**1. Introduction**

Liposomes are spherical particles composed of a phospholipid bilayer encircling an aqueous centre [1]. First described in 1965, liposomes, particularly nano-sized liposomes, have since been widely investigated as drug-delivery carriers, and were the first nanomedicine platform to bridge the gap between in vitro studies and clinical use [2]. Liposomes have since become established as drug-delivery carriers [2]. In recent years a number of groups have been investigating the use of "empty" liposomes with no drug loaded as scavengers both for exogenous intoxicants (intoxicants) and endogenous toxic molecules (endogenous toxins), which accumulate due to diminished excretion in cases of organ failure. Preclinical trials have demonstrated that repurposing liposomes to sequester such compounds may prove clinically useful [3].

Studies have shown that intravascular "empty" liposomes can sequester compounds in vivo, thus acting as detoxification vehicles or "sinks" [4]. The first work in this field investigated detoxification in drug overdose and has since expanded into use in hepatic and renal failure. There are dose limitations to the intravenous (IV) dosing route, as many nanoparticles, including liposomes, can cause complement activation-related pseudoallergy (CARPA) when delivered intravenously [5,6]. This has led to the investigation of the use of liposomes in dialysate.

**Citation:** Hart, K.; Harvey, M.; Tang, M.; Wu, Z.; Cave, G. Liposomes to Augment Dialysis in Preclinical Models: A Structured Review. *Pharmaceutics* **2021**, *13*, 395 . https:// doi.org/10.3390/pharmaceutics 13030395

Academic Editor: Ana Catarina Silva

Received: 1 February 2021 Accepted: 13 March 2021 Published: 16 March 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

The predominant clinical use of dialysis is to facilitate the clearance of water-soluble toxic substances which accumulate in the blood of patients with renal failure. In clinical dialysis, blood flows over a semi-permeable membrane, with molecules moving into dialysate on the other side of the membrane via diffusion or convection [7]. Blood is never in contact with the dialysate. The pore size and configuration in the membrane of both peritoneal and haemodialysis (HD) does not allow the passage of the large complement proteins. The diameter of the main complement regulatory protein C3 is >100 Angstroms, compared to the pore size in dialysis of 5–50 Angstroms, which largely shields the components of dialysate from complement surveillance [8–10]. The addition of liposomes to dialysate in peritoneal dialysis (PD) or haemodialysis (HD) thus reduces the potential for CARPA, allowing for the protected introduction and removal of liposomes, which sequester the toxin. The use of liposomes in dialysate may also increase the reach of dialysis to molecules that were not previously removable.

PD uses the membrane lining the abdominal cavity, the peritoneum, as the dialysis membrane. Fluid introduced into the abdominal cavity dialyses against blood across the peritoneal membrane. PD is less invasive than HD, in which blood flows through an extracorporeal circuit across a dialysis membrane with countercurrent dialysate flow. In renal failure, HD is considered more effective than PD due to higher blood flows across the dialysis membrane, a higher ratio of dialysate to blood flow and the countercurrent dialysate flow in HD. PD is only used in approximately 10% of dialysed patients worldwide [11]. Increasing the effective "volume" of dialysate for any given molecule by entrapping the target molecule in liposomes suspended within peritoneal dialysate could increase the efficacy of PD to extract the target molecule. The basic principle involves introducing liposomes as a constituent of the dialysate in the patient's peritoneal cavity, using the binding characteristics of the liposome to entrap the toxin of interest as it diffuses from blood perfusing the peritoneal cavity, then extracting the toxin-laden dialysate [1,4]. The use of liposomes in this way has been described as liposome-supported peritoneal dialysis (LSPD).

HD is currently used in some cases of poisoning, but limitations mean that dialysis is useful only in specific intoxications [12]. It is presently considered that only "free" toxins i.e., those that are not bound to plasma proteins, can by effectively dialysed. For that reason, in intoxications with drugs exhibiting protein binding of 80% or more, dialysis is not the usual treatment. Furthermore, compounds with a high volume of distribution also pose difficulties, as dialysis can only remove toxins contained in the blood compartment. Liposomes hold some promise as a means of addressing the first of these limitations and have been investigated as a means of ameliorating the second.

The use of lipid-based nanoparticles to augment dialysis is a nascent field with significant potential to improve clinical outcomes in a number of areas. In this review, we aim to provide a summary of current research to increase awareness and inform further research. As such, we present a review of the published literature on the use of liposomes to augment dialysis in preclinical models for both endogenous toxins and intoxicants. We focus most on repurposing the use of liposomes into new indications in areas of unmet clinical need.
