Pegylation, a Successful Strategy to Address the Storage and Instability
Problems of Blood Products: Review 2011-2021

Tahereh   Zadeh   Mehrizi; Mehdi      Mirzaei; Mehdi   Shafiee   Ardestani
Abstract

Conjugation of polyethylene glycol (PEGylation) to blood proteins and cells has emerged as a successful approach to address some of the issues attributed to the storage of blood products, including their short half-life and instability. In this regard, this review study aims to compare the influence of different PEGylation strategies on the quality of several blood products like red blood cells (RBCs), platelets, plasma proteins, i.e., albumin, coagulation factor VIII, and antibodies. The results indicated that conjugating succinimidyl carbonate methoxyPEG (SCmPEG) to platelets could improve blood transfusion safety by preventing these cells from being attached to low-load hidden bacteria in blood products. Moreover, coating of 20 kD succinimidyl valerate (SVA)-mPEG to RBCs was able to extend the half-life and stability of these cells during storage, as well as immune camouflage their surface antigens to prevent alloimmunisation. As regards albumin products, PEGylation improved the albumin stability, especially during sterilization, and there was a relationship between the molecular weight (MW) of PEG molecules and the biological half-life of the conjugate. Although coating antibodies with short-chain PEG molecules could enhance their stabilities, these modified proteins were cleared from the blood faster. Also, branched PEG molecules enhanced the retention and shielding of the fragmented and bispecific antibodies. Overall, the results of this literature review indicate that PEGylation can be considered a useful tool for enhancing the stability and storage of blood components.
Keywords: Polyethylene glycol, RBC, platelets, albumin, plasma, SCmPEG, PEG molecules.
Graphical Abstract

[1]
Hess, J.R. Conventional blood banking and blood component storage regulation: opportunities for improvement. Blood Transfus.,  2010, 8(S3), s9-s15.
 [PMID: 20606757]

[2]
Medvecz, A.; Bernard, A.; Hamilton, C.; Schuster, K.M.; Guillamondegui, O.; Davenport, D. Transfusion rates in emergency general surgery: High but modifiable. Trauma Surg. Acute Care Open,  2020, 5(1), e000371.
 [http://dx.doi.org/10.1136/tsaco-2019-000371] [PMID: 32154373]

[3]
Wang, D.; Kyluik, D.L.; Murad, K.L.; Toyofuku, W.M.; Scott, M.D. Polymer-mediated immunocamouflage of red blood cells: Effects of polymer size on antigenic and immunogenic recognition of allogeneic donor blood cells. Sci. China Life Sci.,  2011, 54(7), 589-598.
 [http://dx.doi.org/10.1007/s11427-011-4190-x] [PMID: 21701803]

[4]
Tarasev, M.; Chakraborty, S.; Light, L.; Davenport, R. Impact of environment on red blood cell ability to withstand mechanical stress. Clin. Hemorheol. Microcirc.,  2016, 64(1), 21-33.
 [http://dx.doi.org/10.3233/CH-152037] [PMID: 26890109]

[5]
Mehrizi, T.Z. Hemocompatibility and hemolytic effects of functionalized nanoparticles on red blood cells: A recent review study. Nano,  2021, 16(8), 2130007.
 [http://dx.doi.org/10.1142/S1793292021300073]

[6]
Zadeh Mehrizi, T.; Amini Kafiabad, S. Evaluation of the effects of nanoparticles on the therapeutic function of platelet: A review. J. Pharm. Pharmacol.,  2022, 74(2), 179-190.
 [http://dx.doi.org/10.1093/jpp/rgab089] [PMID: 34244798]

[7]
Mehrizi, T.Z. An overview of the latest applications of platelet-derived microparticles and nanoparticles in medical technology 2010-2020. Curr. Mol. Med.,  2022, 22(6), 524-539.
 [http://dx.doi.org/10.2174/1566524021666210928152015] [PMID: 34602037]

[8]
Zadeh, M.T.; Mousavi, H.K. An overview on the investigation of nanomaterials’ effect on plasma components: Immunoglobulins and coagulation factor VIII, 2010–2020 review. Nanoscale Adv.,  2021, 3(13), 3730-3745.
 [http://dx.doi.org/10.1039/D1NA00119A] [PMID: 36133015]

[9]
Zadeh, M.T.; Pirali, H.M.; Ebrahimi, S.H.; Mirzaei, M.; Shafiee, A.M.; Haji, M.H.M.; Mosaffa, N.; Khamesipour, A.; Javanmard, A.; Rezazadeh, S.; Ramezani, A. Effective materials of medicinal plants for leishmania treatment in vivo environment. Faslnamah-i Giyahan-i Daruyi,  2020, 19(74), 39-62.
 [http://dx.doi.org/10.29252/jmp.19.74.39]

[10]
Zadeh, M.T.; Mosaffa, N.; Shafiee, A.M.; Khamesipour, A.; Ebrahimi, S.H.; Pirali, H.M. In vivo therapeutic effects of four synthesized antileishmanial nanodrugs in the treatment of Leishmaniasis. Arch. Clin. Infect. Dis.,  2018, 13(5)
 [http://dx.doi.org/10.5812/archcid.80314]

[11]
Shahabi, J.; Shahmabadi, H.E.; Alavi, S.E.; Movahedi, F.; Esfahani, M.K.M.; Mehrizi, T.Z.; Akbarzadeh, A. Effect of gold nanoparticles on properties of nanoliposomal hydroxyurea: an in vitro study. Indian J. Clin. Biochem.,  2014, 29(3), 315-320.
 [http://dx.doi.org/10.1007/s12291-013-0355-7] [PMID: 24966479]

[12]
Fatemeh, D.R.A.; Ebrahimi, S.H.; Abedi, A.; Alavi, S.E.; Movahedi, F.; Koohi, M.E.M.; Zadeh, M.T.; Akbarzadeh, A. Polybutylcyanoacrylate nanoparticles and drugs of the platinum family: last status. Indian J. Clin. Biochem.,  2014, 29(3), 333-338.
 [http://dx.doi.org/10.1007/s12291-013-0364-6] [PMID: 24966482]

[13]
Mehrizi, T.Z.; Ardestani, M.S.; Kafiabad, S.A. A review study of the influences of dendrimer nanoparticles on stored platelet in order to treat patients (2001-2020). Curr. Nanosci.,  2022, 18(3), 304-318.
 [http://dx.doi.org/10.2174/1566524021666210708154736]

[14]
Mehrizi, T.Z.; Kafiabad, S.A.; Eshghi, P. Effects and treatment applications of polymeric nanoparticles on improving platelets’ storage time: A review of the literature from 2010 to 2020. Blood Res.,  2021, 56(4), 215-228.
 [http://dx.doi.org/10.5045/br.2021.2021094] [PMID: 34880140]

