PEGylated nanomedicines: Recent progress and remaining concerns

Expert Opinion on Drug Delivery

Volumn 11, Issue 1, 2014, Pages 139-154

  Vllasaliu, Driton ^a   Fowler, Robyn ^b   Stolnik, Snow ^c  

^a UNIVERSITY OF LINCOLN   (United Kingdom)

^b GfK   (United Kingdom)

^c UNIVERSITY OF NOTTINGHAM   (United Kingdom)

Author keywords

Drug delivery; Liposomes; Nanomedicines; Nanoparticles; PEGylated nanomedicines; Polyethylene glycol

Indexed keywords

DOXORUBICIN; MACROGOL; NANOCARRIER; POLY(ALKYL 2 CYANOACRYLATE); POLYACRYLIC ACID; POLYCAPROLACTONE; POLYETHYLENEIMINE; POLYGLACTIN; POLYGLYCOLIC ACID; POLYLACTIDE; POLYMER; UNCLASSIFIED DRUG; DRUG; DRUG CARRIER; MACROGOL DERIVATIVE; NANOMATERIAL;

DRUG BINDING; DRUG DELIVERY SYSTEM; DRUG FORMULATION; DRUG SAFETY; DRUG TARGETING; HUMAN; LIPOSOMAL DELIVERY; NANOMEDICINE; PROTEIN PROTEIN INTERACTION; RETICULOENDOTHELIAL SYSTEM; REVIEW; ANIMAL; CHEMISTRY;

ANIMALS; DRUG CARRIERS; HUMANS; NANOSTRUCTURES; PHARMACEUTICAL PREPARATIONS; POLYETHYLENE GLYCOLS;

EID: 84890677997     PISSN: 17425247     EISSN: 17447593     Source Type: Journal    
DOI: 10.1517/17425247.2014.866651     Document Type: Review

References (179)

