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ISSN:1369 7021 © Elsevier Ltd 2009 VOLUME 12 – ELECTRON MICROSCOPY SPECIAL ISSUE24

Nanotechnology tools inpharmaceutical R&D

Global pharmaceutical industry is at cross roads. On one hand

the big pharmaceutical companies are enjoying enormous profits.

The combined annual net income for the top 10 pharmaceutical

companies (ranked by market capitalization) is currently around

$73 billion. The average price of a new drug has been rising much

faster than the rate of inflation. The drug companies continue to

charge high retail prices for new drugs that are only incrementally

different from older drugs whose prices have fallen. On the other

hand, there are increasing costs of R&D spending as the companies

are faced with the expiration of the patent protection on their

main profit generators. Even though there is a growing knowledge

of how diseases work at the genetic and molecular levels opening

up new drug targets, there have been relatively few new products

or new molecular entities (NME) in the pipeline as the strategy is

to continue to follow the ‘blockbuster drug’ model; which is like

searching for a needle in a haystack (Fig. 1).

The ‘blockbuster drug’ model in itself is questionable as standard drug

treatments for a number of therapeutic areas provide a therapeutic

benefit only to a limited percentage of patients who receive it

Nanotechnology is a new approach to problem solving and can be

considered as a collection of tools and ideas which can be applied

in pharmaceutical industry. Application of nanotechnology tools inpharmaceutical R&D is likely to result in moving the industry from

‘blockbuster drug’ model to ‘personalized medicine’. There are

compelling applications in pharmaceutical industry where inexpensive

nanotechnology tools can be utilized. The review explores the possibility

of categorizing various nanotechnology approaches to meet the

requirements in pharmaceutical R&D.

Challa S.S.R. Kumar1, 2

1 Center for Advanced Microstructures and Devices, Louisiana State University, 6980 Jefferson Hwy, Baton Rouge, LA 708062Magnano Technologies, 12538 Frankfurt Ave, Baton Rouge, LA 70816.

Email: [email protected] ; [email protected]

Fig. 1 NME approvals and drug companies’ spending on research and development (a congressional budget office study on R&D in the pharmaceutical industry, 2006).

mailto:[email protected]








Nanotechnology tools in pharmaceutical R&D REVIEW

VOLUME 12 – ELECTRON MICROSCOPY SPECIAL ISSUE

(Fig. 2)1,2. The irony is that medical diagnostics account for just 1%of healthcare spending, yet it is the basis for 60% of all healthcare

decision-making. Let us look at the cancer pharmaceutical industry

more closely as within the next decade cancer is likely to replace heart

disease as the leading cause of U.S. deaths; according to forecasts

by the National Cancer Institute (NCI) and the Centers for Disease

Control and Prevention. Having approximately published more than

1.5 million scientific publications on cancer and cancer drugs, carried

out more than 150 000 studies on mice, with an annual R&D funding

of $15 billion and an annual cost of treatment around $65 billion, we

are nowhere near to developing drugs that completely cure cance r3.

It is quite evident that the pharmaceutical industry has become less

innovative. Therefore, new approaches are required not only to changethe pace but also the direction of innovation.

The emergence of nanoscience and nanotechnology, which is

creation and utilization of materials and tools at the nanometer scale,

has been a great influence on a number of industries and particularly

the pharmaceutical industry. Just as recombinant technology and

biotechnology changed the landscape of pharmaceutical industry,

nanotechnology is poised to lift the pharmaceutical industry that is at

cross roads today, to new levels. However, unlike the biotechnology

industry which influenced primarily the pharmaceutical industry,

nanotechnology has broader applications and therefore, the

nanotechnology tools and materials developed for other industries

also have potential opportunities in the pharmaceutical industry as

well. In addition, there is a prevalent notion that nanotechnology

tools are exotic, too futuristic, disruptive and not suitable for quick

commercialization of products. This notion is far from truth as

nanotechnology tools are being shown to add value to existing

products for existing markets as well as opening opportunities in new

markets. This is true not only for the pharmaceutical industry but

also for other industries. However, what is clearly lacking is a model

for sorting out the plethora of nanotechnology tools that exists and

strategically correlating with potential opportunities into differentsegments of pharmaceutical R&D4-6. In addition, there is going to be

