Synthesis and Characterization of Lipid–Polymer Hybrid Nanoparticles with pH-Triggered Poly(ethylene glycol) Shedding

Abstract

Novel lipid-polymer hybrid nanoparticles are designed with a poly(ethylene glycol) coating that is shed in response to a low pH trigger. This allows the nanoparticles to be stable during systemic circulation and at neutral pH, but destabilize and fuse with lipid membranes in acidic environments. The hybrid nanoparticles consist of a poly(lactic-co-glycolic acid) core with a lipid and lipid-PEG monolayer shell. To make the hybrid nanoparticles pH sensitive, a lipid-(succinate)-mPEG conjugate is synthesized to provide a hydrolysable PEG stealth layer that is shed off the particle surface at low pH. The pH-sensitivity of the nanoparticles is tunable using the molar concentration of the lipid-(succinate)-mPEG incorporated in the lipid shell of the particles. Possible uses of these pH-sensitive nanoparticles include aggregating in the acidic tumor microenvironments, escaping the acidified endosomes, or aggregating in deep lung tissue for improved inhalation administration.

Lipid-based surface engineering of PLGA nanoparticles for drug and gene delivery applications

“…Collectively, all of these features make the lipid-based surface engineering strategies ideal for improving the clinical performance of PNPs [18, 24]. Although enormous progress has been made in the area of nanoengineering, many challenges remain that potentially hinder the translation of PNPs to the clinical arena [5, 54].…”

“…Differentially charged synthetic phospholipids, such as zwitterionic, cationic, anionic, and neutral phospholipids (e.g., DOTAP, and sterol lipids such as cholesterol), are often used in biomedical engineering [13, 15]. Polyethylene glycol (PEG) is a hydrophilic lipid that has been largely applied to improve the circulation half-life of NPs in blood [17, 18, 23, 24]. The amphiphilic nature of phospholipids allows them to form organized structures, such as vesicles or membranes, when immersed in an aqueous environment.…”

Polyethylene glycol–poly(ε-benzyloxycarbonyl-L-lysine)-conjugated VEGF siRNA for antiangiogenic gene therapy in hepatocellular carcinoma

“…22 To solve these issues, PEG shedding in response to intracellular environments has been proposed. [23][24][25] More recently, a novel biocompatible and biodegradable PEG-polypeptide catiomers bearing a PEG-sheddable shell and a disulfide-linked PEG-poly(ε-benzyloxycarbonyl-l-lysine) block copolymer (PEG-SS-PLL) was developed in our laboratory. It was found that the PEG-SS-PLL catiomer effectively delivered plasmid DNA into HeLa cells in vitro with negligible cytotoxicity.…”

Design, Development and Evaluation of Erlotinib-Loaded Hybrid Nanoparticles for Targeted Drug Delivery to NonSmall Cell Lung Cancer

“…Another surface modification relates to the acidic environment of tumors. A pH-sensitive PEG coating shed its coating under the acidic condition, fused with cell membrane and entered into tumor cells (92). A red blood cell approach to particle surface functionalization was made by coating biodegradable PNPs with natural erythrocyte membranes.…”

“…Various classes of LPHNPs are summarized in Table 1-1 and are classified depending on the arrangement of lipid and polymer in the hybrid system. Due to their perceived advantages over other existing hybrid systems, significant effort has been directed towards the understanding of CSLPHNPs (92)(93)(94)(95)(96)(97)(98)(99)(100)(101). The primary objective of this review article is to discuss CSLPHNPs which are composed of polymeric core and lipid shell.…”