1. Bind Therapeutics. Available from: Http://bindtherapeutics.com/ newsevents/ releases/2013 0403 BINDPfizer.html [Cited 02 July 2013
2. Etheridge ML, Campbell SA, Erdman AG, et al. The big picture on nanomedicine: The state of investigational and approved nanomedicine products. Nanomedicine 2013;9:1-14
3. Maeda H, Wu J, Sawa T, et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review. J Control Release 2000;65:271-84
4. Brannon-Peppas L, Blanchette JO. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 2004;56:1649-59
5. Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 2010;7:653-64
6. Kamaly N, Fredman G, Subramanian M, et al. Development and in vivo efficacy of targeted polymeric inflammationresolving nanoparticles. Proc Natl Acad Sci USA 2013;110:6506-11
7. Radovic-Moreno AF, Lu TK, Puscasu VA, et al. Surface chargeswitching polymeric nanoparticles for bacterial cell wall-Targeted delivery of antibiotics. ACS Nano 2012;6:4279-87
8. Lammers T, Aime S, Hennink WE, et al. Theranostic nanomedicine. Acc Chem Res 2011;44:1029-38
9. Medicines in Development: Biotechnology: Pharmaceutical Research and Manufacturers of America; 2013
10. Vllasaliu D, Casettari L, Fowler R, et al. Absorption-promoting effects of chitosan in airway and intestinal cell lines: A comparative study. Int J Pharm 2012;430:151-60
11. Vllasaliu D, Shubber S, Garnett M, et al. Evaluation of calcium depletion as a strategy for enhancement of mucosal absorption of macromolecules. Biochem Biophys Res Commun 2012;418:128-33
12. Davis FF. Commentary -The origin of pegnology. Adv Drug Deliv Rev 2002;54:457-8
13. Davis ME, Chen ZG, Shin DM. Nanoparticle therapeutics: An emerging treatment modality for cancer. Nat Rev Drug Discov 2008;7:771-82
14. Kamaly N, Xiao Z, Valencia PM, et al. Targeted polymeric therapeutic nanoparticles: Design, development and clinical translation. Chem Soc Rev 2012;41:2971-3010
15. Hughes JA, Rao GA. Targeted polymers for gene delivery. Expert Opin Drug Deliv 2005;2:145-57
16. Salazar MD, Ratnam M. The folate receptor: What does it promise in tissuetargeted therapeutics? Cancer Metastasis Rev 2007;26:141-52
17. Mehra NK, Mishra V, Jain NK. Receptor-based targeting of therapeutics. Ther Deliv 2013;4:369-94
18. Sudimack J, Lee RJ. Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev 2000;41:147-62
19. Leamon CP, Reddy JA. Folate-Targeted chemotherapy. Adv Drug Deliv Rev 2004;56:1127-41
20. Daniels TR, Bernabeu E, Rodriguez JA, et al. The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim Biophys Acta 2012;1820:291-317
21. Allen TM. Ligand-Targeted therapeutics in anticancer therapy. Nat Rev Cancer 2002;2:750-63
22. Weaver M, Laske DW. Transferrin receptor ligand-Targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J Neurooncol 2003;65:3-13
23. Xu L, Pirollo KF, Tang WH, et al. Transferrin-liposome-mediated systemic p53 gene therapy in combination with radiation results in regression of human head and neck cancer xenografts. Hum Gene Ther 1999;10:2941-52
24. Cheng J, Teply BA, Sherifi I, et al. Formulation of functionalized PLGAPEG nanoparticles for in vivo targeted drug delivery. Biomaterials 2007;28:869-76
25. McNamara JO II, Andrechek ER, Wang Y, et al. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol 2006;24:1005-15
26. Gu F, Zhang L, Teply BA, et al. Precise engineering of targeted nanoparticles by using self-Assembled biointegrated block copolymers. Proc Natl Acad Sci USA 2008;105:2586-91
27. Mackowiak SA, Schmidt A, Weiss V, et al. Targeted drug delivery in cancer cells with red-light photoactivated mesoporous silica nanoparticles. Nano Lett 2013;13:2576-83
28. Sadhukha T, Wiedmann TS, Panyam J. Inhalable magnetic nanoparticles for targeted hyperthermia in lung cancer therapy. Biomaterials 2013;34:5163-71