a paradigm shift in the pharmaceutical industry towards personalized

medicine as a new standard of care integrating therapeutics with

diagnostics. It is, therefore, important to develop a more scientific

approach for strategic implementation of nanotechnology tools in

the pharmaceutical industry. The goal of this article is to explore a

model for strategic decision making, termed as Innovation Box for

Implementation of Nanotech Tools (IBINT©) and its utility specifically

tailored for the pharmaceutical industry. This approach, as explained

below, is likely to be more versatile, valuable and practical than

traditional/current classification of nanotechnology in medicine (or

nanobiotechnology) into segments such as drug discovery, diagnosticsand drug delivery7. The new approach proposed here relies on taking

into consideration all the nanotechnology tools, from the more

expensive to the less expensive, and sorting them based on their

utility into three major categories of pharmaceutical R&D- Process

development, product development and personalized medicine (Fig. 3).

The concept of IBINT© is pictorially represented in Fig. 4. The basic

premise of IBINT© rests in its broad applicability of nanotechnology

tools influencing three major parts of pharmaceutical R&D-Process

development, product development and personalized medicine. These

three parts have different value propositions which in turn vary

depending on the types of targeted markets. While the traditional/

existing model limits the utility of nanotechnology tools to highly

complex, costly, risky and time consuming segments of pharmaceutical

R&D, IBINT© provides a scaffold for strategic development of

application of nanotechnology tools both in high cost as well as low

cost segments. A number of examples of nanotechnology tools can be

classified using IBINT© and are described briefly below. However, one

needs to keep in mind that the application of IBINT© becomes more

valuable when it is used for strategic decision making keeping in view

specific needs of individual pharmaceutical companies.

Fig. 2 The limitations of standard drug treatment as seen from the responserates of patients from selected group of therapeutic areas (Source: TRENDS inMolecular Medicine, 2001).

Fig. 3 Development of a model for application of nanotechnology tools in pharmaceutical industry.



REVIEW Nanotechnology tools in pharmaceutical R&D

VOLUME 12 – ELECTRON MICROSCOPY SPECIAL ISSUE26

Nanotechnology tools for

process developmentThere are already several nanotechnology tools available that can be

utilized in process development. The term process development refers

to both synthesis of drugs, drug intermediates and to development

of analytical tools for diagnostics. One of the most important

tools is miniaturization and automation in organic synthesis and

biological screening on a nanoscale. Two examples of such tools are

the NanoSynTestTM-system8 and the X-cubeTM system9. The central

feature of these systems is the ability to manipulate reactions in

nano-size titer plates with a density of about 100 wells/cm2 and the

capability to handle nano liter volumes. While the NanoSynTestTM

offers several modules for simultaneous drug synthesis and ultra

high throughput screening, the X-cubeTM allows organic reactionsto be performed in a flow manner at high temperatures and

pressures. Such tools in automation and miniaturization coupled with

nanotechnological approaches are expected to lead to efficient cost

reductions in process development of existing as well as new products.

In addition to the miniaturization of synthetic methods,

nanomaterials are being developed as efficient catalysts and supports

for solid-phase organic synthesis. Magnetic nanoparticle-supported

chiral Ru complexes are known to catalyze heterogeneous asymmetric

hydrogenation of aromatic ketones with remarkably high activity

and enantioselectivity10. Magnesium oxide nanoparticles are utilized

for residue-free catalytic process for production of Nabumetone, an

anti-inflammatory agent, in high yield and high selectivity11. Recently,

functionalized cobalt core carbon shell nanoparticles with excellent

magnetic properties and high stability in air and at temperatures up to

190°C have been reported12. Such nanobeads with high capacity for

ligand binding and ability to rapidly remove them from the reaction

mixture make them excellent solid supports in organic synthesis and

biotechnological applications.

Additionally, futuristic and more expensive nanotechnology tools

such as nano devices (nanoelectromechanical resonators) that can

weigh individual molecules13 and ultrafast electron imaging tools

for monitoring reactions as they happen14 are going to revolutionizequality control during process development of drug molecules.

