Preparation and in vivo evaluation of PEGylated spherulite formulations

Abstract

Spherulites are multilamellar vesicles obtained by shearing a lamellar phase of lipids and surfactants. They consist of concentric bilayers of amphiphiles alternating with layers of aqueous medium in which hydrophilic drugs can be sequestered with high yield. To be useful for drug targeting applications, spherulites should be small and long circulating. The objectives of this work were threefold. First, the spherulite size was optimized to obtain a mean diameter of less than 300 nm. Second, the vesicle composition was adjusted to minimize in vitro leakage of internal content. Third, the spherulites were coated with 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[methoxy poly(ethylene glycol)] (DSPE-PEG) to impart them with a long half-life. Then, the PEGylated spherulites (Phospholipon 90G/Solutol HS15/cholesterol/DSPE-PEG 2000 or 5000) were loaded with 1-beta-d-arabinofuranosylcytosine (ara-C) and injected intravenously to rats. They were compared to uncoated spherulites and to an ara-C solution. The surface-modified vesicles exhibited long circulation times with areas under the blood concentration vs. time curve exceeding by 3.1- to 6.9-fold that of uncoated spherulites. Similarly, blood levels of ara-C encapsulated in PEGylated vesicles were higher than those of the controls, but they did not parallel the carrier pharmacokinetics. Two hours post-injection, most of the drug was cleared from the systemic circulation, reflecting rapid leakage of ara-C from the vesicles.

Characterization of Spherulites as a Lipidic Carrier for Low and High Molecular Weight Agents

“…TW80-containing spherulites (formulation 1–3 ) had substantially smaller sizes (170–200 nm in diameter), suggesting that the structure of surfactants has a significant effect in controlling the sizes of the spherulites. This is consistent with the study by Simard et al, in which they showed that Tween 20 and 80 provided spherulites with smaller sizes than another surfactant, Solutol HS 15 (25). The underlying mechanism for the reduced size of TW80 formulations is likely due to its relatively high HLB value and small packing parameter based on its relatively large hydrophilic head group.…”

“…We also did not quantitatively measure the amounts of PEG conjugates incorporated into the spherulites considering the high efficiency of postinsertion approach with both unilamellar liposomes and spherulites (23, 25). More studies are needed in the future to define the optimal amounts of PEG-lipid and ligand-derivatized PEG-lipid for in vivo drug delivery.…”

Rescue of amitriptyline-intoxicated hearts with nanosized vesicles

“…After administration, spherulites should exhibit long in vivo circulation times to maximize their detoxification efficiency in the body. This could be easily achieved by incorporating poly(ethylene glycol) lipid derivatives in the vesicle membrane [24]. Future studies in live animal models should provide a comprehension of the relationship between in vivo circulation of the formulation and drug transfer kinetics to the prompt alleviation of drug-induced toxicity.…”

Preparation and characterization of PEG-modified PCL nanoparticles for oxygen carrier: a new application of Fourier transform infrared spectroscopy for quantitative analysis of the hemoglobin in nanoparticles

“…Up to now, many studies have highlighted that the physicochemical characteristics of nanoparticles are influenced by PEG molecule's weight (Simard et al 2005). However, details on the effect of PEG molar ratio have never been discussed, let alone investigating the potential mechanism.…”