29. Master A, Malamas A, Solanki R, et al. A cell-Targeted photodynamic nanomedicine strategy for head and neck cancers. Mol Pharm 2013;10:1988-97
30. Wang Y, Liu P, Du J, et al. Targeted siRNA delivery by anti-HER2 antibodymodified nanoparticles of mPEGchitosan diblock copolymer. J Biomater Sci Polym Ed 2013;24:1219-32
31. Kolhar P, Anselmo AC, Gupta V, et al. Using shape effects to target antibodycoated nanoparticles to lung and brain endothelium. Proc Natl Acad Sci USA 2013;110:10753-8
32. Bai F, Wang C, Lu Q, et al. Nanoparticle-mediated drug delivery to tumor neovasculature to combat P-gp expressing multidrug resistant cancer. Biomaterials 2013;34:6163-74
33. Shahin M, Soudy R, El-Sikhry H, et al. Engineered peptides for the development of actively tumor targeted liposomal carriers of doxorubicin. Cancer Lett 2013;334:284-92
34. Koivistoinen A, Ilonen II, Punakivi K, et al. A novel peptide (Thx) homing to non-small cell lung cancer identified by ex vivo phage display. Clin Transl Oncol 2013;15:492-8
35. Sa LT, Simmons S, Missailidis S, et al. Aptamer-based nanoparticles for cancer targeting. J Drug Target 2013;21:427-34
36. Xiao ZY, Levy-Nissenbaum E, Alexis F, et al. Engineering of targeted nanoparticles for cancer therapy using internalizing aptamers isolated by cell-uptake selection. ACS Nano 2012;6:696-704
37. Li ZH, Liu Z, Yin ML, et al. Aptamer-capped multifunctional mesoporous strontium hydroxyapatite nanovehicle for cancer-cell-responsive drug delivery and imaging. Biomacromolecules 2012;13:4257-63
38. Vllasaliu D, Casettari L, Bonacucina G, et al. Folic acid conjugated chitosan nanoparticles for tumor targeting of therapeutic and imaging agents. Pharm Nanotechnol 2013;1:184-203
39. Wang S, Low PS. Folate-mediated targeting of antineoplastic drugs, imaging agents, and nucleic acids to cancer cells. J Control Release 1998;53:39-48
40. Stella B, Arpicco S, Peracchia MT, et al. Design of folic acid-conjugated nanoparticles for drug targeting. J Pharm Sci 2000;89:1452-64
41. Quintana A, Raczka E, Piehler L, et al. Design and function of a dendrimerbased therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm Res 2002;19:1310-16
42. Saeed AO, Magnusson JP, Moradi E, et al. Modular construction of multifunctional bioresponsive celltargeted nanoparticles for gene delivery. Bioconjug Chem 2011;22:156-68
43. Lu Y, Low PS. Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv Drug Deliv Rev 2002;54:675-93
44. Lee D, Lockey R, Mohapatra S. Folate receptor-mediated cancer cell specific gene delivery using folic acid-conjugated oligochitosans. J Nanosci Nanotechnol 2006;6:2860-6
45. Torchilin VP. Multifunctional nanocarriers. Adv Drug Deliv Rev 2006;58:1532-55
46. Lu Y, Sega E, Leamon CP, Low PS. Folate receptor-Targeted immunotherapy of cancer: Mechanism and therapeutic potential. Adv Drug Deliv Rev 2004;56:1161-76
47. Pan D, Turner JL, Wooley KL. Folic acid-conjugated nanostructured materials designed for cancer cell targeting. Chem Commun 2003;9:2400-1
48. Sudimack J, Lee RJ. Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev 2000;41:147-62
49. Xia W, Low PS. Folate-Targeted therapies for cancer. J Med Chem 2010;53:6811-24
50. Park TG, Yoo HS. Folate receptor targeted biodegradable polymeric doxorubicin micelles. J Control Release 2004;96:273-83
51. Choi H, Sr C, Zhou R, et al. Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor-Targeted delivery. Acad Radiol 2004;11:996-1004
52. Dixit V, Van den Bossche J, Sherman DM, et al. Synthesis and grafting of thioctic acid-PEG-folate conjugates onto Au nanoparticles for selective targeting of folate receptorpositive tumor cells. Bioconjug Chem 2006;17:603-9
53. Oyewumi MO, Mumper RJ. Influence of formulation parameters on gadolinium entrapment and tumor cell uptake using folate-coated nanoparticles. Int J Pharm 2003;251:85-97