An overview of some of these nanotechnology tools for process

development is depicted in Fig. 5.

Nanotechnology tools forproduct developmentSome of the tools described above can also be utilized for product

development. The term product development encompasses drug

discovery as well as development of diagnostic tools. One of the most

obvious and important nanotechnology tools for product development

is the opportunity to convert existing drugs having poor water

solubility and dissolution rate into readily water soluble dispersionsby converting them into nano-size drugs15,16. Simply by reducing the

particle size of drugs to the nanometer range, the exposed surface area

of the drug is increased and hence its ability to be absorbed. Once the

drug is in nano form, it can be converted into different dosage forms

such as oral, inhalation, nasal and injectable. Key implication of this

approach is the possibility of life cycle extension for existing drugs, for

existing markets. There are a number of well known drugs that have

already been commercialized using this approach for existing markets.

For example, immunosuppressant drug Rapamune® (sirolimus),

Emend® (aprepitant, MK 869), a substance P antagonist (SPA) for

prevention of acute and delayed chemotherapy-induced nausea and

vomiting (CINV) and for prevention of postoperative nausea and

vomiting, have nano-size drugs made by Elan Corporation using

nanocrystal™ technology17. Using micro emulsions as templates for

solid nanoparticles, NanoMed Pharmaceuticals is currently developing

a number of nano-size drugs using its patented Nanotemplate

Engineering™ technology. The insoluble drug delivery (IDD®)

technology platform from SkyePharma is utilized in several drugs

currently on the market such as SOLARAZE® for skin cancer and anti-

depressant PAXIL CR™. Finally, RBC Life Sciences® is developing a new

Fig. 4 An approach for strategic implementation of nanotechnology tools in the pharmaceutical industry. Fig. 5 Some of the nanotechnology tools for process development.





line of nutritional and skincare supplements called NanoCeuticals™

with nanoscale ingredients. This allows RBC to create products which,

when consumed, reduce the surface tension of foods and supplements

to increase the wetness and absorption of nutrients.

As emphasis in drug development is towards controlled delivery

and release, nanotechnology offers a number of tools in order to

transform current drugs with these capabilities15,18-20. Nanotechnology

tools for developing drug delivery systems and devices are valued at

around $300 billion capturing significant applications in the health

care market. As controlled release and delivery technologies are

patentable, old ‘blockbuster drugs’ can have continued protection at a

relatively low cost. This is immensely attractive for the pharmaceutical

industry in order to ward off the generics industry away from their

hard earned profits. Additionally, drugs with these new capabilities

will likely find applications in new markets. Simplest in this category

are polymer encapsulated drugs such as MutliSal™, DermaSal™ and

MatrixSal™ from the company Salvona. Such polymer encapsulateddrugs can be fine tuned to deliver the drugs using a number of

stimuli such as pH, temperature, and water. In addition to simple

polymer encapsulation, more sophisticated nanotechnology tools,

such as nano core-shell designs, are also being developed in order

to further fine tune delivery and release. For example, in a recent

work Sengupta et al.21 demonstrated a novel approach for treating

angiogenesis using a core-shell architecture wherein the polymer core

has cytotoxic agent with the encapsulation of the anti-angiogenesis

agent in the surrounding phospholipid block-copolymer22 (Fig. 6). Such

a design enables temporal targeting of the tumor vasculature, resulting

in the intra-tumoural trapping of the nanoparticles. This resulted in

slow release and focal build-up of the cytotoxic agent within thetumor thereby prolonging exposure and an increase in the apoptotic

potential, which can overcome hypoxia-induced reactive resistance.

Yet another interesting example is gene delivery using multi-segment

Au-Ni nanorods23. By attaching selectively plasmids to the nickel

segment and a cell-targeting protein, transferrin, to spatially separated

Au region, the gene delivery system provides precise control of

composition, size and multi-functionality. Such nanotechology tools

have potential applications in genetic vaccination.

