Académique Documents
Professionnel Documents
Culture Documents
Biomedical Applications
Submitted by
to
The Department of Science and Technology
Technology Bhavan, New Mehrauli Road
New Delhi-110016, INDIA
Origin of proposal
Quantum Dots (QDs), also known as nanocrystals (NCs), are crystals composed of
periodic groups of II-VI, III-V, or IV-VI materials. QDs are unique class of semiconductor
(or non-traditional semiconductors) because they are so small, ranging from 2-10 nanometers
(10-50 atoms) in diameter. At these small sizes materials behave differently, giving QDs
unprecedented tunability and enabling never before seen applications to science and
technology. The fundamental reasons were first explored by Steigerwald and Brus that
semiconductor NCs are strongly dimension dependent.1 When at least one of the physical
dimensions of NCs is smaller than the diameter of the bulk exciton of the given material the
exciton becomes quantum-confined along that dimension. The confinement energy, as a
significant part of the total energy of the electrons and holes, increases as the dimension
decreases. Since most chemical properties are largely determined by energy levels, these
properties become size-dependent. A dot-shaped semiconductor NC (quantum dot) is three1. L. E. Brus, J Chem. Phys. 1983, 79, 5566.
dimensionally confined if the size of the NC is smaller than the diameter of the bulk exciton.
Dots are the most common shape for NCs and have been widely studied in the past.
QDs addressing biomedical application have become an important subject of
investigation worldwide. Over past few decades, significant advances have been made
towards the synthesis of colloidal QDs, nanorods and nanowires. Owing to their novel optical
properties, semiconductor NCs are of great interest to many fields such as field-effect
transistors,2 waveguides,3 nanolasers,4 photovoltaics,5 electronics,6 and biolabels.7 Specific
applications, for example, biolabels, require these NCs to be not only highly luminescent but
also water-soluble. Recently, inorganic QDs composed of group II and VI metals have
emerged as potential optical imaging tools in the biomedical field. A widespread use of QDs
instead of organic fluorophores is for the reason that organic dyes are generally vulnerable to
the physiological environment and are quickly photobleached under normal imaging
conditions. They are also not good for multicolor imaging because of two inherent properties:
a) organic dyes have relatively broad emission spectra and hence result in the signal overlap
from different dyes; and b) one organic dye can only be suitably excited by the lights within
a certain narrow wavelength range and it thus needs nearly the same numbers of excitation
light sources as the dyes used.
On the other hand, QDs are robust inorganic fluorophores that exhibit size-dependent
fluorescence emission spectra that span the visible-NIR spectrum. Their broad emission
spectra allow simultaneous excitation of different particle sizes at a single wavelength with
emission at multiple wavelengths. In addition, QDs provide the benefit of a good quantum
yield and high photochemical stability. QD fluorophores enable multiplex assays requiring a
single excitation source far from the QD emission peaks. Since the introduction of
compatible QDs in 1998,7a,b the potential of QDs to address multiplexing was quickly
realized and remarked;8 however, demonstrations of this ability have only recently started to
appear.
J. Goldberger, A. I. Hochbaum, R. Fan, P. D. Yang, Nano Lett. 2006, 6, 973.
M. Law, D. J. Sirbuly, J. C. Johnson, J. Goldberger, R. J. Saykally, P. D. Yang, Science 2004, 305, 1269.
J. C. Johnson, H. J. Choi, K. P. Knutsen, R. D. Schaller, P. D. Yang, R. J. Saykally, Nat. Mater. 2002, 1,
106.
5. I. Gur, N. A. Fromer, M. L. Geier, A. P. Alivisatos, Science 2005, 310, 462.
6. X. F. Duan, Y. Huang, Y. Cui, J. F. Wang, C. M. Lieber, Nature 2001, 409, 66.
7. a) M. Bruchez, Jr., M. Moronne, P. Gin, S. Weiss, A. P. Alivisatos, Science 1998, 281, 2013; b) W. C. W.
