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Effects of stability of PEGylated micelles on the accelerated blood clearance phenomenon

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Abstract

Accelerated blood clearance (ABC) is a phenomenon where the blood clearance rate of the carrier system is substantially raised. It can be induced by repetitive injections of polyethylene glycol (PEG) (molecular weight 2000)-modified micelles (PM2000). To determine whether the PEG chain length and PEGylated micelle injection dose can have an effect on the ABC phenomenon, micelles were modified with PEGs of varying molecular weights; PEGs with molecular weights of 350, 550, 2000, 5000, 10,000, and 20,000 were used to generate the PEGylated micelles PM350, PM550, PM2000, PM10000, and PM20000, respectively. One special carrier, MCT-PM2000, was prepared with the original PM2000 formulation but also included extra medium-chain triglycerides. Our experimental results showed that PM2000 and PM5000 exhibit superior storage stability compared to that of PM350, PM550, PM10000, and PM20000. MCT-PM2000 demonstrated stronger dilution stability than PM2000. As expected, PM2000 and PM5000 induced the strongest enhancement in blood elimination rate compared to that of PM350, PM550, PM10000, and PM20000; MCT-PM2000 exhibited more intense ABC phenomenon compared to that of PM2000. In addition, induction of the ABC phenomenon by PM2000 and MCT-PM2000 was augmented when the injection dose was increased from 0.05 to 5 μmol phospholipid·kg−1. Based on our findings, we suggest that there is a positive linear relationship between stability of PEG-modified micelles and susceptibility to the ABC phenomenon. The results may be valuable for designing PEGylated micelles for multiple drug therapy.

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Abbreviations

5%Glu:

5% (m/v) glucose for injection

HLB:

the hydrophilic lipophilic balance

CMC:

critical micellization concentration;

AUC:

area under the curve

MRT:

mean residence time

DSPE-PEGx:

1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-x] (x = 350, 550, 2000, 5000, 10,000 and 20,000)

MCT:

medium-chain triglycerides

PM:

PEGylated micelles

PE:

PEGylated emulsion

PMy (y = 350, 550, 2000, 5000, 10,000 and 20,000):

micelles composed of DSPE-PEGx, x = 350, 550, 2000, 5000, 10,000 and 20,000, respectively

MCT-PM2000:

micelles composed of DSPE-PEG2000 with MCT in the inner core (Weight of DSPE-PEG2000 weight of MCT, 14: 1, w/w)

PMy-PE:

PMy were pre-administered into rats, and PE were injected 7 days later

PM2000(zCMC)-PE:

PM2000 were pre-administered into rats at a dose of z-fold of the CMC of DSPE-PEG2000, and PE were injected 7 days later

MCT-PM2000(zCMC)-PE:

MCT-PM2000 were pre-administered into rats at a dose of z-fold of the CMC of DSPE-PEG2000, and PE were injected 7 days later

CMC2000:

the CMC value of the DSPE-PEG2000

EE:

encapsulation efficiency

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Funding

This research was supported by the National Natural Science Foundation of China (Grant Nos. 81072602, 81373334).

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Authors and Affiliations

  1. School of Pharmacy, Shenyang Pharmaceutical University, 26 Huatuo Road, Benxi, 117004, People’s Republic of China

    Yuqing Su, Mengyang Liu, Yan Xiong, Junqiang Ding, Xinrong Liu, Yanzhi Song & Yihui Deng

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  1. Yuqing Su
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  2. Mengyang Liu
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Correspondence to Yanzhi Song or Yihui Deng.

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All institutional and national guidelines for the care and use of laboratory animals were followed.

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The authors declare that they have no conflicts of interest.

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Su, Y., Liu, M., Xiong, Y. et al. Effects of stability of PEGylated micelles on the accelerated blood clearance phenomenon. Drug Deliv. and Transl. Res. 9, 66–75 (2019). https://doi.org/10.1007/s13346-018-0588-3

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