[15]
Mehrizi, T.Z. Impact of metallic, quantum dots and carbon-based nanoparticles on quality and storage of albumin products for clinical use. Nano,  2021, 16(14), 2130013.
 [http://dx.doi.org/10.1142/S1793292021300139]

[16]
Mehrizi, T.Z.; Rezayat, S.M.; Ardestani, M.S.; Shahmabadi, H.E.; Ramezani, A. A review study about the effect of chitosan nanocarrier on improving the efficacy of amphotericin b in the treatment of leishmania from 2010 to 2020. Curr. Drug Deliv.,  2021, 18(9), 1234-1243.
 [http://dx.doi.org/10.2174/1567201818666210316111941] [PMID: 33726648]

[17]
Zadeh, M.T.; Shafiee, A.M.; Haji, M.H.M.; Khamesipour, A.; Mosaffa, N.; Ramezani, A. Novel nanosized chitosan-betulinic acid against resistant leishmania major and first clinical observation of such parasite in kidney. Sci. Rep.,  2018, 8(1), 11759.
 [http://dx.doi.org/10.1038/s41598-018-30103-7] [PMID: 30082741]

[18]
Zadeh, M.T.; Khamesipour, A.; Shafiee, A.M.; Ebrahimi, A.H.; Haji, M.H.M.; Mosaffa, N.; Ramezani, A. Comparative analysis between four model nanoformulations of amphotericin B-chitosan, amphotericin B-dendrimer, betulinic acid-chitosan and betulinic acid-dendrimer for treatment of Leishmania major: real-time PCR assay plus. Int. J. Nanomedicine,  2019, 14, 7593-7607.
 [http://dx.doi.org/10.2147/IJN.S220410] [PMID: 31802863]

[19]
Zadeh, M.T.; Mosaffa, N.; Khamesipour, A.; Haji, M.H.M.; Ebrahimi, S.H.; Shafiee, A.M. A novel nanoformulation for reducing the toxicity and increasing the efficacy of betulinic acid using anionic globular dendrimer. J Nanostruct.,  2020, 11(1), 143-152.

[20]
Mangla, S. Engineering PEGylated Antibody Fragments for Enhanced Properties and Cancer Detection; The Ohio State University, 2016. 

[21]
Abuchowski, A.; van Es, T.; Palczuk, N.C.; Davis, F.F. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J. Biol. Chem.,  1977, 252(11), 3578-3581.
 [http://dx.doi.org/10.1016/S0021-9258(17)40291-2] [PMID: 405385]

[22]
Freches, D.; Rocks, N.; Patil, H.P.; Perin, F.; Van Snick, J.; Vanbever, R.; Cataldo, D. Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity. Int. J. Pharm. X,  2019, 1, 100019.
 [http://dx.doi.org/10.1016/j.ijpx.2019.100019] [PMID: 31517284]

[23]
D’souza, A.A.; Shegokar, R. Polyethylene glycol (PEG): A versatile polymer for pharmaceutical applications. Expert Opin. Drug Deliv.,  2016, 13(9), 1257-1275.
 [http://dx.doi.org/10.1080/17425247.2016.1182485] [PMID: 27116988]

[24]
Roque, C.; Sheung, A.; Rahman, N.; Ausar, S.F. Effect of polyethylene glycol conjugation on conformational and colloidal stability of a monoclonal antibody antigen-binding fragment (Fab’). Mol. Pharm.,  2015, 12(2), 562-575.
 [http://dx.doi.org/10.1021/mp500658w] [PMID: 25548945]

[25]
Bjørnsdottir, I.; Støvring, B.; Søeborg, T.; Jacobsen, H.; Sternebring, O. Plasma polyethylene glycol (PEG) levels reach steady state following repeated treatment with N8-GP (Turoctocog Alfa Pegol; Esperoct®). Drugs R D.,  2020, 20(2), 75-82.
 [http://dx.doi.org/10.1007/s40268-020-00297-1] [PMID: 32152818]

[26]
Wynn, T.; Gumuscu, B. Potential role of a new PEGylated recombinant factor VIII for hemophilia A. J. Blood Med.,  2016, 7, 121-128.
 [http://dx.doi.org/10.2147/JBM.S82457] [PMID: 27382347]

[27]
Zhang, F.; Liu, M.; Wan, H. Discussion about several potential drawbacks of PEGylated therapeutic proteins. Biol. Pharm. Bull.,  2014, 37(3), 335-339.
 [http://dx.doi.org/10.1248/bpb.b13-00661] [PMID: 24334536]

[28]
Garay, R.P.; El-Gewely, R.; Armstrong, J.K.; Garratty, G.; Richette, P. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin. Drug Deliv.,  2012, 9(11), 1319-1323.
 [http://dx.doi.org/10.1517/17425247.2012.720969] [PMID: 22931049]

[29]
Baumann, A. PEGylated biologics in haemophilia treatment: Current understanding of their long-term safety. Haemophilia,  2020, 26(1), e11-e13.
 [http://dx.doi.org/10.1111/hae.13875] [PMID: 31742794]

[30]
Scott, M.D.; Nakane, N. Maurer-Spurej, E Cryoprotection of Platelets by Grafted Polymers. Cryopreservation-Current Advances and Evaluations; IntechOpen, 2019. 

[31]
Sauter, A.; Richter, G.; Micoulet, A.; Martinez, A.; Spatz, J.P.; Appel, S. Effective polyethylene glycol passivation for the inhibition of surface interactions of peripheral blood mononuclear cells and platelets. Biointerphases,  2013, 8(1), 14.
 [http://dx.doi.org/10.1186/1559-4106-8-14] [PMID: 24706127]

[32]
Maurer, E.; Scott, M.D.; Kitamura, N. Cold storage of pegylated platelets at about or below 0°C. Patent US8067151B2, 2011.

[33]
Tarrand, J.; Andersson, B. Compositions and methods for prolonged cell storage. Patent US20180070581A1, 2021.

