GREEN NANOTECHNOLOGY IN NUCLEAR MEDICINE—TUMOR SPECIFIC RADIOACTIVE
GOLD NANOPARTICLES FOR NEW APPROACHES IN CANCER THERAPY
Kattesh V. Katti MSc.Ed, PhD, DSC, FRSC, FNAI
Menka Khoobchandani, Kavita Katti, Amal Y. Al-Yasiri, Cathy S. Cutler,
Sudarshan Loyalka and
*Ademar Benévolo Lugão,
Kattesh V. Katti: Distinguished Curators’ Professor of Radiology and Physics
Margaret Proctor Mulligan Distinguished Professor of Cancer Research
Director, Institute of Green Nanotechnology; School of Medicine, University of MissouriColumbia, Missouri, USA
Ademar Benévolo Lugão : * Nuclear and Energy Research Institute – IPEN/CNEN/Sao
Paulo, Brazil
International Conference on Applications of Radiation Science and
Technology (ICARST-2017)
THREE FDA APPROVED DRUGS
First to
discover,
develop, and
commercialize
an imaging
agent for use in
humans.
First to
develop bone
cancer
therapy
agents
Therasphere:
http://www.cytogen.com/prof
essional/quadramet/pi.php
Ceretec™(technetium Tc-99m
exametazime)
An imaging agent with 2 distinct
indications. One is for visualization
of cerebral blood flow.
The other is for labeling of white
blood cells to localize sites of
infection and inflammation.
http://www.amershamhealth-us.com/ceretec/
For liver
tumor
therapy
MU-Gold:
Chemotherapy for
prostate tumor
Green
Nanotechnology
In Nanomedicine
TheraSphereTM
Liver cancer--- ranks #3 in deaths due to cancer---kills
more that one million persons per year worldwide.
71 treatment sites in 33 states, ~ 170 world-wide
tumor
human
hair
Yttria alumina silica glass
meets stringent
requirements --chemically durable, high
yttria content.
TheraSphereTM ---Safe---Minimum side effects ---
increased life expectancy
3
Radioactive Gold
Ideal For Theranostics Applications
• Tremendous interest
in gold due to
favorable nuclear
properties
– Au-198: 2.70 day
half life, 961 keV β-,
411 keV γ (96%)
– Au-199: 3.14 day
half life, 453 keV β,158 keV γ (40%)
Treatment Options for Prostate
Cancer
•
•
•
•
•
•
•
·
·
·
·
·
·
·
SURGERY
CHEMOTHERAPY
EXTERNAL BEAM RADIATION THERAPY
IMMUNOTHERAPY
BRACHYTHERAPY
HORMONE THERAPY
STEREOTACTIC RADIOSURGERY
Mangiferin a xanthonoid phenol from Mango peel
Mangiferin—An electron-rich phytochemical transforms
198-gold precursor(s) into Gold Nanoparticles
HO
HO
HO
+
=
HO
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
HO
HO
OH
HO
A
u
OH
HO
NaAuCl4
HO
Mangifer
in
OH
OH
OH HO
OHHO
HO
OH
A
u
OH
HO
OH
HO
OH
HO
OH
HO
HO
HO
OH
A
u
OH
HO
OH
HO
OH
HO
HO
OH
HO
OH
HO
HO
OH
HO
OH
OH
OH
OH
OH
OH
HO
OH
OH
OH
HO
OH
HO
HO
OH
HO
OH
A
u
OH
HO
HO
HO
HO
OH
HO
OH
OH
OH
OH
OH
535 nm
Hydrodynamic size=
60±2 nm
Zeta potential = 31.5±3 mV
Characterization of AuNPs
by TEM, UV-vis
spectrophotometry and by
zeta size instrument
TEM image
Synthesis of MGF-AuNPs and MGF-198AuNPs
NaAuCl4
+
MGF-AuNPs
Mangiferin (MGF)
Mangiferin from
mango peel
H198AuCl4
MGF-198AuNPs
Prostate Tumor Therapy Agent: Clinical Candidates Identified
MGF-AuNPs gold Nanoconstructs:
MGF-AuNPs
Size:
TEM, CPS-Disc centrifuge systems= 35 nm
Toxicity:
35 nm
55 nm
Stability:
Stable in vitro
Stable in vivo (mice)
MGF-AuNPs Cellular Internalization
Cellular trafficking pathways of MGF-AuNPs
( PC-3 cells)
Nucleus
AuNPs
Cytoplasm
MGF-AuNPs treated
Control- PC-3 cells
without treatment
Chlorpromazine treated,
Indicated clathrin mediated endocytosis
Treated with anti-clathrin AB;
Confirmed clathrin mediated endocytosis
Receptor blocked with
dynamin inhibitor,
Indicated: clathrin or caveolae pathways
Treated with anti-caveolae AB;
Particles internalized which confirmed
caveolae independent endocytosis
Dark field microscope images showing MGF-AuNPs uptake into PC-3 cells
Incubated with and without inhibitors, post treated with MGF-AuNPs with dose- 8.2 µg Au/mL, incubated for 90 min.
