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. Author manuscript; available in PMC: 2016 Sep 1.
Published in final edited form as: Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015 Feb 23;7(5):655–677. doi: 10.1002/wnan.1339

Table 1.

Examples of α-PEG Ab and/or accelerated blood clearance responses to PEGylated systems.

Type of PEGylated
system		 Animal model Dose*,† Dosing
interval* 		Parameters of initial or
control dose		 Parameters of
subsequent dose(s)		 Fold change in
parameters‡ 		α-PEG Ab
response# 		Ref
PEGylated liposome Balb/c mice 0.01–1 μmol PL/kg 5–7 d N.D. N.D. - IgM + (no to weak) IgG 48
PEGylated liposome Std:ddY mice 25 μmol PL/kg 10 d t1/2,β 12.9 h
Cl 0.07 mL/h
AUC0-24h 486%dose h/mL		 t1/2,β 6.3 h
Cl 0.2 mL/h
AUC0-24h 221%dose h/mL		 0.5 (t1/2,β)
2.9 (Cl)
0.5 (AUC0-24h)		 N.D. 33
PEGylated liposome KM mice 0.1 μmol PL/kg (initial); 5 μmol PL/kg (subsequent) 6 d 44%IDblood,4h
13%IDliver,4h
12%IDspleen,4h 		14%IDblood,4h
28%IDliver,4h
18%IDspleen,4h 		0.3 (%IDblood,4h)
2.2 (%IDliver,4h)
1.5 (%IDspleen,4h)
0.2 (t1/2), 0.2 (AUC)° 		IgM§ 54
PEGylated liposome Wistar rats 0.001 μmol PL/kg - N.D - - IgM + (weak) IgG 39
PEGylated liposome Wistar rats 5 μmol PL/kg 7 d t1/2,α 2.4 h
52.5%IDblood,4h
8.1%IDliver,4h
2.2%IDspleen,4h 		t1/2,α 0.1 h
0.6%IDblood,4h
46.4%IDliver,4h
6.3%IDspleen,4h 		0.04 (t1/2,α)
0.01 (%IDblood,4h)
5.7 (%IDliver,4h)
2.9 (%IDspleen,4h)		 N.D. 7
PEGylated liposome Wistar rats 0.001 μmol PL/kg (initial); 5 μmol PL/kg (subsequent) 4–6 d t1/2 14.8 h
Clh <1 mL/min
8%IDliver,24h
8%IDspleen,24h 		t1/2 0.3–1.8 h
Clh 25–55 mL/min
67–72%IDliver,24h
8–12%IDspleen,24h 		0.02–0.12 (t1/2)
>25–55 (Clh)
8.4–9.0 (%IDliver,24h)
1.0–1.5 (%IDspleen,24h)		 IgM 47
PEGylated liposome Wistar rats 0.001 μmol PL/kg (initial); 5 μmol PL/kg (subsequent) 5 d 51%IDblood,24h
6%IDliver,24h 		<2%IDblood,24h
68%IDliver,24h 		<0.02 (%IDblood,24h)
11 (%IDliver,24h)		 IgM + (weak) IgG 37
PEGylated liposome Wistar rats 5 μmol PL/kg 7 d 76.4%IDblood,4h
15%IDliver,4h 		0.6%IDblood,4h
68%IDliver,4h 		0.01 (%IDblood,4h)
4.5 (%IDliver,4h)		 N.D. 36
PEGylated liposome Sprague-Dawley rats 7 μmol PL/kg 7 d t1/2 16.7 h
Cl 1.7 mL/h
AUC 856 μg h/mL		 t1/2 0.2 h
Cl 74.3 mL/h
AUC 17 μg h/mL		 0.01 (t1/2)
43.7 (Cl)
0.02 (AUC)		 IgM§ 44
PEGylated liposome Dunkin-Hartley guinea pigs 0.1 μmol PL/kg (initial); 5 μmol PL/kg (subsequent) 6 d 34%IDblood,4h
12%IDliver,4h
<2%IDspleen,4h 		12%IDblood,4h
37%IDliver,4h
<2%IDspleen,4h 		0.4 (%IDblood,4h)
3.1 (%IDliver,4h)
~1 (%IDspleen,4h)
0.6 (t1/2), 0.6 (AUC)° 		IgM§ 54
PEGylated liposome Rabbits 9 mg PL/animal 7 d N.D. N.D - IgG,Δ 49