[34]
Greco, C.A.; Maurer-Spurej, E.; Scott, M.D.; Kalab, M.; Nakane, N.; Ramírez-Arcos, S.M. PEGylation prevents bacteria-induced platelet activation and biofilm formation in platelet concentrates. Vox Sang.,  2011, 100(3), 336-339.
 [http://dx.doi.org/10.1111/j.1423-0410.2010.01419.x] [PMID: 21392023]

[35]
Wufuer, Y.; Shan, X.; Sailike, M.; Adilaimu, K.; Ma, S.; Wang, H. GPVI-Fc-PEG improves cerebral infarct volume and cerebral thrombosis in mouse model with cerebral thrombosis. Mol. Med. Rep.,  2017, 16(5), 7561-7568.
 [http://dx.doi.org/10.3892/mmr.2017.7556] [PMID: 28944903]

[36]
Bakhaidar, R.; Green, J.; Alfahad, K.; Samanani, S.; Moollan, N.; O’Neill, S.; Ramtoola, Z. Effect of size and concentration of PLGA-PEG nanoparticles on activation and aggregation of washed human platelets. Pharmaceutics,  2019, 11(10), 514.
 [http://dx.doi.org/10.3390/pharmaceutics11100514] [PMID: 31590303]

[37]
Fuentes, E.; Yameen, B.; Bong, S.J.; Salvador-Morales, C.; Palomo, I.; Vilos, C. Antiplatelet effect of differentially charged PEGylated lipid-polymer nanoparticles. Nanomedicine,  2017, 13(3), 1089-1094.
 [http://dx.doi.org/10.1016/j.nano.2016.10.010] [PMID: 27789259]

[38]
Mehrizi, T.Z.; Ardestani, M.S.; Molla Hoseini, M.H.; Khamesipour, A.; Mosaffa, N.; Ramezani, A. Novel nano-sized chitosan amphotericin B formulation with considerable improvement against Leishmania major. Nanomedicine,  2018, 13(24), 3129-3147.
 [http://dx.doi.org/10.2217/nnm-2018-0063] [PMID: 30463469]

[39]
Mehrizi, T.Z.; Ardestani, M.S.; Khamesipour, A.; Hoseini, M.H.M.; Mosaffa, N.; Anissian, A.; Ramezani, A. Reduction toxicity of Amphotericin B through loading into a novel nanoformulation of anionic linear globular dendrimer for improve treatment of leishmania major. J. Mater. Sci. Mater. Med.,  2018, 29(8), 125-138.
 [http://dx.doi.org/10.1007/s10856-018-6122-9] [PMID: 30056571]

[40]
Zadeh, M.T.; Shafiee, A.M.; Mirzaei, M.J. review study on the application of polymeric-based nanoparticles as a novel approach for enhancing the stability of albumins. Nanomed. J.,  2022, 9(4), 261-272.

[41]
Belousov, A; Malygon, E; Yavorskiy, V; Belousova, E Stabilization of molecular structure membranes of preserved rbcs by means nanotechnology. Ann Med & Surg Case Rep: AMSCR.,  2019, 2019(100001)

[42]
Bakhaidar, R.; O’Neill, S.; Ramtoola, Z. PLGA-PEG nanoparticles show minimal risks of interference with platelet function of human platelet-rich plasma. Int. J. Mol. Sci.,  2020, 21(24), 9716.
 [http://dx.doi.org/10.3390/ijms21249716] [PMID: 33352749]

[43]
Wang, W.; Xiong, W.; Zhu, Y.; Xu, H.; Yang, X. Protective effect of PEGylation against poly(amidoamine) dendrimer-induced hemolysis of human red blood cells. J. Biomed. Mater. Res. B Appl. Biomater.,  2010, 9999B(1), NA.
 [http://dx.doi.org/10.1002/jbm.b.31558] [PMID: 20186802]

[44]
Gholami, Z.; Hashemi Najafabadi, S.; Soleimani, M. Simultaneous camouflage of major and minor antigens on red blood cell surface with activated mPEGs. Iran. J. Biotechnol.,  2014, 12(2), 15-25.
 [http://dx.doi.org/10.5812/ijb.17776]

[45]
Scott, M.; Toyofuku, W.; Yang, X.; Raj, M.; Kang, N. Immunocamouflaged RBC for alloimmunized patients. In: Transfusion Medicine and Scientific Developments Croatia; INTECH, 2017; pp. 23-42.
 [http://dx.doi.org/10.5772/intechopen.68647]

[46]
Rzigalinski, B.A.; Giovinco, H.M.; Cheatham, B.J. Cerium oxide nanoparticles improve lifespan of stored blood. Mil. Med.,  2020, 185(S1), 103-109.
 [http://dx.doi.org/10.1093/milmed/usz210] [PMID: 32074312]

[47]
Webster, K.D.; Dahhan, D.; Otto, A.M.; Frosti, C.L.; Dean, W.L.; Chaires, J.B.; Olsen, K.W. “Inside-Out” PEGylation of bovine β-cross-linked hemoglobin. Artif. Organs,  2017, 41(4), 351-358.
 [http://dx.doi.org/10.1111/aor.12928] [PMID: 28321886]

[48]
Webster, K.D. Development of” inside-out” PEGylated crosslinked hemoglobin polymers: Novel hemoglobin-based oxygen carriers (HBOC); Loyola University Chicago, 2016. 

[49]
Wang, Q.; Sun, L.; Ji, S.; Zhao, D.; Liu, J.; Su, Z.; Hu, T. Reversible protection of Cys-93(β) by PEG alters the structural and functional properties of the PEGylated hemoglobin. Biochim. Biophys. Acta. Proteins Proteomics,  2014, 1844(7), 1201-1207.
 [http://dx.doi.org/10.1016/j.bbapap.2014.04.005] [PMID: 24747784]

[50]
Chapanian, R.; Constantinescu, I.; Rossi, N.A.A.; Medvedev, N.; Brooks, D.E.; Scott, M.D.; Kizhakkedathu, J.N. Influence of polymer architecture on antigens camouflage, CD47 protection and complement mediated lysis of surface grafted red blood cells. Biomaterials,  2012, 33(31), 7871-7883.
 [http://dx.doi.org/10.1016/j.biomaterials.2012.07.015] [PMID: 22840223]

[51]
Chapanian, R.; Constantinescu, I.; Medvedev, N.; Scott, M.D.; Brooks, D.E.; Kizhakkedathu, J.N. Therapeutic cells via functional modification: influence of molecular properties of polymer grafts on in vivo circulation, clearance, immunogenicity, and antigen protection. Biomacromolecules,  2013, 14(6), 2052-2062.
 [http://dx.doi.org/10.1021/bm4003943] [PMID: 23713758]

[52]
Wang, D.; Toyofuku, W.M.; Scott, M.D. The potential utility of methoxypoly(ethylene glycol)-mediated prevention of rhesus blood group antigen RhD recognition in transfusion medicine. Biomaterials,  2012, 33(10), 3002-3012.
 [http://dx.doi.org/10.1016/j.biomaterials.2011.12.041] [PMID: 22264524]

[53]
Leung, V.L.; Kizhakkedathu, J.N. The mechanism and modulation of complement activation on polymer grafted cells. Acta Biomater.,  2016, 31, 252-263.
 [http://dx.doi.org/10.1016/j.actbio.2015.11.022] [PMID: 26593783]