Results indicated clathrin mediated endocytosis
In vivo tumor retention of MGF-198AuNPs (PC-3 Xenografts)
30 min
1 hour
2 hour
4 hour
24 hour
100.00
60.00
40.00
20.00
Organs
Tumor
Carcass
Pancreas
Brain
Bladder
Bone
Muscle
Feces
Urine
Kidney
Sm Int
L Int
Stomach
Liver
Lung
Spleen
-20.00
Heart
0.00
Blood
Average % Dose
80.00
Therapeutic Efficacy Study of MGF-AuNPs
New Generation of Green Nanotechnology-BasedRadioactive Gold Nanoparticles with Optimum Tumor
Retention
Avg % Dose per Organ comparison chart
GA (aver)
EGCG
Pomegranate
MGNF
100.00
80.00
% Dose/organ
60.00
40.00
20.00
-20.00
Time
24 hour
4 hour
2 hour
1 hour
30 min
0.00
Tumor
Control
Group
Tumor
Treated
Group
2005-2015
2015
2013-2018
2020
Long Term Systemic Toxicity
First Complete In vivo Toxicology Measurement in
a Human Mimicking Model—Dogs!!!
Katti, Bechtel et al: International Journal of Nanomedicine: 2014:9 5001–5011
• Intralesional administration of GA-198AuNP (with 85% Non Radioactive
Gold Nanoparticles) caused no acute systemic toxicity
• Overall well tolerated
• No evidence of abscess formation at 3-4 weeks
• Monitoring for urethral obstruction paramount
EGCG-198AuNPs: In vivo therapeutic efficacy(PNAS 2012)
Therapeutic Efficacy Studies of MGF-198-AuNPs
(JCS Dalton in Press-2017)
Intratumoral delivery stops complete tumor propagation
Normal Cells
Intratumoral Injection
Cancer Cells
Malignant Cancer
Cells
Tumor
Cancer Stem Cells
Cancer cells + Normal
cells
Malignant + Mutated cancer
cells
Cancer Stem Cells
Complete inhibition of
Tumor propagation
Mutated Cancer
Cells
ACKNOWLEDGEMENTS
Ademar Lugao
Jeff Smith
Wynn Volkert
Carolyn Henry
Aslam Khan
Tamer Hafez
Cathy Cutler
David Robertson
Stan Casteel
Jeffrey Bryan
Sandra Bechtel
Kavita Katti
Menka Khoobchandani, Velapi Thipe, Kiandokht Amiri, Tamer Hafez, Sager
Gupta, Melissa Zaidi, Kattumuri Vijayalakshmi, Satish Nune, Nripin
Chanda, Ravi Pandrapragada, Rajesh Kulkarni, Sharanya Bhaskaran, and
Kishore Pillarsetty, Ravi Shukla,
FUNDING: NCI-CANCER NANOTECHNOLOGY PLATFORM; IAEA, Brazilian CNPQ
NANOCHARACTERIZATION LABORATORY, NCL; NIH;
(National Institutes of Health: Grant No:1R01CA119412-01 KATTI (PI)),
MU-OFFICE OF RESEARCH, RADIOLOGY & MURR