Liposome-based mucus-penetrating particles (MPP) for mucosal theranostics: Demonstration of diamagnetic chemical exchange saturation transfer (diaCEST) magnetic resonance imaging (MRI)

Abstract

Mucus barriers lining mucosal epithelia reduce the effectiveness of nanocarrier-based mucosal drug delivery and imaging (“theranostics”). Here, we describe liposome-based mucus-penetrating particles (MPP) capable of loading hydrophilic agents, e.g., the diaCEST MRI contrast agent barbituric acid (BA). We observed that polyethylene glycol (PEG)-coated liposomes containing ≥7 mol% PEG diffused only ~10-fold slower in human cervicovaginal mucus (CVM) compared to their theoretical speeds in water. 7 mol%-PEG liposomes contained sufficient BA loading for diaCEST contrast, and provided improved vaginal distribution compared to 0 and 3 mol%-PEG liposomes. However, increasing PEG content to ~12 mol% compromised BA loading and vaginal distribution, suggesting that PEG content must be optimized to maintain drug loading and in vivo stability. Non-invasive diaCEST MRI illustrated uniform vaginal coverage and longer retention of BA-loaded 7 mol %-PEG liposomes compared to unencapsulated BA. Liposomal MPP with optimized PEG content hold promise for drug delivery and imaging at mucosal surfaces.

PEGylation as a strategy for improving nanoparticle-based drug and gene delivery

“…The presence of PEG on the liposome surface can prevent aggregation of liposomes, though incorporating too much PEG can compromise liposome formation and stability. Yu and coworkers reported that when the PEG-lipid conjugate content was increased to 12 mol%, both the drug loading and in vivo vaginal distribution was reduced [139]. …”

“…Yu and coworkers prepared liposomes composed of standard neutrally charged lipids (DSPC), cholesterol, and different amounts of lipids conjugated to 2 kDa PEG (DSPE-PEG 2k ) to produce liposomes with a range of PEG surface densities [139]. They found that the non-PEGylated liposome formulation was relatively polydisperse and showed some signs of aggregation, whereas the PEGylated liposomes were relatively uniform in size, highlighting the added stability provided by PEG coatings.…”

“…Upon observation of transport behavior in human CVM, it was evident that the contrast between PEGylated and non-PEGylated liposomes was not as drastic as what was observed previously with polymeric NPs, though the PEGylated liposomes uniformly diffused more rapidly. The authors concluded that the zwitterionic DSPC headgroups may have reduced interactions with mucus compared to hydrophobic polymer NPs like PS, but nonetheless, adhesion and aggregation of the liposomes in mucus was reduced by PEG coatings [139]. They then went on to investigate the impact of the PEG coatings on vaginal distribution in vivo , and found that the non-PEGylated liposomes distributed very poorly.…”

“…The authors concluded that the further increase in PEG content may have created some instability of the 12 mol% liposomes in the complex vaginal environment in vivo . They then went on to demonstrate that the 7 mol% liposomes containing a novel diamagnetic chemical exchange saturation transfer (diaCEST) magnetic resonance imaging (MRI) contrast agent provided increased retention of the contrast agent for non-invasive monitoring of vaginally administered liposomes [139]. In similar studies using biodegradable NPs, Xu and coworkers formulated PEG-coated PLGA NPs with various PEG surface densities by blending PLGA and PLGA-PEG (5 kDa PEG) block copolymers [140].…”

Cellular and Molecular Imaging Using Chemical Exchange Saturation Transfer

“…As a result of the interest in developing agents for detection on 3 T and lower field scanners, recent studies have emphasized the design of compounds with chemical shifts from water (Δω) > 4 ppm (27). Based on this criteria, barbituric acid (28,29), thymidine analogs (30), iodinated compounds (31-33), imidazoles (34) salicylic acid and anthranilic acid analogs have come to the forefront. The salicylates and anthranillates are particularly appealing based on their chemical structure consisting of a phenol proton hydrogen bonded to a carboxylate, which has been known with large chemical shift (35-37) which is particularly favorable for 3 T scanners based on their Δω = 6 -12 ppm and the capability of tuning k ex from 400 - 3000 s −1 , suitable rates for detection of CEST contrast.…”