PEGylated liposome Japanese white rabbits 0.1 μmol PL/kg (initial); 5 μmol PL/kg (subsequent) 6 d 47%IDblood,4h
15%IDliver
4%IDspleen 		13%IDblood,4h
35%IDliver
6%IDspleen 		0.3 (%IDblood,4h)
2.3 (%IDliver,4h)
1.5 (%IDspleen,4h)
0.5 (t1/2), 0.4 (AUC)° 		IgM§ 54
PEGylated liposome Rhesus monkey 5 μmol PL/kg 7 d t1/2 87.5 h
17.6%IDliver,4h 		t1/2 14.2 h
41.2%IDliver,4h 		0.2 (t1/2)
2.3 (%IDliver,4h)		 N.D. 7
PEGylated pDNA liposome ICR mice 100 μg pDNA/animal 7 d 80%IDblood,1h
8%IDliver,1h
2%IDspleen,1h 		23%IDblood,1h
41%IDliver,1h
4%IDspleen,1h 		0.3 (%IDblood,1h)
5.1 (%IDliver,1h)
2.0 (%IDspleen,1h)		 IgG + IgMΔ 41
PEGylated ODN vesicles ICR mice 50 mg PL/kg, 10 mg ODN/kg 7 d 70%IDblood,1h 6%IDblood,1h 0.1 (%IDblood,1h) IgM§ 57
PEGylated Gd liposome C57BL/6 and Balb/c mice 5 μmol PL/kg 7 d 11%IDblood,6h
9%IDliver,6h
10%IDspleen,6h 		<0.5%IDblood,6h
31%IDliver,6h
1%IDspleen,6h 		<0.05(%IDblood,6h)
3.4 (%IDliver,6h)
0.1 (%IDspleen,6h)		 IgMΔ 45
PEGylated Hb vesicles ddY mice 0.1 mg Hb/kg 7 d t1/2 2.7 h
Cl 3.7 mL/h
AUC 27.1%dose h/mL		 t1/2 1.3 h
Cl 22.3 mL/h
AUC 4.5%dose h/mL		 0.5 (t1/2)
6.0 (Cl)
0.2 (AUC)		 IgM 98
PEGylated EPI liposome Wistar rats 1 μmol PL/kg, 0.08 EPI/kg (initial); 5 μmol PL/kg, 0.4 mg EPI/kg (subsequent) 7 d 52%IDblood,4h
16%IDliver,4h
8%IDspleen,4h 		8%IDblood,4h
36%IDliver,4h
15%IDspleen,4h 		0.2 (%IDblood,4h)
2.3 (%IDliver,4h)
1.9 (%IDspleen,4h)		 IgM§ 53
PEGylated DXR liposome Beagle dogs 0.67 μmol PL/kg and 2 mg DXR/m2 3 wk t1/2 24.1 h
Cl 1.5 mL/h/kg
AUC0-∞ 76.0 μg h/mL		 t1/21.5 h
Cl 127.8 mL/h/kg
AUC0-∞ 0.6 μg h/mL		 0.06 (t1/2)
85.2 (Cl)
0.01 (AUC0-∞)		 IgM§ 96
PEGylated TOPO liposome Beagle dogs 0.5 mg TOPO/kg 7 d Cmax 7.9 mg/L
Cl 0.4 mL/min/kg
AUC0-t 1.4 mg min/mL		 Cmax 1.7 mg/L
Cl 6.7 mL/min/kg
AUC0-t 0.1 mg min/mL		 0.2 (C max)
16.8 (Cl)
0.07 (AUC0-t)		 IgM§ 42
PEGylated solid lipid nanoparticle Wistar rats 5 μmol PL/kg (initial s.c., subsequent i.v.) 7 d AUC0-4h 27.3 mg h/L
8 μg/g (liver, 4 h)
9 μg/g (spleen, 4 h)		 AUC0-4h 6.6 mg h/L
25 μg/g (liver, 4 h)
26 μg/g (spleen, 4 h)		 0.2 (AUC0-4h)
3.1 (liver, 4 h)
2.9 (spleen, 4 h)		 IgM§ 64
PEGylated solid lipid nanoparticle Kunming mice 10 μmol PL/kg 7 d 71.3%IDblood,0.5h
5.4%IDliver,0.5h
4%IDspleen,0.5h 		42.6%IDblood,0.5h
23.3%IDliver,0.5h
9%IDspleen,0.5h 		0.6 (%IDblood,0.5h)
4.3 (%IDliver,0.5h)
2.3 (%IDspleen,0.5h)		 N.D. 46
PEGylated solid lipid nanoparticle Beagle dogs 2 μmol PL/kg 7 d t1/2,β 3.4 h
Cl 0.2 mL/min/kg
AUC0-24h 90.6 mg h/L		 t1/2,β 1.6 h
Cl 0.4 mL/min/kg
AUC0-24h 34.0 mg h/L		 0.5 (t1/2,β)
2.0 (Cl)
0.4 (AUC0-24h)		 IgM§ 46
PEGylated emulsion Wistar rats 5 μmol PL/kg 7 d AUC0-0.5h 30.8 mg h/L
50%IDblood,1h
11 μg/g (liver, 12 h)
14 μg/g (spleen, 12 h)		 AUC0-0.5h 10.8 mg h/L