Chan, S. M. Nie, Science 1998, 281, 2016; c) I. L. Medintz, A. R. Clapp, H. Mattoussi, E. R. Goldman,
B. Fisher, J. M. Mauro, Nat. Mater. 2003, 2, 630; d) S. Kim et al. Nat. Biotech. 2004, 22, 93.
8. C. M. Niemeyer, Angew. Chem., Int. Ed. 2001, 40, 4128.
2.
3.
4.
in the Pohang University of Science and Technology, South Korea, I worked on the synthesis
of QDs (CdSe, and InP) and rendered them water soluble with dihydrolipoic acid. This water
soluble QDs were finally used as fluorescent probe in cell imaging. Recently, I have joined
IIT Patna and looking for fund to start research work in this emerging interdisciplinary field.
9.
a) Y. Wang, Z. Tang, M. A. Correa-Duarte, I. Pastoriza-Santos, M. Giersig, N. A. Kotov, L. M. LizMarzan, J. Phys. Chem. B. 2004, 108,15461; b) J. Zhuang, X. Zhang, G. Wang, D. Li, W. Yang, T. Li, J.
Mater. Chem.2003, 13, 1853; c) R. Kho, C. L. Torres-Martinez, R. K. Mehra, J. Colloid Interface Sci.
2000, 227, 561; d) J. O. Winter, T. Y. Liu, B. A. Korgel, C. E. Schmidt, Adv. Mater. 2001, 13, 1673.
10. a) C. B. Murray, D. J. Norris, M. G. Bawendi, J. Am. Chem. Soc. 1993, 115, 8706; b) Z. A. Peng, X. Peng,
J. Am. Chem. Soc. 2002, 123, 183; c) W. W. Yu, Y. A. Wang, X. Peng, Chem. Mater. 2003, 15, 4300; d)
W. W. Yu, X. Peng, Angew. Chem. Int. Ed. 2002, 41, 2368; e) D. Battaglia, X. Peng, Nano Lett. 2002, 2,
1027; f) R. E. Bailey, S. Nie, J. Am. Chem. Soc. 2003, 125, 7100.
Review of R&D in the proposed area (National & International Status, Importance,
Patents etc.)
The term quantum dots (QDs) was coined by Mark Reed and was first discovered by
Brus. The quantum confinement effect in the semiconductor NCs made them interesting
which leads to have different optical properties with size. Dots are the most common shape
for NCs and have been widely studied in the past, which is why, in most of the literature,
dimension-dependent properties are called size-dependent properties, and also why synthesis
of quantum dots is the most advanced. Inspection of patents and literature reveled that many
different methods have been explored for controlled synthesis of colloidal NCs.
Organometallic approaches in coordinating solvents, invented in the early 1990s by
Steigerwald et al.11 and developed to a practical level by Murray et al.,10a are regarded as
having been the first major breakthrough that yielded CdSe NCs of contemporary quality.
Very recently, alternative approaches using air-stable precursors, such as inorganic salts,
organic salts, oxides, and metals have been found to be possible,12 and even more recently,
non-coordinating solvents were also introduced.10d The mechanism of the growth of
monodisperse NCs plays a critical role in the development of synthetic chemistry.
11. M. L. Steigerwald, L. E. Brus, Acc. Chem. Res. 1990, 23, 183.
12. a) Z. A. Peng, X. Peng, J. Am. Chem. Soc. 2001, 123, 183; b) L. Qu, Z. A. Peng, X. X. Peng, Nano Lett.
2001, 1, 333.
Owing to a lack of knowledge of crystallization, studies on formation of NCs are essential for
good progress in the synthesis of colloidal NCs. In fact, the first introduction of these
alternative approaches12 was a direct result of the study of the growth mechanism of CdSe
NCs using traditional organometallic approaches.13 Surface effects on the optical properties
of semiconductor NCs have been noted for a long time,14 and a few results on this issue were
reported recently.15
QDs are mostly synthesized in nonpolar organic solvents. If they are to be solubilized in
aqueous buffers, their hydrophobic surface ligands must be replaced by amphiphilic ones.
