 64Cu labeled PEG-lipo (Fig. 1). IVIS experiment in 4T1 tumor bearing mice showed similar result. PEG-lipo showed similar tumor uptake in 1st and 2nd injection, however, rHSA-lipo showed significantly decreased tumor uptake in 2nd injection compared to 1st injection (Fig. 2a). Tumor to liver ratio of rHSA-lipo significantly decreased between 1st and 2nd injection (from 0.21 ± 0.07 to 0.052 ± 0.01, * p < 0.01, **p < 0.05) (Fig. 2b). Conclusions: Although human serum albumin is not immunogenic, we unexpectedly found that rHSA-lipo could induce ABC phenomenon upon repeated injection. Further experiment is warranted to elucidate the underlying mechanism of this intriguing finding.