New tools for the quantitative assessment of prodrug delivery and neurotoxicity.
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, ND(PXL), is activated following proteolytic cleavage by MMP9, resulting in localized cytotoxic chemotherapy. Using click chemistry, we combined ND(PXL) with a traceable beacon, ND(PB), yielding ND(PXL)-ND(PB) 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 ND(PXL) 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.
Department of Cancer Biology; Vanderbilt University, Nashville TN.
Lynn E
LE
Samuelson
Department of Cancer Biology; Vanderbilt University, Nashville TN.|Interdisciplinary Materials Science and Engineering Department; Vanderbilt University, Nashville TN.
Randy L
RL
Scherer
Department of Surgery; Vanderbilt University, Nashville TN.|Department of Cancer Biology; Vanderbilt University, Nashville TN.
Michael N
MN
VanSaun
Department of Biostatistics; Vanderbilt University, Nashville TN.
Kang-Hsien
KH
Fan
Department of Cancer Biology; Vanderbilt University, Nashville TN.
E Ashley
EA
Dozier
Department of Cancer Biology; Vanderbilt University, Nashville TN.
Kathy J
KJ
Carter
Department of Biostatistics; Vanderbilt University, Nashville TN.
Tatsuki
T
Koyama
Department of Biostatistics; Vanderbilt University, Nashville TN.
Yu
Y
Shyr
Department of Pediatrics; Vanderbilt University, Nashville TN.
Michael
M
Aschner
Department of Pharmacology; Vanderbilt University, Nashville TN.
Gregg D
GD
Stanwood
Department of Chemistry; Vanderbilt University, Nashville TN.
Darryl J
DJ
Bornhop
Department of Cancer Biology; Vanderbilt University, Nashville TN.|The Vanderbilt-Ingram Cancer Center; Vanderbilt University, Nashville TN.
Lynn M
LM
Matrisian
Department of Cancer Biology; Vanderbilt University, Nashville TN.|The Vanderbilt-Ingram Cancer Center; Vanderbilt University, Nashville TN.|Department of Radiology and Radiological Sciences; Vanderbilt University, Nashville TN.
J Oliver
JO
McIntyre
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D016503:Drug Delivery Systems; D064593:Heterografts; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D059225:Nociception / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D017239:Paclitaxel
Neuropathy; Protease-mediated drug delivery; Protease-mediated imaging; Theranostic paclitaxel; Toxicity assessment