PEGylation as a strategy for improving nanoparticle-based drug and gene delivery☆
Graphical abstract
Introduction
In order to deliver adequate concentrations of systemically administered therapeutics to target tissues, these materials must circulate in the blood stream for as long as possible. However, proteins and peptides are rapidly degraded and cleared from the blood stream, necessitating approaches for increasing circulation time. One such approach is to coat the surface of the therapeutic with an inert polymer that resists interactions with components of the blood stream, imparting “stealth” properties. Polyethylene glycol (PEG) is the most widely used “stealth” polymer in the drug delivery field, due to its long history of safety in humans and classification as Generally Regarded as Safe (GRAS) by the FDA. Considered the first reports of PEGylation for drug delivery, Davis and Abuchowski described in 1977 the covalent attachment of PEG to bovine serum albumin and liver catalase proteins [1]. They found that by optimizing the PEGylation chemistry and the extent of PEGylation, they could increase the systemic circulation time and decrease the immunogenicity of the proteins without significantly compromising activity. In 1990, the FDA approved the first PEGylated protein product, Adagen®, a PEGylated adenosine deaminase enzyme for severe combined immunodeficiency disease [2]. Since then, 8 other PEGylated protein therapeutics have been FDA approved for treatment of diseases ranging from rheumatoid arthritis to age-related macular degeneration [2].
The success of protein PEGylation as a method for producing longer circulating, and thus, more efficacious intravenous therapies led to investigations of nanoparticle (NP) PEGylation for systemic applications in the early 80s and 90s [3], [4], [5]. Recognized as foreign objects, NPs are readily cleared from systemic circulation by the cells of the mononuclear phagocyte system (MPS), precluding accumulation in target cells and tissues. However, similar to what was observed with PEGylated proteins, PEG coatings on NPs shield the surface from aggregation, opsonization, and phagocytosis, thereby prolonging circulation time. The first FDA approval of a PEGylated nanoparticle (NP) product, Doxil®, came in 1995. Doxil “Stealth®” liposomes increased doxorubicin bioavailability nearly 90-fold at 1 week from injection versus free drug, with a drug half-life of 72 h and circulation half-life of 36 h [6], [7], [8]. In the years since, PEGylation has become a mainstay in NP formulation. Although much of the initial development of PEGylated NPs focused on systemic administration, in this review we also highlight the benefits of NP PEGylation for overcoming biological barriers to effective delivery associated with numerous modes of delivery, ranging from injection into the eye to topical mucosal applications. Special emphasis is given to studies that directly compare PEGylated to non-PEGylated formulations to specifically demonstrate the benefits of NP PEGylation. Further, we discuss common methods for PEGylating NPs, as well as quantifying a critical parameter that influences the efficiency of delivery, the surface PEG density.
Section snippets
The potential fates of systemically administered nanoparticles
Systemically administered NPs can potentially reach and deliver therapeutic payloads to every vascularized organ/tissue in our body. Prolonging the retention time in the blood has been accepted as the frontline strategy, since it provides higher probability of circulating NPs to encounter, and partition into, the targets of interest. However, this task has been challenging primarily due to the presence of the MPS. The MPS consists of dendritic cells, blood monocytes, granulocytes, and
Non-systemic applications for improved delivery with PEGylated nanoparticles
For many applications, local rather than systemic delivery can improve efficacy while minimizing off-target side effects, but every mode of administration has associated barriers to effective delivery. Although PEGylation was first employed to increase circulation time, improve stability in circulation, and reduce interactions with serum components, benefits of coating NPs with PEG have also be observed with various other non-systemic modes of administration. Discussed in this section, PEG
Methods for nanoparticle PEGylation and quantification of PEG surface density
In this section, we highlight the various techniques that can be employed for formulating PEGylated NPs with a primary focus on polymeric formulations followed by a brief discussion of lipid-based and micelle type NPs. In general, the methods either involve self-assembly of PEG-containing molecules, or surface modification of pre-formed NPs with PEG. As described in previous sections, the surface density of PEG on NPs is a key factor that influences delivery, so here we also describe methods
Conclusion
Building on the success of protein PEGylation for improved systemic delivery of therapeutic proteins, PEGylation of NPs has also proven to be a highly effective approach for improving systemic delivery of therapeutic cargo. Furthermore, we highlighted here how NP PEGylation has also been used as an approach to overcome various extracellular barriers associated with other modes of administration, ranging from mucosal delivery to delivery to brain tissue. Undoubtedly, PEG coatings will continue
Acknowledgments
This work was supported by National Institutes of Health grants U19AI133127 (J.H., L.M.E.), R01HL127413 (J.H., J.S.S.), R33AI094519 (J.H., L.M.E.), and R01EB020147 (J.H.); the Johns Hopkins University Center for AIDS Research P30AI094189 (L.M.E.); the 2015 Burroughs Wellcome Fund Preterm Birth Initiative (L.M.E); the Raymond Kwok Family Research Fund, USA (J.H. and Q.X.); and the Cystic Fibrosis Foundation (J.H., J.S.S.).