[54]
Brockman, E.C.; Jackson, T.C.; Dixon, C.E.; Bayɪr, H.; Clark, R.S.B.; Vagni, V.; Feldman, K.; Byrd, C.; Ma, L.; Hsia, C.; Kochanek, P.M. Polynitroxylated pegylated hemoglobin—a novel, small volume therapeutic for traumatic brain injury resuscitation: Comparison to whole blood and dose response evaluation. J. Neurotrauma,  2017, 34(7), 1337-1350.
 [http://dx.doi.org/10.1089/neu.2016.4656] [PMID: 27869558]

[55]
Moore, M.S.; Okelberry, E.; Cordingley, K.; Drake, A.; Robinett, Z. DePEGylation studies: PEG-RBC stability in conditions consistent with massive transfusion. Clin. Lab. Sci.,  2011, 24(4), 227-232.
 [http://dx.doi.org/10.29074/ascls.24.4.227] [PMID: 22288221]

[56]
Li, L.; Noumsi, G.T.; Kwok, Y.Y.E.; Moulds, J.M.; Scott, M.D. Inhibition of phagocytic recognition of anti-D opsonized Rh D+ RBC by polymer-mediated immunocamouflage. Am. J. Hematol.,  2015, 90(12), 1165-1170.
 [http://dx.doi.org/10.1002/ajh.24211] [PMID: 26440218]

[57]
Kyluik-Price, D.L.; Li, L.; Scott, M.D. Comparative efficacy of blood cell immunocamouflage by membrane grafting of methoxypoly(ethylene glycol) and polyethyloxazoline. Biomaterials,  2014, 35(1), 412-422.
 [http://dx.doi.org/10.1016/j.biomaterials.2013.09.016] [PMID: 24074839]

[58]
Chapanian, R.; Constantinescu, I.; Brooks, D.E.; Scott, M.D.; Kizhakkedathu, J.N. In vivo circulation, clearance, and biodistribution of polyglycerol grafted functional red blood cells. Biomaterials,  2012, 33(10), 3047-3057.
 [http://dx.doi.org/10.1016/j.biomaterials.2011.12.053] [PMID: 22261097]

[59]
Haghdoost, S.; Hashemi-Najafabadi, S.; Soleimani, M. Investigating the stability of polymer coating of methoxy polyethylene glycol activated by succinimidyl valerate on the surface of red blood cells under in vitro and in vivo conditions. Pathobiology Research.,  2015, 18(2), 13-26.

[60]
Zemlianskykh, N.G.; Babijchuk, L.A. The changes in erythrocyte Ca2+-ATPase activity induced by PEG-1500 and low temperatures. Cell Tissue Biol.,  2017, 11(2), 104-110.
 [http://dx.doi.org/10.1134/S1990519X17020109]

[61]
Abuchowski, A. PEGylated bovine carboxyhemoglobin (SANGUINATE™): results of clinical safety testing and use in patients. Oxygen transport to tissue XXXVII; Springer, 2016, pp. 461-467.

[62]
Romito, B.T.; McBroom, M.M.; Bryant, D.; Gamez, J.; Merchant, A.; Hill, S.E. The effect of SANGUINATE ® (PEGylated carboxyhemoglobin bovine) on cardiopulmonary bypass functionality using a bovine whole blood model of normovolemic hemodilution. Perfusion,  2020, 35(1), 19-25.
 [http://dx.doi.org/10.1177/0267659119850681] [PMID: 31144581]

[63]
Abuchowski, A. SANGUINATE (PEGylated carboxyhemoglobin bovine): Mechanism of action and clinical update. Artif. Organs,  2017, 41(4), 346-350.
 [http://dx.doi.org/10.1111/aor.12934] [PMID: 28397407]

[64]
Misra, H.; Bainbridge, J.; Berryman, J.; Abuchowski, A.; Galvez, K.M.; Uribe, L.F.; Hernandez, A.L.; Sosa, N.R. A Phase Ib open label, randomized, safety study of SANGUINATE™ in patients with sickle cell anemia. Rev. Bras. Hematol. Hemoter.,  2017, 39(1), 20-27.
 [http://dx.doi.org/10.1016/j.bjhh.2016.08.004] [PMID: 28270341]

[65]
Ananthakrishnan, R.; Li, Q.; O’Shea, K.M.; Quadri, N.; Wang, L.; Abuchowski, A.; Schmidt, A.M.; Ramasamy, R. Carbon monoxide form of PEGylated hemoglobin protects myocardium against ischemia/reperfusion injury in diabetic and normal mice. Artif. Cells Nanomed. Biotechnol.,  2013, 41(6), 428-436.
 [http://dx.doi.org/10.3109/21691401.2012.762370] [PMID: 23342967]

[66]
Buontempo, P.; Jubin, R.G.; Buontempo, C.; Real, R.; Kazo, F.; O’Brien, S. Pegylated carboxyhemoglobin bovine (SANGUINATE®) restores RBCs roundness and reduces pain during a sickle cell vaso-occlusive crisis; American Society of Hematology Washington: DC, 2017. 
 [http://dx.doi.org/10.1182/blood.V130.Suppl_1.969.969]

[67]
Nugent, W.H.; Cestero, R.F.; Ward, K.; Jubin, R.; Abuchowski, A.; Song, B.K. Effects of Sanguinate on systemic and microcirculatory variables in a model of prolonged hemorrhagic shock. Shock,  2019, 52(1S), 108-115.
 [http://dx.doi.org/10.1097/SHK.0000000000001082] [PMID: 29252939]

[68]
Wang, Q.; Hu, T.; Sun, L.; Ji, S.; Zhao, D.; Liu, J.; Ma, G.; Su, Z. CO binding improves the structural, functional, physical and antioxidation properties of the PEGylated hemoglobin. Artif. Cells Nanomed. Biotechnol.,  2015, 43(1), 18-25.
 [http://dx.doi.org/10.3109/21691401.2014.885444] [PMID: 24641771]

[69]
Cooper, C.E.; Silkstone, G.G.A.; Simons, M.; Gretton, S.; Rajagopal, B.S.; Allen-Baume, V.; Syrett, N.; Shaik, T.; Popa, G.; Sheng, X.; Bird, M.; Choi, J.W.; Piano, R.; Ronda, L.; Bettati, S.; Paredi, G.; Mozzarelli, A.; Reeder, B.J. Engineering hemoglobin to enable homogenous PEGylation without modifying protein functionality. Biomater. Sci.,  2020, 8(14), 3896-3906.
 [http://dx.doi.org/10.1039/C9BM01773A] [PMID: 32539053]