Different QDs solubilization strategies have been devised over the past few years including
(i) ligand exchange with simple thiol-containing molecules7b or more sophisticated ones such
as oligomericphosphines,16 dendrons17, and peptides;18 (ii) encapsulation by a layer of
Fluorescent
Biocompatible
Quantum Dots
Phase II
Phase III
Development of
New Methods for
Synthesis of QDs
Developmet of
Cationic, Anionic
and Zweterionic
Ligands
Stability Test at
Physiological
Conditions
Development of
Core/Shell QDs
Development of
New Ligand
Exchange Methods
Development of
Water Soluble
Core/Shell QDs
(i) In our strategy of synthesis, easily accessible starting materials will be used. As evident
from the literature preparation of well crystallized QDs is little difficult and suffers from poor
luminescence efficiency, reduced control of size distribution, less size tenability and poor
stability. It is very difficult to obtain a controllable nucleation burst because this brust
depends on various parameters such as polarity, surfactant and coordination property of
solvent. Depending on the type of reactants involved in QDs choice of solvent may be made.
In strong coordinating solvents, there may be unselective coordination to the reactant results
in either very slow and continuous nucleation or very fast reaction yielding in amorphous or
bulk compounds which on prolong heating for few days gives slower nucleation to NCs.
Whereas in non coordinating solvents the surfactant used in the synthesis such as carboxylate
and amine groups offer an in situ high selective coordination that led to the controlled
nucleation and growth. We beleive that a weak coordinatig solvent and judicious amount
and choice of surfactant not only offer polarity to the reaction matrix that control the reaction
but also provide surface stability to the QDs (Fig. 2). Apart from these, all the synthesis uses
solvents like trioctylphosphine oxide, trioctylphosphine, trioctyl amine, high fatty acid ester
and/or octadecene, neither of which are separable nor were any attempts made for
reuse/recycling these solvent to our knowledge. This results in burdening the environment
and high cost as well. We intend to use such solvents which may be seperable or reusable.
7
I, II, III-Precursor
+
VI-Precursor
Ligand, Solvent
QDs
Core
Low temperature
I = Cu, Ag
II = Cd, Zn
III = In, Ga
VI = S, Se, Te
Shell
precursor
QDs
Core
QDs
Core/Shell
have some functional groups which either can be used for conjugation or for electrostatic
interaction with some antibody, receptors or carrier proteins for smooth endocytosis and
targeted delivery. Keeping mind in those facts a few cationic, anionic, zwitterionic and neutal
ligands is being proposed. The synthesis for the ligands is under Scheme 1. Synthesis of
those ligands will be done from the commercially available lipoic acid.
Cationic Ligand
O
N
N
H
SH HS
OO
Zwitterionic Ligand
Neutral Ligand
NH
OH
O
LA(Lipoic acid)
NH
O
SH
H
N
O
O
SH
S
SH HS
O
H
N
SH HS
SH
N
H
Anionic Ligand
SH
O
S
Ligand exchange
QDs
Core/Shell
QDs
Core/Shell
(v) After the ligand exchange, purification will be a major task. The purification will be done
by centrifugation with MW cut filter. And then the hydrodynamic size and zeta potential of
the water soluble QDs will be measured. These two factors are crucial for the biomedical
applications.
Time schedule:
First 12 months
Development
13-18 months
of Development a
19-24 months
Synthesis of
Development Screening of
surface
with
functional
I-III-VI
groups
ligands of
new stability of
for water soluble
different strategy
QDs at
ligand
characterization
Yield
and
of
characterization
remains
unchanged or
slightly
changed.
In conclusion, the fellowship will contribute to a research effort to develop new route
for the synthesis of QDs from the readily available starting materials and render them water
soluble via ligand exchange. This water soluble QDs will be used for cell imaging. The
results obtained will be of interest to a broad spectrum of people starting from chemistry,
physics to nanotechnology and nanobiotechnology.
Future plans
Once we achieve our target plan we will turn our attention to use this water soluble
QDs for cell imaging and will further be conjugated with DNA oligonucleotide or aptamer,
antibody, receptors for target specific applications.
