TY - JOUR
T1 - Effects of core titanium crystal dimension and crystal phase on ROS generation and tumour accumulation of transferrin coated titanium dioxide nanoaggregates
AU - Lane, Daniel D.
AU - Black, Kvar C.L.
AU - Raliya, Ramesh
AU - Reed, Nathan
AU - Kotagiri, Nalinikanth
AU - Gilson, Rebecca
AU - Tang, Rui
AU - Biswas, Pratim
AU - Achilefu, Samuel
N1 - Publisher Copyright:
© The Royal Society of Chemistry.
PY - 2020/6/23
Y1 - 2020/6/23
N2 - Radionuclide-stimulated therapy (RaST), which is enhanced by Cherenkov radiation, has enabled deep tissue stimulation of UV photosensitizers, providing a new path for cancer treatment. Previous reports have shown UV-active titanium dioxide (TiO2) nanoparticles (NPs) modified with transferrin inhibit tumour growth after orthogonal treatment with Cherenkov radiation-emitting radionuclides such as 18F-fluorodeoxyglucose (FDG). However, poor understanding of TiO2 NP parameters on reactive oxygen species (ROS) generation and particle distribution limits effective therapy. Here we sought to delineate the effects of crystal phase and core TiO2 crystal dimension (cTd) on ROS production and particle morphology. We prepared Transferrin (Tf)-TiO2 nanoaggregates (NAGs) using solvothermally synthesized cTd sizes from 5 to 1000 nm diameter and holo- or apo-transferrin. Holo-transferrin was unable to stabilize TiO2 NPs while apo-transferrin stabilized TiO2 into uniform nanoaggregates (NAGs), which were invariant with differing cTd, averaging 116 ± 1.04 nm for cTds below 100 nm. ROS production increased from 5 to 25 nm cTd, attaining a peak at 25 nm before decreasing with larger sizes. The supra-25 nm ROS production decrease was partially driven by a ∼1/r3 surface area decline. Additionally, amorphous TiO2 of equal core size exhibited a 2.6-fold increase in ROS production compared to anatase NAGs, although limited stability halted further use. Although both 5 and 25 nm anatase cTds formed similarly sized NAGs, 5 nm anatase showed a four-fold higher tumour-to-muscle ratio than the 25 nm NPs in tumour-bearing mice, demonstrating the intricate relationships between physical and biological properties of NAGs. The combined in vivo and ROS results demonstrate that anatase crystals and cTd size of 25 nm or less are ideal particle parameters to balance biodistribution with ROS production efficiency.
AB - Radionuclide-stimulated therapy (RaST), which is enhanced by Cherenkov radiation, has enabled deep tissue stimulation of UV photosensitizers, providing a new path for cancer treatment. Previous reports have shown UV-active titanium dioxide (TiO2) nanoparticles (NPs) modified with transferrin inhibit tumour growth after orthogonal treatment with Cherenkov radiation-emitting radionuclides such as 18F-fluorodeoxyglucose (FDG). However, poor understanding of TiO2 NP parameters on reactive oxygen species (ROS) generation and particle distribution limits effective therapy. Here we sought to delineate the effects of crystal phase and core TiO2 crystal dimension (cTd) on ROS production and particle morphology. We prepared Transferrin (Tf)-TiO2 nanoaggregates (NAGs) using solvothermally synthesized cTd sizes from 5 to 1000 nm diameter and holo- or apo-transferrin. Holo-transferrin was unable to stabilize TiO2 NPs while apo-transferrin stabilized TiO2 into uniform nanoaggregates (NAGs), which were invariant with differing cTd, averaging 116 ± 1.04 nm for cTds below 100 nm. ROS production increased from 5 to 25 nm cTd, attaining a peak at 25 nm before decreasing with larger sizes. The supra-25 nm ROS production decrease was partially driven by a ∼1/r3 surface area decline. Additionally, amorphous TiO2 of equal core size exhibited a 2.6-fold increase in ROS production compared to anatase NAGs, although limited stability halted further use. Although both 5 and 25 nm anatase cTds formed similarly sized NAGs, 5 nm anatase showed a four-fold higher tumour-to-muscle ratio than the 25 nm NPs in tumour-bearing mice, demonstrating the intricate relationships between physical and biological properties of NAGs. The combined in vivo and ROS results demonstrate that anatase crystals and cTd size of 25 nm or less are ideal particle parameters to balance biodistribution with ROS production efficiency.
UR - http://www.scopus.com/inward/record.url?scp=85088142311&partnerID=8YFLogxK
U2 - 10.1039/d0ra01878c
DO - 10.1039/d0ra01878c
M3 - Article
C2 - 32774845
AN - SCOPUS:85088142311
SN - 2046-2069
VL - 10
SP - 23759
EP - 23766
JO - RSC Advances
JF - RSC Advances
IS - 40
ER -