7%IDblood,1h
22 μg/g (liver, 12 h)
23 μg/g (spleen, 12 h)		 0.4 (AUC0-0.5h)
0.1 (%IDblood,1h)
2.0 (liver, 12 h)
1.6 (spleen, 12 h)		 IgM§ 68
PEGylated micelle Sprague-Dawley rats 7 μmol PL/kg 7 d t1/2 8.8 h
Cl 3.3 mL/h
AUC 442 μg h/mL		 t1/2 9.6 h
Cl 3.5 mL/h
AUC 408 μg h/mL		 1.1 (t1/2)⋄
0.9 (Cl)⋄
1.1 (AUC)⋄ 		IgM§ 44
PEG-PBLA micelles C57BL/6 and Balb/c mice 3 mg/kg 7 d 65%IDblood,6h 50%IDblood,6h 0.8 (%IDblood,6h)⋄ IgMΔ 45
PEG-PLGA ETO nanoparticles Wistar rats 0.01–1 mg polymer/kg (initial); 20 mg polymer/kg, 8 mg/kg ETO (subsequent) 7 d t1/2 3.5 h
Cl 0.6 mL/min
AUC 3.7 mg min/mL		 t1/2 1.0–1.2 h
Cl 3.2–3.3 mL/min
AUC 0.6 mg min/mL		 0.3 (t1/2)
5.3–5.5 (Cl)
0.2 (AUC)		 IgM§ 43
PEG-PLA PGE1 nanoparticles Wistar rats 133 μg PGE1/kg 7 d AUC 0-24h 6.4 μg min/mL
50%IDblood,3h 		AUC 1.1 μg min/mL
3% IDblood,3h 		0.2 (AUC0-24h)
0.06 (%IDblood,3h)		 IgM§,Δ 55
Poloxamine-coated polystyrene nanoparticles Wistar rats 3.5 mg polystyrene/kg, 5–7 mg poloxamine/kg 4 d 66.3%IDblood,3h
9.4%IDliver,3h
1.1%IDspleen,3h 		11.5%IDblood,3h
50.1%IDliver,3h
6.1%IDspleen,3h 		0.2 (%IDblood,3h)
5.3 (%IDliver,3h)
5.5 (%IDspleen,3h)		 N.D. 32
PEG-adenovirus Wistar rats 1011 particles/animal - N.D. - - IgM§,Δ 30
PEG-BSA Wistar rats 1 μg/animal - N.D. - - IgM§,Δ 30
PEG-uricase Sprague-Dawley rats 1 mg/kg 7 d 20–26 h (t1/2,β) N.D. - IgMΔ 99
PEG-uricase, PEG-IFNα, PEG-HSA New Zealand white rabbits N.D. 7 d N.D. N.D. - Igϕ,Δ 28
PEG-OVA, PEG-SOD, PEG-Rag New Zealand white rabbits 100 μg/animal (i.m.) with Freund’s adjuvant 4 wk N.D. N.D. - Igϕ,£,Δ 27
*

Treatment conditions that generated a maximal ABC and/or α-PEG Ab response;

†

i.v. administration, unless otherwise indicated;

‡

fold change calculated as (subsequent dose)/(initial dose);

#

α-PEG Ab detection was performed using ELISA, unless otherwise indicated;

°

data not available for individual injections;

§

anti-PEG IgG was not evaluated;

anti-PEG IgG detection was performed using Western blotting and IgM was not evaluated;

Δ

antibody specificity to PEG confirmed through cross-reactivity and/or competition with other PEGylated agents or free PEG;

⋄

no ABC effect was observed;

£

α-PEG Abs were detected using passive hemagglutination and radial immunodiffusion;

ϕ

antibody isotype was not evaluated or could not be determined.

N.D., not determined or not stated; PL, phospholipid; pDNA, plasmid DNA; ODN, oligonucleotide; Hb, hemoglobin; EPI, epirubicin; DXR, doxorubicin; TOPO, topotecan; ETO, etoposide, PGE1, prostaglandin E1; BSA, bovine serum albumin; IFN, interferon; HSA, human serum albumin; OVA, ovalbumin; SOD, superoxide dismutase; Rag, ragweed pollen extract.