Clinically approved PEGylated nanoparticles are covered by a protein corona that boosts the uptake by cancer cells

Abstract

Today, liposomes are an advanced technology of drug carriers with a dozen drugs in clinical practice and many more in clinical trials. A bottleneck associated with the clinical translation of liposomes has long been 'opsonization', i.e. the adsorption of plasma proteins at the liposome surface resulting in their rapid clearance from circulation. For decades, the most popular way to avoid opsonization has been grafting polyethylene glycol (PEG) onto the liposome surface. Recent studies have clarified that grafting PEG onto the liposome surface reduces, but does not completely prevent protein binding. In this work, we employed dynamic light scattering, zeta-potential analysis, one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE), semi-quantitative densitometry and cell imaging to explore the bio-nano-interactions between human plasma (HP) and Onivyde, a PEGylated liposomal drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). To properly evaluate the role of PEGylation, an unPEGylated variant of Onivyde was used as a reference. Collectively, our findings suggest that: (i) although PEGylated, Onivyde is not "stealth" in HP; (ii) surface chemistry is more important than PEGylation in controlling the bio-nano-interactions between Onivyde and plasma components. Of note is that the PC was found to boost the cellular uptake of Onivyde in the pancreas ductal adenocarcinoma cell line (PANC-1) thus suggesting its prominent role in its indication for PDAC treatment. Relevant implications for drug delivery and drug design are discussed.

Protein denaturation caused by heat inactivation detrimentally affects biomolecular corona formation and cellular uptake

“…However, recently several research groups reported that protein adsorption is not completely prevented for PEGylated nanocarriers. [37][38][39] In fact, in our previous studies, we were able to show that distinct proteins preferably adsorb to stealth nanocarriers. 35 These so called 'stealth' proteins (e.g.…”

Induction of Cytochrome P450 Involved in the Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomes In Vivo

“…Apart from P450 induction and anti-PEG IgM, a number of other factors might contribute to the ABC phenomenon, including the protein corona and lipoprotein receptor. Recently, it has been reported that the protein corona (which mainly consists of complement proteins and apolipoproteins with or without immunoglobulins) formed on polymer nanoparticles including PEG-L plays a predominant role in the clearance of the liposomes from the blood (Pozzi et al, 2014;Papi et al, 2017). In addition, it has been demonstrated that serum albumin and apolipoprotein low-densitylipoprotein receptors also have a positive impact on this phenomenon (Bertrand et al, 2017; Kari et al, 2017).…”

A health concern regarding the protein corona, aggregation and disaggregation

“…Depending on the NP dimension, pH of the medium, surface chemistry and type of NPs and proteins, proteins can mediate the formation of a corona at the external surface of NPs [16][17][18]. The unique protein coronas of differently modified or differently sized NPs affect all features of NP -biological systems interactions ranging from induced cytotoxicity to the mechanism of infiltration [19][20][21][22][23]. NPs after uptaking by a physiological environment are coated with biomolecules almost spontaneously [24,25].…”