TY - JOUR
T1 - CNS Drug Delivery in Stroke
T2 - Improving Therapeutic Translation From the Bench to the Bedside
AU - Ronaldson, Patrick T.
AU - Williams, Erica I.
AU - Betterton, Robert D.
AU - Stanton, Joshua A.
AU - Nilles, Kelsy L.
AU - Davis, Thomas P.
N1 - Publisher Copyright:
© 2023 American Heart Association, Inc.
PY - 2024/1/1
Y1 - 2024/1/1
N2 - Drug development for ischemic stroke is challenging as evidenced by the paucity of therapeutics that have advanced beyond a phase III trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit. Such knowledge will permit the innate biology of the BBB/neurovascular unit to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. In this review, we will highlight key aspects of BBB/neurovascular unit pathophysiology and describe state-of-the-art approaches for optimization of central nervous system drug delivery (ie, passive diffusion, mechanical opening of the BBB, liposomes/nanoparticles, transcytosis, intranasal drug administration). Additionally, we will discuss how endogenous BBB transporters represent the next frontier of drug delivery strategies for stroke. Overall, this review will provide cutting edge perspective on how central nervous system drug delivery must be considered for the advancement of new stroke drugs toward human trials.
AB - Drug development for ischemic stroke is challenging as evidenced by the paucity of therapeutics that have advanced beyond a phase III trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit. Such knowledge will permit the innate biology of the BBB/neurovascular unit to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. In this review, we will highlight key aspects of BBB/neurovascular unit pathophysiology and describe state-of-the-art approaches for optimization of central nervous system drug delivery (ie, passive diffusion, mechanical opening of the BBB, liposomes/nanoparticles, transcytosis, intranasal drug administration). Additionally, we will discuss how endogenous BBB transporters represent the next frontier of drug delivery strategies for stroke. Overall, this review will provide cutting edge perspective on how central nervous system drug delivery must be considered for the advancement of new stroke drugs toward human trials.
KW - blood-brain barrier
KW - drug delivery systems
KW - drug therapy
KW - ischemic stroke
KW - OATP transporters
KW - organic cation transport proteins
UR - http://www.scopus.com/inward/record.url?scp=85180986083&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85180986083&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.123.043764
DO - 10.1161/STROKEAHA.123.043764
M3 - Review article
C2 - 38134249
AN - SCOPUS:85180986083
SN - 0039-2499
VL - 55
SP - 190
EP - 202
JO - Stroke
JF - Stroke
IS - 1
ER -