As mentioned earlier, medical diagnostics account for just 1%

of the total health care costs, even though at least 60% of all

healthcare decision-making is based on diagnosis. Limitations in

existing medical detection technologies – complexity, cost and time

consuming - have led to the development of several nanotechnology

tools for ultra-sensitive and fast diagnosis of disease conditions

and biomarkers20. Such nanotechnology diagnostic tools are driving

the product development not only in drug discovery process but

also in sensitive and timely disease detection. The majority of the

commercialized nanotechnology diagnostic tools involve either

quantum dots or gold nanoparticles. For example, biological barcode

assay utilizing gold nanoparticles has become a powerful analytical

tool for detection of both protein and nucleic acids in zepto molar

concentrations, much higher than those possible using the PCR or

ELISA techniques24. The company, Nanosphere, is using these tools to

develop rapid, multiplex clinical tests for some of the most common

inherited genetic disorders, including certain types of thrombophilia,alterations of folate metabolism, and cystic fibrosis25. Similarly,

hitherto undetectable pathogenic Alzheimer’s disease markers in

cerebral spinal fluid are being detected using these tools26. Quantum

dot-based nanotechnology tools have been instrumental in visualizing

not only cells but also specific components in the cell such as

proteins and to follow the growth of an organism through live cell

imaging7. They are also utilized for multiplexed and quantitative

immunohistochemistry for evaluating biomarkers on intact cells

and tissue specimens27. The companies, Invitrogen and Evident

technologies, offer a wide range of quantum dots for a variety of

applications in product development.

High throughput synthesis and screening is yet another importantrequirement in product development and nanotechnology is

offering several effective tools. The aim is to go beyond the current

ultrahigh-throughput screening levels of more than 100 000

assays per day covering not only larger hits but also qualified leads

through simultaneous screening for ADME (adsorption, distribution,

metabolism, and excretion) and toxicity testing. Efforts towards

miniaturization in high throughput parallel and combinatorial synthesis,

as described earlier, coupled with novel technological tools for

screening and bioinformatics for process integration are likely to bring

out a paradigm shift in product development. Some of the exciting

nanotechnology tools for such ultrahigh throughput screening are

described below.

Dip Pen Lithography is one such tool. The challenge of precision

nanoscale deposition of a wide range of molecules onto diverse

surfaces is overcome by Dip Pen Nanolithography® (DPN®), a high

resolution scanning probe-based direct-write technology. It satisfies

and exceeds these fundamental requirements through massive

scalability of the process with two dimensional probe arrays. The

researchers at Northwestern University28 demonstrated massively

parallel nanoscale deposition with a 2D array of 55 000 pens on a

Fig. 6 Polymer core-lipid shell nanoparticles carrying drug for anti-angiogenesiswithin the lipid shell and a chemotherapeutic drug within the polymer core.(Reprinted from22 with permission from Macmillan Publishers Ltd).





centimeter square probe chip. Fig. 7 shows SEM image of a portion

of an 88 000 000 gold dot array (40 × 40 within each block) on an

oxidized silicon substrate. On the right-hand side is a representative

AFM topographical image of part of a block28. The technique, therefore,

enables direct-writing of flexible patterns with a variety of molecules;

simultaneously generating 55 000 duplicates at the resolution of

single-pen DPN®. To date, there is no other way to accomplish thiskind of patterning at this unprecedented nano-resolution. The 2D

nano PrintArray™ from the company Nanoink is based on the DPN®

technology. Such advances enable ultrahigh throughput screening

for biological interactions at single molecular level. Similarly, the

company Nanostream offers a wide range of nanotechnology-based

tools for high throughput design and conduct of challenging biological

assays, screening compounds for purity and solubility, profiling

of ADME properties, accelerate formulation studies and perform

comparative stability screening29. The company Nanosys’s nanowire-

based microarrays is providing a 100-fold higher binding area without

reducing binding kinetics. While such nanostructured microarrays have

the flexibility of being compatible with today’s microarray platforms,the technology can be used to create, in principle, arrays of any

dimensions. Similarly, the company Bio Trove30 offers microarrays

with over 24 000 nano-liter reactions chambers for PCR amplifications

thereby reducing the reaction volumes at least 200 times smaller than

in current micro plate screening, making PCR an inexpensive option in

ultrahigh throughput screening.

An overview of some of these nanotechnology tools for product

development is depicted in Fig. 8.

