Dose ranging, expanded acute toxicity and safety pharmacology studies for intravenously administered functionalized graphene nanoparticle formulations.
Graphene nanoparticle dispersions show immense potential as multifunctional agents for in vivo biomedical applications. Herein, we follow regulatory guidelines for pharmaceuticals that recommend safety pharmacology assessment at least 10-100 times higher than the projected therapeutic dose, and present comprehensive single dose response, expanded acute toxicology, toxicokinetics, and respiratory/cardiovascular safety pharmacology results for intravenously administered dextran-coated graphene oxide nanoplatelet (GNP-Dex) formulations to rats at doses between 1 and 500 mg/kg. Our results indicate that the maximum tolerable dose (MTD) of GNP-Dex is between 50 mg/kg ≤ MTD < 125 mg/kg, blood half-life < 30 min, and majority of nanoparticles excreted within 24 h through feces. Histopathology changes were noted at ≥250 mg/kg in the heart, liver, lung, spleen, and kidney; we found no changes in the brain and no GNP-Dex related effects in the cardiovascular parameters or hematological factors (blood, lipid, and metabolic panels) at doses < 125 mg/kg. The results open avenues for pivotal preclinical single and repeat dose safety studies following good laboratory practices (GLP) as required by regulatory agencies for investigational new drug (IND) application.
Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
Shruti
S
Kanakia
Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
Jimmy D
JD
Toussaint
Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
Sayan
S
Mullick Chowdhury
Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
Tanuf
T
Tembulkar
Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
Stephen
S
Lee
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA.
Ya-Ping
YP
Jiang
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA.
Richard Z
RZ
Lin
Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
Kenneth R
KR
Shroyer
Department of Radiology, Stony Brook University, Stony Brook, NY, USA.
William
W
Moore
Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA. Electronic address: balaji.sitharaman@stonybrook.edu.
Balaji
B
Sitharaman
D061605:Administration, Intravenous; D000818:Animals; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000494:pharmacology; D003911:Dextrans / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006108:Graphite / Q000008:administration & dosage* / Q000737:chemistry; D006207:Half-Life; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D053758:Nanoparticles / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D023382:Toxicity Tests, Acute
D020099:Coated Materials, Biocompatible; D003911:Dextrans; D006108:Graphite
Biodistribution; Dextran; Dose range; Graphene nanoplatelets; Maximum tolerated dose; Toxicity