'Aggregation Induced Emission + Excited State Intramolecular Proton Transfer (AIE + ESIPT)'-assisted photorelease of an anticancer drug by a p-hydroxyphenacyl (pHP) phototrigger with real-time monitoring has been demonstrated.
Despite significant progress in neurosurgery and radiation therapy during the past decade, overall survivability (OS) of glioblastoma patients continues to be less than 2 years. The scope of systemic chemotherapy is greatly limited by poor drug transport across the blood brain barrier (BBB) and, thereby, suboptimal drug accumulation in glioma tissue. To this end, use of large amino acid transporter-1 (LAT1) overexpressed both on brain capillary endothelial cells (BCECs) and glioma cells has begun. Prior reports on the use of LAT1 mediated delivery of model drugs showed their brain accumulations. However, in depth in vivo glioblastoma regression studies aimed at examining the therapeutic potential of LAT1 mediated delivery of potent chemotherapeutics to brain tumor tissues have not yet been undertaken. Herein, we report on the development of a nanometric (100-135 nm) promising LAT1 selective liposomal drug carrier prepared from a novel l-3,4-dihydroxyphenylalanine (l-DOPA) functionalized amphiphile (Amphi-DOPA). In vitro studies using Rh-PE labeled liposomes of Amphi-DOPA both in untreated glioma (GL261) cells and in GL261cells preincubated with LAT1 antibody revealed LAT1 mediated cellular uptake. Intravenously administered NIR-dye labeled liposomes of Amphi-DOPA in glioblastoma-bearing mice showed preferential accumulation of the dye in brain tissue. Notably iv administration of WP1066-loaded liposomes of Amphi-DOPA enhanced the overall survivability of C57BL/6J mice bearing orthotopically established mouse glioblastoma by ∼60% compared to that for the untreated mouse group. Furthermore, we show that the OS of established glioblastoma-bearing mice can be significantly enhanced (by >300% compared to that for the untreated mouse group) when the presently described LAT1 mediated targeted chemotherapy with WP1066-loaded liposomes of Amphi-DOPA is combined with in vivo DC-targeted DNA vaccination using a survivin (a glioblastoma antigen) encoded DNA vaccine. The present findings open a new door for LAT1 mediated systemic chemotherapy of glioblastoma.
Glioblastoma multiforme (GBM) is
one of the most aggressive tumors
with a median survival of only 15 months. Effective therapeutics need
to overcome the formidable challenge of crossing the blood–brain
barrier (BBB). Receptors and transporters overexpressed on BCECs are
being used for designing liposomes, polymers, polymeric micelles,
peptides, and dendrimer-based drug carriers for combating brain tumors.
Herein, using the orthotopic mouse glioblastoma model, we show that
codelivering a small-molecule inhibitor of the JAK/STAT pathway (WP1066)
and STAT3siRNA with nanometric (100–150 nm) α5β1
integrin receptor-selective liposomes of RGDK-lipopeptide holds therapeutic
promise in combating glioblastoma. Rh-PE (red)-labeled liposomes of
RGDK-lipopeptide were found to be internalized in GL261 cells via
integrin α5β1 receptors. Intravenously administered near-infrared
(NIR)-dye-labeled α5β1 integrin receptor-selective liposomes
of RGDK-lipopeptide were found to be accumulated preferentially in
the mouse brain tumor tissue. Importantly, we show that iv injection
of WP1066 (a commercially sold small-molecule inhibitor of the JAK/STAT
pathway) and STAT3siRNA cosolubilized within the liposomes of RGDK-lipopeptide
leads to significant inhibition (>350% compared to the untreated
mice
group) of orthotopically growing mouse glioblastoma. The present strategy
may find future use in combating GBM.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.