Nanotechnology tools forpersonalized medicineScientific advances in genetic engineering, identification of biomarkers,

and mapping of molecular pathways for diseases coupled with explosive

growth of nanotechnology tools are driving the pharmaceutical industry

towards personalized medicine31-33. The pharmaceutical industry today

is already practicing the personalized medicine in a limited way. For

example, selective prescription of antidepressant drugs, anticoagulants

and proton pump inhibitors based on Cytochrome P450 (CYP450) test.

Similarly Herceptin, a breast cancer drug made by Genentech, is only

given to patients that test for unusual gene called HER2, which hasbeen implicated in cancer growth. As more and more drugs are getting

personalized, there is more pressure for pharmaceutical industries to

move from blockbuster business model to tailored therapies. This in

turn is leading to the development of novel nanotechnology tools

for personalized medicine. The model IBINT©, therefore, considers

personalized medicine as an important segment for the strategic

growth of pharmaceutical industry. There is a number of exciting

nanotechnology tools currently finding applications in the development

of personalized therapies16,19 and some of them are given below.

One of the most important nanotechnology tools for personalized

medicine is ultrasensitive molecular imaging. There are several novel

techniques that are currently under development. One such techniqueis HYPER-CEST molecular magnetic resonance imaging (MRI) which

allows for detection of signals from individual molecules within a

cell at about 10 000 times lower concentration than conventional

MRI techniques. The technique uses chemical exchange saturation

transfer (CEST) between the biosensor-encapsulated Xe and the

easily detectable pool of free Xe34. The various components of the

Xe biosensor are cryptophane-A cage, the linker, the targeting moiety

(biotin in this case), and the peptide chain. The 129Xe NMR spectrum of

this construct through chemical exchange with free Xe outside the cage

(resonance d1) enables sensitivity enhancement by depolarizing the

d3 nuclei and detecting at d1. Yet another tool is in situ atomic force

microscopy (AFM) with simultaneous confocal and epifluorescence

microscopes. It has been recently utilized to investigate the interactions

of enzymes and proteins within lipid bilayers35.

Surface-enhanced Raman spectroscopy (SERS) using nanoparticle

tags for detection and identification of biomarkers is gaining a lot

of prominence. Recently, PEGylated gold nanoparticles coupled with

targeting agents and small-molecule Raman reporters such as organic

dyes were found to be >200 times brighter than near infrared-emitting

quantum dots, and allowed spectroscopy imaging of tumors as small as

Fig. 7 SEM image of gold dot arrays on a silicon substrate. (Reprinted from 28 with permission from Macmillan Publishers Ltd)

Fig. 8 Some of the nanotechnology tools for product development.





300 μm3 at a penetration depth of 1-2 cm36. Fig. 9 shows in-vivo SERS

spectra obtained from PEGgylated gold nanoparticles injected into

subcutaneous and deep muscular sites in a nude mouse. In addition to

cancer diagnosis, SERS is also proving to be a valuable technique for

carrying out a number of sensitive immune assays37, for example in the

diagnosis of musculoskeletal diseases38.

Yet another promising tool is the Sensation Detection Platform

from Nanomix39. This tool enables direct, electronic, label-free

detection of gases and biomarkers based on the changes in the

electronic characteristics of random networks of carbon nanotubes.

These devices are arrayed on silicon and plastic substrates and provide

multi-plexed, multi-analyte detection and pattern analysis for ultra-sensitive, specific, and reproducible bio-assays. For example, the

Nanomix asthma monitor in development is a small, inexpensive unit

that measures the level of nitric oxide (NO) in exhaled breath. Such

devices could reduce needed medicines such as inhaled corticosteroids,

reduction of traumatic and costly asthma attacks. Also, monitoring

of the progression and regression of a disease pre-symptomatically

enables a whole range of new medical decision-making. In addition

to carbon nanotubes, semiconducting nanowires have been shown

to be promising as highly sensitive and selective sensors for label-

free detection40. Similarly, analysis of various biomarkers in human

breath is anticipated to lead to point of care diagnosis of diseases

such as virus, lung or breast cancers, liver disease, gastrointestinal

problems, and many others. In general, explosion of highly sensitive

nanotechnology diagnostic tools is driving a change from empirically

based, trial-and-error medicine, to more evidence-based, personalized

solutions. These techniques enable simple, cost-effective, point-of-care

results for critical decision-making.