[70]
Matsuhira, T.; Kure, T.; Yamamoto, K.; Sakai, H. Analysis of dimeric αβ subunit exchange between pegylated and native hemoglobins (α 2 β 2 Tetramer) in an equilibrated state by intramolecular ββ-cross-linking. Biomacromolecules,  2018, 19(8), 3412-3420.
 [http://dx.doi.org/10.1021/acs.biomac.8b00728] [PMID: 29952544]

[71]
Meng, F.; Tsai, A.G.; Intaglietta, M.; Acharya, S.A. PEGylation of αα-Hb using succinimidyl propionic acid PEG 5K: Conjugation chemistry and PEG shell structure dictate respectively the oxygen affinity and resuscitation fluid like properties of PEG αα-Hbs. Artif. Cells Nanomed. Biotechnol.,  2015, 43(4), 270-281.
 [http://dx.doi.org/10.3109/21691401.2014.885443] [PMID: 24597567]

[72]
Hu, T.; Li, D.; Meng, F.; Prabhakaran, M.; Acharya, S.A. Increased inter dimeric interaction of oxy hemoglobin is necessary for attenuation of reductive pegylation promoted dissociation of tetramer. Artif. Cells Blood Substit. Immobil. Biotechnol.,  2011, 39(2), 69-78.
 [http://dx.doi.org/10.3109/10731199.2010.501756] [PMID: 20653337]

[73]
Coppola, D.; Bruno, S.; Ronda, L.; Viappiani, C.; Abbruzzetti, S.; di Prisco, G.; Verde, C.; Mozzarelli, A. Low affinity PEGylated hemoglobin from trematomus bernacchii, a model for hemoglobin-based blood substitutes. BMC Biochem.,  2011, 12(1), 66.
 [http://dx.doi.org/10.1186/1471-2091-12-66] [PMID: 22185675]

[74]
Kawaguchi, A.T.; Salybekov, A.A.; Yamano, M.; Kitagishi, H.; Sekine, K.; Tamaki, T. PEGylated carboxyhemoglobin bovine (SANGUINATE) ameliorates myocardial infarction in a rat model. Artif. Organs,  2018, 42(12), 1174-1184.
 [http://dx.doi.org/10.1111/aor.13384] [PMID: 30375680]

[75]
Wang, Y.; Wang, L.; Yu, W.; Gao, D.; You, G.; Li, P.; Zhang, S.; Zhang, J.; Hu, T.; Zhao, L.; Zhou, H. A PEGylated bovine hemoglobin as a potent hemoglobin-based oxygen carrier. Biotechnol. Prog.,  2017, 33(1), 252-260.
 [http://dx.doi.org/10.1002/btpr.2380] [PMID: 27696787]

[76]
Nalley, C.M.; Abuchowski, A.; Hsu, S.; Lanzkron, S. Successful Use of Pegylated Carboxyhemoglobin Bovine As an Emergency Treatment for Severe Anemia in a Patient with Sickle Cell Disease and Hyperhemolysis: A Case Report; American Society of Hematology Washington: DC, 2014. 
 [http://dx.doi.org/10.1182/blood.V124.21.4928.4928]

[77]
Zhang, L.; Wang, X.; Qi, D. The study of terminated PEG maleimide synthesis and modification of hemoglobin. Proceedings of the 2nd International Conference on Electronic & Mechanical Engineering and Information Technology (EMEIT 2012),  2012, pp. 1951-6851.
 [http://dx.doi.org/10.2991/emeit.2012.222]

[78]
Cao, S.; Zhang, J.; Ma, L.; Hsia, C.J.C.; Koehler, R.C. Transfusion of polynitroxylated pegylated hemoglobin stabilizes pial arterial dilation and decreases infarct volume after transient middle cerebral artery occlusion. J. Am. Heart Assoc.,  2017, 6(9), e006505.
 [http://dx.doi.org/10.1161/JAHA.117.006505] [PMID: 28899897]

[79]
Shellington, D.K.; Du, L.; Wu, X.; Exo, J.; Vagni, V.; Ma, L.; Janesko-Feldman, K.; Clark, R.S.B.; Bayir, H.; Dixon, C.E.; Jenkins, L.W.; Hsia, C.J.C.; Kochanek, P.M. Polynitroxylated pegylated hemoglobin: A novel neuroprotective hemoglobin for acute volume-limited fluid resuscitation after combined traumatic brain injury and hemorrhagic hypotension in mice. Crit. Care Med.,  2011, 39(3), 494-505.
 [http://dx.doi.org/10.1097/CCM.0b013e318206b1fa] [PMID: 21169820]

[80]
Brockman, E.C.; Bayir, H.; Blasiole, B.; Shein, S.L.; Fink, E.L.; Dixon, C.E.; Clark, R.S.B.; Vagni, V.A.; Ma, L.; Hsia, C.J.C.; Tisherman, S.A.; Kochanek, P.M. Polynitroxylated-pegylated hemoglobin attenuates fluid requirements and brain edema in combined traumatic brain injury plus hemorrhagic shock in mice. J. Cereb. Blood Flow Metab.,  2013, 33(9), 1457-1464.
 [http://dx.doi.org/10.1038/jcbfm.2013.104] [PMID: 23801241]

[81]
Akbarzadehlaleh, P.; Mirzaei, M.; Mashahdi-keshtiban, M.; Heidari, H.R. The effect of length and structure of attached polyethylene glycol chain on hydrodynamic radius, and separation of pegylated human serum albumin by chromatography. Adv. Pharm. Bull.,  2020, 11(4), 728-738.
 [http://dx.doi.org/10.34172/apb.2021.082] [PMID: 34888220]

[82]
Plesner, B.; Fee, C.J.; Westh, P.; Nielsen, A.D. Effects of PEG size on structure, function and stability of PEGylated BSA. Eur. J. Pharm. Biopharm.,  2011, 79(2), 399-405.
 [http://dx.doi.org/10.1016/j.ejpb.2011.05.003] [PMID: 21620970]

[83]
Zhao, T.; Yang, Y.; Zong, A.; Tan, H.; Song, X.; Meng, S.; Song, C.; Pang, G.; Wang, F. N-terminal PEGylation of human serum albumin and investigation of its pharmacokinetics and pulmonary microvascular retention. Biosci. Trends,  2012, 6(2), 81-88.
 [http://dx.doi.org/10.5582/bst.2012.v6.2.81] [PMID: 22621990]

[84]
Akbarzadehlaleh, P.; Mirzaei, M.; Mashahdi-Keshtiban, M.; Shamsasenjan, K.; Heydari, H. PEGylated human serum albumin: Review of PEGylation, purification and characterization methods. Adv. Pharm. Bull.,  2016, 6(3), 309-317.
 [http://dx.doi.org/10.15171/apb.2016.043] [PMID: 27766215]

