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Methotrexate-Loaded Extracellular Vesicles Functionalized with Therapeutic and Targeted Peptides for the Treatment of Glioblastoma Multiforme
journal contribution
posted on 2018-03-22, 00:00 authored by Zhilan Ye, Tao Zhang, Wenshan He, Honglin Jin, Cuiwei Liu, Zhe Yang, Jinghua RenDespite promising
in vitro evidence for effective glioblastoma
treatment, most drugs are hindered from entering the central nervous
system because of the presence of the blood–brain barrier (BBB).
Thus, successful modification of drug delivery and novel therapeutic
strategies are needed to overcome this obstacle. Extracellular vesicles
(EVs), cell-derived membrane-encapsulated structures with diameters
ranging from 50 to 1000 nm, have been explored as the drug delivery
system to deliver their cargo to the brain tissue. Moreover, tumor
targeting and selective drug delivery has been facilitated by engineering
their parent cells to secrete modified EVs. However, the method suffers
from many shortcomings including poor repeatability and complex and
time-consuming operations. In this context, we present an easy-to-adapt
and highly versatile methodology to modify EVs with an engineered
peptide capable of recognition and eradication of glioma. On the basis
of molecular recognition between phospholipids on EV lipid bilayer
membranes and ApoA-I mimetic peptides, we have developed methotrexate
(MTX)-loaded EVs functionalized with therapeutic [Lys-Leu-Ala (KLA)]
and targeted [low-density lipoprotein (LDL)] peptides. In vitro experiments
demonstrated that EVs decorated with LDL or KLA-LDL could obviously
ameliorate their uptake by human primary glioma cell line U87 and
permeation into three-dimensional glioma spheroids in contrast to
blank EVs, and consequently, the treatment outcome of the payload
is improved. Both ex vivo and in vivo imaging experiments revealed
that peptide LDL could obviously promote EV extravasation across the
BBB and distribution in the glioma site. Furthermore, compared with
the mice administrated with MTX and MTX@EVs, MTX@EVs-KLA-LDL-treated
mice showed the longest median survival period. In conclusion, functionalizing
with the peptide onto EV surfaces may provide a substantial advancement
in the application of EVs for selective target binding as well as
therapeutic effects for brain tumor treatment.