Novel concepts such as ‘body-on-a-chip’ which can mimic human

cells and human body and their reaction to different therapeutic

conditions help reduce the need for testing ADME in animals and

hence lower the cost of developing new drugs. The new body-on-a-

chip device, being developed by Cornell biomedical engineers, is lined

with human cells and reacts the way tissues and organs would do to

drugs41. In the same way, implantable micro chips such as those being

developed by MIT researchers will ensure continuous monitoring of

diseases and detection of biomarkers42. The concept is based on what

is called magnetic relaxation switches wherein shortening of transverse

relaxation time (T2) on aggregation of magnetic nanoparticles was

observed using MRI. By combining the sensing capabilities of nanoscale

magnetic relaxation switches (MRS) within multi-reservoir micro

structures made from Polydimethylsiloxane (PDMS), they have recently

demonstrated possible in vivo detection of soluble biomarkers forovarian cancer such as β-hCG. A prototype of such an implantable chip

is schematically represented in the figure below. In addition to body-

on-a-chip and implantable microchips, a new class of nanostructured

hybrid systems such as those consisting of neuronal cells grown on

nanoporous membranes coupled with microfluidic devices are likely

to lead to the development of artificial chemical synapse interface 43.

Similarly, artificially modulated neuronal connections between the

neuronal cells and silicon nanowires have been recently reported to

have potential opportunities to develop artificial neural networks44.

Finally, the most promising of all the nanotechnology tools for

personalized medicine is the ability to carry out integrated imaging

and therapy. The nanotechnology tools based on both optical and

magnetically tunable systems are currently under development. For

example, immunotargeted nanoshells consisting of dielectric silica

core gold shell nanoparticles coupled to targeting agents that have

the ability to either scatter or absorb light in the near infrared (NIR)

region are being developed to detect tumors using optical imaging and

destroy them using photo thermal therap y45.

An overview of some of these nanotechnology tools for personalized

medicine is depicted in Fig. 11.

Fig. 9 In-vivo SERS spectra obtained from PEGylated gold nanoparticles injected into subcutaneous and deep muscular sites in a nude mouse. (Reprinted from36 with permission from Macmillan Publishers Ltd).

Fig. 10 Multi-reservoir devices for detecting a soluble cancer biomarker (Reproduced from42 with permission of The Royal Society of Chemistry).





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ConclusionsNanotechnology is all about an innovative approach to problem solving

and is simply a collection of tools and ideas which have potential

applications in the pharmaceutical industry. Unlike the widespread

notion that nanotechnology tools are exotic, too futuristic, disruptive

and not suitable for quick commercialization of products, there

are compelling applications in the pharmaceutical industry where

inexpensive nanotechnology tools can be utilized. While it is true that

many tools in the nanotechnology toolbox are still at the concept level,

there are also a number of them that can be applied to process and

product development of pharmaceuticals. In order to strategically bring

together available nanotechnology solutions to pharmaceutical R&D,

the concept of Innovation Box for Implementation of Nanotech Tools

(IBINT©) is proposed. The ultimate application of nanotechnology

tools in pharmaceutical R&D is to move the industry from ‘blockbuster

drug’ model to ‘personalized medicine.’ Huge commitments to the

development of nanotechnology tools have already been made by

both governmental and private agencies all over the world46-49. It

is, therefore, important to continue to find models to strategically

match nanotechnology tools with appropriate requirements in the

pharmaceutical industry.

AcknowledgementsThe author gratefully acknowledges support from the Center for Advanced

Microstructures and Devices (CAMD), Louisiana State University, Baton

Rouge. The author is also thankful to Pharma IQ, a division of international

quality and productivity center (IQPC) for the invitation to deliver a

lecture during the meeting on The Future of Nanotechnology for Targeted

Drug Delivery, February 25 – 27, 2008 at Hyatt Harborside, Boston, MA.

The inspiration for this article is based on that lecture.

Fig. 11 Some of the nanotechnology tools for personalized medicine

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