Cleavable PEGylation: a strategy for overcoming the “PEG dilemma” in efficient drug delivery

Abstract

To prolong the circulation time of drug, PEGylation has been widely used via the enhanced permeability and retention (EPR) effect, thereby providing new hope for better treatment. However, PEGylation also brings the "PEG dilemma", which is difficult for the cellular absorption of drugs and subsequent endosomal escape. As a result, the activity of drugs is inevitably lost after PEG modification. To achieve successful drug delivery for effective treatment, the crucial issue associated with the use of PEG-lipids, that is, "PEG dilemma" must be addressed. In this paper, we introduced the development and application of nanocarriers with cleavable PEGylation, and discussed various strategies for overcoming the PEG dilemma. Compared to the traditional ones, the vehicle systems with different environmental-sensitive PEG-lipids were discussed, which cleavage can be achieved in response to the intracellular as well as the tumor microenvironment. This smart cleavable PEGylation provides us an efficient strategy to overcome "PEG dilemma", thereby may be a good candidate for the cancer treatment in future.

A combinatorial biomolecular strategy to identify peptides for improved transport across the sputum of cystic fibrosis patients and the underlying epithelia

“…Cellpenetrating peptides have recently demonstrated the potential to enhance the mucosal delivery of drugs and particles [84,85]; however these positively charged peptides form strong interactions with the negatively charged mucin glycoproteins, thereby hindering transport and actually, preventing their ability to achieve cell-penetration [86]. Furthermore, while promising, net-neutral charge polymers and polymer conjugates demonstrate improved mucus transport, they may face hindered cellular internalization and escape [16,[33][34][35][36][37][87][88][89], thereby dampening the enthusiasm for their therapeutic use. Hence, we confirmed the ability of our peptides to achieve both mucus penetration and cellular internalization by measuring transport of the identified mucus-penetrating peptides conjugated to 100 nm nanoparticles in a co-culture assay of CF sputum and lung epithelial cells possessing the prevalent cystic fibrosis homozygous delta F508 mutation.…”

“…After mucus penetration, drug delivery systems must enter target cells to efficiently deliver their therapeutic payload. Although PEGylated systems demonstrate improved diffusion in mucus via decreased hydrophobic and electrostatic interactions, PEGylation can hinder cellular uptake of the drug carrier system [33][34][35][36][37]. PEGylation has been shown to increase serum protein binding of lipid/DNA complexes in vitro and decrease gene delivery in vivo [38,39].…”

Lipid Nanoparticles for Cell-Specific <i>in Vivo</i> Targeted Delivery of Nucleic Acids

“…25,26) Furthermore, as the amount of cationic lipid used in LPXs is increased, the toxicity and immunogenicity of NPs increase. 27) Nonspecific interactions with serum proteins can be decreased by coating LPXs with hydrophilic polymers like polyethylene glycol (PEG), resulting in long-term circulation of NPs. Although these long-circulating PEGylated LPXs have greater potential for accumulation in tumor tissues through the enhanced permeability and retention effect, they are not highly internalized into tumor cells and show limited transfection efficiency.…”

Ditelluride-Bridged PEG-PCL Copolymer as Folic Acid-Targeted and Redox-Responsive Nanoparticles for Enhanced Cancer Therapy

“…Among the nanoparticles reported, most of them have been decorated by PEGylation to improve the biocompatibility and stability after the administration (Butcher et al, 2016;Huckaby and Lai, 2018;Suh et al, 2019). Although outside PEG layer can validly preserve nanoparticles from rapid clearance by the reticuloendothelial system (RES) to extend their blood circulation, its application would significantly impede cellular uptake by tumor cells and result in unsatisfactory therapeutic efficiency (Zhu et al, 2012;Fang et al, 2017;Chen et al, 2018). Accordingly, optimization of the carriers with active targeting moieties are of great interest in drug delivery field.…”