TY - JOUR
T1 - Tumor Targeted Delivery of an Anti-Cancer Therapeutic
T2 - An In Vitro and In Vivo Evaluation
AU - Kang, You Jung
AU - Holley, Claire K.
AU - Abidian, Mohammad Reza
AU - Madhankumar, Achuthamangalam B.
AU - Connor, James
AU - Majd, Sheereen
N1 - Funding Information:
Y.J.K. and C.K.H. contributed equally to this work. The authors would like to thank Becky S. Webb for her assistance with animal care and animal studies. This work was partially supported by a Grace Woodward Grant (S.M. and J.C.) from Pennsylvania State University and a GEAR (Grants to Enhance and Advance Research) award (S.M.) from University of Houston.
Publisher Copyright:
© 2020 Wiley-VCH GmbH
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/20
Y1 - 2021/1/20
N2 - The limited effectiveness of current therapeutics against malignant brain gliomas has led to an urgent need for development of new formulations against these tumors. Chelator Dp44mT (di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone) presents a promising candidate to defeat gliomas due to its exceptional anti-tumor activity and its unique ability to overcome multidrug resistance. The goal of this study is to develop a targeted nano-carrier for Dp44mT delivery to glioma tumors and to assess its therapeutic efficacy in vitro and in vivo. Dp44mT is loaded into poly(ethylene glycol) (PEG)ylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) decorated with glioma-targeting ligand Interlukin 13 (IL13). IL13-conjugation enhanced the NP uptake by glioma cells and also improved their transport across an in vitro blood-brain-barrier (BBB) model. This targeted formulation showed an outstanding toxicity towards glioma cell lines and patient-derived stem cells in vitro, with IC50 values less than 125 nM, and caused no significant death in healthy brain microvascular endothelial cells. In vivo, when tested on a xenograft mouse model, IL13-conjugated Dp44mT-NPs reduced the glioma tumor growth by ≈62% while their untargeted counterparts reduced the tumor growth by only ≈16%. Notably, this formulation does not cause any significant weight loss or kidney/liver toxicity in mice, demonstrating its great therapeutic potential.
AB - The limited effectiveness of current therapeutics against malignant brain gliomas has led to an urgent need for development of new formulations against these tumors. Chelator Dp44mT (di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone) presents a promising candidate to defeat gliomas due to its exceptional anti-tumor activity and its unique ability to overcome multidrug resistance. The goal of this study is to develop a targeted nano-carrier for Dp44mT delivery to glioma tumors and to assess its therapeutic efficacy in vitro and in vivo. Dp44mT is loaded into poly(ethylene glycol) (PEG)ylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) decorated with glioma-targeting ligand Interlukin 13 (IL13). IL13-conjugation enhanced the NP uptake by glioma cells and also improved their transport across an in vitro blood-brain-barrier (BBB) model. This targeted formulation showed an outstanding toxicity towards glioma cell lines and patient-derived stem cells in vitro, with IC50 values less than 125 nM, and caused no significant death in healthy brain microvascular endothelial cells. In vivo, when tested on a xenograft mouse model, IL13-conjugated Dp44mT-NPs reduced the glioma tumor growth by ≈62% while their untargeted counterparts reduced the tumor growth by only ≈16%. Notably, this formulation does not cause any significant weight loss or kidney/liver toxicity in mice, demonstrating its great therapeutic potential.
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U2 - 10.1002/adhm.202001261
DO - 10.1002/adhm.202001261
M3 - Article
C2 - 33191612
AN - SCOPUS:85096688003
VL - 10
JO - Advanced healthcare materials
JF - Advanced healthcare materials
SN - 2192-2640
IS - 2
M1 - 2001261
ER -