The mucus-penetrating particle technology described in this publication is
References (245)
- et al.
Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase
J. Biol. Chem.
(1977) - et al.
Acrylic microspheres in vivo IX: blood elimination kinetics and organ distribution of microparticles with different surface characteristics
J. Pharm. Sci.
(1983) - et al.
Surface modification of nanoparticles by PEO/PPO block copolymers to minimize interactions with blood components and prolong blood circulation in rats
Biomaterials
(1993) - et al.
Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes
FEBS Lett.
(1990) - et al.
Combined radiofrequency ablation and adjuvant liposomal chemotherapy: effect of chemotherapeutic agent, nanoparticle size, and circulation time
J. Vasc. Interv. Radiol.
(2005) - et al.
Parameters influencing the stealthiness of colloidal drug delivery systems
Biomaterials
(2006) - et al.
Nanoparticles with decreasing surface hydrophobicities: influence on plasma protein adsorption
Int. J. Pharm.
(2000) - et al.
Surface-modified biodegradable albumin nano- and microspheres. II: effect of surface charges on in vitro phagocytosis and biodistribution in rats
Eur. J. Pharm. Biopharm.
(1998) - et al.
Interpretation of protein adsorption phenomena onto functional microspheres
Colloids Surf. B
(1998) - et al.
Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages
Eur. J. Pharm. Biopharm.
(2011)
Serum independent liposome uptake by mouse liver
Bba-Biomembranes
Mind the gap: a survey of how cancer drug carriers are susceptible to the gap between research and practice
J. Control. Release
Enhancing the therapeutic efficacy of adenovirus in combination with biomaterials
Biomaterials
State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines
J. Control. Release
Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status
Adv. Drug Deliv. Rev.
Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood–brain barrier using MRI-guided focused ultrasound
J. Control. Release
High-intensity focused ultrasound for the treatment of liver tumours
Ultrasonics
‘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
Colloids Surf. B: Biointerfaces
Tuning PEGylation of mixed micelles to overcome intracellular and systemic siRNA delivery barriers
Biomaterials
Influence of the steric barrier activity of amphipathic poly(ethyleneglycol) and ganglioside GM1 on the circulation time of liposomes and on the target binding of immunoliposomes in vivo
FEBS Lett.
The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres
Adv. Drug Deliv. Rev.
Influence of poly(ethylene glycol) grafting density and polymer length on liposomes: relating plasma circulation lifetimes to protein binding
Biochim. Biophys. Acta
Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles
Int. J. Pharm.
The effect of PEGylation of mesoporous silica nanoparticles on nonspecific binding of serum proteins and cellular responses
Biomaterials
Stealth Me.PEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system
J. Pharm. Sci.
In vivo tumor targeting of tumor necrosis factor-alpha-loaded stealth nanoparticles: effect of MePEG molecular weight and particle size
Eur. J. Pharm. Sci.
Stealth PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting
J. Control. Release
Effect of PEO surface density on long-circulating PLA-PEO nanoparticles which are very low complement activators
Biomaterials
In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis
Biomaterials
Potential induction of anti-PEG antibodies and complement activation toward PEGylated therapeutics
Drug Discov. Today
The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage
J. Control. Release
Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes
J. Control. Release
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
PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles
Eur. J. Cell Biol.
Transport of PEGylated liposomes from the splenic marginal zone to the follicle in the induction phase of the accelerated blood clearance phenomenon
Immunobiology
Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes
J. Control. Release
The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats
J. Control. Release
PEGylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner
J. Control. Release
Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA
J. Control. Release
Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: a possible mechanism and the potential for clinical application
Int. J. Pharm.
Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection
J. Control. Release
CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes
J. Control. Release
Nanopharmaceuticals (part 1): products on the market
Int. J. Nanomedicine
Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies
Clin. Pharmacokinet.
Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer tumors
Clin. Cancer Res.
Long-circulating and target-specific nanoparticles: theory to practice
Pharmacol. Rev.
Contribution of high-resolution correlative imaging techniques in the study of the liver sieve in three-dimensions
Microsc. Res. Tech.
Factors affecting the clearance and biodistribution of polymeric nanoparticles
Mol. Pharm.
Mechanisms of phagocytosis in macrophages
Annu. Rev. Immunol.
Serum opsonins and liposomes: their interaction and opsonophagocytosis
Crit. Rev. Ther. Drug Carrier Syst.
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This article is part of the Advanced Drug Delivery Reviews theme issue on “Non-Antigenic Regulators-Maiseyeu”.