[85]
Yu, M.; Ding, Z.; Jiang, F.; Ding, X.; Sun, J.; Chen, S.; Lv, G. Analysis of binding interaction between pegylated puerarin and bovine serum albumin by spectroscopic methods and dynamic light scattering. Spectrochim. Acta A Mol. Biomol. Spectrosc.,  2011, 83(1), 453-460.
 [http://dx.doi.org/10.1016/j.saa.2011.08.065] [PMID: 21945127]

[86]
Hightower, C.M.; Salazar Vázquez, B.Y.; Cabrales, P.; Tsai, A.G.; Acharya, S.A.; Intaglietta, M. Plasma expander and blood storage effects on capillary perfusion in transfusion after hemorrhage. Transfusion,  2013, 53(1), 49-59.
 [http://dx.doi.org/10.1111/j.1537-2995.2012.03679.x] [PMID: 22554380]

[87]
Hill, JA. Characterization of Multi-Albumin Pegylated Complexes Synthesized Using" Click" Chemistry as Drug Delivery Systems; Loyola University Chicago, 2017. 

[88]
Samanta, N.; Mahanta, D.D.; Hazra, S.; Kumar, G.S.; Mitra, R.K. Short chain polyethylene glycols unusually assist thermal unfolding of human serum albumin. Biochimie,  2014, 104, 81-89.
 [http://dx.doi.org/10.1016/j.biochi.2014.05.009] [PMID: 24911290]

[89]
Hoorang, M.; Tamaddon, A.; Yousefi, G. Synthesis of PEGylated human serum albumin by maleimide-thiol chemistry and histopathological evaluation in a mice model of carrageenan-induced inflammation. Trends Pharmacol. Sci.,  2019, 5(1), 47-56.

[90]
Zhao, T.; Cheng, Y.N.; Tan, H.N.; Liu, J.F.; Xu, H.L.; Pang, G.L.; Wang, F.S. Site-specific chemical modification of human serum albumin with polyethylene glycol prolongs half-life and improves intravascular retention in mice. Biol. Pharm. Bull.,  2012, 35(3), 280-288.
 [http://dx.doi.org/10.1248/bpb.35.280] [PMID: 22382312]

[91]
Sriram, K.; Tsai, A.G.; Cabrales, P.; Meng, F.; Acharya, S.A.; Tartakovsky, D.M.; Intaglietta, M. PEG-albumin supraplasma expansion is due to increased vessel wall shear stress induced by blood viscosity shear thinning. Am. J. Physiol. Heart Circ. Physiol.,  2012, 302(12), H2489-H2497.
 [http://dx.doi.org/10.1152/ajpheart.01090.2011] [PMID: 22505638]

[92]
Chatpun, S.; Cabrales, P. Effects on cardiac function of a novel low viscosity plasma expander based on polyethylene glycol conjugated albumin. Minerva Anestesiol.,  2011, 77(7), 704-714.
 [PMID: 21709658]

[93]
Acharya, S.A.; Intaglietta, M. Method of enhancing efficacy of blood transfusions. Patent US9498537B2, 2014.

[94]
Chatpun, S.; Nacharaju, P.; Cabrales, P. Improving cardiac function with new-generation plasma volume expanders. Am. J. Emerg. Med.,  2013, 31(1), 54-63.
 [http://dx.doi.org/10.1016/j.ajem.2012.05.031] [PMID: 22867830]

[95]
Ananda, K.; Manjula, B.N.; Meng, F.; Acharya, V.N.; Intaglietta, M.; Acharya, S.A. Packing density of the PEG-shell in PEG-albumins: PEGylation induced viscosity and COP are inverse correlate of packing density. Artif. Cells Blood Substit. Immobil. Biotechnol.,  2012, 40(1-2), 14-27.
 [http://dx.doi.org/10.3109/10731199.2011.579568] [PMID: 21623695]

[96]
Munasinghe, A.; Mathavan, A.; Mathavan, A.; Lin, P.; Colina, C.M. Atomistic insight towards the impact of polymer architecture and grafting density on structure-dynamics of PEGylated bovine serum albumin and their applications. J. Chem. Phys.,  2021, 154(7), 075101.
 [http://dx.doi.org/10.1063/5.0038306] [PMID: 33607915]

[97]
Munasinghe, A.; Mathavan, A.; Mathavan, A.; Lin, P.; Colina, C.M. Molecular insight into the protein–polymer interactions in N-terminal PEGylated bovine serum albumin. J. Phys. Chem. B,  2019, 123(25), 5196-5205.
 [http://dx.doi.org/10.1021/acs.jpcb.8b12268] [PMID: 30939013]

[98]
Di Minno, M.N.D.; Di Minno, A.; Calcaterra, I.; Cimino, E.; Dell’Aquila, F.; Franchini, M. Eds. Enhanced half-life recombinant factor VIII concentrates for hemophilia A: insights from pivotal and extension studies. Seminars in Thrombosis and Hemostasis; Thieme Medical Publishers, Inc., 2020. 

[99]
Pastoft, A.E.; Ezban, M.; Tranholm, M.; Lykkesfeldt, J.; Lauritzen, B. Prolonged effect of a new O-glycoPEGylated FVIII (N8-GP) in a murine saphenous vein bleeding model. Haemophilia,  2013, 19(6), 913-919.
 [http://dx.doi.org/10.1111/hae.12198] [PMID: 23730746]

[100]
Stennicke, H.R.; Kjalke, M.; Karpf, D.M.; Balling, K.W.; Johansen, P.B.; Elm, T.; Øvlisen, K.; Möller, F.; Holmberg, H.L.; Gudme, C.N.; Persson, E.; Hilden, I.; Pelzer, H.; Rahbek-Nielsen, H.; Jespersgaard, C.; Bogsnes, A.; Pedersen, A.A.; Kristensen, A.K.; Peschke, B.; Kappers, W.; Rode, F.; Thim, L.; Tranholm, M.; Ezban, M.; Olsen, E.H.N.; Bjørn, S.E. A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models. Blood,  2013, 121(11), 2108-2116.
 [http://dx.doi.org/10.1182/blood-2012-01-407494] [PMID: 23335368]

[101]
Tiede, A.; Brand, B.; Fischer, R.; Kavakli, K.; Lentz, S.R.; Matsushita, T.; Rea, C.; Knobe, K.; Viuff, D. Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J. Thromb. Haemost.,  2013, 11(4), 670-678.
 [http://dx.doi.org/10.1111/jth.12161] [PMID: 23398640]

[102]
Rasmussen, C.E.; Nowak, J.; Larsen, J.M.; Moore, E.; Bell, D.; Liu, K.C. Long-term safety of PEGylated coagulation factor VIII in the immune-deficient Rowett nude rat. J. Toxicol.,  2017, 2017, 8496246.
 [http://dx.doi.org/10.1155/2017/8496246]

[103]
Hampton, K.; Chowdary, P.; Dunkley, S.; Ehrenforth, S.; Jacobsen, L.; Neff, A.; Santagostino, E.; Sathar, J.; Takedani, H.; Takemoto, C.M.; Négrier, C. First report on the safety and efficacy of an extended half-life glycoPEGylated recombinant FVIII for major surgery in severe haemophilia A. Haemophilia,  2017, 23(5), 689-696.
 [http://dx.doi.org/10.1111/hae.13246] [PMID: 28470862]

[104]
Chowdary, P. N8‐GP: A new extended half‐life recombinant factor VIII product for hemophilia A; Wiley Online Library, 2020. 

