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 Missouri-Columbia, 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)

First to discover,

develop, and commercialize

an imaging agent for use in

humans.

First to develop bone

cancer therapy agents

Therasphere:

For liver tumor

therapy

MU-Gold: Chemotherapy for

prostate tumor

Green Nanotechnology In Nanomedicine

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.

THREE FDA APPROVED DRUGS

http://www.amershamhealth-us.com/ceretec/

http://www.cytogen.com/professional/quadramet/pi.php

TheraSphereTM

TheraSphereTM ---Safe---Minimum side effects ---

Liver cancer--- ranks #3 in deaths due to cancer---kills more that one million persons per year worldwide.

Yttria alumina silica glass meets stringent requirements --- chemically durable, high yttria content.

tumor

71 treatment sites in 33 states, ~ 170 world-wide

3

human hair

increased life expectancy

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

+ NaAuCl4

OH

OH HO

HO

=

Au OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO Au OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

Au OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO Au OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

OH

OH HO

HO

Characterization of AuNPs by TEM, UV-vis spectrophotometry and by zeta size instrument

535 nm

Hydrodynamic size= 60±2 nm Zeta potential = -31.5±3 mV

TEM image

Mangiferin—An electron-rich phytochemical transforms 198-gold precursor(s) into Gold Nanoparticles

Synthesis of MGF-AuNPs and MGF-198AuNPs

Mangiferin from

mango peel

+ Mangiferin (MGF)

NaAuCl4

H198AuCl4

MGF-198AuNPs

MGF-AuNPs

Prostate Tumor Therapy Agent: Clinical Candidates Identified

55 nm

35 nm

Size: TEM, CPS-Disc centrifuge systems= 35 nm Toxicity: Stability: Stable in vitro Stable in vivo (mice)

MGF-AuNPs gold Nanoconstructs: MGF-AuNPs

MGF-AuNPs Cellular Internalization

Cellular trafficking pathways of MGF-AuNPs

( PC-3 cells)

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.

Control- PC-3 cells without treatment

MGF-AuNPs treated Receptor blocked with dynamin inhibitor, Indicated: clathrin or caveolae pathways

Chlorpromazine treated, Indicated clathrin mediated endocytosis

Treated with anti-clathrin AB; Confirmed clathrin mediated endocytosis

Treated with anti-caveolae AB; Particles internalized which confirmed caveolae independent endocytosis

Nucleus

Cytoplasm

AuNPs

Results indicated clathrin mediated endocytosis

In vivo tumor retention of MGF-198-

AuNPs (PC-3 Xenografts)

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20.00

40.00

60.00

80.00

100.00

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Sple

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Bo

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Bla

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Bra

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Pan

cre

as

Car

cass

Tum

or

Ave

rage

% D

ose

Organs

30 min 1 hour 2 hour 4 hour 24 hour

Therapeutic Efficacy Study of MGF-AuNPs

New Generation of Green Nanotechnology-Based-

Radioactive Gold Nanoparticles with Optimum Tumor Retention

-20.00

0.00

20.00

40.00

60.00

80.00

100.00

30

min

1 h

ou

r

2 h

ou

r

4 h

ou

r

24

ho

ur

% D

ose

/org

an

Time

Avg % Dose per Organ comparison chart GA (aver) EGCG Pomegranate MGNF

Control Group

Treated Group

Tumor

Tumor

2005-2015 2015 2013-2018 2020

• 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

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

EGCG-198AuNPs: In vivo therapeutic efficacy(PNAS 2012)

Therapeutic Efficacy Studies of MGF-198-AuNPs

(JCS Dalton in Press-2017)

Intratumoral Injection

Complete inhibition of

Tumor propagation

Tumor

Cancer cells + Normal

cells

Malignant + Mutated cancer

cells

Cancer Stem Cells

Intratumoral delivery stops complete tumor propagation

Normal Cells Cancer Cells

Malignant Cancer Cells

Mutated CancerCells

Cancer Stem Cells

Ademar Lugao

Jeff Smith

Wynn Volkert

Carolyn Henry

Aslam Khan

Tamer Hafez

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,

ACKNOWLEDGEMENTS

Cathy Cutler

David Robertson

Stan Casteel

Jeffrey Bryan

Sandra Bechtel

Kavita Katti

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