Poly(Sarcosine) Surface Modification Imparts Stealth‐Like Properties to Liposomes

Abstract

Thereby, one of the main goals of liposomes is to protect the entrapped drug while also reducing its off-site toxicity, as shown for multiple formulations. [5][6][7][8] To this end, increasing on-target tissue concentration is a key aspect which can be achieved both by nontargeted and targeted liposomes. [9][10][11][12] In this regard, a crucial point is the prolongation of systemic circulation lifetime. It is well-known that upon injection the majority of conventional (plain) liposomes are cleared rapidly from the blood stream by cells of the mononuclear phagocyte system. [13][14][15] To enhance circulation times, a variety of approaches to modify the surface of liposomes emerged, [16][17][18] yet ultimately polyethylene glycol (PEG) established itself as gold standard in the early 1990s aiming at decreasing opsonization. [19][20][21] PEGylation not only reduces but also alternates the recognition of nanoparticles by complement factors and opsonins, resulting in a decreased nanoparticle recognition and clearance by macrophages. [22,23] Manipulating opsonization, including the reduction of complement activation thus is one of the main goals in preventing rapid clearance.Today, surface modifications of liposomes are mostly realized with amphiphilic lipid-polymer conjugates like 1,2-distearoyl-snglycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-mPEG2k). [24,25] Despite the benefits and being considered mostly nonimmunogenic, phospholipid-PEG conjugates have also demonstrated some drawbacks over the Circulation lifetime is a crucial parameter for a successful therapy with nanoparticles. Reduction and alteration of opsonization profiles by surface modification of nanoparticles is the main strategy to achieve this objective. In clinical settings, PEGylation is the most relevant strategy to enhance blood circulation, yet it has drawbacks, including hypersensitivity reactions in some patients treated with PEGylated nanoparticles, which fuel the search for alternative strategies. In this work, lipopolysarcosine derivatives (BA-pSar, bisalkyl polysarcosine) with precise chain lengths and low polydispersity indices are synthesized, characterized, and incorporated into the bilayer of preformed liposomes via a post insertion technique. Successful incorporation of BA-pSar can be realized in a clinically relevant liposomal formulation. Furthermore, BA-pSar provides excellent surface charge shielding potential for charged liposomes and renders their surface neutral. Pharmacokinetic investigations in a zebrafish model show enhanced circulation properties and reduction in macrophage recognition, matching the behavior of PEGylated liposomes. Moreover, complement activation, which is a key factor in hypersensitivity reactions caused by PEGylated liposomes, can be reduced by modifying the surface of liposomes with an acetylated BA-pSar derivative. Hence, this study presents an alternative surface modification strategy with similar benefits as the established PEGylation of nanoparticles, but with the potential...

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms, and future perspectives

“…It cannot be ignored that PEG is immunogenic and non-degradable 36 , 37 , 38 . Therefore, developing alternative polymers to PEG have received great attention in the pharmaceutical industry 39 , 40 , 41 .…”

Optimized Photoactivatable Lipid Nanoparticles Enable Red Light Triggered Drug Release

“…Quantitative image analysis was performed as previously described. [34,42] Dox Release Studies in Zebrafish Embryos: 48 hpf embryos from Tg(abc/ tu) were injected with 2 nL of 3 mg mL −1 Dox containing LNPs into the duct of Cuvier and incubated at 28 °C in PTU containing zebrafish culture media. 24 hpi, one set of zebrafish was irradiated with pulsedlight for additional 24 h. For quantitative analysis, confocal images of five fishes were processed applying a defined threshold, followed by area calculation in Fiji (ImageJ) 2.1.0.…”

“…As demonstrated previously by our team, zebrafish embryos are a reliable and predictive in vivo tool to investigate liposomal circulation behavior and clearance mechanisms. [34,35] First, we intravenously injected fluorescently labeled control-LNP, paLNP, and red-paLNP (1 nL) into transgenic zebrafish expressing green fluorescent protein in their vascular endothelial cells (Tgkdrl:EGFP) at total lipid concentrations of 10 mg mL −1 . Next, we performed confocal microscopy imaging of the tail region 2 and 24 h post-injection (hpi).…”

A transient initiator for polypeptoids post-polymerization α-functionalization via activation of thioester group

“…These side effects have been associated with any of the vaccine components, including PEG and PEG derivatives [62,63]. Among some other polypeptides, polypeptoids, and poly(2oxazoline)s, have been suggested as excellent candidates to substitute PEG [23,[64][65][66][67].…”