[105]
Giangrande, P.; Andreeva, T.; Chowdary, P.; Ehrenforth, S.; Hanabusa, H.; Leebeek, F.W.G.; Lentz, S.R.; Nemes, L.; Poulsen, L.H.; Santagostino, E.; You, C.W.; Ong Clausen, W.H.; Jönsson, P.G.; Oldenburg, J. Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A. Thromb. Haemost.,  2017, 117(2), 252-261.
 [http://dx.doi.org/10.1160/TH16-06-0444] [PMID: 27904904]

[106]
Meunier, S.; Alamelu, J.; Ehrenforth, S.; Hanabusa, H.; Karim, F.A.; Kavakli, K.; Khodaie, M.; Staber, J.; Stasyshyn, O.; Yee, D.; Rageliene, L. Safety and efficacy of a glycoPEGylated rFVIII (turoctocog alpha pegol, N8-GP) in paediatric patients with severe haemophilia A. Thromb. Haemost.,  2017, 117(9), 1705-1713.
 [http://dx.doi.org/10.1160/TH17-03-0166] [PMID: 28692108]

[107]
Rode, F.; Almholt, K.; Petersen, M.; Kreilgaard, M.; Kjalke, M.; Karpf, D.M.; Groth, A.V.; Johansen, P.B.; Larsen, L.F.; Loftager, M.; Haaning, J. Preclinical pharmacokinetics and biodistribution of subcutaneously administered glycoPEGylated recombinant factor VIII (N8‐GP) and development of a human pharmacokinetic prediction model. J. Thromb. Haemost.,  2018, 16(6), 1141-1152.
 [http://dx.doi.org/10.1111/jth.14013] [PMID: 29582559]

[108]
Ivens, I.A.; Banczyk, D.; Gutberlet, K.; Jackman, S.; Vauléon, S.; Frisk, A.L. Nonclinical safety assessment of a long-acting recombinant PEGylated factor eight (BAY 94-9027) with a 60 kDa PEG. Toxicol. Pathol.,  2019, 47(5), 585-597.
 [http://dx.doi.org/10.1177/0192623319852300] [PMID: 31132933]

[109]
Solms, A.; Shah, A.; Berntorp, E.; Tiede, A.; Iorio, A.; Linardi, C.; Ahsman, M.; Mancuso, M.E.; Zhivkov, T.; Lissitchkov, T. Direct comparison of two extended half-life PEGylated recombinant FVIII products: A randomized, crossover pharmacokinetic study in patients with severe hemophilia A. Ann. Hematol.,  2020, 99(11), 2689-2698.
 [http://dx.doi.org/10.1007/s00277-020-04280-3] [PMID: 32974838]

[110]
Santagostino, E.; Kenet, G.; Fischer, K.; Biss, T.; Ahuja, S.; Steele, M.; Martínez, M.; Male, C.; van Geet, C.; Mondelaers, V.; Kaleva, V.; Stoyanova-Deleva, A.; Bobev, D.; Blanchette, V.; Zanon, E.; Gagliano, F.; Rageliene, L.; Peters, M.; Mlynarski, W.; Badowska, W.; Serban, M.; Rusen, L.; Uscatescu, V.; Will, A.; Payne, J.; Tunstall, O.; Kerlin, B.; Gruppo, R.; Eyster, M.E.; Ducore, J.; Schwartz, J. PROTECT VIII kids: BAY 94‐9027 (PEGylated recombinant factor VIII) safety and efficacy in previously treated children with severe haemophilia A. Haemophilia,  2020, 26(3), e55-e65.
 [http://dx.doi.org/10.1111/hae.13963] [PMID: 32212300]

[111]
Mullins, E.S.; Stasyshyn, O.; Alvarez-Román, M.T.; Osman, D.; Liesner, R.; Engl, W.; Sharkhawy, M.; Abbuehl, B.E. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia,  2017, 23(2), 238-246.
 [http://dx.doi.org/10.1111/hae.13119] [PMID: 27891721]

[112]
Konkle, B.A.; Stasyshyn, O.; Chowdary, P.; Bevan, D.H.; Mant, T.; Shima, M.; Engl, W.; Dyck-Jones, J.; Fuerlinger, M.; Patrone, L.; Ewenstein, B.; Abbuehl, B. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood,  2015, 126(9), 1078-1085.
 [http://dx.doi.org/10.1182/blood-2015-03-630897] [PMID: 26157075]

[113]
Schermeyer, M-T.; Wöll, A.K.; Kokke, B.; Eppink, M.; Hubbuch, J. Eds. Characterization of highly concentrated antibody solution-A toolbox for the description of protein long-term solution stability. MAbs; Taylor & Francis, 2017. 

[114]
Heywood, S.P.; Humphreys, D.P. Polymer Fusions to Increase Antibody Half-Lives: PEGylation and Other Modifications; Recombinant Antibodies for Immunotherapy, 2009, p. 275.

[115]
Pasut, G. Pegylation of biological molecules and potential benefits: pharmacological properties of certolizumab pegol. BioDrugs,  2014, 28(S1), 15-23.
 [http://dx.doi.org/10.1007/s40259-013-0064-z] [PMID: 24687235]

[116]
Jevševar, S.; Kusterle, M.; Kenig, M. PEGylation of antibody fragments for half-life extension. Antibody methods and protocols; Springer, 2012, pp. 233-246.

