TY - JOUR
T1 - Strategies to enhance the distribution of nanotherapeutics in the brain
AU - Zhang, Clark
AU - Mastorakos, Panagiotis
AU - Sobral, Miguel
AU - Berry, Sneha
AU - Song, Eric
AU - Nance, Elizabeth
AU - Eberhart, Charles G.
AU - Hanes, Justin
AU - Suk, Jung Soo
N1 - Funding Information:
The funding is provided by the National Institutes of Health (R01CA164789, R01EB020147, R01CA197111, R01CA204968 and P30EY001765) and W.W. Smith Charitable Trust (J.S.S). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank Benjamin Schuster and Gregg Duncan for their help in high-throughput MPT analysis.
Funding Information:
The funding is provided by the National Institutes of Health ( R01CA164789 , R01EB020147 , R01CA197111 , R01CA204968 and P30EY001765 ) and W.W. Smith Charitable Trust (J.S.S). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank Benjamin Schuster and Gregg Duncan for their help in high-throughput MPT analysis.
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/12/10
Y1 - 2017/12/10
N2 - Convection enhanced delivery (CED) provides a powerful means to bypass the blood-brain barrier and drive widespread distribution of therapeutics in brain parenchyma away from the point of local administration. However, recent studies have detailed that the overall distribution of therapeutic nanoparticles (NP) following CED remains poor due to tissue inhomogeneity and anatomical barriers present in the brain, which has limited its translational applicability. Using probe NP, we first demonstrate that a significantly improved brain distribution is achieved by infusing small, non-adhesive NP via CED in a hyperosmolar infusate solution. This multimodal delivery strategy minimizes the hindrance of NP diffusion imposed by the brain extracellular matrix and reduces NP confinement within the perivascular spaces. We further recapitulate the distributions achieved by CED of this probe NP using a most widely explored biodegradable polymer-based drug delivery NP. These findings provide a strategy to overcome several key limitations of CED that have been previously observed in clinical trials.
AB - Convection enhanced delivery (CED) provides a powerful means to bypass the blood-brain barrier and drive widespread distribution of therapeutics in brain parenchyma away from the point of local administration. However, recent studies have detailed that the overall distribution of therapeutic nanoparticles (NP) following CED remains poor due to tissue inhomogeneity and anatomical barriers present in the brain, which has limited its translational applicability. Using probe NP, we first demonstrate that a significantly improved brain distribution is achieved by infusing small, non-adhesive NP via CED in a hyperosmolar infusate solution. This multimodal delivery strategy minimizes the hindrance of NP diffusion imposed by the brain extracellular matrix and reduces NP confinement within the perivascular spaces. We further recapitulate the distributions achieved by CED of this probe NP using a most widely explored biodegradable polymer-based drug delivery NP. These findings provide a strategy to overcome several key limitations of CED that have been previously observed in clinical trials.
KW - Brain extracellular matrix
KW - Convection enhanced delivery
KW - Drug delivery
KW - Nanoparticle
KW - Perivascular space
UR - http://www.scopus.com/inward/record.url?scp=85026453085&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026453085&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2017.07.028
DO - 10.1016/j.jconrel.2017.07.028
M3 - Article
C2 - 28739449
AN - SCOPUS:85026453085
SN - 0168-3659
VL - 267
SP - 232
EP - 239
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -