TY - JOUR
T1 - New tools for the quantitative assessment of prodrug delivery and neurotoxicity
AU - Samuelson, Lynn E.
AU - Scherer, Randy L.
AU - VanSaun, Michael N.
AU - Fan, Kang Hsien
AU - Dozier, E. Ashley
AU - Carter, Kathy J.
AU - Koyama, Tatsuki
AU - Shyr, Yu
AU - Aschner, Michael
AU - Stanwood, Gregg D.
AU - Bornhop, Darryl J.
AU - Matrisian, Lynn M.
AU - McIntyre, J. Oliver
N1 - Funding Information:
This work was supported in part by Susan G. Komen for the Cure ® Grant KG090434 (J.O.M. and D.J.B.), NCI P30 CA68485 (small animal imaging center, VUIIS), NIH/NCI P50 CA128323 (J.O.M. and L.M.M), NSF IGERT , 0333392 (R.L.S.), DOD BCRP , BC073450 (R.L.S.) and NCI R25CA092043 (L.E.S.). Behavioral work was performed at the Vanderbilt Mouse Neurobehavioral Core, which is supported in part by P30HD15052. The sponsors had no involvement in: study design; collection, analysis or interpretation of data; the writing of the manuscript; or the decision to submit the article for publication. MA was supported in part by NIH grants R01 ES07331 and R01 ES10563 . We thank: Michelle Martin and Barbara Fingleton for providing R221A-luc cells and advice on the orthotopic immunocompetent FVB tumor model; Conor Lynch for providing training in tissue culture and animal procedures; John Allison for providing training and expertise on mouse behavior assessment; Paul E. Matrisian for assistance with quantifying the beacon; and John Wikswo and Todd Peterson for advice on the manuscript and data presentation.
Funding Information:
Dr. McIntyre reports grants from Susan G. Komen for the Cure ® , grants from NCI, grants from NIH, grants from DOD, grants from NSF, during the conduct of the study. All other authors have no conflict of interest.
Publisher Copyright:
© 2015.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - Systemic off-target toxicities, including neurotoxicity, are prevalent side effects in cancer patients treated with a number of otherwise highly efficacious anticancer drugs. In the current study, we have: (1) developed a new analytical metric for the in vivo preclinical assessment of systemic toxicities/neurotoxicity of new drugs and delivery systems; and (2) evaluated, in mice, the in vivo efficacy and toxicity of a versatile and modular NanoDendron (ND) drug delivery and imaging platform that we recently developed. Our paclitaxel-carrying ND prodrug, NDPXL, is activated following proteolytic cleavage by MMP9, resulting in localized cytotoxic chemotherapy. Using click chemistry, we combined NDPXL with a traceable beacon, NDPB, yielding NDPXL-NDPB that functions as a theranostic compound. In vivo fluorescence FRET imaging of this theranostic platform was used to confirm localized delivery to tumors and to assess the efficiency of drug delivery to tumors, achieving 25-30% activation in the tumors of an immunocompetent mouse model of breast cancer. In this model, ND-drug exhibited anti-tumor efficacy comparable to nab-paclitaxel, a clinical formulation. In addition, we combined neurobehavioral metrics of nociception and sensorimotor performance of individual mice to develop a novel composite toxicity score that reveals and quantifies peripheral neurotoxicity, a debilitating long-term systemic toxicity of paclitaxel therapy. Importantly, mice treated with nab-paclitaxel developed changes in behavioral metrics with significantly higher toxicity scores indicative of peripheral neuropathy, while mice treated with NDPXL showed no significant changes in behavioral responses or toxicity score. Our ND formulation was designed to be readily adaptable to incorporate different drugs, imaging modalities and/or targeting motifs. This formulation has significant potential for preclinical and clinical tools across multiple disease states. The studies presented here report a novel toxicity score for assessing peripheral neuropathy and demonstrate that our targeted, theranostic NDs are safe and effective, providing localized tumor delivery of a chemotherapeutic and with reduced common neurotoxic side-effects.
AB - Systemic off-target toxicities, including neurotoxicity, are prevalent side effects in cancer patients treated with a number of otherwise highly efficacious anticancer drugs. In the current study, we have: (1) developed a new analytical metric for the in vivo preclinical assessment of systemic toxicities/neurotoxicity of new drugs and delivery systems; and (2) evaluated, in mice, the in vivo efficacy and toxicity of a versatile and modular NanoDendron (ND) drug delivery and imaging platform that we recently developed. Our paclitaxel-carrying ND prodrug, NDPXL, is activated following proteolytic cleavage by MMP9, resulting in localized cytotoxic chemotherapy. Using click chemistry, we combined NDPXL with a traceable beacon, NDPB, yielding NDPXL-NDPB that functions as a theranostic compound. In vivo fluorescence FRET imaging of this theranostic platform was used to confirm localized delivery to tumors and to assess the efficiency of drug delivery to tumors, achieving 25-30% activation in the tumors of an immunocompetent mouse model of breast cancer. In this model, ND-drug exhibited anti-tumor efficacy comparable to nab-paclitaxel, a clinical formulation. In addition, we combined neurobehavioral metrics of nociception and sensorimotor performance of individual mice to develop a novel composite toxicity score that reveals and quantifies peripheral neurotoxicity, a debilitating long-term systemic toxicity of paclitaxel therapy. Importantly, mice treated with nab-paclitaxel developed changes in behavioral metrics with significantly higher toxicity scores indicative of peripheral neuropathy, while mice treated with NDPXL showed no significant changes in behavioral responses or toxicity score. Our ND formulation was designed to be readily adaptable to incorporate different drugs, imaging modalities and/or targeting motifs. This formulation has significant potential for preclinical and clinical tools across multiple disease states. The studies presented here report a novel toxicity score for assessing peripheral neuropathy and demonstrate that our targeted, theranostic NDs are safe and effective, providing localized tumor delivery of a chemotherapeutic and with reduced common neurotoxic side-effects.
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U2 - 10.1016/j.neuro.2015.02.005
DO - 10.1016/j.neuro.2015.02.005
M3 - Article
C2 - 25732874
AN - SCOPUS:84924625852
SN - 0161-813X
VL - 47
SP - 88
EP - 98
JO - NeuroToxicology
JF - NeuroToxicology
ER -