54. Jing XB, Lu TC, Sun J, et al. Folate-conjugated micelles and their folate-receptor-mediated endocytosis. Macromol Biosci 2009;9:1059-68
55. Kelemen LE. The role of folate receptor alpha in cancer development, progression and treatment: Cause, consequence or innocent bystander? Int J Cancer 2006;119:243-50
56. Lam JK, Armes SP, Lewis AL, Stolnik S. Folate conjugated phosphorylcholinebased polycations for specific targeting in nucleic acids delivery. J Drug Target 2009;17:512-23
57. Low PS, Antony AC. Folate receptortargeted drugs for cancer and inflammatory diseases -Preface. Adv Drug Deliv Rev 2004;56:1055-8
58. Yang DC, Wang F, Elliott RL, Head JF. Expression of transferrin receptor and ferritin H-chain mRNA are associated with clinical and histopathological prognostic indicators in breast cancer. Anticancer Res 2001;21:541-9
59. Prior R, Reifenberger G, Wechsler W. Transferrin receptor expression in tumours of the human nervous system: Relation to tumour type, grading and tumour growth fraction. Virchows Arch A Pathol Anat Histopathol 1990;416:491-6
60. Das Gupta A, Shah VI. Correlation of transferrin receptor expression with histologic grade and immunophenotype in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Hematol Pathol 1990;4:37-41
61. Habeshaw JA, Lister TA, Stansfeld AG, Greaves MF. Correlation of transferrin receptor expression with histological class and outcome in non-Hodgkin lymphoma. Lancet 1983;1:498-501
62. Kondo K, Noguchi M, Mukai K, et al. Transferrin receptor expression in adenocarcinoma of the lung as a histopathologic indicator of prognosis. Chest 1990;97:1367-71
63. Seymour GJ, Walsh MD, Lavin MF, et al. Transferrin receptor expression by human bladder transitional cell carcinomas. Urol Res 1987;15:341-4
64. Ciechanover A, Schwartz AL, Lodish HF. Sorting and recycling of cell surface receptors and endocytosed ligands: The asialoglycoprotein and transferrin receptors. J Cell Biochem 1983;23:107-30
65. Fowler R, Vllasaliu D, Trillo FF, et al. Nanoparticle transport in epithelial cells: Pathway switching through bioconjugation. Small 2013;9:3282-94
66. Davis ME, Zuckerman JE, Choi CH, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010;464:1067-70
67. Peer D, Karp JM, Hong S, et al. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2007;2:751-60
68. Ferrari M. Cancer nanotechnology: Opportunities and challenges. Nat Rev Cancer 2005;5:161-71
69. Riehemann K, Schneider SW, Luger TA, et al. Nanomedicine-challenge and perspectives. Angew Chem Int Ed Engl 2009;48:872-97
70. Moghimi SM, Hunter AC, Murray JC. Nanomedicine: Current status and future prospects. FASEB J 2005;19:311-30
71. Stolnik S, Illum L, Davis SS. Long circulating microparticulate drug carriers. Adv Drug Deliv Rev 1995;16:195-214
72. Saba TM. Physiology and physiopathology of reticuloendothelial system. Arch Intern Med 1970;126:1031-52
73. Owens DE III, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 2006;307:93-102
74. Jokerst JV, Lobovkina T, Zare RN, Gambhir SS. Nanoparticle PEGylation for imaging and therapy. Nanomedicine 2011;6:715-28
75. Allen TM, Hansen C, Rutledge J. Liposomes with prolonged circulation times: Factors affecting uptake by reticuloendothelial and other tissues. Biochim Biophys Acta 1989;981:27-35
76. Moghimi SM, Porter CJ, Muir IS, et al. Non-phagocytic uptake of intravenously injected microspheres in rat spleen: Influence of particle size and hydrophilic coating. Biochem Biophys Res Commun 1991;177:861-6
77. Casals E, Pfaller T, Duschl A, et al. Time evolution of the nanoparticle protein corona. ACS Nano 2010;4:3623-32
78. Ehrenberg MS, Friedman AE, Finkelstein JN, et al. The influence of protein adsorption on nanoparticle association with cultured endothelial cells. Biomaterials 2009;30:603-10
