Multifunctional LUV liposomes decorated for BBB and amyloid targeting - B. In vivo brain targeting potential in wild-type and APP/PS1 mice

Abstract

Multifunctional liposomes (mf-LIPs) having a curcumin-lipid ligand (to target amyloids) together with two ligands to target the transferrin, and the low-density apolipoprotein receptor of the blood-brain-barrier (BBB) on their surface, were previously studied (in vitro) as potential theranostic systems for Alzheimer's disease (AD) (Papadia et al., 2017, Eur. J. Pharm. Sciences; 101:140-148). Herein, the targeting potential of mf-LIPs was compared to that of BBB-LIPs (liposomes having only the two BBB-specific ligands) in FVB mice (normal), as well as in double transgenic mice (APP/PS1) and their corresponding littermates (WT), by live-animal (in vivo) and explanted organ (ex vivo) imaging. In FVB mice, the head-signals of mf-LIPs and BBB-LIPs are either similar, or signals from mf-LIP are higher, suggesting that the co-presence of the curcumin derivative on the liposome surface does not disturb the functionality of the BBB-specific ligands. Higher brain/liver+spleen ratios (ex vivo) were calculated post-injection of mf-LIP, compared to those found after BBB-LIP injection, due to the reduced distribution of mf-LIPs in the liver and spleen; showing that the curcumin ligand increases the stealth properties of liposomes by reducing their uptake by liver and spleen. The later effect is more pronounced when the density of the BBB-specific ligands on the mf-LIPs is 0.1mol%, compared to 0.2%, highlighting the importance of this parameter. When a high lipid dose (4mg/mouse) is injected in WT and APP/PS1 mice, the head-signals of mf-LIPs are significantly higher than those of BBB-LIPs, but no differences are observed between WT and APP/PS1 mice. However, after administration of a low liposome dose (0.05mg/mouse) of mf-LIPs, significant differences in the head-signals are found between WT and transgenic mice, highlighting the AD theranostic potential of the multifunctional liposomes, as well as the importance of the experimental parameters used in such in vivo screening studies.

Preparation, Physicochemical Properties, and In Vitro Toxicity towards Cancer Cells of Novel Types of Arsonoliposomes

“…After confirming the capability to formulate stable nanosized TREG-ARSL that incorporate the complete amount of TREG added in the lipid phase during their preparation, and demonstrate high physical stability during storage at 4 • C (Figure 2), their integrity in the presence of serum proteins was evaluated. The current results demonstrated that the incorporation of TREG in ARSL had a marginal effect to increase their stability towards any disruptive actions of serum proteins, and confirmed previous findings about the stabilizing (towards disruption by serum proteins) effect of TREG on TREG-LIP [20,21].…”

“…A lipid derivative of curcumin, TREG, was previously synthesized and incorporated in liposomes, as an approach for development of nanoparticulate therapeutics for Alzheimer's disease (AD) [18]. In addition to their high affinity for amyloid species [18,19], TREG-liposomes demonstrated increased brain targeting potential, while the integrity of TREG-incorporating liposomes during incubation in presence of serum proteins was increased, as demonstrated in the case of non-targeted as well as brain-targeted liposomes (compared to control liposomes without TREG, in both cases) [20,21].…”

<p>Transferrin-Modified Osthole PEGylated Liposomes Travel the Blood-Brain Barrier and Mitigate Alzheimer’s Disease-Related Pathology in APP/PS-1 Mice</p>

“…16 Research has shown that liposomes modified with Tf can penetrate the BBB and subsequently target neural cells. 17,18 Osthole, a natural coumarin derivative (7-methoxy-8-isopen-tenoxycoumarin, Ost, C 15 O 16 O 3 , 244.39 Da), has been isolated from some medicinal plants, such as Radix Angelicae pubescentis, Cnidium monnieri, Angelica pubescens, and Peucedanum ostruthium. The compound has attracted much attention due to its broad pharmacological effects, including its anti-inflammatory, anti-apoptotic, anti-oxidative stress, and neurotrophic factor-like properties.…”

Phyto-Therapeutic and Nanomedicinal Approaches to Cure Alzheimer’s Disease: Present Status and Future Opportunities

“… Papadia et al (2017) synthesized multifunctional liposomal NPs decorated with curcumin–lipid ligand (TREG) with affinity toward amyloid species along with ligands to target the transferrin and the LDL receptors of the BBB. The study showed successful targeting of brain and inhibition of amyloid peptide aggregation ( Papadia et al, 2017 ).…”

“… Papadia et al (2017) synthesized multifunctional liposomal NPs decorated with curcumin–lipid ligand (TREG) with affinity toward amyloid species along with ligands to target the transferrin and the LDL receptors of the BBB. The study showed successful targeting of brain and inhibition of amyloid peptide aggregation ( Papadia et al, 2017 ). Similarly, Rotman et al (2015) have also developed two liposomal formulations based on 1,2-dimyristoyl-sn-glycero-3-phosphocholine and egg-yolk PC encapsulating indium-111-labeled Aβ-binding llama single-domain antibody fragments (VHH-pa2H) and were coated with glutathione–PEG.…”