# Presentation: 527194

## In Vivo Applications of Near-Infrared Quantum Dots

- John V. Frangioni, M.D., Ph.D.
- Assistant Professor of Medicine
- Assistant Professor of Radiology
- Harvard Medical School
- Moungi G. Bawendi, Ph.D.
- Professor of Chemistry
- Massachusetts Institute of Technology

## Outline

**I.****	****The Clinical Problem**
**II.****	****The Nanotechnology Solution**
**III.****	****The Regulatory Conundrum**

## I.	The Clinical Problem

_**Outline**_

**II.****	****The Nanotechnology Solution**
**III.****	****The Regulatory Conundrum**

## The Cancer Detection Problem

_**The Cancer Detection Problem**_

- Time

- Cell
- Number

- 1012

- 109

- Threshold for
- Detection

- Death of Patient

- 1 kg

- 1 g

- “Remission”

## Cancer Fates in the United States

- Cured
- By
- Surgery

- Not
- Cured

- Cured by Chemotherapy and/or
- Radiotherapy

- Approximately 1.3 x 106 Non-Skin Cancers Diagnosed
- Each Year  in the U.S.

## Cancer Fates in the United States

- Cured
- By
- Surgery

- Not
- Cured

- Cured by Chemotherapy and/or
- Radiotherapy

**Chemistry (Molecular Targeting)**
**Engineering (Instrumentation)**

## I.	The Clinical Problem

**III.****	****The Regulatory Conundrum**

**II.****	****The Nanotechnology Solution**

_**Outline**_

## The Nanotechnology Solution

_**Requires the Synergy of:**_
- _Engineering_:	Intraoperative Near-Infrared Fluorescence Imaging System
- _Chemistry_:  Highly Sensitive, Properly-Sized, and Stable Near-Infrared Fluorescent Contrast Agents (Quantum Dots)

## Near-Infrared Fluorescent Surgical Imaging System

- † Nakayama et al., _Mol. Imaging_, 2002; 1(4): 365-377

- Surgical
- Field

- 785 nm
- Dichroic
- Mirror

- NIR
- Camera

- Video
- Camera

- 810 ± 20 nm NIR Emission Filter

- 400 nm - 700 nm Bandpass Filter

- Zoom
- Lens

- 771 nm, 250 mW
- Laser Diode System

- NIR-Depleted
- 150 W Halogen
- White Light Source

- = Visible Light Path

- = NIR Fluorescence Light Path

## Computer &

- Electronics
- Cart

- Excitation/
- Emission
- Module

- Articulated
- Arm

- _Mobile Large Animal Intraoperative Imaging System_

- † DeGrand & Frangioni, Submitted

## A.

- B.

- _Deployment in the Surgical Suite_

- † DeGrand & Frangioni, Submitted

## The Surgeon’s View

- _The Surgeon’s View_

- † DeGrand & Frangioni, Submitted

## Fluorescent Semiconductor Nanocrystals (Quantum Dots)

- M.G. Bawendi and S.J. Kim (MIT)

- _Potential Advantages_	_Potential Disadvantages_
- Peak emission tunable anywhere from UV to IR	Potential toxicity of materials
- High non-aqueous QYs	Difficult to synthesize
- Broadband absorption increasing to the blue	Size/material limitations (?solved)
- High photostability
- Conjugatable to tumor targeting ligands

## Modeling of Near-Infrared and Infrared Photon Transmission

- † Lim et al., _Mol. Imaging_, 2003; 2(1): 50-64

## Infrared (1320 nm) QDs vs. NIR (840 nm) QDs

- _Infrared (1320 nm) QDs vs. NIR (840 nm) QDs_

- † Lim et al., _Mol. Imaging_, 2003; 2(1): 50-64

## Near-Infrared Fluorescent (Quantum Dots)

_**Near-Infrared Fluorescent (Quantum Dots)**_

- _IRDye78-CA_

- _NIR QDs_

- † Kim et al., Manuscript Submitted

## Movie

- (15-20 nm hydrodynamic diameter)
- Pig Femoral Lymph Node Model
- 200 μL of 2 μM Solution (400 pmol) of CdTe(CdSe)
- QDs in PBS Injected Intradermally

## Immediate Clinical Applications of NIR QDs

- • Image guidance during sentinel lymph
- 	node mapping
- • Image guidance during cancer resection
- • Image guidance for avoidance of critical
- 	structures (e.g., nerves and blood vessels)
- 	during general surgery
- • High sensitivity tool for surgical pathologists

## III.	The Regulatory Conundrum

_**Outline**_

**I.****	****The Clinical Problem**
**II.****	****The Nanotechnology Solution**

## We have the clinical need.

- NIBIB has funded the science.
- We now have the
- nanotechnology solution.
**But, can NIR and IR Fluorescent Quantum Dots ever be Translated**
**to the Clinic?**

## Summary of Quantum Dots for In Vivo Applications

- Reported Data

- Theoretical Data

## 	Summary of QD	Possible	

**	****Summary of QD****	****Possible****	**
**	****Semiconductor****	****Routes of**
_**	**__**Materials**__**	**__**Administration**_
- 	Antimonide	Intravenous
- 	Arsenide	Intraperitoneal
- 	Cadmium	Subcutaneous
- 	Gallium	Subdermal
- 	Indium	Intravaginal
- 	Lead	PO
- 	Mercury	Per-rectum
- 	Phosphide	Intravesical
- 	Selenide	Aerosol
- 	Sulfide
- 	Telluride
- 	Zinc

## Unresolved Regulatory/Toxicity Issues

_**Unresolved Regulatory/Toxicity Issues**_
- Will QDs be regulated as devices or drugs?
- Will QDs be regulated based on their
- chemical form (i.e., salts), or as individual metals?
- Does route of administration matter or do
- individual materials prevail?
- Special design of toxicity studies?
- Disposal of medical waste containing QDs

## What We Need as Investigators

_**What We Need as Investigators**_
- Guidance regarding “acceptable” materials or
- early indication that translation to the clinic
- is not possible
- Assistance with the design and implementation
- of toxicity studies
- Interagency cooperation regarding issues of
- drug delivery and disposal of QD-
- containing biological material

## Acknowledgements (Presented Data)

- _Frangioni Laboratory_:	Yong Taik Lim
- 		Jaihyoung Lee
- 		Alec M. DeGrand
- _Bawendi Laboratory_:	Sungjee Kim
- 		Nathan E. Stott
- 		Jonathan Steckel
- _Mihaljevic Laboratory_:	Edward G. Soltesz
- 		Rita Laurence
- 		Delphine Dor
- 		Lawrence Cohn

## NIBIB EB-00673

- _Funding_
**NIBIB EB-00673**
- NIH R21/R33 CA88245
- NIH R21 CA88870
- DOE DE-FG02-01ER63188
- Doris Duke Charitable Foundation
- CaPCURE
- Stewart Trust of Washington DC