79. Gref R, Luck M, Quellec P, et al. 'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG): Influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloid Surf B 2000;18:301-13
80. Lundqvist M, Stigler J, Elia G, et al. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci USA 2008;105:14265-70
81. Leroux JC, Dejaeghere F, Anner B, et al. An investigation on the role of plasma and serum opsonins on the internalization of biodegradable poly(D, L-Lactic Acid) nanoparticles by human monocytes. Life Sci 1995;57:695-703
82. Salvati A, Pitek AS, Monopoli MP, et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat Nanotechnol 2013;8:137-43
83. Poon Z, Lee JA, Huang S, et al. Highly stable, ligand-clustered "patchy" micelle nanocarriers for systemic tumor targeting. Nanomedicine 2011;7:201-9
84. Poon Z, Chen S, Engler AC, et al. Ligand-clustered "patchy" nanoparticles for modulated cellular uptake and in vivo tumor targeting. Angew Chem Int Ed Engl 2010;49:7266-70
85. Moradi E, Vllasaliu D, Garnett M, et al. Ligand density and clustering effects on endocytosis of folate modified nanoparticles. Rsc Adv 2012;2:3025-33
86. D'Addio SM, Baldassano S, Shi L, et al. Optimization of cell receptor-specific targeting through multivalent surface decoration of polymeric nanocarriers. J Control Release 2013;168:41-9
87. Mahmoudi M, Sant S, Wang B, et al. Superparamagnetic iron oxide nanoparticles (SPIONs): Development, surface modification and applications in chemotherapy. Adv Drug Deliv Rev 2011;63:24-46
88. Mahmoudi M, Lynch I, Ejtehadi MR, et al. Protein-nanoparticle interactions: Opportunities and challenges. Chem Rev 2011;111:5610-37
89. Nel AE, Madler L, Velegol D, et al. Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 2009;8:543-57
90. Cedervall T, Lynch I, Lindman S, et al. Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci USA 2007;104:2050-5
91. Abuchowski A, van Es T, Palczuk NC, Davis FF. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J Biol Chem 1977;252:3578-81
92. Gref R, Minamitake Y, Peracchia MT, et al. Biodegradable long-circulating polymeric nanospheres. Science 1994;263:1600-3
93. Otsuka H, Nagasaki Y, Kataoka K. PEGylated nanoparticles for biological and pharmaceutical applications. Adv Drug Deliv Rev 2003;55:403-19
94. Klibanov AL, Maruyama K, Torchilin VP, Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 1990;268:235-7
95. Tirosh O, Barenholz Y, Katzhendler J, Priev A. Hydration of polyethylene glycol-grafted liposomes. Biophys J 1998;74:1371-9
96. Barenholz Y. Doxil (R) -The first FDAapproved nano-drug: Lessons learned. J Control Release 2012;160:117-34
97. Immordino ML, Dosio F, Cattel L. Stealth liposomes: Review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine 2006;1:297-315
98. Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces 2010;75:1-18
99. Malmsten M, Emoto K, Van Alstine JM. Effect of chain density on inhibition of protein adsorption by poly(ethylene glycol) based coatings. J Colloid Interface Sci 1998;202:507-17
100. Mosqueira VCF, Legrand P, Morgat JL, et al. Biodistribution of long-circulating PEG-grafted nanocapsules in mice: Effects of PEG chain length and density. Pharm Res 2001;18:1411-19
101. Benhabbour SR, Sheardown H, Adronov A, Protein resistance of PEGfunctionalized dendronized surfaces: Effect of PEG molecular weight and dendron generation. Macromolecules 2008;41:4817-23
102. Zahr AS, Davis CA, Pishko MV. Macrophage uptake of core-shell nanoparticles surface modified with poly (ethylene glycol). Langmuir 2006;22:8178-85
103. Damodaran VB, Fee CJ, Popat KC. Prediction of protein interaction behaviour with PEG-grafted matrices using X-ray photoelectron spectroscopy. Appl Surf Sci 2010;256:4894-901
104. Meng FH, Engbers GHM, Feijen J. Polyethylene glycol-grafted polystyrene particles. J Biomed Mater Res A 2004;70A:49-58