10
Details of the research funding received in the past and/ongoing projects: NIL
6. Name and address of the institution where the proposal will be/likely to be executed:
Department of Chemistry
Indian Institute of Technology Patna
New Govt. polytechnic campus
Patliputra colony
Patna-800 013, Bihar, INDIA
7. Facilities provided/to be made available at the host institute:
IIT Patna will provide basic facilities such as required workspace to carryout
experimental (ventilated hood, work bench) and theoretical work (computer desk with online
access to databases). In addition, electricity, library as well as water supply facilities will also
be provided. The purchase of some modern and state of the art instrument such as UVVisible, Fluorescence and FTIR-spectrometer, are under process. For characterization of QDs
by powder-XRD, TEM and EDX will be carried out elsewhere.
9. Details of financial requirements for three years (with justifications) and phasing for
each year:
1st Year
NA
2nd Year
NA
3rd Year
NA
Total
-----------
2
3.
Head
Fellowship @Rs.20,000/p.m.*
Manpower (JRF/SRF)**
Consumables
1,72,800a
2,50,000
1,72,800a
2,50,000
2,01,600b
2,00,000
5,47,200
7,00,000
4.
30,000
30,000
40,000
1,00,000
5.
6.
Contingency
Equipment (Generic Name
with minimum required
accessories, make & model
& Cost in Indian Rupees)
50,000
50,000
50,000
1,50,000
S. No
1
USB2000-FLG Miniature
Fiber Optic Spectrometer
with Computer and
accessories
(1 unit)
7.
3,50,000
-
Fridge (1 unit)
30,000
45,000
15,000
UV lamp (1 unit)
30,000
1,94,560
1,00,560
98,320
4,70,000
3,93,440
Total 23,60,640
[Total = Rupees twenty three lakhs sixty thousands six hundred forty only]
* applicable to scientist having no regular employment and are not drawing any fellowship
during the project tenure
** applicable for researcher holding regular position.
a
2,01,600
12
13
Detailed Biodata
1. Name of the Applicant: Dr. Sahid Hussain
2. Mailing Address (Indicate Telephone, Fax, E-mail, etc.)
Dr. Sahid Hussain
Assistant Professor
Department of Chemistry
Indian Institute of Technology Patna
New Govt. Polytechnic campus
Patliputra colony, Patna-800013, Bihar
E-mail: sahid@iitp.ac.in and sahid.iitg@gmail.com
Tel (O): +91-612-2552022; Mobile: +91-9471830688; Fax: +91-612-2277383
3. Date of Birth : 10/02/1978
Gender: Male
University
Year
Subjects
Percentage
B. Sc.
Dibrugarh University
1999
62.6
M. Sc.
Gauhati University
2002
3.
Ph. D.
Indian Institute of
Technology Guwahati
2008
Chemistry (Major),
Physics, Mathematics
Organic
Chemistry
Catalysis
66.3
8.0/10 CPI
14
15
Annexure-I
(Statement from Employer)
This is to certify that:
I. Dr. Sahid Hussain, the Principal Investigator in the project entitled Fabrication of Highly
Fluorescent Quantum Dots for Biomedical Applications will assume full responsibility for
implementing the project.
II. The date of appointment starts from the date on which the University/Institute receives
the bank draft/cheque from the Department of Science & Technology.
III. The Investigator will be governed by the rules and regulations of the University/
Institute and will be under administrative control of the University/ Institute for the duration
of the project.
IV. The grant-in-aid by the Department of Science & Technology will be used to meet the
expenditure on the project and for the period for which the project has been sanctioned as
indicated in the sanction letter/ order.
V. No administrative or other liability will be attached to the Department of Science &
Technology at the end of the project.
VI. The University/ Institute will provide basic infrastructure and other required facilities to
the investigator for undertaking the research project.
VII. The University/ Institute will take into its books all assets received under this sanction
and its disposal would be at the discretion of Department of Science & Technology.
VIII. Institute assumes to undertake the financial and other management responsibilities of
the project.
17