Targeting the brain with PEG–PLGA nanoparticles modified with phage-displayed peptides

Abstract

The relative impermeability of the blood-brain barrier (BBB) results from tight junctions and efflux transport systems limits drug delivery to the central nervous system (CNS), and thus severely restricts the therapy of many central nervous system diseases. In order to enhance the brain-specific drug delivery, we employed a 12-mer phage display peptide library to isolate peptides that could target the drug delivery system to the brain. A 12-amino-acid-peptide (denoted as Pep TGN) which was displayed by bacteriophage Clone 12-2 was finally selected by rounds of in vivo screening. Pep TGN was covalently conjugated onto the surface of poly (ethyleneglycol)-poly (lactic-co-glycolic acid) (PEG-PLGA) based nanoparticles (NPs). The cellular uptake of Pep TGN decorated nanoparticles was significantly higher than that of unmodified nanoparticles when incubated with bEnd.3 cells. Enhanced brain accumulation efficiency together with lower accumulation in liver and spleen was observed in the nude mice intravenously injected with Pep TGN conjugated nanoparticles compared with those injected with plain nanoparticles, showing powerful brain selectivity of Pep TGN. Coumarin 6 was used as a fluorescent probe for the evaluation of brain delivery properties. The brain Drug Targeting Index (DTI) of coumarin 6 incorporated in targeted nanoparticles was significantly higher than that of coumarin 6 incorporated in plain nanoparticles. In conclusion, the Pep TGN is a motif never been reported before and Pep TGN modified nanoparticles showed great potential in targeted drug delivery across the blood brain barrier.

PLA/PLGA nanoparticles for delivery of drugs across the blood-brain barrier

“…Different cells including MDCK cells [17,20,24,29] , BCECs [19,26,33,40] , bEnd.3 cells [28,39] , and glioma cells [20,34,37,41] were used as in vitro cell models treated at doses ranging from 10 to 15,000 μ g/ml. Small size, positively charged and less hydrophilic NPs were associated with enhanced cellular uptake [17] .…”

“…A number of in vitro experiments have demonstrated that surface functionalized NPs enhanced the therapeutic efficacy of antitumor drugs against the glioma cells such as RG2 and C6 glioma cells when compared with that of free drugs in solution and unmodified NPs with entrapped drugs [17,20,28,32,37,41] . Besides cell viability, IC 50 , the concentration of the drug required to kill 50 % of the incubated cells over a fixed time period, was employed to quantify and evaluate the cytotoxicity of NPs loaded with chemotherapeutic drugs, and their therapeutic efficiency.…”

“…PEG-containing NPs were demonstrated to have advantages such as stabi lity, prolonged blood circulation time, reduced liver distribution and enhanced brain uptake as PEG chains can help adsorb less opsonins and immunoglobulin G, but more apolipoprotein (Apo) E/B [3] . PEGylated NPs PEG-PLGA and PEG-PLA were reported in 10 papers [19,21,25,26,28,32,35,37,39,41] , and were included in the discussion.…”

“…Different peptides functionalized NPs were constructed to activate receptor-mediated endocytosis, which could enhance brain-targeted delivery. Four synthetic opioid peptides [27] , a 120 amino acid peptide screened from in vivo phage display [28] , trans-activating transcriptor (TAT) peptide [29] and g7 [30] were successfully conjugated to PLGA/PLA NPs and the conjugation was shown to improve brain delivery of nanocarriers. Tf is another commonly used ligand for targeted brain delivery and it was proven to interact with the corresponding receptor in the brain to induce RMT [33 -35, 40] .…”

“…Among 29 papers cited in this review, 9 papers performed in vitro studies [20,23,24,31,33,37,38,40] , 8 papers focused on in vivo studies [13,15,16,18,21,25,27,30] , and 12 papers did both in vitro and in vivo studies [14,17,19,22,26,28,29,32,34,35,39,41] .…”