105. Walkey CD, Olsen JB, Guo HB, et al. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J Am Chem Soc 2012;134:2139-47
106. Fang C, Shi B, Pei YY, et al. In vivo tumor targeting of tumor necrosis factor-Alpha-loaded stealth nanoparticles: Effect of MePEG molecular weight and particle size. Eur J Pharm Sci 2006;27:27-36
107. Li SD, Huang L. Nanoparticles evading the reticuloendothelial system: Role of the supported bilayer. Biochim Biophys Acta 2009;1788:2259-66
108. Perry JL, Reuter KG, Kai MP, et al. PEGylated PRINT nanoparticles: The impact of PEG density on protein binding, macrophage association, biodistribution, and pharmacokinetics. Nano Lett 2012;12:5304-10
109. Avgoustakis K. Pegylated poly(lactide) and poly(lactide-co-glycolide) nanoparticles: Preparation, properties and possible applications in drug delivery. Curr Drug Deliv 2004;1:321-33
110. Bhadra D, Bhadra S, Jain P, Jain NK. Pegnology: A review of PEG-ylated systems. Pharmazie 2002;57:5-29
111. Howard MD, Jay M, Dziublal TD, Lu XL. PEGylation of nanocarrier drug delivery systems: State of the art. J Biomed Nanotechnol 2008;4:133-48
112. Woodle MC. Sterically Stabilized Liposome Therapeutics. Adv Drug Deliv Rev 1995;16:249-65
113. Fowler R, Vllasaliu D, Falcone FH, et al. Uptake and transport of B-conjugated nanoparticles in airway epithelium. J Control Release 2013;172:374-81
114. Mrsny RJ. Lessons from nature: "Pathogen-Mimetic" systems for mucosal nano-medicines. Adv Drug Deliv Rev 2009;61:172-92
115. Jung T, Kamm W, Breitenbach A, et al. Biodegradable nanoparticles for oral delivery of peptides: Is there a role for polymers to affect mucosal uptake? Eur J Pharm Biopharm 2000;50:147-60
116. Morishita M, Peppas NA. Is the oral route possible for peptide and protein drug delivery? Drug Discov Today 2006;11:905-10
117. Perakslis E, Tuesca A, Lowman A. Complexation hydrogels for oral protein delivery: An in vitro assessment of the insulin transport-enhancing effects following dissolution in simulated digestive fluids. J Biomater Sci Polym Ed 2007;18:1475-90
118. Vllasaliu D, Fowler R, Garnett M, et al. Barrier characteristics of epithelial cultures modelling the airway and intestinal mucosa: A comparison. Biochem Biophys Res Commun 2011;415:579-85
119. Merkus FW, Verhoef JC, Schipper NG, Marttin E. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Deliv Rev 1998;29:13-38
120. Lee VH. Protease inhibitors and penetration enhancers as approaches to modify peptide absorption. J Control Release 1990;13:213-23
121. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 2000;11:1-18
122. Stolnik S, Shakesheff K. Formulations for delivery of therapeutic proteins. Biotechnol Lett 2009;31:1-11
123. Bansil R, Turner BS. Mucin structure, aggregation, physiological functions and biomedical applications. Curr Opin Colloid Interface Sci 2006;11:164-70
124. Thornton DJ, Sheehan JK. From mucins to mucus: Toward a more coherent understanding of this essential barrier. Proc Am Thorac Soc 2004;1:54-61
125. Lafitte G, Thuresson K, Soderman O. Mixtures of mucin and oppositely charged surfactant aggregates with varying charge density. Phase behavior, association, and dynamics. Langmuir 2005;21:7097-104
126. Albanese CT, Cardona M, Smith SD, et al. Role of intestinal mucus in transepithelial passage of bacteria across the intact ileum in vitro. Surgery 1994;116:76-82
127. Lai SK, O'Hanlon DE, Harrold S, et al. Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc Natl Acad Sci USA 2007;104:1482-7
128. Wang YY, Lai SK, Suk JS, et al. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that "slip" through the human mucus barrier. Angew Chem Int Ed Engl 2008;47:9726-9
129. Cu Y, Saltzman WM. Controlled surface modification with poly(ethylene)glycol enhances diffusion of PLGA nanoparticles in human cervical mucus. Mol Pharm 2009;6:173-81