[117]
Toprani, V.M.; Joshi, S.B.; Kueltzo, L.A.; Schwartz, R.M.; Middaugh, C.R.; Volkin, D.B. A micro–polyethylene glycol precipitation assay as a relative solubility screening tool for monoclonal antibody design and formulation development. J. Pharm. Sci.,  2016, 105(8), 2319-2327.
 [http://dx.doi.org/10.1016/j.xphs.2016.05.021] [PMID: 27368120]

[118]
Lee, W.; Bobba, K.N.; Kim, J.Y.; Park, H.; Bhise, A.; Kim, W.; Lee, K.; Rajkumar, S.; Nam, B.; Lee, K.C.; Lee, S.H.; Ko, S.; Lee, H.J.; Jung, S.T.; Yoo, J. A short PEG linker alters the in vivo pharmacokinetics of trastuzumab to yield high-contrast immuno-PET images. J. Mater. Chem. B Mater. Biol. Med.,  2021, 9(13), 2993-2997.
 [http://dx.doi.org/10.1039/D0TB02911D] [PMID: 33725072]

[119]
Wälchli, R.; Fanizzi, F.; Massant, J.; Arosio, P. Relationship of PEG-induced precipitation with protein-protein interactions and aggregation rates of high concentration mAb formulations at 5°C. Eur. J. Pharm. Biopharm.,  2020, 151, 53-60.
 [http://dx.doi.org/10.1016/j.ejpb.2020.03.011] [PMID: 32197816]

[120]
Satzer, P.; Burgstaller, D.; Krepper, W.; Jungbauer, A. Fractal dimension of antibody‐PEG precipitate: Light microscopy for the reconstruction of 3D precipitate structures. Eng. Life Sci.,  2020, 20(3-4), 67-78.
 [http://dx.doi.org/10.1002/elsc.201900110] [PMID: 32874171]

[121]
Chan, L.J.; Ascher, D.B.; Yadav, R.; Bulitta, J.B.; Williams, C.C.; Porter, C.J.H.; Landersdorfer, C.B.; Kaminskas, L.M. Conjugation of 10 kDa linear PEG onto trastuzumab Fab′ is sufficient to significantly enhance lymphatic exposure while preserving in vitro biological activity. Mol. Pharm.,  2016, 13(4), 1229-1241.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.5b00749] [PMID: 26871003]

[122]
Kholodenko, I.V.; Kalinovsky, D.V.; Svirshchevskaya, E.V.; Doronin, I.I.; Konovalova, M.V.; Kibardin, A.V.; Shamanskaya, T.V.; Larin, S.S.; Deyev, S.M.; Kholodenko, R.V. Multimerization through pegylation improves pharmacokinetic properties of scFv fragments of GD2-specific antibodies. Molecules,  2019, 24(21), 3835.
 [http://dx.doi.org/10.3390/molecules24213835] [PMID: 31653037]

[123]
Koussoroplis, S.J.; Paulissen, G.; Tyteca, D.; Goldansaz, H.; Todoroff, J.; Barilly, C.; Uyttenhove, C.; Van Snick, J.; Cataldo, D.; Vanbever, R. PEGylation of antibody fragments greatly increases their local residence time following delivery to the respiratory tract. J. Control. Release,  2014, 187, 91-100.
 [http://dx.doi.org/10.1016/j.jconrel.2014.05.021] [PMID: 24845126]

[124]
Reichard, E.E.; Nanaware-Kharade, N.; Gonzalez, G.A., III; Thakkar, S.; Owens, S.M.; Peterson, E.C. PEGylation of a high-affinity anti-(+) methamphetamine single chain antibody fragment extends functional half-life by reducing clearance. Pharm. Res.,  2016, 33(12), 2954-2966.
 [http://dx.doi.org/10.1007/s11095-016-2017-y] [PMID: 27620175]

[125]
Patil, H.P.; Freches, D.; Karmani, L.; Duncan, G.A.; Ucakar, B.; Suk, J.S.; Hanes, J.; Gallez, B.; Vanbever, R. Fate of PEGylated antibody fragments following delivery to the lungs: Influence of delivery site, PEG size and lung inflammation. J. Control. Release,  2018, 272, 62-71.
 [http://dx.doi.org/10.1016/j.jconrel.2017.12.009] [PMID: 29247664]

[126]
Storage stability studies of anti-VEGF FpF antibody mimetics. Khalili, H.; Brocchini, S.; Khaw, P.T.; Filippov, S., Eds.; 2016 AAPS Annual Meeting and Exposition, 2016.

[127]
Davarpanah, F.; Khalili Yazdi, A.; Barani, M.; Mirzaei, M.; Torkzadeh-Mahani, M. Magnetic delivery of antitumor carboplatin by using PEGylated-Niosomes. Daru,  2018, 26(1), 57-64.
 [http://dx.doi.org/10.1007/s40199-018-0215-3] [PMID: 30209759]

[128]
Howard, C.B.; Fletcher, N.; Houston, Z.H.; Fuchs, A.V.; Boase, N.R.B.; Simpson, J.D.; Raftery, L.J.; Ruder, T.; Jones, M.L.; de Bakker, C.J.; Mahler, S.M.; Thurecht, K.J. Overcoming instability of antibody‐nanomaterial conjugates: Next generation targeted nanomedicines using bispecific antibodies. Adv. Healthc. Mater.,  2016, 5(16), 2055-2068.
 [http://dx.doi.org/10.1002/adhm.201600263] [PMID: 27283923]

[129]
Selis, F.; Focà, G.; Sandomenico, A.; Marra, C.; Di Mauro, C.; Saccani Jotti, G.; Scaramuzza, S.; Politano, A.; Sanna, R.; Ruvo, M.; Tonon, G. Pegylated trastuzumab fragments acquire an increased in vivo stability but show a largely reduced affinity for the target antigen. Int. J. Mol. Sci.,  2016, 17(4), 491.
 [http://dx.doi.org/10.3390/ijms17040491] [PMID: 27043557]

[130]
Kim, S-H.; Lee, Y-S.; Hwang, S-Y.; Bae, G-W.; Nho, K.; Kang, SW.; Kwak, Y.G.; Moon, C.S.; Han, Y.S.; Kim, T.Y.; Kho, W.G. Effects of PEGylated scFv antibodies against Plasmodium vivax duffy binding protein on the biological activity and stability in vitro. J. Microbiol. Biotechnol.,  2007, 17(10), 1670-1674.
 [PMID: 18156783]

[131]
Freches, D.; Patil, H.P.; Machado Franco, M.; Uyttenhove, C.; Heywood, S.; Vanbever, R. PEGylation prolongs the pulmonary retention of an anti-IL-17A Fab’ antibody fragment after pulmonary delivery in three different species. Int. J. Pharm.,  2017, 521(1-2), 120-129.
 [http://dx.doi.org/10.1016/j.ijpharm.2017.02.021] [PMID: 28192159]
Cite As
Current Pharmaceutical Biotechnology

Pegylation, a Successful Strategy to Address the Storage and Instability Problems of Blood Products: Review 2011-2021

Abstract

Graphical Abstract
