@article{4d0d25b989304faea0c84f8bd26737d7,
title = "Ultrasound-mediated delivery of flexibility-tunable polymer drug conjugates for treating glioblastoma",
abstract = "Effective chemotherapy delivery for glioblastoma multiforme (GBM) is limited by drug transport across the blood–brain barrier and poor efficacy of single agents. Polymer–drug conjugates can be used to deliver drug combinations with a ratiometric dosing. However, the behaviors and effectiveness of this system have never been well investigated in GBM models. Here, we report flexible conjugates of hyaluronic acid (HA) with camptothecin (CPT) and doxorubicin (DOX) delivered into the brain using focused ultrasound (FUS). In vitro toxicity assays reveal that DOX-CPT exhibited synergistic action against GBM in a ratio-dependent manner when delivered as HA conjugates. FUS is employed to improve penetration of DOX-HA-CPT conjugates into the brain in vivo in a murine GBM model. Small-angle x-ray scattering characterizations of the conjugates show that the DOX:CPT ratio affects the polymer chain flexibility. Conjugates with the highest flexibility yield the highest efficacy in treating mouse GBM in vivo. Our results demonstrate the association of FUS-enhanced delivery of combination chemotherapy and the drug-ratio-dependent flexibility of the HA conjugates. Drug ratio in the polymer nanocomplex may thus be employed as a key factor to modulate FUS drug delivery efficiency via controlling the polymer flexibility. Our characterizations also highlight the significance of understanding the flexibility of drug carriers in ultrasound-mediated drug delivery systems.",
keywords = "chemotherapy, drug delivery, focused ultrasound, glioblastoma, hyaluronic acid",
author = "Tao Sun and Vinu Krishnan and Pan, {Daniel C.} and Filippov, {Sergey K.} and Sagi Ravid and Apoorva Sarode and Jayoung Kim and Yongzhi Zhang and Chanikarn Power and Sezin Aday and Junling Guo and Karp, {Jeffrey M.} and McDannold, {Nathan J.} and Mitragotri, {Samir S.}",
note = "Funding Information: NIH/National Cancer Center Support, Grant/Award Number: NIH 5 P30 CA06516; Dana‐Farber/Harvard Cancer Center; Harvard University; National Science Foundation, Grant/Award Number: 1541959; Ministry of Science, Republic of Kazakhstan, Grant/Award Number: BR05236446; National Institutes of Health, Grant/Award Number: R01EB028686 Funding information Funding Information: Samir S. Mitragotri acknowledges support from Harvard John A. Paulson School of Engineering and Applied Sciences. Nathan J. McDannold acknowledges support from National Institutes of Health (NIH, R01EB028686). Tao Sun acknowledges support from a Pilot Imaging Grant from the Brigham and Women's Hospital Research Imaging Core/Small Animal Imaging Lab. Sergey K. Filippov acknowledges grant support from the Ministry of Science, Republic of Kazakhstan (BR05236446). This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network, which is supported by the National Science Foundation Award No. 1541959. CNS is part of Harvard University. In addition, the authors thank the Specialized Histopathology Core (Dana‐Farber/Harvard Cancer Center), which provided histology and immunohistochemistry service. Dana‐Farber/Harvard Cancer Center is supported in part by an NIH/National Cancer Center Support Grant # NIH 5 P30 CA06516. Funding Information: Samir S. Mitragotri acknowledges support from Harvard John A. Paulson School of Engineering and Applied Sciences. Nathan J. McDannold acknowledges support from National Institutes of Health (NIH, R01EB028686). Tao Sun acknowledges support from a Pilot Imaging Grant from the Brigham and Women's Hospital Research Imaging Core/Small Animal Imaging Lab. Sergey K. Filippov acknowledges grant support from the Ministry of Science, Republic of Kazakhstan (BR05236446). This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network, which is supported by the National Science Foundation Award No. 1541959. CNS is part of Harvard University. In addition, the authors thank the Specialized Histopathology Core (Dana-Farber/Harvard Cancer Center), which provided histology and immunohistochemistry service. Dana-Farber/Harvard Cancer Center is supported in part by an NIH/National Cancer Center Support Grant # NIH 5 P30 CA06516. Publisher Copyright: {\textcopyright} 2022 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.",
year = "2023",
month = mar,
doi = "10.1002/btm2.10408",
language = "English",
volume = "8",
journal = "Bioengineering and Translational Medicine",
issn = "2380-6761",
publisher = "John Wiley & Sons Inc.",
number = "2",
}