130. Ensign LM, Henning A, Schneider CS, et al. Ex vivo characterization of particle transport in mucus secretions coating freshly excised mucosal tissues. Mol Pharm 2013;10:2176-82
131. Miyamoto M, Natsume H, Satoh I, et al. Effect of poly-L-Arginine on the nasal absorption of FITC-dextran of different molecular weights and recombinant human granulocyte colonystimulating factor (rhG-CSF) in rats. Int J Pharm 2001;226:127-38
132. Tuma P, Hubbard AL. Transcytosis: Crossing cellular barriers. Physiol Rev 2003;83:871-932
133. Vllasaliu D, Alexander C, Garnett M, et al. Fc-mediated transport of nanoparticles across airway epithelial cell layers. J Control Release 2012;158:479-86
134. Fowler R, Vllasaliu D, Falcone FH, et al. Uptake and transport of B-conjugated nanoparticles in airway epithelium. J Control Release 2013;172:374-81
135. Alconcel SNS, Baas AS, Maynard HD. FDA-Approved poly(ethylene glycol)-protein conjugate drugs. Polym Chem 2011;2:1442-8
136. Veronese FM, Harris JM. Preface -introduction and overview of peptide and protein pegylation. Adv Drug Deliv Rev 2002;54:453-6
137. Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov Today 2005;10:1451-8
138. Roberts MJ, Bentley MD, Harris JM. Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev 2002;54:459-76
139. Fishburn CS. The pharmacology of PEGylation: Balancing PD with PK to generate novel therapeutics. J Pharm Sci 2008;97:4167-83
140. Berkrot B. Celgene's Abraxane increases survival in pancreatic cancer. Available from: Http://www.reuters.com/article/ 2013/01/22/us-celgene- canceridUSBRE90L14O20130122 [Cited 18 July 2013
141. Venditto VJ, Szoka FC Jr. Cancer nanomedicines: So many papers and so few drugs!. Adv Drug Deliv Rev 2013;65:80-8
142. Drugs@FDA. Available from: Http:// www.accessdata.fda.gov/scripts/cder/ drugsatfda/index.cfm?fuseaction=Search. DrugDetails
143. Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal doxorubicin -Review of animal and human studies. Clin Pharmacokinet 2003;42:419-36
144. O'Brien MER, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX (TM)/Doxil (R)) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440-9
145. Symon Z, Peyser A, Tzemach D, et al. Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes. Cancer 1999;86:72-8
146. Plosker GL. Pegylated liposomal doxorubicin a review of its use in the treatment of relapsed or refractory multiple myeloma. Drugs 2008;68:2535-51
147. Karra N, Benita S. The ligand nanoparticle conjugation approach for targeted cancer therapy. Curr Drug Metab 2012;13:22-41
148. Hrkach J, Von Hoff D, Mukkaram Ali M, et al. Preclinical development and clinical translation of a PSMA-Targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med 2012;4:128ra39
149. Reddy LH, Couvreur P. Nanotechnology for therapy and imaging of liver diseases. J Hepatol 2011;55:1461-6
150. Service RF. Nanotechnology. Nanoparticle Trojan horses gallop from the lab into the clinic. Science 2010;330:314-15
151. Kim HR, Andrieux K, Gil S, et al. Translocation of poly(ethylene glycol-cohexadecyl) cyanoacrylate nanoparticles into rat brain endothelial cells: Role of apolipoproteins in receptor-mediated endocytosis. Biomacromolecules 2007;8:793-9
152. Peracchia MT, Harnisch S, Pinto-Alphandary H, et al. Visualization of in vitro protein-rejecting properties of PEGylated stealth polycyanoacrylate nanoparticles. Biomaterials 1999;20:1269-75
153. Brambilla D, Verpillot R, Le Droumaguet B, et al. PEGylated nanoparticles bind to and alter amyloidbeta peptide conformation: Toward engineering of functional nanomedicines for Alzheimer's disease. ACS Nano 2012;6:5897-908
154. Talelli M, Rijcken CJF, van Nostrum CF, et al. Micelles based on HPMA copolymers. Adv Drug Deliv Rev 2010;62:231-9
155. Lee KS, Chung HC, Im SA, et al. Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res Treat 2008;108:241-50
156. Available from: Http:// sorrentotherapeutics.com/cynviloq/
157. Libutti SK, Paciotti GF, Byrnes AA, et al. Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal Gold-rhTNF nanomedicine. Clin Cancer Res 2010;16:6139-49
158. Farma JM, Puhlmann M, Soriano PA, et al. Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor. Int J Cancer 2007;120:2474-80
159. Duncan R, Gaspar R. Nanomedicine(s) under the microscope. Mol Pharm 2011;8:2101-41
160. Available from: Http://www.cytimmune. com/go.cfm?do=page.view&pid=26
161. Karakoti AS, Das S, Thevuthasan S, Seal S. PEGylated inorganic nanoparticles. Angew Chem Int Ed 2011;50:1980-94
162. Hong RL, Huang CJ, Tseng YL, et al. Direct comparison of liposomal doxorubicin with or without polyethylene glycol coating in C-26 tumor-bearing mice: Is surface coating with polyethylene glycol beneficial? Clin Cancer Res 1999;5:3645-52
163. Amoozgar Z, Yeo Y. Recent advances in stealth coating of nanoparticle drug delivery systems. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2012;4:219-33
164. Zalipsky S, Qazen M, Walker JA II, et al. New detachable poly(ethylene glycol) conjugates: Cysteine-cleavable lipopolymers regenerating natural phospholipid, diacyl phosphatidylethanolamine. Bioconjug Chem 1999;10:703-7
165. Takae S, Miyata K, Oba M, et al. PEG-detachable polyplex micelles based on disulfide-linked block catiomers as bioresponsive nonviral gene vectors. J Am Chem Soc 2008;130:6001-9
166. Moghimi SM, Hamad I, Andresen TL, et al. Methylation of the phosphate oxygen moiety of phospholipid-methoxy (polyethylene glycol) conjugate prevents PEGylated liposome-mediated complement activation and anaphylatoxin production. Faseb J 2006;20:2591-3
167. Hamad I, Hunter AC, Szebeni J, Moghimi SM. Poly(ethylene glycol)s generate complement activation products in human serum through increased alternative pathway turnover and a MASP-2-dependent process. Mol Immunol 2008;46:225-32
168. Ishida T, Ichihara M, Wang X, et al. Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J Control Release 2006;112:15-25
169. Ishida T, Masuda K, Ichikawa T, et al. Accelerated clearance of a second injection of PEGylated liposomes in mice. Int J Pharm 2003;255:167-74
170. Ishida T, Maeda R, Ichihara M, et al. Accelerated clearance of PEGylated liposomes in rats after repeated injections. J Control Release 2003;88:35-42
171. Dams ET, Laverman P, Oyen WJ, et al. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J Pharmacol Exp Ther 2000;292:1071-9
172. Webster R, Didier E, Harris P, et al. PEGylated proteins: Evaluation of their safety in the absence of definitive metabolism studies. Drug Metab Dispos 2007;35:9-16
173. Markovsky E, Baabur-Cohen H, Eldar-Boock A, et al. Administration, distribution, metabolism and elimination of polymer therapeutics. J Control Release 2012;161:446-60
174. Robert NJ, Vogel CL, Henderson IC, et al. The role of the liposomal anthracyclines and other systemic therapies in the management of advanced breast cancer. Semin Oncol 2004;31:106-46
175. Jager E, Jager A, Etrych T, et al. Self-Assembly of biodegradable copolyester and reactive HPMA-based polymers into nanoparticles as an alternative stealth drug delivery system. Soft Mater 2012;8:9563-75
176. Hu CM, Zhang L, Aryal S, et al. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc Natl Acad Sci USA 2011;108:10980-5
177. Rodriguez PL, Harada T, Christian DA, et al. Minimal "Self" peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science 2013;339:971-5
178. Medicines in Development Biotechnology 2011 report. Available from: Http://www.phrma.org/sites/ default/files/pdf/biotech2011.pdf
179. Hubbell JA, Thomas SN, Swartz MA. Materials engineering for immunomodulation. Nature 2009;462:449-60