Nanotechnology For Oncology (Dr. Sujoy Dutta, SCR)

Speciality Consulting & Research Pvt. Ltd.
- White Paper Series, 2008
Nano-vehicles: Nanotechnology-enabled Drug Delivery Modules in Oncology
ABSTRACT: The field of Nanotechnology has witnessed evolutionary landmarks at an accelerated pace.
In a sense, the birth and growth of Nanotechnology was spurred by a historic speech delivered by the
visionary Richard Feynman in 1959. Today, Nanotechnology is qualified as a disruptive technology that
has made outstanding contributions across multiple areas including Medicine, Biology, Electronics, and
Coatings & Materials. Nanotechnology’s contributions to Medicine are particularly strong in the areas
of Diagnostics (both in-vitro and in-vivo) and Oncology-related Drug Delivery wherein a host of novel
‘nano-vehicles’ have been created to facilitate targeted delivery of drugs and agents into cancer
cells/tissues. The following is an outline on the story so far. Unless expressly indicated, the information
stated herein is the result of research conducted by the team of experts at Speciality Consulting &
Research (SCR).
Introduced as a fantastic concept by Dr. Richard Feynman during a speech at the annual meeting of the
American Physical Society in 19591 , Nanotechnology has become one of the most eagerly watched frontiers
in “Next Level” Science. The coinage of the term “Nanotechnology” is attributed to a Japanese engineer
who reportedly used it for the first time in 1974 (Klaes, 2004) 2 . Nanotechnology was brought into popular
lexicon through a landmark book “Engines of Creation” written by Dr. Eric K. Drexler - acknowledged as
the Father of Nanotechnology 3 .
As currently defined by the National Science Foundation (NSET February 2000), Nanotechnology refers to
“Research and technology development at the atomic, molecular or macromolecular levels, in the length
scale of approximately 1 - 100 nanometer range, to provide a fundamental understanding of phenomena
and materials at the nanoscale and to create and use structures, devices and systems that have novel
properties and functions because of their small and/or intermediate size. The novel and differentiating
properties and functions are developed at a critical length scale of matter typically under 100 nm.”
Widespread dissent exists regarding the accuracy of the above definition. This is because nanotechnology is
a paradox - it’s both a hybrid and a standalone (science) that harnesses processes and tools produced
through a convergence of three basic sciences - Physics, Chemistry and Biology (in context of Life
Sciences). Consequently, a basic referral to nanotechnology encompasses R& D aimed at creation,
manipulation or modification at a scale of ~10-9 - 10-7.
Sundry path-breaking innovations followed over the decades since Dr. Feynman’s historic introduction of
this fantastic possibility.
The first noteworthy landmark occurred in 1980, when IBM used ST Microscopy to image atoms. This was
a step in the direction of enabling high-power Vision & Imaging (VI) that would later evolve into a critical
tool to “see” the nanoscale view. Another milestone followed with the development of the Atomic Forces
Microscope to enhance imaging capabilities in the mid-1980s. In 1985, Richard Smalley (with two
colleagues) created “Buckyballs” by exposing carbon to high temperature, following it up with the
1
There's Plenty of Room at the Bottom: Dr. Richard Feynman Speaks
2
Wharton School of Management
3
Green University
Speciality Consulting & Research Pvt. Ltd. - White Paper Series, 2008 (Nanotechnology)
Speciality Consulting & Research Pvt. Ltd. - White Paper Series, 2008
discovery of Fullerenes. Smalley’s work opened an entire frontier in nano-development (a.k.a Nanoscale
Science and Engineering or NSE).
In 1990, IBM reiterated it’s strengths in nano-manipulation by creating the IBM logo through a
rearrangement of 35 Xenon atoms. Multiple advancements have been effected since, including the creation
of an ATP-coupler/uncoupler engine (currently a prototype).
As the pace of developments and findings increased rapidly, the United States formally initiated work on
NSE through a formal body – the National Science Foundation. Initiated with a funding of USD 6 million in
1991, the NSF quickly ramped up to over USD 950 million within just over a decade (2004). The increased
funding may be construed as a corollary to the increasing significance of the NSF as perceived by the US
government.
Speciality Consulting & Research (SCR)’s review (and assessment) of findings obtained from multiple
sources indicates that by the year 2000, nanotechnology had become a priority area of research in the
United States. Japan, another leader in the global technology arena, formalized similar guidelines in 2001-
2002.
Today, nanotechnology is not merely a “next frontier” paradigm, but a powerful crowd-puller with proven
appeal. Nanotechnology’s mass appeal is testified to by the release of well over 25 science-fiction works in
the period 1985 – 2000 4 . This mass-appeal surged around late 2000, driven by media hype, layman’s
(artist’s) impressions of its potential, and a generalized “fear of the unknown” with regards to the
outcomes nanotechnology could bring about. This surge was fuelled in large measure by a now popular
article “Why the Future Doesn’t Need Us” by Bill Joy, Sun Microsystems 5 . Published in a magazine called
Wired, the article conveyed an air of foreboding and doom for Mankind in view of the (potentially)
uncontrollable competencies possessed by three, concomitantly developing disruptive fields of Genetic
Engineering, Nanotechnology and Robotics.
A flash poll conducted by SCR indicates that mostly, people are attracted to the “mystery and foreboding”
represented by potentially threatening outcomes that a combination of these three sciences can bring about.
Specifically, people are attracted to these technologies’ potential for creating self-replicating, evolvable
entities. Further, SCR’s poll indicates that leading works of fiction (incl. Prey by Michael Crichton) and
sundry comic books drive mass imagination through characters and artful leverage of terms like Nanites,
Nanobots, Nanoids and Nanobes etc. Coupled with strong narratives, artists’ impressions and the audience’s
fertile imagination, Nanotechnology creates a proven recipe for sci-fi success with practically guaranteed
Brand Recall.
Nanotechnology is often qualified as a “disruptive technology” due to its flexibility, dynamism and
compatibility across multiple technologies 6 . Like most disruptive technologies, nanotechnology has the
potential to make a host of existing technologies obsolete either by way of cost management (reduction and
savings), operational superiority, or both. The world has witnessed similar performances from disruptive
technologies that have come before. Prominent examples from the recent past include “Lab on Chip (LOC)”
modules and Optical Storage Disks. Both have revolutionized their respective fields of application, creating
4
Internal Analyses - Speciality Consulting & Research Pvt. Ltd. (SCR)
5
Why the Future Doesn't Need Us
6
EU Nanotechnology
economic and operational advantages in the process. While nanotechnology has the potential to
constructively contribute across multiple fields, its current contributions are the strongest in four fields 7 ,
namely: Electronics, Medicine, Biology (including life sciences) and Coatings & Materials.
SCR is of the opinion that the market for nanotechnology has demonstrated double-digit growth for the past
several years 8 . The progressive growth in forecast revenues (USD Billions) is displayed in Figure 1 below:
Figure 1: Nanotechnology Revenues (Forecast to 2015), SCR Analysis

70 63.3
60 52.3
USD Billions
50 43.2
40 35.7
29.5
24.2 Nanotechnology Revenues (Forecast,
30
16 20 USD Bn)
20 12.8
8.6 10.5
10
0
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
The following graph (Graph 1) offers a rough guide as to the relative share of nanotechnology-related
funding received by various areas that eventually lend support to Medicine. Interestingly, the funding break-
up has remained relatively constant over the last few years (since 2005) 9 . SCR attributes this performance to
the fact that nanotechnology has already made initial, strong contributions towards two key areas in
contemporary Medicine - Diagnostics and Drug Delivery.
Graph 1: VC Funding Break-up, 2008

VC Funding (Percentages), 2008
6% 12%
30%
52%
Total VC Funds: USD6.6 Bn
Materials Devices Nanotechnology in Biology Tools
Source: Internal Analysis, Speciality Consulting & Research
SCR further believes that in the context of Nanotech in Medicine/Pharma/Biotech (hereinafter referred to as
NMPB), despite its currently strong popularity, the ‘nanotech hype’ has not reached its peak as yet. When
this is achieved, the markets would notice a peak/ ‘boom’ in VC funding and IPO-uptake for nanotech
players that claim to pursue ambitions to address goals in Medicine/ Pharma/ Biotech.
7
8
9
The NMPB peak in VC/IPO performance would be similar to that noticed for Genomics when the
‘genomics hype’ was at its peak during years 1999-2000 10 . While this hype might enable NMPB to
outperform sundry stocks in the near – term (say, 1-3 years), the ongoing sustainability of this performance
would depend exclusively on how favorably the VC community perceives players for NMPB on parameters
of Promised vs. Delivered. If even one player were to deliver per expectations, all NMPB players’ll benefit.
To achieve this, SCR advises players keen on positioning themselves in the NMPB space to choose value
proposition carefully, bearing in mind the global audience’s perception of potentially high-success areas 11 :
1. Area #1: (Active) Drug Delivery: Nanotechnology has spawned a whole new frontier in “Active Drug
Delivery”. The incorporation of nanotechnology has resulted in the introduction of newer baselines in
the area of “Active Concentration” and “Targeted Delivery” for drugs and agents. These developments
have been extensively incorporated in Medicine’s ongoing battle against Cancer - the most confounding
cluster of diseases known to mankind today 12 .
2. Area #2: Diagnostics (in-vitro and in-vivo): Nanotechnology can serve as a strong platform for the
creation of novel (potentially personalized) diagnostic tests that would improve the powers
represented by the field of Preventive Medicine. Harnessing selectively concentrable nanoparticles to
identify and image inflamed organs and biochemically anomalous organelles is already commonplace in
modalities such as x-ray mammography. Taking a step further, the use of nanotechnology to qualify,
isolate and quantify existing (as well as future) biomarkers 13 could help diagnose conditions at very
early stages. It is possible that if conditions were diagnosed early enough, most of the existing
treatments would prove helpful in curing them.
3. Area #3: Advanced surgical polymers/Materials: Nanotechnology’s ability for sub-molecular

manipulation can help create biomimetic intelligent materials that would represent a low/negligible risk
of host-rejection. Further, these could be used in implants and as aids to the regeneration of damaged
parts. Nanotechnology can facilitate the generation of biocompatible, bioactive topographies for the
cellular/tissue interface of the nanotech-developed biomimetic intelligent materials. SCR’s analysis of
certain firms involved in this area indicates that the sustainable development of such materials is a
feasible prototype already. It is only a matter of time before the referred firms arrive on a commercially
viable protocol for mass producing these materials.
4. Area #4: Surgery (Procedural advances): Nanotechnology could facilitate an entire wave of
miniaturization, which coupled with intelligent guiding systems, would enable a paradigm shift from
conventional surgical procedures to minimally-invasive surgery. This is very likely since, in the recent
past, the birth of minimally-invasive Coronary Artery Bypass Grafting (CABG) revolutionized
cardiovascular surgery along a roughly similar paradigm, albeit without the assistance of miniaturization
through nanotechnology. SCR believes that, in the above context, nanotechnology represents immense
(potential) value for the following areas (ranked in order of value): Cardiovascular conditions,
Oncology and Degenerative disorders (myoskeletal and neurodegenerative).
10
11
12
13
Biomarker: Speciality Consulting defines a biomarker as a universally agreed and uniformly defined and standardized
indicator of a biological process, state, or function. The Biomarker may be indicative of the normalcy (or anomaly) in a process,
state, or function – its assessment and analysis may enable better diagnoses, treatments and outcomes analyses.
NMPB can make strong contributions to (active) Delivery Systems in relation to Cancer – best characterized
as a cluster of diseases rather than one disease.
The result of cellular mechanisms gone awry, cancer cells represent distinct features and anomalies that
serve as targets for existing and future therapies. Cancerous cells usually possess strong, elaborate
vasculature that allows them to subvert the body’s machinery to receive supernormal amounts of
nourishment. This also makes them targets for therapies that can be delivered through the vascular system.
Often, the cancerous cells are characterized by anomalies in the DNA, replication machinery as well as
basement membranes and endothelia – all serve as potential or current targets in medicine’s fight against
cancer. For example, the DNA of cancerous cells possesses more pores (in its framework) as compared to
normal cells. This allows for the use of Dendrimers – new age long chain macromolecular entities, to
facilitate the destruction of anomalous DNA. Further, the cancerous cells’ predilection for ‘hoarding’ bodily
supplies makes them particularly susceptible to targeted destruction by multiple methods that leverage the
concept of ‘preferential concentration’ and ‘differential concentration’ as the first step in that direction.
Conventional drug delivery causes very high concentrations of treatment agents (incl. heavy metals) in the
cancerous cells, inducing death by toxicity. However, since current conventional therapy achieves this
through passive concentration, iatrogenic toxicity to healthy tissues has remained a strong concern. While
nanotechnology replicates the approach (of inducing super-high concentration/accumulation of treating
agents), the side effects are significantly mitigated. This is because nano-vehicles enable targeted delivery
to cancerous cells with significantly lower adverse fallouts in healthy tissues.
As is widely known, Nanotechnology utilizes specially generated entities (broadly referred to as

Nanoparticles) to facilitate delivery. Based on origin, Nanoparticles can be broadly classified as either
organic or inorganic. Refer Figure 1 for an artist’s impression on what the organic nanoparticle looks like.
Figure 1: Organic Nanoparticle (Paclitaxel – Doxorubicin Combo)
From an Intellectual Property standpoint, it is noteworthy that the ability of nano-vehicles to facilitate
preferential concentration/targeted super-concentration is being assessed as a means to secure patented
products by sundry pharmaceutical and drug-delivery companies that create nano-enabled versions of
patent-expired oncology drugs. Subsequently, these companies (can) file for “reformulation/novel delivery”
patents, thereby creating value without evolving an entirely new product. India-based Natco
Pharmaceutical’s Albupax is a case in point. It is a nanotechnology – based version of a patent expired drug
(Abraxane) that was successfully used for the treatment of metastatic breast cancer.
SCR further learnt that Dabur Research Foundation (India) was actively pursuing clinical trials in
achieving nanoparticle delivery of Paclitaxel as well. Yet another Indian pioneer – Panacea Biotec is
reportedly conducting extensive studies in novel drug delivery research, including the use of muco-adhesive
nanoparticles.
Sundry publications indicate that the Department of Science and Technology (India) proposes to invest
close to USD20 million within 2009 towards a nanotech-centered program called Nanomaterials Science
and Technology Initiative.
Incidentally, Abraxis Biosciences (under the guidance of Dr. Neil Desai) created Abraxane, to deliver
formulations of Paclitaxel – a pre-existing oncology drug/agent into cancer cells through novel nano-
vehicles called Nabs, that is – “Nanoparticles, Albumin-bound” albumin-bound nanoparticles (with or
without the use of caveolar systems). Ensuing pharmacokinetic studies indicated significantly stronger
onco-static outcomes for Paclitaxel when delivered through the said nano-vehicle. In January 2005, the FDA
approved Abraxane for the treatment of “combination chemotherapy resistant” metastatic breast cancer and
(for) such patients of breast cancer as demonstrated a relapse within six months of adjuvant chemotherapy. 14
In the light of the foregoing success (Abraxane), nanotechnology is widely being reviewed for its potential
to create vessels to optimize delivery of drugs and agents to multiple targets including the tumor site. The
commonly available options for drug delivery “nano-vehicles” are characterized in Table-1 below 15 :
Table 1: Nanovehicles & Role Characterization

Vehicle Range Role in drug delivery
Carbon 40-50 nm For enabling drug delivery and targeted
magnetic (can be in the range of 10-100 destruction of cells through multiple
Nanoparticles nm) methods including induced hyperthermia.
Ceramics 10 - 30 nm Preferential accumulation in the tumor
Nanoparticles tissues. Can be used to induce
(incl. ITO photoactivable/sonoactivable agents into
Nanoparticles target tissues. May also be used to allow the
and Nabs*) drug to act as sensitizer for photodynamics
therapy without being released.
Chitosan 80-180 nm These have demonstrated good results in

Nanoparticles encapsulation operations with sustained in
vitro release.
14
FDA Website, Internal Analyses - Speciality Consulting & Research Pvt. Ltd. (SCR)
15

Dendrimers 1-15 nm These agents are really used as 'trapping
agents' or 'meshes' to enable and facilitate
selective concentration of chosen molecules
and agents by a process called target
sequestration. The trapping activity targets
DNA – holding it in place, or holding
smaller agent molecules in the pores within
DNA. Currently used in MRI as contrast
agents.
Liposomes 20-25 nm Here, the preferred delivery molecule is

(Closed Colloid (can go up to 180 nm) negatively charged (such as plasmids, RNAi,
Structures) etc). So, cationic lipids readily form an outer
shell surrounding them. A new generation of
liposomes also incorporates fullerenes to
deliver drug that are not water soluble, that
tend to have large molecules. May
incorporate specific lipids, proteins and
lipoproteins for optimized anchorage,
dissolution and delivery of drugs and agents
(including Lipofection). Examples incl.
Albumin & sundry LDLs.
Nanoemulsions 20-25 nm Drug dispersed in oil or in liquid, to improve
site-specific solubility and absorption.
Nanolipospheres 25-50 nm Harnessed as a carrier for poorly soluble
drugs and agents, incorporation of lipophilic
drugs, hydrophilic drugs.
Nanoparticle 25-45 nm Attached to guiding molecules such as
composites MAbs for targeted drug delivery.
Nano-micelle 25-45 nm Combination of copolymers/homopolymers
in pairs, such that one is hydrophobic and the
other hydrophilic. Draws from the Singer-
Nicholson model of the Plasma Membrane
and liposomes. The liposome's concept
enables self assembly into a sphere called a
micelle to deliver drugs and agents into
specific structures within specific cells.
When created from self-assembling closed
colloids these are called Liposomal Micelles.

Nanospheres/ 50-550 nm Hollow ceramic nanospheres that are created
Nanoseres by stable cavitation and sonoporation
(ultrasound). These can be created through
self-assembly also. Used for targeted
thermablation of tumors and for tumor
imagery (contrasted).
Nanovesicles 25-3000 nm Uni, bi, multilamellar bilayer spheres to
carry drugs dissolved or dispersed in lipids.
Polymer 50-200 nm Generic nanovehicles used for encapsulating
Nanocapsules or enclosing drugs.
*Nabs are nanoparticles-albumin bound, invented by Dr. Neil Desai- creator of Abraxane.
Source: Internal Analysis, Speciality Consulting & Research Pvt Ltd.
Sundry organizations across the globe are now positioning themselves with capabilities in nano-
structuring/nano-sizing existing drugs and agents. The need for such players is evident since the path-
breaker Abraxane (cited elsewhere in this paper) comprises nanometer-sized particles of Paclitaxel that are
stabilized with human albumin, held together through hydrophobic associations 16 . Further, the nanometer-
sized particles of Paclitaxel are reportedly in a higher state of bioavailability vis-à-vis the conventional
formulation 17 .
SCR believes that eventual synergies between nano-structuring/nano-sizing firms, nano-layering (nano-
coating) companies and existing pharmaceuticals/drug delivery players will start reshaping the future of
medicine within 2010. SCR also predicts a strong future for companies that successfully integrate drug
development and drug delivery technologies. This would prove especially beneficial for companies dealing
in biopharmaceuticals and biologicals.
SCR’s analysis of the nano-vehicles landscape across the EU and US leads us to believe that the EU has a
better plan in place for the development of nano-vehicles as an integral component of pre-existing, critical
fields like medicine, material sciences and computational sciences (incl. robotics). Compared to the US, the
EU has already demonstrated better preparedness in Biopharmaceuticals (and biogenerics) vis-à-vis
regulatory/approval protocols and the introduction of Biopharmaceuticals into managed care. The
biopharmaceuticals success story is likely to be replicated by the EU yet again since it has already put in
place pioneering bodies like the European Technology Platform on NanoMedicine as an adjunct to the
European Technology Platform on Innovative Medicines – the apex platform driving innovations that
successfully combine the frontiers of medicine and advanced technology. Further, based on an assessment
of the EU and the US, we believe that the EU has:
• Stronger regulatory protocols for relatively novel areas like biopharmaceuticals
• Rapid acceptance and uptake of novel technologies and innovations by its citizens
16
17
Abraxis Biosciences Website
• Faster pace of broad-level state-initiated directives aimed at the “managed development” of

relatively innovative fields like SmartSystems – development in this area is formally directed and
monitored through the European Technology Platform on Smart System Integration (EpoSS).
Based on the afore-stated, SCR believes that despite the path-breaking Abraxane, relatively lower funding
towards nanotechnology (than the US), the EU is strongly positioned (vis-à-vis the US) to gift the world a
truly novel nano-vehicle marvel in the field of active drug delivery. The current financial crisis in the United
States would adversely impact its nanotechnology game plan also. SCR further believes it highly probable
that the proposed “gift” would be of outstanding relevance to the context of either cancer management OR
advanced imaging techniques as opposed to any other area since the pre-existing body of well-documented,
evidence-based research in these areas could help firms cover critical developmental ground in record time.
The readers are requested to note that the current paper does not discuss or allude to technologies/
developments that SCR deems potentially ‘non-vehicular’ in nature. These non-vehicular entities include
trans-dermal patches that incorporate nanotechnology (for e.g. Microarrays, Microneedle arrays etc.)
However, further reading may be directed towards novel systems like the MAP (MicroArray Patches) that
are under development at sundry organizations, including Nanotechnology Victoria Ltd (Australia).

Nanotechnology For Oncology (Dr. Sujoy Dutta, SCR)

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Speciality Consulting & Research Pvt. Ltd.

- White Paper Series, 2008

Nano-vehicles: Nanotechnology-enabled Drug Delivery Modules in Oncology

Figure 1: Nanotechnology Revenues (Forecast to 2015), SCR Analysis

Graph 1: VC Funding Break-up, 2008

Materials Devices Nanotechnology in Biology Tools

Source: Internal Analysis, Speciality Consulting & Research

3. Area #3: Advanced surgical polymers/Materials: Nanotechnology’s ability for sub-molecular

As is widely known, Nanotechnology utilizes specially generated entities (broadly referred to as

Figure 1: Organic Nanoparticle (Paclitaxel – Doxorubicin Combo)

Table 1: Nanovehicles & Role Characterization

Chitosan 80-180 nm These have demonstrated good results in

Vehicle Range Role in drug delivery

Liposomes 20-25 nm Here, the preferred delivery molecule is

Vehicle Range Role in drug delivery

Source: Internal Analysis, Speciality Consulting & Research Pvt Ltd.

• Stronger regulatory protocols for relatively novel areas like biopharmaceuticals

• Faster pace of broad-level state-initiated directives aimed at the “managed development” of

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