In vitro and in vivo studies on gelatin-siloxane nanoparticles conjugated with SynB peptide to increase drug delivery to the brain

Abstract

Background: Nanobiotechnology can provide more efficient tools for diagnosis, targeted and personalized therapy, and increase the chances of brain tumor treatment being successful. Use of nanoparticles is a promising strategy for overcoming the blood-brain barrier and delivering drugs to the brain. Gelatin-siloxane (GS) nanoparticles modified with Tat peptide can enhance plasmid DNA transfection efficiency compared with a commercial reagent. Methods: SynB-PEG-GS nanoparticles are membrane-penetrable, and can cross the bloodbrain barrier and deliver a drug to its target site in the brain. The efficiency of delivery was investigated in vivo and in vitro using brain capillary endothelial cells, a cocultured blood-brain barrier model, and a normal mouse model. Results: Our study demonstrated that both SynB-PEG-GS and PEG-GS nanoparticles had a spherical shape and an average diameter of 150-200 nm. It was shown by MTT assay that SynB-PEG-GS nanoparticles had good biocompatibility with brain capillary endothelial cells. Cellular uptake by SynB-PEG-GS nanoparticles was higher than that for PEG-GS nanoparticles for all incubation periods. The amount of SynB-PEG-GS nanoparticles crossing the cocultured blood-brain barrier model was significantly higher than that of PEG-GS nanoparticles at all time points measured (P , 0.05). In animal testing, SynB-PEG-GS nanoparticle levels in the brain were significantly higher than those of PEG-GS nanoparticles at all time points measured (P , 0.01). In contrast with localization in the brain, PEG-GS nanoparticle levels were significantly higher than those of SynB-PEG-GS nanoparticles (P , 0.01) in the liver. Conclusion: This study indicates that SynB-PEG-GS nanoparticles have favorable properties with regard to morphology, size distribution, and toxicity. Moreover, the SynB-PEG-GS nanoparticles exhibited more efficient brain capillary endothelial cell uptake and improved crossing of the blood-brain barrier. Further, biodistribution studies of rhodamine-loaded nanoparticles demonstrated that modification with the SynB peptide could not only improve the ability of PEG-GS nanoparticles to evade capture in the reticuloendothelial system but also enhance their efficiency in crossing the blood-brain barrier.

Key for crossing the BBB with nanoparticles: the rational design

“…In the case of BBB crossing, their positive charge might induce their transcytosis through the AMT pathway. Multiple CPPs have been used to deliver nanoparticles to the brain such as the HIV-1 trans-activating transcriptor (TAT) [77,106,107], penetratin [108] or SynB [109].…”

Nanoparticles for Brain Drug Delivery

“…A second possibility is to functionalize the NPs surface with positively charged biomolecules combining their physicochemical features with biological activity. This is the case of cell-penetrating peptides (e.g., TAT peptides derived from HIV, gH625 derived from Herpes simplex virus type 1) and cationic proteins (e.g., albumin) [ 59 ] that have been extensively used for NPs decoration, facilitating the BBB passage of drugs [ 60 ]. As for example, Rao et al [ 61 ] after administration of ritonavir via TAT-conjugated NPs demonstrated approximately an 800-fold higher level of drug in the brain when compared to that with free drug, with a remarkable enhancement of drug delivery.…”

Enhanced uptake of gH625 by blood brain barrier compared to liver in vivo: characterization of the mechanism by an in vitro model and implications for delivery

“…To better understand and ameliorate the physicochemical properties of peptide drug delivery vectors to improve accumulation on target tissue, biodistribution studies are of great relevance. As a general rule, organs with high blood flow and rich in reticulo-endothelial system such as liver, could accumulate cell penetrating peptides 63 , 64 . Biodistribution analysis on other CPPs showed that the distribution among the different tissue depends on the peptide but all present a high liver distribution 9 , 13 .…”